STORAGE AND HANDLING SECTION.


Store at 25 (77 F); excursions permitted to 15 C-30 (59 F-86 F).

ADVERSE REACTIONS SECTION.


6ADVERSE REACTIONS. The following adverse reactions are discussed in other sections of the labeling:Lactic acidosis/severe hepatomegaly with steatosis [See Boxed Warning, Warnings and Precautions (5.1)]. Severe acute exacerbations of Hepatitis [See Boxed Warning, Warnings and Precautions (5.2)]. Immune reconstitution syndrome [See Warnings and Precautions (5.6)] Lactic acidosis/severe hepatomegaly with steatosis [See Boxed Warning, Warnings and Precautions (5.1)]. Severe acute exacerbations of Hepatitis [See Boxed Warning, Warnings and Precautions (5.2)]. Immune reconstitution syndrome [See Warnings and Precautions (5.6)] 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. 6.1Adverse Reactions from Clinical Trials Experience. Adult PatientsMore than 2,000 adult patients 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.Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The most common adverse reactions (incidence >=10%, any severity) identified from any of the large controlled clinical trials include headache, diarrhea nausea, fatigue, dizziness, depression, insomnia, abnormal dreams, rash, abdominal pain, asthenia, increased cough, and rhinitis.. Studies 301A and 303 Treatment Emergent Adverse Reactions: The most common adverse reactions that occurred in patients receiving EMTRIVA with other antiretroviral agents in clinical studies 301A and 303 were headache, diarrhea, nausea, and rash, which were generally of mild to moderate severity. Approximately 1% of patients discontinued participation in the clinical studies due to these events. All adverse reactions were reported with similar frequency in EMTRIVA and control treatment groups with the exception of skin discoloration which was reported with higher frequency in the EMTRIVA treated group. Skin discoloration, manifested by hyperpigmentation on the palms and/or soles was generally mild and asymptomatic. The mechanism and clinical significance are unknown.A summary of EMTRIVA treatment emergent clinical adverse reactions in studies 301A and 303 is provided in Table 2.Table Selected Treatment-Emergent Adverse Reactions (All Grades, Regardless of Causality) Reported in >=3% of EMTRIVA-Treated Patients in Either Study 301A or 303 (0-48 Weeks)303301AEMTRIVA ZDV/d4T NNRTI/PI (N=294)Lamivudine ZDV/d4T NNRTI/PI (N=146)EMTRIVA didanosine efavirenz (N=286)Stavudine didanosine efavirenz (N=285)Body as Whole Abdominal pain8%11%14%17% Asthenia16%10%12%17% Headache13%6%22%25%Digestive System Diarrhea23%18%23%32% Dyspepsia4%5%8%12% Nausea18%12%13%23% Vomiting9%7%9%12%Musculoskeletal Arthralgia3%4%5%6% Myalgia4%4%6%3%Nervous System Abnormal dreams2%<1%11%19% Depressive disorders6%10%9%13% Dizziness4%5%25%26% Insomnia7%3%16%21% Neuropathy/peripheral neuritis4%3%4%13% Paresthesia5%7%6%12%Respiratory Increased cough14%11%14%8% Rhinitis18%12%12%10%Skin Rash eventRash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, pustular rash, and allergic reaction. 17%14%30%33%. Studies 301A and 303 Laboratory Abnormalities:Laboratory abnormalities in these studies occurred with similar frequency in the EMTRIVA and comparator groups. summary of Grade and laboratory abnormalities is provided in Table below.Table Treatment-Emergent Grade 3/4 Laboratory Abnormalities Reported in >=1% of EMTRIVA-Treated Patients in Either Study 301A or 303303301AEMTRIVA ZDV/d4T NNRTI/PI (N=294)Lamivudine ZDV/d4T NNRTI/PI (N=146)EMTRIVA Didanosine Efavirenz (N=286)Stavudine Didanosine Efavirenz (N=285)Percentage with grade or grade laboratory abnormality31%28%34%38%ALT (>5.0 ULNULN 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 mm3)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%. Study 934 Treatment Emergent Adverse Reactions: In Study 934, 511 antiretroviral-naive patients received either VIREAD EMTRIVA administered in combination with efavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz (N=254). Adverse reactions observed in this study were generally consistent with those seen in previous studies in treatment-experienced or treatment-naive patients (Table 4).Table Selected Treatment-Emergent Adverse ReactionsFrequencies 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 Study 934 (0-144 Weeks)TDFFrom Weeks 96 to 144 of the study, patients received TRUVADA with efavirenz in place of VIREAD EMTRIVA with efavirenz. EMTRIVA EFVAZT/3TC EFVN=257N=254Gastrointestinal Disorder Diarrhea9%5% Nausea9%7% Vomiting2%5%General Disorders and Administration Site Condition Fatigue9%8%Infections and Infestations Sinusitis8%4% Upper respiratory tract infections8%5% Nasopharyngitis5%3%Nervous System Disorders Headache6%5% Dizziness8%7%Psychiatric Disorders Depression9%7% Insomnia5%7%Skin and Subcutaneous Tissue Disorders Rash eventRash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and rash vesicular. 7%9%. Study 934 Laboratory Abnormalities: Significant laboratory abnormalities observed in this study are shown in Table 5.Table Significant Laboratory Abnormalities Reported in >=1% of Patients in Any Treatment Group in Study 934 (0-144 Weeks)TDFFrom Weeks 96 to 144 of the study, patients received TRUVADA with efavirenz in place of VIREAD EMTRIVA with efavirenz. EMTRIVA EFVAZT/3TC EFVN=257N=254Any >= Grade Laboratory Abnormality30%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/mm3)3%5%Fasting Triglycerides (>750 mg/dL)4%2%. Pediatric PatientsAssessment of adverse reactions is based on data from Study 203, an open label, uncontrolled study of 116 HIV-1-infected pediatric patients who received emtricitabine through 48 weeks. The adverse reaction profile in pediatric patients was generally comparable to that observed in clinical studies of EMTRIVA in adult patients [See Adverse Reactions (6.1)]. Hyperpigmentation was more frequent in children. Additional adverse reactions identified from this study include anemia.Selected treatment-emergent adverse events, regardless of causality, reported in patients 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 grade 3/4 laboratory abnormalities were experienced by 9% of pediatric patients, including amylase >2.0 ULN (n=4), neutrophils <750/mm3 (n=3), ALT >5 ULN (n=2), elevated CPK (>4 ULN) (n=2) and one patient each with elevated bilirubin (>3.0 ULN), elevated GGT (>10 ULN), elevated lipase (>2.5 ULN), decreased hemoglobin (<7 g/dL), and decreased glucose (<40 mg/dL).

BOXED WARNING SECTION.


WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS B. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with other antiretrovirals [See Warnings and Precautions (5.1)]. EMTRIVA is not approved for the treatment of chronic hepatitis virus (HBV) infection and the safety and efficacy of EMTRIVA have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis have been reported in patients who have discontinued EMTRIVA. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue EMTRIVA. If appropriate, initiation of anti-hepatitis therapy may be warranted [See Warnings and Precautions (5.2)]. WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS BSee full prescribing information for complete boxed warning.Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs. (5.1)Emtriva is not approved for the treatment of chronic Hepatitis virus (HBV) infection. Severe acute exacerbations of Hepatitis have been reported in patients who have discontinued EMTRIVA. Hepatic function should be monitored closely in patients coinfected with HIV-1 and HBV. If appropriate, initiation of anti-Hepatitis therapy may be warranted. (5.2). Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs. (5.1). Emtriva is not approved for the treatment of chronic Hepatitis virus (HBV) infection. Severe acute exacerbations of Hepatitis have been reported in patients who have discontinued EMTRIVA. Hepatic function should be monitored closely in patients coinfected with HIV-1 and HBV. If appropriate, initiation of anti-Hepatitis therapy may be warranted. (5.2).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. In long-term oral carcinogenicity studies of emtricitabine, no drug-related increases in tumor incidence were found in mice at doses up to 750 mg/kg/day (26 times the human systemic exposure at the therapeutic dose of 200 mg/day) or in rats at doses up to 600 mg/kg/day (31 times the human systemic exposure at the therapeutic dose). Emtricitabine was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or mouse micronucleus assays.Emtricitabine did not affect fertility in male rats at approximately 140-fold or in male and female mice at approximately 60-fold higher exposures (AUC) than in humans given the recommended 200 mg daily dose. Fertility was normal in the offspring of mice exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60-fold higher than human exposures at the recommended 200 mg daily dose.

CLINICAL PHARMACOLOGY SECTION.


12CLINICAL PHARMACOLOGY. 12.1Mechanism of Action. Emtricitabine is an antiviral drug. [See Clinical Pharmacology (12.4)] 12.3Pharmacokinetics. Adult SubjectsThe pharmacokinetics of emtricitabine were evaluated in healthy volunteers and HIV-1-infected individuals. Emtricitabine pharmacokinetics are similar between these populations.Figure shows the mean steady-state plasma emtricitabine concentration-time profile in 20 HIV-1-infected subjects receiving EMTRIVA capsules.Figure Mean (+- 95% CI) Steady-State Plasma Emtricitabine Concentrations in HIV-1-Infected Adults (N=20). AbsorptionEmtricitabine is rapidly and extensively absorbed following oral administration with peak plasma concentrations occurring at 1-2 hours post-dose. Following multiple dose oral administration of EMTRIVA capsules to 20 HIV-1-infected subjects, the (mean +- SD) steady-state plasma emtricitabine peak concentration (Cmax) was 1.8 +- 0.7 ug/mL and the area-under the plasma concentration-time curve over 24-hour dosing interval (AUC) was 10.0 +- 3.1 ughr/mL. The mean steady state plasma trough concentration at 24 hours post-dose was 0.09 ug/mL. The mean absolute bioavailability of EMTRIVA capsules was 93% while the mean absolute bioavailability of EMTRIVA oral solution was 75%. The relative bioavailability of EMTRIVA oral solution was approximately 80% of EMTRIVA capsules.The multiple dose pharmacokinetics of emtricitabine are dose proportional over dose range of 25-200 mg.. DistributionIn vitro binding of emtricitabine to human plasma proteins was <4% and independent of concentration over the range of 0.02-200 ug/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.. MetabolismIn vitro studies indicate that emtricitabine is not an inhibitor of human CYP450 enzymes. Following administration of 14C-emtricitabine, 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 emtricitabine 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.. EliminationThe plasma emtricitabine half-life is approximately 10 hours. The renal clearance of emtricitabine 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 AbsorptionEMTRIVA capsules and oral solution may be taken with or without food. Emtricitabine systemic exposure (AUC) was unaffected while Cmax decreased by 29% when EMTRIVA capsules were administered with food (an approximately 1000 kcal high-fat meal). Emtricitabine systemic exposure (AUC) and Cmax were unaffected when 200 mg EMTRIVA oral solution was administered with either high-fat or low-fat meal.. Special Populations. Race, GenderThe pharmacokinetics of emtricitabine were similar in adult male and female patients and no pharmacokinetic differences due to race have been identified.. Pediatric PatientsThe pharmacokinetics of emtricitabine at steady state were determined in 77 HIV-1-infected children, and the pharmacokinetic profile was characterized in four age groups (Table 6). The emtricitabine exposure achieved in children receiving daily dose of mg/kg up to maximum of 240 mg oral solution or 200 mg capsule is similar to exposures achieved in adults receiving once-daily dose of 200 mg.The pharmacokinetics of emtricitabine were studied in 20 neonates born to HIV-1-positive mothers. Each mother received prenatal and intrapartum combination antiretroviral therapy. Neonates received up to weeks of zidovudine prophylactically after birth. The neonates were administered two short courses of emtricitabine oral solution (each mg/kg once daily 4 days) during the first months of life. The AUC observed in neonates who received daily dose of mg/kg of emtricitabine was similar to the AUC observed in pediatric patients >=3 months to 17 years who received daily dose of emtricitabine as 6 mg/kg oral solution up to 240 mg or as 200 mg capsule (Table 6). Table Mean +- SD Pharmacokinetic Parameters by Age Groups for Pediatric Patients and Neonates Receiving EMTRIVA Capsules or Oral SolutionHIV-1-exposed NeonatesHIV-1-infected Pediatric PatientsAge0-3 mo (N=20)Two pharmacokinetic evaluations were conducted in 20 neonates over the first months of life. Median (range) age of infant on day of pharmacokinetic evaluation was 26 (5-81) days. 3-24 mo (N=14)25 mo-6 yr (N=19)7-12yr (N=17)13-17 yr (N=27)Formulation Capsule (n)0001026 Oral Solution (n)20141971Dose (mg/kg)Mean (range) 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)Cmax (ug/mL) 1.6 +- 0.61.9 +- 0.61.9 +- 0.72.7 +- 0.82.7 +- 0.9AUC (ughr/mL)11.0 +- 4.28.7 +- 3.29.0 +- 3.012.6 +- 3.512.6 +- 5.4T1/2 (hr)12.1 +- 3.18.9 +- 3.211.3 +- 6.48.2 +- 3.28.9 +- 3.3. Geriatric PatientsThe pharmacokinetics of emtricitabine have not been fully evaluated in the elderly.. Patients with Impaired Renal FunctionThe pharmacokinetics of emtricitabine are altered in patients with renal impairment [See Warnings and Precautions (5.4)]. In adult patients with creatinine clearance <50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, Cmax and AUC of emtricitabine were increased due to reduction in renal clearance (Table 7). It is recommended that the dosing interval for EMTRIVA be modified in adult patients with creatinine clearance <50 mL/min or in adult patients with ESRD who require dialysis [See Dosage and Administration (2.5)]. The effects of renal impairment on emtricitabine pharmacokinetics in pediatric patients are not known.Table Mean +- SD Pharmacokinetic Parameters in Adult Patients with Varying Degrees of Renal FunctionCreatinine Clearance (mL/min)>80 (N=6)50-80 (N=6)30-49 (N=6)<30 (N=5)ESRDESRD patients requiring dialysis <30 (N=5)Baseline creatinine clearance (mL/min)107 +- 2159.8 +- 6.540.9 +- 5.122.9 +- 5.38.8 +- 1.4Cmax (ug/mL)2.2 +- 0.63.8 +- 0.93.2 +- 0.62.8 +- 0.72.8 +- 0.5AUC (ughr/mL)11.8 +- 2.919.9 +- 1.225.1 +- 5.733.7+- 2.153.2 +- 9.9CL/F (mL/min)302 +- 94168 +- 10138 +- 2899 +- 664 +- 12CLr (mL/min)213 +- 89121 +- 3969 +- 3230 +- 11NULLNULL Not Applicable Hemodialysis: Hemodialysis treatment removes approximately 30% of the emtricitabine dose over 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and dialysate flow rate of 600 mL/min). It is not known whether emtricitabine can be removed by peritoneal dialysis.. Patients with Hepatic ImpairmentThe pharmacokinetics of emtricitabine have not been studied in patients with hepatic impairment, however, emtricitabine is not metabolized by liver enzymes, so the impact of liver impairment should be limited.. Assessment of Drug InteractionsAt concentrations up to 14-fold higher than those observed in vivo, emtricitabine did not inhibit in vitro drug metabolism mediated by any of the following human CYP isoforms: CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Emtricitabine 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 emtricitabine, the potential for CYP mediated interactions involving emtricitabine with other medicinal products is low.EMTRIVA has been evaluated in healthy volunteers in combination with tenofovir disoproxil fumarate (DF), zidovudine, indinavir, famciclovir, and stavudine. Tables and summarize the pharmacokinetic effects of coadministered drug on emtricitabine pharmacokinetics and effects of emtricitabine on the pharmacokinetics of coadministered drug.Table Drug Interactions: Change in Pharmacokinetic Parameters for Emtricitabine in the Presence of the Coadministered DrugAll interaction studies conducted in healthy volunteers. Coadministered DrugDose of Coadministered Drug (mg)Emtricitabine Dose (mg)N% Change of Emtricitabine Pharmacokinetic Parameters Increase; Decrease; No Effect; NULL Not Applicable (90% CI)Cmax AUCCmin Tenofovir DF300 once daily 7 days200 once daily 7 days17 20 12 to 29)Zidovudine300 twice daily 7 days200 once daily 7 days27Indinavir800 1200 112NULLFamciclovir500 1200 112NULLStavudine40 1200 16NULLTable Drug Interactions: Change in Pharmacokinetic Parameters for Coadministered Drug in the Presence of EmtricitabineAll interaction studies conducted in healthy volunteers. Coadministered DrugDose of Coadministered Drug (mg)Emtricitabine Dose (mg)N% Change of Coadministered Drug Pharmacokinetic Parameters Increase; Decrease; No Effect; NULL Not Applicable (90% CI)Cmax AUCCmin Tenofovir DF300 once daily 7 days200 once daily 7 days17Zidovudine300 twice daily 7 days200 once daily 7 days27 17 0 to 38) 13 5 to 20)Indinavir800 1200 112NULLFamciclovir500 1200 112NULLStavudine40 1200 16NULL. 12.4Microbiology. Mechanism of ActionEmtricitabine, synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5-triphosphate. Emtricitabine 5-triphosphate inhibits the activity of the HIV-1 reverse transcriptase by competing with the natural substrate deoxycytidine 5-triphosphate and by being incorporated into nascent viral DNULL which results in chain termination. Emtricitabine 5-triphosphate is weak inhibitor of mammalian DNULL polymerase , and mitochondrial DNULL polymerase .. Antiviral ActivityThe antiviral activity in cell culture of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The 50% effective concentration (EC50) value for emtricitabine was in the range of 0.0013-0.64 uM (0.0003-0.158 ug/mL). In drug combination studies of emtricitabine with nucleoside reverse transcriptase inhibitors (abacavir, lamivudine, stavudine, tenofovir, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and (EC50 values ranged from 0.007-0.075 uM) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007-1.5 uM).The in vivo activity of emtricitabine was evaluated in two clinical trials in which 101 patients were administered 25-400 mg day of EMTRIVA as monotherapy for 10-14 days. dose-related antiviral effect was observed, with median decrease from baseline in plasma HIV-1 RNULL of 1.3 log10 at dose of 25 mg once daily and 1.7 log10 to 1.9 log10 at dose of 200 mg once daily or twice daily.. ResistanceEmtricitabine-resistant isolates of HIV-1 have been selected in cell culture and in vivo. Genotypic analysis of these isolates showed that the reduced susceptibility to emtricitabine was associated with substitution in the HIV-1 reverse transcriptase gene at codon 184 which resulted in an amino acid substitution of methionine by valine or isoleucine (M184V/I).Emtricitabine-resistant isolates of HIV-1 have been recovered from some patients treated with emtricitabine alone or in combination with other antiretroviral agents. In clinical study of treatment-naive patients treated with EMTRIVA, didanosine, and efavirenz [See Clinical Studies (14.1)], viral isolates from 37.5% of patients with virologic failure showed reduced susceptibility to emtricitabine. Genotypic analysis of these isolates showed that the resistance was due to M184V/I substitutions in the HIV-1 reverse transcriptase gene. In clinical study of treatment-naive patients treated with either EMTRIVA, VIREAD, and efavirenz or zidovudine/lamivudine and efavirenz [See Clinical Studies (14.1)], resistance analysis was performed on HIV-1 isolates from all confirmed virologic failure patients with >400 copies/mL of HIV-1 RNULL at Week 144 or early discontinuation. Development of efavirenz resistance-associated substitutions occurred most frequently and was similar between the treatment arms. The M184V amino acid substitution, associated with resistance to EMTRIVA and lamivudine, was observed in 2/19 analyzed patient isolates in the EMTRIVA VIREAD group and in 10/29 analyzed patient isolates in the lamivudine/zidovudine group. Through 144 weeks of Study 934, no patients have developed detectable K65R substitution in their HIV-1 as analyzed through standard genotypic analysis.. Cross ResistanceCross-resistance among certain nucleoside analog reverse transcriptase inhibitors has been recognized. Emtricitabine-resistant isolates (M184V/I) were cross-resistant to lamivudine and zalcitabine but retained sensitivity in cell culture to didanosine, stavudine, tenofovir, zidovudine, and NNRTIs (delavirdine, efavirenz, and nevirapine). HIV-1 isolates containing the K65R substitution, selected in vivo by abacavir, didanosine, tenofovir, and zalcitabine, demonstrated reduced susceptibility to inhibition by emtricitabine. Viruses harboring substitutions conferring reduced susceptibility to stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) or didanosine (L74V) remained sensitive to emtricitabine. HIV-1 containing the K103N substitution associated with resistance to NNRTIs was susceptible to emtricitabine.

CLINICAL STUDIES SECTION.


14CLINICAL STUDIES. 14.1Treatment-Naive Adult Patients. Study 934Data through 144 weeks are reported for Study 934, randomized, open-label, active-controlled multicenter study comparing EMTRIVA VIREAD administered in combination with efavirenz versus zidovudine/lamivudine fixed-dose combination administered in combination with efavirenz in 511 antiretroviral-naive patients. From Weeks 96 to 144 of the study, patients received emtricitabine tenofovir disoproxil fumarate (tenofovir DF) with efavirenz in place of EMTRIVA tenofovir DF with efavirenz. Patients had mean age of 38 years (range 18-80), 86% were male, 59% were Caucasian and 23% were Black. The mean baseline CD4+ cell count was 245 cells/mm3 (range 2-1191) and median baseline plasma HIV-1 RNULL was 5.01 log10 copies/mL (range 3.56-6.54). Patients were stratified by baseline CD4+ cell count (< or >=200 cells/mm3); 41% had CD4+ cell counts <200 cells/mm3 and 51% of patients had baseline viral loads >100,000 copies/mL. Treatment outcomes through 48 and 144 weeks for those patients who did not have efavirenz resistance at baseline are presented in Table 10.Table 10 Outcomes of Randomized Treatment at Week 48 and 144 (Study 934)OutcomesWeek 48Week 144EMTRIVA +TDF +EFV (N=244)AZT/3TC +EFV (N=243)EMTRIVA +TDF +EFV (N=227)Patients who were responders at Week 48 or Week 96 (HIV-1 RNULL <400 copies/mL) but did not consent to continue study after Week 48 or Week 96 were excluded from analysis. AZT/3TC +EFV (N=229) ResponderPatients achieved and maintained confirmed HIV-1 RNULL <400 copies/mL through Weeks 48 and 144. 84%73%71%58%Virologic failureIncludes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Weeks 48 and 144. 2%4%3%6% Rebound1%3%2%5% Never suppressed0%0%0%0% Change in antiretroviral regimen1%1%1%1%Death<1%1%1%1%Discontinued due to adverse event4%9%5%12%Discontinued for other reasonsIncludes lost to follow-up, patient withdrawal, noncompliance, protocol violation and other reasons. 10%14%20%22%Through Week 48, 84% and 73% of patients in the EMTRIVA tenofovir DF group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNULL <400 copies/mL (71% and 58% through Week 144). The difference in the proportion of patients who achieved and maintained HIV-1 RNULL <400 copies/mL through 48 weeks largely results from the higher number of discontinuations due to adverse events and other reasons in the zidovudine/lamivudine group in this open-label study. In addition, 80% and 70% of patients in the EMTRIVA tenofovir DF group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNULL <50 copies/mL through Week 48 (64% and 56% through Week 144). The mean increase from baseline in CD4+ cell count was 190 cells/mm3 in the EMTRIVA tenofovir DF group and 158 cells/mm3 in the zidovudine/lamivudine group at Week 48 (312 and 271 cells/mm3 at Week 144).Through 48 weeks, patients in the EMTRIVA tenofovir DF group and patients in the zidovudine/lamivudine group experienced new CDC Class event (10 and patients through 144 weeks).. Study 301AStudy 301A was 48 week double-blind, active-controlled multicenter study comparing EMTRIVA (200 mg once daily) administered in combination with didanosine and efavirenz versus stavudine, didanosine and efavirenz in 571 antiretroviral naive adult patients. Patients had mean age of 36 years (range 18-69), 85% were male, 52% Caucasian, 16% African-American and 26% Hispanic. Patients had mean baseline CD4+ cell count of 318 cells/mm3 (range 5-1317) and median baseline plasma HIV-1 RNULL of 4.9 log10 copies/mL (range 2.6-7.0). Thirty-eight percent of patients had baseline viral loads >100,000 copies/mL and 31% had CD4+ cell counts <200 cells/mL. Treatment outcomes are presented in Table 11 below.Table 11 Outcomes of Randomized Treatment at Week 48 (Study 301A)OutcomesEMTRIVA Didanosine Efavirenz (N=286)Stavudine Didanosine Efavirenz (N=285)ResponderPatients achieved and maintained confirmed HIV RNULL <400 copies/mL (<50 copies/mL) through Week 48. 81% (78%)68% (59%)Virologic FailureIncludes patients who failed to achieve virologic suppression or rebounded after achieving virologic suppression. 3%11%Death0%<1%Study Discontinuation Due to Adverse Event7%13%Study Discontinuation for Other ReasonsIncludes lost to follow-up, patient withdrawal, non-compliance, protocol violation and other reasons. 9%8%The mean increase from baseline in CD4+ cell count was 168 cells/mm3 for the EMTRIVA arm and 134 cells/mm3 for the stavudine arm.Through 48 weeks in the EMTRIVA group, patients (1.7%) experienced new CDC Class event, compared to patients (2.5%) in the stavudine group.. 14.2Treatment-Experienced Adult Patients. Study 303Study 303 was 48 week, open-label, active-controlled multicenter study comparing EMTRIVA (200 mg once daily) to lamivudine, in combination with stavudine or zidovudine and protease inhibitor or NNRTI in 440 adult patients who were on lamivudine-containing triple-antiretroviral drug regimen for at least 12 weeks prior to study entry and had HIV-1 RNULL <=400 copies/mL.Patients were randomized 1:2 to continue therapy with lamivudine (150 mg twice daily) or to switch to EMTRIVA (200 mg once daily). All patients were maintained on their stable background regimen. Patients had mean age of 42 years (range 22-80), 86% were male, 64% Caucasian, 21% African-American and 13% Hispanic. Patients had mean baseline CD4+ cell count of 527 cells/mm3 (range 37-1909), and median baseline plasma HIV-1 RNULL of 1.7 log10 copies/mL (range 1.7-4.0).The median duration of prior antiretroviral therapy was 27.6 months. Treatment outcomes are presented in Table 12 below.Table 12 Outcomes of Randomized Treatment at Week 48 (Study 303)OutcomesEMTRIVA ZDV/d4T NNRTI/PI (N=294)Lamivudine ZDV/d4T NNRTI/PI (N=146)ResponderPatients achieved and maintained confirmed HIV RNULL <400 copies/mL (<50 copies/mL) through Week 48. 77% (67%)82% (72%)Virologic FailureIncludes patients who failed to achieve virologic suppression or rebounded after achieving virologic suppression. 7%8%Death0%<1%Study Discontinuation Due to Adverse Event4%0%Study Discontinuation for Other ReasonsIncludes lost to follow-up, patient withdrawal, non-compliance, protocol violation and other reasons. 12%10%The mean increase from baseline in CD4+ cell count was 29 cells/mm3 for the EMTRIVA arm and 61 cells/mm3 for the lamivudine arm.Through 48 weeks, in the EMTRIVA group patients (0.7%) experienced new CDC Class event, compared to patients (1.4%) in the lamivudine group.. 14.3 Pediatric Patients. In three open-label, non-randomized clinical studies, emtricitabine was administered to 169 HIV-1 infected treatment-naive and experienced (defined as virologically suppressed on lamivudine containing regimen for which emtricitabine was substituted for lamivudine) patients between months and 21 years of age. Patients received once-daily EMTRIVA oral solution (6 mg/kg to maximum of 240 mg/day) or EMTRIVA capsules (a single 200 mg capsule once daily) in combination with at least two other antiretroviral agents. Patients had mean age of 7.9 years (range 0.3-21), 49% were male, 15% Caucasian, 61% Black and 24% Hispanic. Patients had median baseline HIV-1 RNULL of 4.6 log10 copies/mL (range 1.7-6.4) and mean baseline CD4+ cell count of 745 cells/mm3 (range 2-2650). Through 48 weeks of therapy, the overall proportion of patients who achieved and sustained an HIV-1 RNULL <400 copies/mL was 86%, and <50 copies/mL was 73%. The mean increase from baseline in CD4+ cell count was 232 cells/mm3 (-945, +1512). The adverse reaction profile observed during these clinical trials was similar to that of adult patients, with the exception of the occurrence of anemia and higher frequency of hyperpigmentation in children [See Adverse Reactions (6)]. The pharmacokinetics of emtricitabine were studied in 20 neonates born to HIV-1-positive mothers. Each mother received prenatal and intrapartum combination antiretroviral therapy. Neonates received up to weeks of zidovudine prophylactically after birth. The neonates were administered two short courses of emtricitabine oral solution (each mg/kg once daily 4 days) during the first months of life. Emtricitabine exposures in neonates were similar to the exposures achieved in patients >3 months to 17 years [See Clinical Pharmacology (12.3)]. During the two short dosing periods on emtricitabine there were no safety issues identified in the treated neonates. All neonates were HIV-1 negative at the end of the study; the efficacy of emtricitabine in preventing or treating HIV-1 could not be determined.

CONTRAINDICATIONS SECTION.


4CONTRAINDICATIONS. 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).

DESCRIPTION SECTION.


11DESCRIPTION. EMTRIVA is the brand name of emtricitabine, synthetic nucleoside analog with activity against human immunodeficiency virus type (HIV-1) reverse transcriptase.The chemical name of emtricitabine is 5-fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Emtricitabine is the (-) enantiomer of thio analog of cytidine, which differs from other cytidine analogs in that it has fluorine in the 5-position.It has molecular formula of C8H10FN3O3S and molecular weight of 247.24. It has the following structural formula:Emtricitabine is white to off-white powder with solubility of approximately 112 mg/mL in water at 25 C. The log for emtricitabine is -0.43 and the pKa is 2.65.EMTRIVA is available as capsules or as an oral solution.EMTRIVA capsules are for oral administration. Each capsule contains 200 mg of emtricitabine and the inactive ingredients, crospovidone, magnesium stearate, microcrystalline cellulose, and povidone.EMTRIVA oral solution is for oral administration. One milliliter (1 mL) of EMTRIVA oral solution contains 10 mg of emtricitabine in an aqueous solution with the following inactive ingredients: cotton candy flavor, FD&C yellow No. 6, edetate disodium, methylparaben, and propylparaben (added as preservatives), sodium phosphate (monobasic), propylene glycol, water, and xylitol (added as sweetener). Sodium hydroxide and hydrochloric acid may be used to adjust pH.. Chemical Structure. Figure. Figure.

DOSAGE & ADMINISTRATION SECTION.


2DOSAGE AND ADMINISTRATION. EMTRIVA may be taken without regard to food. (2.1)Adult Patients (18 years of age and older) (2.2): EMTRIVA capsules: one 200 mg capsule administered once daily orally.EMTRIVA oral solution: 240 mg (24 mL) administered once daily orally. Pediatric Patients (0-3 months of age) (2.3): EMTRIVA oral solution: mg/kg administered once daily orally. Pediatric Patients (3 months through 17 years) (2.4): EMTRIVA oral solution: mg/kg up to maximum of 240 mg (24 mL) administered once daily orally.EMTRIVA 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 (2.5):Creatinine Clearance (mL/min)Formulation>=50 mL/min30-49 mL/min15-29 mL/min<15 mL/min or on hemodialysisHemodialysis Patients: If dosing on day of dialysis, give dose after dialysis. Capsule (200 mg)200 mg every 24 hours200 mg every 48 hours200 mg every 72 hours200 mg every 96 hoursOral Solution (10 mg/mL)240 mg every 24 hours (24 mL)120 mg every 24 hours (12 mL)80 mg every 24 hours (8 mL)60 mg every 24 hours (6 mL). EMTRIVA may be taken without regard to food. (2.1). Adult Patients (18 years of age and older) (2.2): EMTRIVA capsules: one 200 mg capsule administered once daily orally.EMTRIVA oral solution: 240 mg (24 mL) administered once daily orally. EMTRIVA capsules: one 200 mg capsule administered once daily orally.. EMTRIVA oral solution: 240 mg (24 mL) administered once daily orally.. Pediatric Patients (0-3 months of age) (2.3): EMTRIVA oral solution: mg/kg administered once daily orally. EMTRIVA oral solution: mg/kg administered once daily orally.. Pediatric Patients (3 months through 17 years) (2.4): EMTRIVA oral solution: mg/kg up to maximum of 240 mg (24 mL) administered once daily orally.EMTRIVA capsules: for children weighing more than 33 kg who can swallow an intact capsule, one 200 mg capsule administered once daily orally. EMTRIVA oral solution: mg/kg up to maximum of 240 mg (24 mL) administered once daily orally.. EMTRIVA 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 (2.5):. 2.1Recommended Dose. EMTRIVA may be taken without regard to food.. 2.2Adult Patients (18 years of age and older). EMTRIVA capsules: one 200 mg capsule administered once daily orally.EMTRIVA oral solution: 240 mg (24 mL) administered once daily orally.. EMTRIVA capsules: one 200 mg capsule administered once daily orally.. EMTRIVA oral solution: 240 mg (24 mL) administered once daily orally.. 2.3Pediatric Patients (0-3 months of age). EMTRIVA oral solution: mg/kg administered once daily orally.. EMTRIVA oral solution: mg/kg administered once daily orally.. 2.4Pediatric Patients (3 months through 17 years). EMTRIVA oral solution: mg/kg up to maximum of 240 mg (24 mL) administered once daily orally.EMTRIVA capsules: for children weighing more than 33 kg who can swallow an intact capsule, one 200 mg capsule administered once daily orally.. EMTRIVA oral solution: mg/kg up to maximum of 240 mg (24 mL) administered once daily orally.. EMTRIVA capsules: for children weighing more than 33 kg who can swallow an intact capsule, one 200 mg capsule administered once daily orally.. 2.5Dose Adjustment in Adult Patients with Renal Impairment. Significantly increased drug exposures were seen when EMTRIVA was administered to patients with renal impairment [See Clinical Pharmacology (12.3)]. Therefore, the dosing interval or dose of EMTRIVA should be adjusted in patients with baseline creatinine clearance <50 mL/min using the following guidelines (see Table 1). The safety and effectiveness of these dose adjustment guidelines have not been clinically evaluated. Therefore, clinical response to treatment and renal function should be closely monitored in these patients.Table Dose Adjustment in Adult Patients with Renal ImpairmentCreatinine Clearance (mL/min)Formulation>=50 mL/min30-49 mL/min15-29 mL/min<15 mL/min or on hemodialysisHemodialysis Patients: If dosing on day of dialysis, give dose after dialysis Capsule (200 mg)200 mg every 24 hours200 mg every 48 hours200 mg every 72 hours200 mg every 96 hoursOral Solution (10 mg/mL)240 mg every 24 hours (24 mL)120 mg every 24 hours (12 mL)80 mg every 24 hours (8 mL)60 mg every 24 hours (6 mL)Although there are insufficient data to recommend specific dose adjustment of EMTRIVA in pediatric patients with renal impairment, reduction in the dose and/or an increase in the dosing interval similar to adjustments for adults should be considered.

DOSAGE FORMS & STRENGTHS SECTION.


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

DRUG INTERACTIONS SECTION.


7DRUG INTERACTIONS. The potential for drug interactions with EMTRIVA has been studied in combination with zidovudine, indinavir, stavudine, famciclovir, and tenofovir disoproxil fumarate. There were no clinically significant drug interactions for any of these drugs Drug interactions studies are described elsewhere in the labeling [See Clinical Pharmacology (12.3)].

GERIATRIC USE SECTION.


8.5Geriatric Use. Clinical studies 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.

HOW SUPPLIED SECTION.


16HOW SUPPLIED/STORAGE AND HANDLING. CapsulesThe size hard gelatin capsules with blue cap and white body contain 200 mg of emtricitabine, are printed with 200 mg in black on the cap and GILEAD and the corporate logo in black on the body, and are available in unit of use bottles (closed with induction sealed child-resistant closures) of: 30 capsules (NDC 61958-0601-1).. 30 capsules (NDC 61958-0601-1).. Store at 25 (77 F); excursions permitted to 15 C-30 (59 F-86 F) Oral SolutionThe oral solution is clear, orange to dark orange liquid, contains 10 mg/mL of emtricitabine, and is available in unit of use plastic, amber bottles closed with child resistant closures and packaged with marked dosing cup) of:170 mL (NDC 61958-0602-1).. 170 mL (NDC 61958-0602-1).. Store refrigerated, 2-8 (36-46 F). Emtriva oral solution should be used within months if stored by the patient at 25 (77 F); excursions permitted to 15-30 (59-86 F).

INDICATIONS & USAGE SECTION.


1INDICATIONS AND USAGE. EMTRIVA(R) is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.Additional important information regarding the use of EMTRIVA for the treatment of HIV-1 Infection:EMTRIVA should not be coadministered with ATRIPLA(R), COMPLERA(TM), TRUVADA(R), or lamivudine-containing products [See Warnings and Precautions (5.3)]. In treatment-experienced patients, the use of EMTRIVA should be guided by laboratory testing and treatment history [See Clinical Pharmacology (12.4)]. EMTRIVA should not be coadministered with ATRIPLA(R), COMPLERA(TM), TRUVADA(R), or lamivudine-containing products [See Warnings and Precautions (5.3)]. In treatment-experienced patients, the use of EMTRIVA should be guided by laboratory testing and treatment history [See Clinical Pharmacology (12.4)]. EMTRIVA, nucleoside analog HIV-1 reverse transcriptase inhibitor, is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. (1).

INFORMATION FOR PATIENTS SECTION.


17PATIENT COUNSELING INFORMATION. See FDA-approved patient labeling (17.2) 17.1Information for Patients. Patients should be advised that:EMTRIVA is not cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of physician when using EMTRIVA.The use of EMTRIVA has not been shown to reduce the risk of transmission of HIV-1 to others through sexual contact or blood contamination.The long term effects of EMTRIVA are unknown.EMTRIVA capsules and oral solution are for oral ingestion only.It is important to take EMTRIVA with combination therapy on regular dosing schedule to avoid missing doses.Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Treatment with EMTRIVA should be suspended in any patient who develops clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity (including nausea, vomiting, unusual or unexpected stomach discomfort, and weakness) [See Warnings and Precautions (5.1)].Patients with HIV-1 should be tested for Hepatitis virus (HBV) before initiating antiretroviral therapy.Severe acute exacerbations of Hepatitis have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued EMTRIVA.EMTRIVA should not be coadministered with ATRIPLA, COMPLERA, or TRUVADA; or with other drugs containing lamivudine, including Combivir (lamivudine/zidovudine), Epivir or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), or Trizivir (abacavir sulfate/lamivudine/zidovudine) [See Warnings and Precautions (5.3)].Dose or dosing interval of EMTRIVA may need adjustment in patients with renal impairment [See Dosage and Administration (2.5)].. EMTRIVA is not cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of physician when using EMTRIVA.. The use of EMTRIVA has not been shown to reduce the risk of transmission of HIV-1 to others through sexual contact or blood contamination.. The long term effects of EMTRIVA are unknown.. EMTRIVA capsules and oral solution are for oral ingestion only.. It is important to take EMTRIVA with combination therapy on regular dosing schedule to avoid missing doses.. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Treatment with EMTRIVA should be suspended in any patient who develops clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity (including nausea, vomiting, unusual or unexpected stomach discomfort, and weakness) [See Warnings and Precautions (5.1)].. Patients with HIV-1 should be tested for Hepatitis virus (HBV) before initiating antiretroviral therapy.. Severe acute exacerbations of Hepatitis have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued EMTRIVA.. EMTRIVA should not be coadministered with ATRIPLA, COMPLERA, or TRUVADA; or with other drugs containing lamivudine, including Combivir (lamivudine/zidovudine), Epivir or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), or Trizivir (abacavir sulfate/lamivudine/zidovudine) [See Warnings and Precautions (5.3)].. Dose or dosing interval of EMTRIVA may need adjustment in patients with renal impairment [See Dosage and Administration (2.5)].. 17.2FDA-Approved Patient Labeling.

MECHANISM OF ACTION SECTION.


12.1Mechanism of Action. Emtricitabine is an antiviral drug. [See Clinical Pharmacology (12.4)].

MICROBIOLOGY SECTION.


12.4Microbiology. Mechanism of ActionEmtricitabine, synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5-triphosphate. Emtricitabine 5-triphosphate inhibits the activity of the HIV-1 reverse transcriptase by competing with the natural substrate deoxycytidine 5-triphosphate and by being incorporated into nascent viral DNULL which results in chain termination. Emtricitabine 5-triphosphate is weak inhibitor of mammalian DNULL polymerase , and mitochondrial DNULL polymerase .. Antiviral ActivityThe antiviral activity in cell culture of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The 50% effective concentration (EC50) value for emtricitabine was in the range of 0.0013-0.64 uM (0.0003-0.158 ug/mL). In drug combination studies of emtricitabine with nucleoside reverse transcriptase inhibitors (abacavir, lamivudine, stavudine, tenofovir, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and (EC50 values ranged from 0.007-0.075 uM) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007-1.5 uM).The in vivo activity of emtricitabine was evaluated in two clinical trials in which 101 patients were administered 25-400 mg day of EMTRIVA as monotherapy for 10-14 days. dose-related antiviral effect was observed, with median decrease from baseline in plasma HIV-1 RNULL of 1.3 log10 at dose of 25 mg once daily and 1.7 log10 to 1.9 log10 at dose of 200 mg once daily or twice daily.. ResistanceEmtricitabine-resistant isolates of HIV-1 have been selected in cell culture and in vivo. Genotypic analysis of these isolates showed that the reduced susceptibility to emtricitabine was associated with substitution in the HIV-1 reverse transcriptase gene at codon 184 which resulted in an amino acid substitution of methionine by valine or isoleucine (M184V/I).Emtricitabine-resistant isolates of HIV-1 have been recovered from some patients treated with emtricitabine alone or in combination with other antiretroviral agents. In clinical study of treatment-naive patients treated with EMTRIVA, didanosine, and efavirenz [See Clinical Studies (14.1)], viral isolates from 37.5% of patients with virologic failure showed reduced susceptibility to emtricitabine. Genotypic analysis of these isolates showed that the resistance was due to M184V/I substitutions in the HIV-1 reverse transcriptase gene. In clinical study of treatment-naive patients treated with either EMTRIVA, VIREAD, and efavirenz or zidovudine/lamivudine and efavirenz [See Clinical Studies (14.1)], resistance analysis was performed on HIV-1 isolates from all confirmed virologic failure patients with >400 copies/mL of HIV-1 RNULL at Week 144 or early discontinuation. Development of efavirenz resistance-associated substitutions occurred most frequently and was similar between the treatment arms. The M184V amino acid substitution, associated with resistance to EMTRIVA and lamivudine, was observed in 2/19 analyzed patient isolates in the EMTRIVA VIREAD group and in 10/29 analyzed patient isolates in the lamivudine/zidovudine group. Through 144 weeks of Study 934, no patients have developed detectable K65R substitution in their HIV-1 as analyzed through standard genotypic analysis.. Cross ResistanceCross-resistance among certain nucleoside analog reverse transcriptase inhibitors has been recognized. Emtricitabine-resistant isolates (M184V/I) were cross-resistant to lamivudine and zalcitabine but retained sensitivity in cell culture to didanosine, stavudine, tenofovir, zidovudine, and NNRTIs (delavirdine, efavirenz, and nevirapine). HIV-1 isolates containing the K65R substitution, selected in vivo by abacavir, didanosine, tenofovir, and zalcitabine, demonstrated reduced susceptibility to inhibition by emtricitabine. Viruses harboring substitutions conferring reduced susceptibility to stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) or didanosine (L74V) remained sensitive to emtricitabine. HIV-1 containing the K103N substitution associated with resistance to NNRTIs was susceptible to emtricitabine.

NONCLINICAL TOXICOLOGY SECTION.


13NONCLINICAL TOXICOLOGY. 13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. In long-term oral carcinogenicity studies of emtricitabine, no drug-related increases in tumor incidence were found in mice at doses up to 750 mg/kg/day (26 times the human systemic exposure at the therapeutic dose of 200 mg/day) or in rats at doses up to 600 mg/kg/day (31 times the human systemic exposure at the therapeutic dose). Emtricitabine was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or mouse micronucleus assays.Emtricitabine did not affect fertility in male rats at approximately 140-fold or in male and female mice at approximately 60-fold higher exposures (AUC) than in humans given the recommended 200 mg daily dose. Fertility was normal in the offspring of mice exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60-fold higher than human exposures at the recommended 200 mg daily dose.

NURSING MOTHERS SECTION.


8.3Nursing Mothers. Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV-1. It is not known whether emtricitabine is excreted in human milk. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving EMTRIVA.

OVERDOSAGE SECTION.


10OVERDOSAGE. There is no known antidote for EMTRIVA. Limited clinical experience is available at doses higher than the therapeutic dose of EMTRIVA. In one clinical pharmacology study single doses of emtricitabine 1200 mg were administered to 11 patients. No severe adverse reactions were reported.The effects of higher doses are not known. If overdose occurs the patient should be monitored for signs of toxicity, and standard supportive treatment applied as necessary.Hemodialysis treatment removes approximately 30% of the emtricitabine dose over 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and dialysate flow rate of 600 mL/min). It is not known whether emtricitabine can be removed by peritoneal dialysis.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL Representative Bottle LabelNDC 54868-4853-0Emtriva(R) (emtricitabine)Capsules, 200 mg30 capsulesRx only. image of 200 mg package label.

PEDIATRIC USE SECTION.


8.4Pediatric Use. The safety and efficacy of emtricitabine in patients between months and 21 years of age is supported by data from three open-label, non-randomized clinical studies in which emtricitabine was administered to 169 HIV-1 infected treatment-naive and experienced (defined as virologically suppressed on lamivudine containing regimen for which emtricitabine was substituted for lamivudine) subjects [See Clinical Studies(14.3)].The pharmacokinetics of emtricitabine were studied in 20 neonates born to HIV-1-positive mothers [See Clinical Studies (14.3)]. All neonates were HIV-1 negative at the end of the study; the efficacy of emtricitabine in preventing or treating HIV-1 could not be determined.

PHARMACOKINETICS SECTION.


12.3Pharmacokinetics. Adult SubjectsThe pharmacokinetics of emtricitabine were evaluated in healthy volunteers and HIV-1-infected individuals. Emtricitabine pharmacokinetics are similar between these populations.Figure shows the mean steady-state plasma emtricitabine concentration-time profile in 20 HIV-1-infected subjects receiving EMTRIVA capsules.Figure Mean (+- 95% CI) Steady-State Plasma Emtricitabine Concentrations in HIV-1-Infected Adults (N=20). AbsorptionEmtricitabine is rapidly and extensively absorbed following oral administration with peak plasma concentrations occurring at 1-2 hours post-dose. Following multiple dose oral administration of EMTRIVA capsules to 20 HIV-1-infected subjects, the (mean +- SD) steady-state plasma emtricitabine peak concentration (Cmax) was 1.8 +- 0.7 ug/mL and the area-under the plasma concentration-time curve over 24-hour dosing interval (AUC) was 10.0 +- 3.1 ughr/mL. The mean steady state plasma trough concentration at 24 hours post-dose was 0.09 ug/mL. The mean absolute bioavailability of EMTRIVA capsules was 93% while the mean absolute bioavailability of EMTRIVA oral solution was 75%. The relative bioavailability of EMTRIVA oral solution was approximately 80% of EMTRIVA capsules.The multiple dose pharmacokinetics of emtricitabine are dose proportional over dose range of 25-200 mg.. DistributionIn vitro binding of emtricitabine to human plasma proteins was <4% and independent of concentration over the range of 0.02-200 ug/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.. MetabolismIn vitro studies indicate that emtricitabine is not an inhibitor of human CYP450 enzymes. Following administration of 14C-emtricitabine, 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 emtricitabine 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.. EliminationThe plasma emtricitabine half-life is approximately 10 hours. The renal clearance of emtricitabine 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 AbsorptionEMTRIVA capsules and oral solution may be taken with or without food. Emtricitabine systemic exposure (AUC) was unaffected while Cmax decreased by 29% when EMTRIVA capsules were administered with food (an approximately 1000 kcal high-fat meal). Emtricitabine systemic exposure (AUC) and Cmax were unaffected when 200 mg EMTRIVA oral solution was administered with either high-fat or low-fat meal.. Special Populations. Race, GenderThe pharmacokinetics of emtricitabine were similar in adult male and female patients and no pharmacokinetic differences due to race have been identified.. Pediatric PatientsThe pharmacokinetics of emtricitabine at steady state were determined in 77 HIV-1-infected children, and the pharmacokinetic profile was characterized in four age groups (Table 6). The emtricitabine exposure achieved in children receiving daily dose of mg/kg up to maximum of 240 mg oral solution or 200 mg capsule is similar to exposures achieved in adults receiving once-daily dose of 200 mg.The pharmacokinetics of emtricitabine were studied in 20 neonates born to HIV-1-positive mothers. Each mother received prenatal and intrapartum combination antiretroviral therapy. Neonates received up to weeks of zidovudine prophylactically after birth. The neonates were administered two short courses of emtricitabine oral solution (each mg/kg once daily 4 days) during the first months of life. The AUC observed in neonates who received daily dose of mg/kg of emtricitabine was similar to the AUC observed in pediatric patients >=3 months to 17 years who received daily dose of emtricitabine as 6 mg/kg oral solution up to 240 mg or as 200 mg capsule (Table 6). Table Mean +- SD Pharmacokinetic Parameters by Age Groups for Pediatric Patients and Neonates Receiving EMTRIVA Capsules or Oral SolutionHIV-1-exposed NeonatesHIV-1-infected Pediatric PatientsAge0-3 mo (N=20)Two pharmacokinetic evaluations were conducted in 20 neonates over the first months of life. Median (range) age of infant on day of pharmacokinetic evaluation was 26 (5-81) days. 3-24 mo (N=14)25 mo-6 yr (N=19)7-12yr (N=17)13-17 yr (N=27)Formulation Capsule (n)0001026 Oral Solution (n)20141971Dose (mg/kg)Mean (range) 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)Cmax (ug/mL) 1.6 +- 0.61.9 +- 0.61.9 +- 0.72.7 +- 0.82.7 +- 0.9AUC (ughr/mL)11.0 +- 4.28.7 +- 3.29.0 +- 3.012.6 +- 3.512.6 +- 5.4T1/2 (hr)12.1 +- 3.18.9 +- 3.211.3 +- 6.48.2 +- 3.28.9 +- 3.3. Geriatric PatientsThe pharmacokinetics of emtricitabine have not been fully evaluated in the elderly.. Patients with Impaired Renal FunctionThe pharmacokinetics of emtricitabine are altered in patients with renal impairment [See Warnings and Precautions (5.4)]. In adult patients with creatinine clearance <50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, Cmax and AUC of emtricitabine were increased due to reduction in renal clearance (Table 7). It is recommended that the dosing interval for EMTRIVA be modified in adult patients with creatinine clearance <50 mL/min or in adult patients with ESRD who require dialysis [See Dosage and Administration (2.5)]. The effects of renal impairment on emtricitabine pharmacokinetics in pediatric patients are not known.Table Mean +- SD Pharmacokinetic Parameters in Adult Patients with Varying Degrees of Renal FunctionCreatinine Clearance (mL/min)>80 (N=6)50-80 (N=6)30-49 (N=6)<30 (N=5)ESRDESRD patients requiring dialysis <30 (N=5)Baseline creatinine clearance (mL/min)107 +- 2159.8 +- 6.540.9 +- 5.122.9 +- 5.38.8 +- 1.4Cmax (ug/mL)2.2 +- 0.63.8 +- 0.93.2 +- 0.62.8 +- 0.72.8 +- 0.5AUC (ughr/mL)11.8 +- 2.919.9 +- 1.225.1 +- 5.733.7+- 2.153.2 +- 9.9CL/F (mL/min)302 +- 94168 +- 10138 +- 2899 +- 664 +- 12CLr (mL/min)213 +- 89121 +- 3969 +- 3230 +- 11NULLNULL Not Applicable Hemodialysis: Hemodialysis treatment removes approximately 30% of the emtricitabine dose over 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and dialysate flow rate of 600 mL/min). It is not known whether emtricitabine can be removed by peritoneal dialysis.. Patients with Hepatic ImpairmentThe pharmacokinetics of emtricitabine have not been studied in patients with hepatic impairment, however, emtricitabine is not metabolized by liver enzymes, so the impact of liver impairment should be limited.. Assessment of Drug InteractionsAt concentrations up to 14-fold higher than those observed in vivo, emtricitabine did not inhibit in vitro drug metabolism mediated by any of the following human CYP isoforms: CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Emtricitabine 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 emtricitabine, the potential for CYP mediated interactions involving emtricitabine with other medicinal products is low.EMTRIVA has been evaluated in healthy volunteers in combination with tenofovir disoproxil fumarate (DF), zidovudine, indinavir, famciclovir, and stavudine. Tables and summarize the pharmacokinetic effects of coadministered drug on emtricitabine pharmacokinetics and effects of emtricitabine on the pharmacokinetics of coadministered drug.Table Drug Interactions: Change in Pharmacokinetic Parameters for Emtricitabine in the Presence of the Coadministered DrugAll interaction studies conducted in healthy volunteers. Coadministered DrugDose of Coadministered Drug (mg)Emtricitabine Dose (mg)N% Change of Emtricitabine Pharmacokinetic Parameters Increase; Decrease; No Effect; NULL Not Applicable (90% CI)Cmax AUCCmin Tenofovir DF300 once daily 7 days200 once daily 7 days17 20 12 to 29)Zidovudine300 twice daily 7 days200 once daily 7 days27Indinavir800 1200 112NULLFamciclovir500 1200 112NULLStavudine40 1200 16NULLTable Drug Interactions: Change in Pharmacokinetic Parameters for Coadministered Drug in the Presence of EmtricitabineAll interaction studies conducted in healthy volunteers. Coadministered DrugDose of Coadministered Drug (mg)Emtricitabine Dose (mg)N% Change of Coadministered Drug Pharmacokinetic Parameters Increase; Decrease; No Effect; NULL Not Applicable (90% CI)Cmax AUCCmin Tenofovir DF300 once daily 7 days200 once daily 7 days17Zidovudine300 twice daily 7 days200 once daily 7 days27 17 0 to 38) 13 5 to 20)Indinavir800 1200 112NULLFamciclovir500 1200 112NULLStavudine40 1200 16NULL.

PREGNULLNCY SECTION.


8.1Pregnancy. Pregnancy Category BThe incidence of fetal variations and malformations was not increased in embryofetal toxicity studies performed with emtricitabine in mice at exposures (AUC) approximately 60-fold higher and in rabbits at approximately 120-fold higher than human exposures at the recommended daily dose. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, EMTRIVA should be used during pregnancy only if clearly needed.. Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to EMTRIVA, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.

RECENT MAJOR CHANGES SECTION.


Indications and Usage (1)11/2011Warnings and Precautions Coadministration with Other Products (5.3)11/2011 Immune Reconstitution Syndrome (5.6) 11/2011.

SPL PATIENT PACKAGE INSERT SECTION.


EMTRIVA(R) (em-treev-ah) capsulesEMTRIVA oral solutionGeneric name: emtricitabine (em tri SIT uh bean)Read the Patient Information that comes with EMTRIVA before you start using it and each time you get refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.You should stay under healthcare providers care when taking EMTRIVA. Do not change or stop your medicine without first talking with your healthcare provider. Talk to your healthcare provider or pharmacist if you have any questions about EMTRIVA.What is the most important information should know about EMTRIVASome people who have taken medicines like EMTRIVA (a nucleoside analog) have developed serious condition called lactic acidosis (buildup of an acid in the blood). Lactic acidosis can be medical emergency and may need to be treated in the hospital. Call your healthcare provider right away if you get the following signs of lactic acidosis. You feel very weak or tired.You have unusual (not normal) muscle pain.You have trouble breathing.You have stomach pain with nausea and vomiting.You feel cold, especially in your arm and legs.You feel dizzy or lightheaded.You have fast or irregular heartbeat. Some people who have taken medicines like EMTRIVA have developed serious liver problems called hepatotoxicity, with liver enlargement (hepatomegaly) and fat in the liver (steatosis). Call your healthcare provider right away if you get the following signs of liver problems.Your skin or the white part of your eyes turns yellow (jaundice).Your urine turns dark.Your bowel movements (stools) turn light in color.You dont feel like eating food for several days or longer.You feel sick to your stomach (nausea).You have lower stomach area (abdominal) pain.You may be more likely to get lactic acidosis or liver problems if you are female, very overweight (obese), or have been taking nucleoside analog medicines, like EMTRIVA, for long time.If you are also infected with the Hepatitis Virus (HBV), you need close medical follow-up for several months after stopping treatment with EMTRIVA. Follow-up includes medical exams and blood tests to check for HBV that is getting worse. Patients with HBV infection, who take EMTRIVA and then stop it, may get flare-ups of their hepatitis. flare-up is when the disease suddenly returns in worse way than before.What is EMTRIVAEMTRIVA is type of medicine called an HIV-1 (human immunodeficiency virus) nucleoside reverse transcriptase inhibitor (NRTI). EMTRIVA is always used with other anti-HIV-1 medicines to treat people with HIV-1 infection. EMTRIVA is for adults and children, but has not been studied fully in adults over age 65. HIV infection destroys CD4+ cells, which are important to the immune system. The immune system helps fight infection. After large number of cells are destroyed, acquired immune deficiency syndrome (AIDS) develops.EMTRIVA helps to block HIV-1 reverse transcriptase, chemical in your body (enzyme) that is needed for HIV-1 to multiply. EMTRIVA may lower the amount of HIV-1 in the blood (viral load). EMTRIVA may also help to increase the number of cells called CD4+ cells. Lowering the amount of HIV-1 in the blood lowers the chance of death or infections that happen when your immune system is weak (opportunistic infections).EMTRIVA does not cure HIV-1 infection or AIDS. The long-term effects of EMTRIVA are not known at this time. People taking EMTRIVA may still get opportunistic infections or other conditions that happen with HIV-1 infection. Opportunistic infections are infections that develop because the immune system is weak. Some of these conditions are pneumonia, herpes virus infections, and Mycobacterium avium complex (MAC) infections. It is very important that you see your healthcare provider regularly while taking EMTRIVA.EMTRIVA does not lower your chance of passing HIV-1 to other people through sexual contact, sharing needles, or being exposed to your blood. For your health and the health of others, it is important to always practice safer sex by using latex or polyurethane condom or other barrier to lower the chance of sexual contact with semen, vaginal secretions, or blood. Never use or share dirty needles.Who should not take EMTRIVADo not take EMTRIVA if you are allergic to EMTRIVA or any of its ingredients. The active ingredient is emtricitabine. See the end of this leaflet for complete list of ingredients.Do not take EMTRIVA if you are already taking ATRIPLA(R), COMPLERA(TM), TRUVADA(R), Combivir, Epivir, Epivir-HBV, Epzicom, or Trizivir because these medicines contain the same or similar active ingredients.What should tell my healthcare provider before taking EMTRIVATell your healthcare providerIf you are pregnant or planning to become pregnant. We do not know if EMTRIVA can harm your unborn child. You and your healthcare provider will need to decide if EMTRIVA is right for you. If you use EMTRIVA while you are pregnant, talk to your healthcare provider about how you can be on the EMTRIVA Antiviral Pregnancy Registry.If you are breast-feeding. You should not breast feed if you are HIV-positive because of the chance of passing the HIV virus to your baby. Also, it is not known if EMTRIVA can pass into your breast milk and if it can harm your baby. If you are woman who has or will have baby, talk with your healthcare provider about the best way to feed your baby.If you have kidney problems. You may need to take EMTRIVA less often.If you have any liver problems including Hepatitis Virus infection.Tell your healthcare provider about all your medical conditions. Tell your healthcare provider about all the medicines you take such as prescription and non-prescription medicines and dietary supplements. Keep complete list of all the medicines that you take. Make new list when medicines are added or stopped. Give copies of this list to all of your healthcare providers and pharmacist every time you visit or fill prescription.How should take EMTRIVATake EMTRIVA by mouth exactly as your healthcare provider prescribed it. Follow the directions from your healthcare provider, exactly as written on the label.Dosing in adults: The usual dose of EMTRIVA is capsule once day.Dosing in children: The childs doctor will calculate the right dose of EMTRIVA (oral solution or capsule) based on the childs weight.EMTRIVA is always used with other anti-HIV-1 medicines.EMTRIVA may be taken with or without meal. Food does not affect how EMTRIVA works.If you forget to take EMTRIVA, take it as soon as you remember that day. Do not take more than dose of EMTRIVA in day. Do not take doses at the same time. Call your healthcare provider or pharmacist if you are not sure what to do. It is important that you do not miss any doses of EMTRIVA or your other anti-HIV-1 medicines. When your EMTRIVA supply starts to run low, get more from your healthcare provider or pharmacy. This is very important because the amount of virus in your blood may increase if the medicine is stopped for even short time. The virus may develop resistance to EMTRIVA and become harder to treat.Stay under healthcare providers care when taking EMTRIVA. Do not change your treatment or stop treatment without first talking with your healthcare provider.If you take too much EMTRIVA, call your local poison control center or emergency room right away.What should avoid while taking EMTRIVADo not breast-feed. See What should tell my healthcare provider before taking EMTRIVA Talk with your healthcare provider about the best way to feed your baby.Avoid doing things that can spread HIV-1 infection since EMTRIVA doesnt stop you from passing the HIV-1 infection to others.Do not share needles or other injection equipment.Do not share personal texts that can have blood or body fluids on them, like toothbrushes or razor blades.Do not have any kind of sex without protection. Always practice safer sex by using latex or polyurethane condom or other barrier to reduce the chance of sexual contact with semen, vaginal secretions, or blood.What are the possible side effects of EMTRIVAEMTRIVA may cause the following serious side effects (See What is the most important information should know about EMTRIVA):lactic acidosis (buildup of an acid in the blood). Lactic acidosis can be medical emergency and may need to be treated in the hospital. Call your doctor right away if you get signs of lactic acidosis. (See What is the most important information should know about EMTRIVA)serious liver problems (hepatotoxicity), with liver enlargement (hepatomegaly) and fat in the liver (steatosis). Call your healthcare provider right away if you get any signs of liver problems. (See What is the most important information should know about EMTRIVA)flare-ups of Hepatitis Virus infection, in which the disease suddenly returns in worse way than before, can occur if you stop taking EMTRIVA. EMTRIVA is not for the treatment of Hepatitis Virus (HBV) infection.Other side effects with EMTRIVA when used with other anti-HIV-1 medicines Include:Changes in body fat have been seen in some patients taking EMTRIVA and other anti-HIV-1 medicines. These changes may include increased amount of fat in the upper back and neck (buffalo hump), breast, and around the main part of your body (trunk). Loss of fat from the legs, arms and face may also happen. The cause and long term health effects of these conditions are not known at this time.The most common side effects of EMTRIVA used with other anti-HIV-1 medicines are headache, diarrhea, and nausea. Other side effects include allergic reaction, dizziness, sleeping problems, abnormal dreams, vomiting, indigestion, stomach pain, pain, weakness and rash. Skin discoloration may also happen with EMTRIVA. There have been other side effects in patients taking EMTRIVA. However, these side effects may have been due to other medicines that patients were taking or to HIV-1 itself. Some of these side effects can be serious.This list of side effects is not complete. If you have questions about side effects, ask your healthcare provider or pharmacist. You should report any new or continuing symptoms to your healthcare provider right away. Your healthcare provider may be able to help you manage these side effects.How do store EMTRIVAKeep EMTRIVA and all other medicines out of reach of children.Store EMTRIVA capsules between 59 and 86 (15 to 30 C).Store EMTRIVA oral solution in refrigerator between 36 and 46 (2-8 C). Do not freeze. Alternatively, the product may be stored at room temperature for up to months and any remaining solution in the bottle must be discarded after the months.Do not keep your medicine in places that are too hot or cold.Do not keep medicine that is out of date or that you no longer need. If you throw any medicines away make sure that children will not find them.General information about EMTRIVA:Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use EMTRIVA for condition for which it was not prescribed. Do not give EMTRIVA to other people, even if they have the same symptoms you have. It may harm them.This leaflet summarizes the most important information about EMTRIVA. If you would like more information, talk with your doctor. You can ask your healthcare provider or pharmacist for information about EMTRIVA that is written for health professionals. For more information, you may also call 1-800-GILEAD5.What are the ingredients of EMTRIVAActive Ingredient: emtricitabineInactive Ingredients for EMTRIVA capsules: crospovidone, magnesium stearate, microcrystalline cellulose, and povidone. Inactive Ingredients for EMTRIVA oral solution: Cotton candy flavor, FD&C yellow No. 6, edetate disodium, methylparaben and propylparaben, sodium phosphate (monobasic), propylene glycol, water, and xylitol. Sodium hydroxide and hydrochloric acid may be used to adjust pH.Rx OnlyNovember 2011COMPLERA, EMTRIVA, TRUVADA, and VIREAD are trademarks or registered trademarks of Gilead Sciences, Inc., or its related companies. ATRIPLA is registered trademark of Bristol-Myers Squibb Gilead Sciences, LLC. All other trademarks referenced herein are the property of their respective owners.21-500-896-GS-015 18112011. Some people who have taken medicines like EMTRIVA (a nucleoside analog) have developed serious condition called lactic acidosis (buildup of an acid in the blood). Lactic acidosis can be medical emergency and may need to be treated in the hospital. Call your healthcare provider right away if you get the following signs of lactic acidosis. You feel very weak or tired.You have unusual (not normal) muscle pain.You have trouble breathing.You have stomach pain with nausea and vomiting.You feel cold, especially in your arm and legs.You feel dizzy or lightheaded.You have fast or irregular heartbeat. You feel very weak or tired.. You have unusual (not normal) muscle pain.. You have trouble breathing.. You have stomach pain with nausea and vomiting.. You feel cold, especially in your arm and legs.. You feel dizzy or lightheaded.. You have fast or irregular heartbeat.. Some people who have taken medicines like EMTRIVA have developed serious liver problems called hepatotoxicity, with liver enlargement (hepatomegaly) and fat in the liver (steatosis). Call your healthcare provider right away if you get the following signs of liver problems.Your skin or the white part of your eyes turns yellow (jaundice).Your urine turns dark.Your bowel movements (stools) turn light in color.You dont feel like eating food for several days or longer.You feel sick to your stomach (nausea).You have lower stomach area (abdominal) pain.. Your skin or the white part of your eyes turns yellow (jaundice).. Your urine turns dark.. Your bowel movements (stools) turn light in color.. You dont feel like eating food for several days or longer.. You feel sick to your stomach (nausea).. You have lower stomach area (abdominal) pain.. You may be more likely to get lactic acidosis or liver problems if you are female, very overweight (obese), or have been taking nucleoside analog medicines, like EMTRIVA, for long time.. If you are also infected with the Hepatitis Virus (HBV), you need close medical follow-up for several months after stopping treatment with EMTRIVA. Follow-up includes medical exams and blood tests to check for HBV that is getting worse. Patients with HBV infection, who take EMTRIVA and then stop it, may get flare-ups of their hepatitis. flare-up is when the disease suddenly returns in worse way than before.. Do not take EMTRIVA if you are allergic to EMTRIVA or any of its ingredients. The active ingredient is emtricitabine. See the end of this leaflet for complete list of ingredients.. Do not take EMTRIVA if you are already taking ATRIPLA(R), COMPLERA(TM), TRUVADA(R), Combivir, Epivir, Epivir-HBV, Epzicom, or Trizivir because these medicines contain the same or similar active ingredients.. If you are pregnant or planning to become pregnant. We do not know if EMTRIVA can harm your unborn child. You and your healthcare provider will need to decide if EMTRIVA is right for you. If you use EMTRIVA while you are pregnant, talk to your healthcare provider about how you can be on the EMTRIVA Antiviral Pregnancy Registry.. If you are breast-feeding. You should not breast feed if you are HIV-positive because of the chance of passing the HIV virus to your baby. Also, it is not known if EMTRIVA can pass into your breast milk and if it can harm your baby. If you are woman who has or will have baby, talk with your healthcare provider about the best way to feed your baby.. If you have kidney problems. You may need to take EMTRIVA less often.. If you have any liver problems including Hepatitis Virus infection.. Tell your healthcare provider about all your medical conditions. Tell your healthcare provider about all the medicines you take such as prescription and non-prescription medicines and dietary supplements. Keep complete list of all the medicines that you take. Make new list when medicines are added or stopped. Give copies of this list to all of your healthcare providers and pharmacist every time you visit or fill prescription.. Take EMTRIVA by mouth exactly as your healthcare provider prescribed it. Follow the directions from your healthcare provider, exactly as written on the label.. Dosing in adults: The usual dose of EMTRIVA is capsule once day.. Dosing in children: The childs doctor will calculate the right dose of EMTRIVA (oral solution or capsule) based on the childs weight.. EMTRIVA is always used with other anti-HIV-1 medicines.. EMTRIVA may be taken with or without meal. Food does not affect how EMTRIVA works.. If you forget to take EMTRIVA, take it as soon as you remember that day. Do not take more than dose of EMTRIVA in day. Do not take doses at the same time. Call your healthcare provider or pharmacist if you are not sure what to do. It is important that you do not miss any doses of EMTRIVA or your other anti-HIV-1 medicines. When your EMTRIVA supply starts to run low, get more from your healthcare provider or pharmacy. This is very important because the amount of virus in your blood may increase if the medicine is stopped for even short time. The virus may develop resistance to EMTRIVA and become harder to treat.. Stay under healthcare providers care when taking EMTRIVA. Do not change your treatment or stop treatment without first talking with your healthcare provider.. If you take too much EMTRIVA, call your local poison control center or emergency room right away.. Do not breast-feed. See What should tell my healthcare provider before taking EMTRIVA Talk with your healthcare provider about the best way to feed your baby.. Avoid doing things that can spread HIV-1 infection since EMTRIVA doesnt stop you from passing the HIV-1 infection to others.. Do not share needles or other injection equipment.. Do not share personal texts that can have blood or body fluids on them, like toothbrushes or razor blades.. Do not have any kind of sex without protection. Always practice safer sex by using latex or polyurethane condom or other barrier to reduce the chance of sexual contact with semen, vaginal secretions, or blood.. lactic acidosis (buildup of an acid in the blood). Lactic acidosis can be medical emergency and may need to be treated in the hospital. Call your doctor right away if you get signs of lactic acidosis. (See What is the most important information should know about EMTRIVA). serious liver problems (hepatotoxicity), with liver enlargement (hepatomegaly) and fat in the liver (steatosis). Call your healthcare provider right away if you get any signs of liver problems. (See What is the most important information should know about EMTRIVA). flare-ups of Hepatitis Virus infection, in which the disease suddenly returns in worse way than before, can occur if you stop taking EMTRIVA. EMTRIVA is not for the treatment of Hepatitis Virus (HBV) infection.. Changes in body fat have been seen in some patients taking EMTRIVA and other anti-HIV-1 medicines. These changes may include increased amount of fat in the upper back and neck (buffalo hump), breast, and around the main part of your body (trunk). Loss of fat from the legs, arms and face may also happen. The cause and long term health effects of these conditions are not known at this time.. Keep EMTRIVA and all other medicines out of reach of children.. Store EMTRIVA capsules between 59 and 86 (15 to 30 C).. Store EMTRIVA oral solution in refrigerator between 36 and 46 (2-8 C). Do not freeze. Alternatively, the product may be stored at room temperature for up to months and any remaining solution in the bottle must be discarded after the months.. Do not keep your medicine in places that are too hot or cold.. Do not keep medicine that is out of date or that you no longer need. If you throw any medicines away make sure that children will not find them.. Additional barcode labeling by:Physicians Total Care, Inc.Tulsa, Oklahoma 74146.

SPL UNCLASSIFIED SECTION.


2.1Recommended Dose. EMTRIVA may be taken without regard to food.

TERATOGENIC EFFECTS SECTION.


Pregnancy Category BThe incidence of fetal variations and malformations was not increased in embryofetal toxicity studies performed with emtricitabine in mice at exposures (AUC) approximately 60-fold higher and in rabbits at approximately 120-fold higher than human exposures at the recommended daily dose. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, EMTRIVA should be used during pregnancy only if clearly needed.. Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to EMTRIVA, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.

USE IN SPECIFIC POPULATIONS SECTION.


8USE IN SPECIFIC POPULATIONS. Nursing mothers: Women infected with HIV should be instructed not to breast feed. (8.3)Pediatrics: Dose adjustment based on age and weight. (2.3, 2.4, 12.3). Nursing mothers: Women infected with HIV should be instructed not to breast feed. (8.3). Pediatrics: Dose adjustment based on age and weight. (2.3, 2.4, 12.3). 8.1Pregnancy. Pregnancy Category BThe incidence of fetal variations and malformations was not increased in embryofetal toxicity studies performed with emtricitabine in mice at exposures (AUC) approximately 60-fold higher and in rabbits at approximately 120-fold higher than human exposures at the recommended daily dose. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, EMTRIVA should be used during pregnancy only if clearly needed.. Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to EMTRIVA, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.. 8.3Nursing Mothers. Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV-1. It is not known whether emtricitabine is excreted in human milk. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving EMTRIVA.. 8.4Pediatric Use. The safety and efficacy of emtricitabine in patients between months and 21 years of age is supported by data from three open-label, non-randomized clinical studies in which emtricitabine was administered to 169 HIV-1 infected treatment-naive and experienced (defined as virologically suppressed on lamivudine containing regimen for which emtricitabine was substituted for lamivudine) subjects [See Clinical Studies(14.3)].The pharmacokinetics of emtricitabine were studied in 20 neonates born to HIV-1-positive mothers [See Clinical Studies (14.3)]. All neonates were HIV-1 negative at the end of the study; the efficacy of emtricitabine in preventing or treating HIV-1 could not be determined.. 8.5Geriatric Use. Clinical studies 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. 8.6Patients with Impaired Renal Function. It is recommended that the dose or dosing interval for EMTRIVA be modified in patients with creatinine clearance <50 mL/min or in patients who require dialysis [See Dosage and Administration (2.5)].

WARNINGS AND PRECAUTIONS SECTION.


5WARNINGS AND PRECAUTIONS. Products with same active ingredient: Do not use with other emtricitabine-containing products (e.g., ATRIPLA, COMPLERA and TRUVADA). (5.3)Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy. (5.5)Immune reconstitution syndrome: May necessitate further evaluation and treatment. (5.6). Products with same active ingredient: Do not use with other emtricitabine-containing products (e.g., ATRIPLA, COMPLERA and TRUVADA). (5.3). Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy. (5.5). Immune reconstitution syndrome: May necessitate further evaluation and treatment. (5.6). 5.1Lactic Acidosis/Severe Hepatomegaly with Steatosis. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination, including emtricitabine and other antiretrovirals. majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver diseases; however, cases have also been reported in patients with no known risk factors. 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).. 5.2Patients Coinfected with HIV-1 and HBV. It is recommended that all patients with HIV-1 be tested for the presence of chronic Hepatitis virus (HBV) before initiating antiretroviral therapy. EMTRIVA is not approved for the treatment of chronic HBV infection and the safety and efficacy of EMTRIVA have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of Hepatitis have been reported in patients after the discontinuation of EMTRIVA. In some patients infected with HBV and treated with EMTRIVA, the exacerbations of hepatitis were associated with liver decompensation and liver failure. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue EMTRIVA. If appropriate, initiation of anti-Hepatitis therapy may be warranted.. 5.3Coadministration with Related Products. EMTRIVA is component of ATRIPLA (a fixed-dose combination of efavirenz, emtricitabine, and tenofovir disoproxil fumarate), COMPLERA (a fixed-dose combination of emtricitabine, rilpivirine, and tenofovir disoproxil fumarate) and TRUVADA (a fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate). EMTRIVA should not be coadministered with ATRIPLA, COMPLERA, or TRUVADA. Due to similarities between emtricitabine and lamivudine, EMTRIVA should not be coadministered with other drugs containing lamivudine, including Combivir (lamivudine/zidovudine), Epivir or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), or Trizivir (abacavir sulfate/lamivudine/zidovudine).. 5.4New 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 (2.5) and Clinical Pharmacology (12.3)]. 5.5Fat Redistribution. Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. causal relationship has not been established.. 5.6Immune 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-Barre 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.