Emtricitabine

1 INDICATIONS AND USAGE Emtricitabine is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. Emtricitabine, a nucleoside analog HIV-1 reverse transcriptase inhibitor, is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. ( 1 )

2 DOSAGE AND ADMINISTRATION Testing: Prior to or when initiating emtricitabine test for hepatitis B virus infection. ( 2.1 ) Emtricitabine may be taken without regard to food. ( 2.2 ) Adult Patients (18 years of age and older) ( 2.3 ): Emtricitabine capsules: One 200 mg capsule administered once daily orally. Pediatric Patients (3 months through 17 years of age) ( 2.5 ): Emtricitabine capsules: For children weighing more than 33 kg who can swallow an intact capsule, one 200 mg capsule administered once daily orally. Dose interval adjustment in adult patients with renal impairment ( 2.6 ): a. Hemodialysis Patients: If dosing on day of dialysis, give dose after dialysis. Formulation Creatinine Clearance (mL/min) ≥50 mL/min 30–49 mL/min 15–29 mL/min <15 mL/min or on hemodialysis a Capsule (200 mg) 200 mg every 24 hours 200 mg every 48 hours 200 mg every 72 hours 200 mg every 96 hours 2.1 Testing Prior to Initiation of Treatment with Emtricitabine Prior to or when initiating emtricitabine, test patients for hepatitis B virus infection [see Warnings and Precautions ( 5.1 )]. 2.2 Recommended Dosage Emtricitabine is taken by mouth once daily and may be taken without regard to food [see Clinical Pharmacology ( 12.3 ) ]. 2.3 Recommended Dosage in Adult Patients (18 years of age and older) Emtricitabine capsules: One 200 mg capsule administered once daily orally. 2.5 Recommended Dosage in Pediatric Patients (3 months through 17 years of age) Emtricitabine capsules: For pediatric patients weighing more than 33 kg who can swallow an intact capsule, one 200 mg capsule administered once daily orally. 2.6 Dosage Adjustment in Patients with Renal Impairment Table 1 provides dosage interval adjustment for patients with renal impairment. No dosage adjustment is necessary for patients with mild renal impairment (creatinine clearance 50–80 mL/min). The safety and effectiveness of dose adjustment recommendations in patients with moderate to severe renal impairment (creatinine clearance below 50 mL/min) have not been clinically evaluated. Therefore, clinical response to treatment and renal function should be closely monitored in these patients [see Warnings and Precautions ( 5.4 ), Use in Specific Populations ( 8.6 )] . Table 1. Dose Interval Adjustment for Adult Patients with Altered Creatinine Clearance Formulation Creatinine Clearance (mL/min) ≥50 mL/min 30–49 mL/min 15–29 mL/min <15 mL/min or on hemodialysis a Capsule (200 mg) 200 mg every 24 hours 200 mg every 48 hours 200 mg every 72 hours 200 mg every 96 hours a. Hemodialysis Patients: If dosing on day of dialysis, give dose after dialysis. There are insufficient data available to make dosage recommendations in pediatric patients with renal impairment.

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV [see Warnings and Precautions ( 5.1 )] . Immune Reconstitution Syndrome [see Warnings and Precautions ( 5.2 )] Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions ( 5.3 )] . Most common adverse reactions (incidence ≥10%) are headache, diarrhea, nausea, fatigue, dizziness, depression, insomnia, abnormal dreams, rash, abdominal pain, asthenia, increased cough, and rhinitis. Skin hyperpigmentation was very common (≥10%) in pediatric patients. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Cipla Ltd. at 1-866-604-3268 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 Adults More than 2,000 adult subjects with HIV-1 infection have been treated with emtricitabine alone or in combination with other antiretroviral agents for periods of 10 days to 200 weeks in clinical trials. The most common adverse reactions (incidence greater than or equal to 10%, any severity) identified from any of the three large, controlled clinical trials include headache, diarrhea, nausea, fatigue, dizziness, depression, insomnia, abnormal dreams, rash, abdominal pain, asthenia, increased cough, and rhinitis. In Trials 301A and 303, the most common adverse reactions that occurred in subjects receiving emtricitabine with other antiretroviral agents were headache, diarrhea, nausea, and rash, which were generally mild to moderate. Approximately 1% of subjects discontinued participation in the clinical trials due to these events. All adverse reactions were reported with similar frequency in emtricitabine and control treatment groups except for skin discoloration, which was reported with higher frequency in the emtricitabine treated group. Skin discoloration, manifested by hyperpigmentation on the palms or soles, was generally mild and asymptomatic. The mechanism and clinical significance are unknown. A summary of emtricitabine treatment-emergent clinical adverse reactions in Trials 301A and 303 is provided in Table 2. Table 2. Selected Treatment-Emergent Adverse Reactions (All Grades, Regardless of Causality) Reported in ≥ 3% of Emtricitabine-Treated Subjects in Either Trial 301A or 303 (0–48 Weeks) 303 301A Emtricitabine+ AZT/d4T + NNRTI/PI (N=294) 3TC + AZT/d4T + NNRTI/PI (N=146) Emtricitabine + didanosine + EFV (N=286) d4T + didanosine + EFV (N=285) Body as a Whole Asthenia 16% 10% 12% 17% Headache 13% 6% 22% 25% Abdominal pain 8% 11% 14% 17% Digestive System Diarrhea 23% 18% 23% 32% Nausea 18% 12% 13% 23% Vomiting 9% 7% 9% 12% Dyspepsia 4% 5% 8% 12% Musculoskeletal Myalgia 4% 4% 6% 3% Arthralgia 3% 4% 5% 6% Nervous System Insomnia 7% 3% 16% 21% Depressive disorders 6% 10% 9% 13% Paresthesia 5% 7% 6% 12% Dizziness 4% 5% 25% 26% Neuropathy/peripheral neuritis 4% 3% 4% 13% Abnormal dreams 2% <1% 11% 19% Respiratory Rhinitis 18% 12% 12% 10% Increased cough 14% 11% 14% 8% Skin Rash event a 17% 14% 30% 33% AZT=zidovudine; d4T=stavudine; NNRTI/PI=non-nucleoside reverse transcriptase inhibitor/protease inhibitor; 3TC=lamivudine; EFV=efavirenz. a. Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, pustular rash, and allergic reaction. Laboratory Abnormalities: Laboratory abnormalities in these trials occurred with similar frequency in the emtricitabine and comparator groups. A summary of Grades 3-4 laboratory abnormalities is provided in Table 3. Table 3. Treatment-Emergent Grades 3-4 Laboratory Abnormalities Reported in ≥1% of Emtricitabine-Treated Subjects in Either Trial 301A or 303 303 301A Emtricitabine + AZT/d4T + NNRTI/PI (N=294) 3TC + AZT/d4T + NNRTI/PI (N=146) Emtricitabine + Didanosine + EFV (N=286) d4T + Didanosine + EFV (N=285) Any ≥ Grade 3 Laboratory Abnormality 31% 28% 34% 38% ALT (>5.0 × ULN a ) 2% 1% 5% 6% AST (>5.0 × ULN) 3% <1% 6% 9% Bilirubin (>2.5 × ULN) 1% 2% <1% <1% Creatine kinase (>4.0 × ULN) 11% 14% 12% 11% Neutrophils (<750 mm 3 ) 5% 3% 5% 7% Pancreatic amylase (>2.0 × ULN) 2% 2% <1% 1% Serum amylase (>2.0 × ULN) 2% 2% 5% 10% Serum glucose <40 or >250 mg/dL) 3% 3% 2% 3% Serum lipase (>2.0 × ULN) <1% <1% 1% 2% Triglycerides (>750 mg/dL) 10% 8% 9% 6% a. ULN = Upper limit of normal In Trial 934, 511 antiretroviral-naïve subjects received efavirenz (EFV) administered in combination with either emtricitabine + tenofovir disoproxil fumarate (TDF) (N=257) or AZT/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 4 provides the treatment-emergent adverse reactions (Grades 2−4) occurring in greater than or equal to 5% of subjects treated in any treatment group. Table 4. Selected Adverse Reactionsa (Grades 2–4) Reported in ≥ 5% in Any Treatment Group in Trial 934 (0–144 Weeks) Emtricitabine + 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% 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 TRUVADA ® with EFV in place of emtricitabine +TDF with EFV. c. Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and rash vesicular. Laboratory Abnormalities: Laboratory abnormalities observed in Trial 934 were generally consistent with those seen in previous trials (Table 5). Table 5. Significant Laboratory Abnormalities Reported in ≥1% of Subjects in Any Treatment Group in Trial 934 (0–144 Weeks) Emtricitabine + 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 (>750mg/dL) 4% 2% a. From Weeks 96 to 144 of the trial, subjects received TRUVADA with EFV in place of emtricitabine +TDF with EFV. Adverse Reactions from Clinical Trials Experience in Pediatric Subjects Assessment of adverse reactions in pediatric subjects is based on data from Trial 203, an open label, uncontrolled trial of 116 HIV-1 infected subjects who received FTC through 48 weeks. The adverse reaction profile in pediatric subjects was generally comparable to that observed in clinical trials of emtricitabine in adult subjects [see Adverse Reactions ( 6.1 )] . Hyperpigmentation was more frequent in children. Additional adverse reactions identified from this trial include anemia. Selected treatment-emergent adverse events, regardless of causality, reported in subjects during 48 weeks of treatment were the following: infection (44%), hyperpigmentation (32%), increased cough (28%), vomiting (23%), otitis media (23%), rash (21%), rhinitis (20%), diarrhea (20%), fever (18%), pneumonia (15%), gastroenteritis (11%), abdominal pain (10%), and anemia (7%). Treatment-emergent Grades 3-4 laboratory abnormalities were experienced by 9% of pediatric subjects, including elevated amylase (>2.0 x ULN) (n=4), decreased neutrophils (<750/mm 3 ) (n=3), elevated ALT (>5 x ULN) (n=2), elevated CPK (>4 x ULN) (n=2) and one subject each with elevated bilirubin (>3.0 x ULN), elevated GGT (>10 x ULN), elevated lipase (>2.5 x ULN), decreased hemoglobin (<7 g/dL), and decreased glucose (<40 mg/dL).

12.3 Pharmacokinetics Adults The pharmacokinetic properties of FTC were evaluated in healthy subjects and HIV- 1-infected subjects. Emtricitabine pharmacokinetics are similar between these populations. Figure 1 shows the mean steady-state plasma FTC concentration-time profile in 20 HIV-1-infected subjects receiving emtricitabine capsules. Figure 1 Mean (± 95% CI) Steady-State Plasma FTC Concentrations in HIV-1-Infected Adults (N=20) Absorption Emtricitabine is rapidly and extensively absorbed following oral administration, with peak plasma concentrations occurring at 1-2 hours postdose. Following multiple dose oral administration of emtricitabine capsules to 20 HIV-1 infected subjects, the (mean ± SD) steady-state plasma FTC peak concentration (C max ) was 1.8 ± 0.7 µg/mL and the area-under the plasma concentration-time curve over a 24-hour dosing interval (AUC) was 10.0 ± 3.1 µg•hr/mL. The mean steady-state plasma trough concentration at 24 hours postdose was 0.09 µg/mL. The mean absolute bioavailability of emtricitabine capsules was 93%, while the mean absolute bioavailability of emtricitabine oral solution was 75%. The relative bioavailability of emtricitabine oral solution was approximately 80% of emtricitabine capsules. The multiple dose pharmacokinetics of FTC are dose proportional over a dose range of 25-200 mg. Distribution In vitro binding of FTC to human plasma proteins was less than 4% and independent of concentration over the range of 0.02-200 µg/mL. At peak plasma concentration, the mean plasma to blood drug concentration ratio was ~1.0 and the mean semen to plasma drug concentration ratio was ~4.0. Metabolism Following administration of radiolabelled FTC, complete recovery of the dose was achieved in urine (~86%) and feces (~14%). Thirteen percent (13%) of the dose was recovered in urine as three putative metabolites. The biotransformation of FTC includes oxidation of the thiol moiety to form the 3'-sulfoxide diastereomers (~9% of dose) and conjugation with glucuronic acid to form 2'-O-glucuronide (~4% of dose). No other metabolites were identifiable. Elimination The plasma FTC half-life is approximately 10 hours. The renal clearance of FTC is greater than the estimated creatinine clearance, suggesting elimination by both glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also renally eliminated. Effects of Food on Oral Absorption Emtricitabine capsules may be taken with or without food. Emtricitabine systemic exposure (AUC) was unaffected while C max decreased by 29% when emtricitabine capsules were administered with food (an approximately 1000 kcal high-fat meal). Specific Populations Geriatric Patients The pharmacokinetics of FTC have not been fully evaluated in the elderly (65 years of age and older). Pediatric Patients The pharmacokinetics of FTC at steady state were determined in 77 HIV-1 infected pediatric subjects, and the pharmacokinetic profile was characterized in four age groups (Table 6). The FTC exposure achieved in pediatric subjects receiving a daily dose of 6 mg/kg up to a maximum of 240 mg oral solution or a 200 mg capsule is similar to exposures achieved in adult subjects receiving a once-daily dose of 200 mg. Table 6. Mean ± SD Pharmacokinetic Parameters by Age Groups for Pediatric Subjects and Neonates Receiving Emtricitabine Capsules HIV-1-exposed Neonates HIV-1-Infected Pediatric Subjects b Mean (range) Age 0-3 mo (N=20) a 3-24 mo (N=14) 25 mo-6 yr (N=19) 7–12yr (N=17) 13–17 yr (N=27) Formulation Capsule (n) 0 0 0 10 26 Dose (mg/kg) b 3.1 (2.9-3.4) 6.1 (5.5-6.8) 6.1 (5.6-6.7) 5.6 (3.1−6.6) 4.4 (1.8−7.0) C max (µg/mL) 1.6 ± 0.6 1.9 ± 0.6 1.9 ± 0.7 2.7 ± 0.8 2.7 ± 0.9 AUC (µg•hr/mL) 11.0 ± 4.2 8.7 ± 3.2 9.0 ± 3.0 12.6 ± 3.5 12.6 ± 5.4 T 1/2 (hr) 12.1 ± 3.1 8.9 ± 3.2 11.3 ± 6.4 8.2 ± 3.2 8.9 ± 3.3 a Two pharmacokinetic evaluations were conducted in 20 neonates over the first 3 months of life. Median (range) age of infant on day of pharmacokinetic evaluation was 26 (5-81) days. Gender FTC pharmacokinetics are similar in adult male and female subjects. Race No pharmacokinetic differences due to race have been identified. Patients with Renal Impairment The pharmacokinetics of FTC are altered in subjects with renal impairment [see Warnings and Precautions ( 5.4 )]. In adult subjects with creatinine clearance below 50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, C max and AUC of FTC were increased (Table 7). The effects of renal impairment on FTC pharmacokinetics in pediatric patients are not known. Table 7. Pharmacokinetic Parameters (Mean ± SD) of FTC in Adult Subjects with Varying Degrees of Renal Function Creatinine Clearance (mL/min) >80 (N=6) 50–80 (N=6) 30–49 (N=6) <30 (N=5) ESRD a <30 (N=5) Baseline creatinine clearance (mL/min) 107 ± 21 59.8 ± 6.5 40.9 ± 5.1 22.9 ± 5.3 8.8 ± 1.4 C max (µg/mL) 2.2 ± 0.6 3.8 ± 0.9 3.2 ± 0.6 2.8 ± 0.7 2.8 ± 0.5 AUC (µg•hr/mL) 11.8 ± 2.9 19.9 ± 1.2 25.1 ± 5.7 33.7± 2.1 53.2 ± 9.9 CL/F (mL/min) 302 ± 94 168 ± 10 138 ± 28 99 ± 6 64 ± 12 CLr (mL/min) 213 ± 89 121 ± 39 69 ± 32 30 ± 11 NA b a. ESRD subjects requiring dialysis b. NA = Not Applicable Patients with Hepatic Impairment The pharmacokinetics of FTC have not been studied in subjects with hepatic impairment; however, FTC is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited. Assessment of Drug Interactions At concentrations up to 14-fold higher than those observed in vivo , FTC did not inhibit in vitro drug metabolism mediated by any of the following human CYP isoforms: CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. FTC did not inhibit the enzyme responsible for glucuronidation (uridine-5'-disphosphoglucuronyl transferase). Based on the results of these in vitro experiments and the known elimination pathways of FTC, the potential for CYP-mediated interactions involving FTC with other medicinal products is low. Emtricitabine has been evaluated in healthy volunteers in combination with TDF, AZT, indinavir, famciclovir, and d4T. Tables 8 and 9 summarize the pharmacokinetic effects of coadministered drug on FTC pharmacokinetics and effects of FTC on the pharmacokinetics of coadministered drug. Table 8. Drug Interactions: Change in Pharmacokinetic Parameters for FTC in the Presence of the Coadministered Druga Coadministered Drug Dose of Coadministered Drug (mg) FTC Dose (mg) N % Change of FTC Pharmacokinetic Parameters b (90% CI) C max AUC C min C max AUC C min C max AUC C min C max AUC C min Famciclovir 500 x 1 200 x 1 12 ⇔ ⇔ NA Indinavir 800 x 1 200 x 1 12 ⇔ ⇔ NA Stavudine 40 x 1 200 x 1 6 ⇔ ⇔ NA Tenofovir DF 300 once daily x 7 days 200 once daily x 7 days 17 ⇔ ⇔ ↑ 20 (↑ 12 to ↑ 29) Zidovudine 300 twice daily x 7 days 200 once daily x 7 days 27 ⇔ ⇔ ⇔ a. All interaction trials conducted in healthy volunteers. b. ↑= Increase; ⇔= No Effect; NA = Not Applicable Table 9. Drug Interactions: Change in Pharmacokinetic Parameters for Coadministered Drug in the Presence of FTCa Coadministered Drug Dose of Coadministered Drug (mg) FTC Dose (mg) N % Change of Coadministered Drug Pharmacokinetic Parameters b (90% CI) C max AUC C min C max AUC C min C max AUC C min C max AUC C min Famciclovir 500 x 1 200 x 1 12 ⇔ ⇔ NA Indinavir 800 x 1 200 x 1 12 ⇔ ⇔ NA Stavudine 40 x 1 200 x 1 6 ⇔ ⇔ NA Tenofovir DF 300 once daily x 7 days 200 once daily x 7 days 17 ⇔ ⇔ ⇔ Zidovudine 300 twice daily x 7 days 200 once daily x 7 days 27 ↑ 17 (↑ 0 to ↑ 38) ↑ 13 (↑ 5 to↑ 20) ⇔ a. All interaction trials conducted in healthy volunteers. b. ↑= Increase; ⇔= No Effect; NA = Not Applicable figure-1