Emtricitabine

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

EMTRIVA is available as capsules or as an oral solution. 200 mg Capsules: 200 mg of emtricitabine (FTC): size 1 hard gelatin capsules with a blue cap and white body, printed with "200 mg" in black on the cap and with "GILEAD" and the corporate logo in black on the body. Oral solution: clear, orange to dark orange liquid containing 10 mg of FTC per mL. Capsules: 200 mg ( 3 ) Oral solution: 10 mg per mL ( 3 )

EMTRIVA is contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the products. EMTRIVA is contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the products. ( 4 )

Immune reconstitution syndrome: May necessitate further evaluation and treatment. ( 5.2 ) Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. ( 5.3 )

5.1 Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV All patients should be tested for the presence of chronic Hepatitis B virus (HBV) before or when initiating EMTRIVA [see Dosage and Administration (2.1) ] . Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued EMTRIVA. Patients who are coinfected with HIV-1 and HBV who discontinue EMTRIVA should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, initiation of anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

5.2 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including EMTRIVA. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.3 Lactic Acidosis/Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including FTC, alone or in combination with other antiretrovirals. Treatment with EMTRIVA should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

5.4 Dose Adjustment in Patients with New Onset or Worsening Renal Impairment Emtricitabine is principally eliminated by the kidney. Reduction of the dosage of EMTRIVA is recommended for patients with impaired renal function [see Dosage and Administration (2.6) , Use in Specific Populations (8.6) , and Clinical Pharmacology (12.3) ].

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 Gilead Sciences, Inc. at 1-800-GILEAD-5 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 EMTRIVA 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 EMTRIVA 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 EMTRIVA and control treatment groups except for skin discoloration, which was reported with higher frequency in the EMTRIVA-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 EMTRIVA 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 EMTRIVA-Treated Subjects in Either Trial 301A or 303 (0–48 Weeks) 303 301A EMTRIVA + AZT/d4T + NNRTI/PI (N=294) 3TC + AZT/d4T + NNRTI/PI (N=146) EMTRIVA + didanosine + EFV (N=286) d4T + didanosine + EFV (N=285) AZT=zidovudine; d4T=stavudine; NNRTI/PI=non-nucleoside reverse transcriptase inhibitor/protease inhibitor; 3TC=lamivudine; EFV=efavirenz. 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 Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, pustular rash, and allergic reaction. 17% 14% 30% 33% Laboratory Abnormalities : Laboratory abnormalities in these trials occurred with similar frequency in the EMTRIVA 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 EMTRIVA-Treated Subjects in Either Trial 301A or 303 303 301A EMTRIVA + AZT/d4T + NNRTI/PI (N=294) 3TC + AZT/d4T + NNRTI/PI (N=146) EMTRIVA + Didanosine + EFV (N=286) d4T + Didanosine + EFV (N=285) Any ≥ Grade 3 Laboratory Abnormality 31% 28% 34% 38% ALT (>5.0 × ULN ULN = Upper limit of normal ) 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% In Trial 934, 511 antiretroviral-naïve subjects received efavirenz (EFV) administered in combination with either EMTRIVA + 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 Reactions Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. (Grades 2–4) Reported in ≥5% in Any Treatment Group in Trial 934 (0–144 Weeks) EMTRIVA + TDF + EFV From Weeks 96 to 144 of the trial, subjects received TRUVADA ® with EFV in place of EMTRIVA + TDF with EFV. 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 Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and rash vesicular. 7% 9% Headache 6% 5% Insomnia 5% 7% Nasopharyngitis 5% 3% Vomiting 2% 5% 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) EMTRIVA + TDF + EFV From Weeks 96 to 144 of the trial, subjects received TRUVADA with EFV in place of EMTRIVA + TDF with EFV. 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% 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 EMTRIVA 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%). […]

The potential for drug interactions with EMTRIVA 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) ].

Lactation: Breastfeeding is not recommended. ( 8.2 ) Pediatrics: Dose adjustment based on age and weight. ( 2.4 , 2.5 , 12.3 )

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to EMTRIVA 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 15–20%. 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 EMTRIVA (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 EMTRIVA.

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-label, nonrandomized clinical trials in which FTC was administered to 169 HIV-1 infected treatment-naïve and experienced (defined as virologically suppressed on a 3TC containing regimen for which FTC was substituted for 3TC) subjects [see Clinical Studies (14.4) ] . The pharmacokinetics of FTC were studied in 20 neonates born to HIV-1 positive mothers [see Clinical Studies (14.4) ] . All neonates were HIV-1 negative at the end of the trial; the efficacy of FTC in preventing or treating HIV-1 could not be determined.

8.5 Geriatric Use Clinical trials of EMTRIVA did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. In general, dose selection for the elderly patient should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy .

8.6 Renal Impairment Modify the dose or dosing interval for EMTRIVA in patients with creatinine clearance below 50 mL/min or in patients with end stage renal disease requiring dialysis [see Dosage and Administration (2.6) ] .

Emtricitabine is an antiretroviral drug [see Microbiology (12.4) ].