Emtricitabine

Boxed Warning 02/2019 Dosage and Administration Testing Prior to Initiation of Treatment with Emtricitabine ( 2.1 ) 12/2018 Recommended Dosage ( 2.2 ) 02/2019 Dosage Adjustment in Patients with Renal Impairment 02/2019 Warnings and Precautions Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV ( 5.1 ) 12/2018 Coadministration with Related Products Removed 12/2018

1 INDICATIONS AND USAGE Emtricitabine capsules are 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.

3 DOSAGE FORMS AND STRENGTHS Emtricitabine Capsules, 200 mg are cream cap/cream body, size ‘1’ hard gelatin capsule filled with white to off-white granular powder and imprinted with ‘F’ on cap and ‘36’ on body with black ink. Capsules: 200 mg ( 3 )

4 CONTRAINDICATIONS Emtricitabine capsules are contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the products. Emtricitabine capsules are contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the products. ( 4 )

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 Aurobindo Pharma USA, Inc. at 1-866-850-2876 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 to 48 Weeks) 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. 303 301A Emtricitabine + AZT/d4T + NNRTI/PI (N=294) 3TC + AZT/d4T + NNRTI/PI (N=146) Emtricitabine + didanosine + EFV (N=286) d4 T + 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% 5.0 × ULN a ) 2% 1% 5% 6% AST (>5.0 × ULN) 3% 2.5 × ULN) 1% 2% 4.0 × ULN) 11% 14% 12% 11% Neutrophils (2.0 × ULN) 2% 2% 2.0 × ULN) 2% 2% 5% 10% Serum glucose 250 mg/dL) 3% 3% 2% 3% Serum lipase (>2.0 × ULN) 750 mg/dL) 10% 8% 9% 6% 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 mo …

7 DRUG INTERACTIONS The potential for drug interactions with emtricitabine has been studied in combination with AZT, indinavir, d4T, famciclovir, and tenofovir DF (TDF). There were no clinically significant drug interactions for any of these drugs. Drug interactions trials are described elsewhere in the labeling [see Clinical Pharmacology ( 12.3 )].

8 USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding is not recommended. ( 8.2 ) Pediatrics: Dose adjustment based on age and weight. ( 2.5 , 12.3 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to emtricitabine during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Available data from the APR show no increase in the overall risk of major birth defects with first trimester exposure for emtricitabine (FTC) (2.3%) 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 for individual drugs is not reported in the APR. In the U.S. general population, the estimated background risk of miscarriage in clinically recognized pregnancies is 15 to 20%. In animal reproduction studies, no adverse developmental effects were observed when FTC was administered at exposures ≥60 times that of the recommended daily dose of emtricitabine (see Data) . Data Human Data Based on prospective reports to the APR of exposures to FTC-containing regimens during pregnancy resulting in live births (including over 2,700 exposed in the first trimester and over 1,200 exposed in the second/third trimester), there was no increase between FTC and overall birth defects compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.4% (95% CI: 1.9% to 3.1%) with first trimester exposure to FTC-containing regimens and 2.3% (95% CI: 1.5% to 3.3%) with the second/third trimester exposure to FTC-containing regimens. Prospective reports from the APR of overall major birth defects in pregnancies exposed to FTC are compared with a U.S. background major birth defect rate. Methodologic limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease. Additionally, published observational studies on FTC exposure in pregnancy have not shown an increased risk for major malformations. Animal Data FTC was administered orally to pregnant mice (at 0, 250, 500, or 1,000 mg/kg/day), and rabbits (at 0, 100, 300, or 1,000 mg/kg/day) through organogenesis (on gestation days 6 through 15, and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with FTC in mice at exposures (AUC) approximately 60 times higher and in rabbits at approximately 120 times higher than human exposures at the recommended daily dose. In a pre/postnatal development study in mice, FTC was administered orally at doses up to 1,000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth ( in utero ) through sexual maturity at daily exposures (AUC) of approximately 60 times higher than human exposures at the recommended daily dose. 8.2 Lactation Risk Summary The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. Based on published data, FTC has been shown to be present in human breast milk. It is not known if FTC affects milk production or has effects on the breastfed child. Because of the potential for: (1) HIV transmission (in HIV-negative infants); (2) developing viral resistance (in HIV-positive infants); and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are taking emtricitabine. 8.4 Pediatric Use The safety and efficacy of FTC in patients between 3 months and 21 years of age is supported by data from three open-lab …

12.1 Mechanism of Action Emtricitabine is an antiretroviral drug [see Microbiology (12.4) ] .

11 DESCRIPTION Emtricitabine (FTC) is a synthetic nucleoside analog with activity against human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. The chemical name of FTC is 5-fluoro-1-(2 R ,5 S )-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Emtricitabine 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 powder with a solubility of approximately 112 mg/mL in water at 25°C. The partition coefficient (log P) for FTC is −0.43 and the pKa is 2.65. Emtricitabine capsules are for oral administration. Each capsule contains 200 mg of FTC and the inactive ingredients: crospovidone, gelatin, magnesium stearate, microcrystalline cellulose, povidone, sodium lauryl sulphate, titanium dioxide and yellow iron oxide. The capsules are imprinted with edible ink containing black iron oxide, potassium hydroxide, propylene glycol, shellac and strong ammonia solution. Figure1

10 OVERDOSAGE If overdose occurs, the patient should be monitored for evidence of toxicity, and standard supportive treatment applied as necessary. 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Emtricitabine Capsules 200mg are size '1' capsules with sky blue cap imprinted with "EMT" in black and white body imprinted with "200" in black. Emtricitabine Capsules, 200mg are available as follows: Bottles of 30 capsules (NDC 69097-642-02) Bottles of 1000 capsules (NDC 69097-642-15) Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F - 86°F) [see USP Controlled Room Temperature]. Dispense only in original container. Keep container tightly closed.