ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS. The following adverse reactions are discussed in other sections of the labeling:Severe Acute Exacerbation of Hepatitis in Patients Coinfected with HIV-1 and HBV [see Warnings and Precautions (5.1)]. Immune Reconstitution Syndrome [see Warnings and Precautions (5.2)]. Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.3)]. Severe Acute Exacerbation of Hepatitis in Patients Coinfected with HIV-1 and HBV [see Warnings and Precautions (5.1)]. Immune Reconstitution Syndrome [see Warnings and Precautions (5.2)]. Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.3)]. Most common adverse reactions (incidence >=10%) are headache, diarrhea, nausea, fatigue, dizziness, depression, insomnia, abnormal dreams, rash, abdominal pain, asthenia, increased cough, and rhinitis. Skin hyperpigmentation was very common (>=10%) in pediatric patients. 6) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Adverse Reactions from Clinical Trials Experience in AdultsMore than 2,000 adult subjects with HIV-1 infection have been treated with EMTRIVA alone or in combination with other antiretroviral agents for periods of 10 days to 200 weeks in clinical trials.The most common adverse reactions (incidence greater than or equal to 10%, any severity) identified from any of the three large, controlled clinical trials include headache, diarrhea, nausea, fatigue, dizziness, depression, insomnia, abnormal dreams, rash, abdominal pain, asthenia, increased cough, and rhinitis.In Trials 301A and 303, the most common adverse reactions that occurred in subjects receiving EMTRIVA with other antiretroviral agents were headache, diarrhea, nausea, and rash, which were generally mild to moderate. Approximately 1% of subjects discontinued participation in the clinical trials due to these events. All adverse reactions were reported with similar frequency in EMTRIVA and control treatment groups except for skin discoloration, which was reported with higher frequency in the EMTRIVA-treated group.Skin discoloration, manifested by hyperpigmentation on the palms or soles, was generally mild and asymptomatic. The mechanism and clinical significance are unknown.A summary of EMTRIVA treatment-emergent clinical adverse reactions in Trials 301A and 303 is provided in Table 2.Table 2Selected Treatment-Emergent Adverse Reactions (All Grades, Regardless of Causality) Reported in >=3% of EMTRIVA-Treated Subjects in Either Trial 301A or 303 (0-48 Weeks)303301AEMTRIVA AZT/d4T NNRTI/PI (N=294) 3TC AZT/d4T NNRTI/PI (N=146) EMTRIVA didanosine EFV (N=286) d4T didanosine EFV (N=285) AZT=zidovudine; d4T=stavudine; NNRTI/PI=non-nucleoside reverse transcriptase inhibitor/protease inhibitor; 3TC=lamivudine; EFV=efavirenz.Body as Whole Asthenia16%10%12%17% Headache13%6%22%25% Abdominal pain8%11%14%17%Digestive System Diarrhea23%18%23%32% Nausea18%12%13%23% Vomiting9%7%9%12% Dyspepsia4%5%8%12%Musculoskeletal Myalgia4%4%6%3% Arthralgia3%4%5%6%Nervous System Insomnia7%3%16%21% Depressive disorders6%10%9%13% Paresthesia5%7%6%12% Dizziness4%5%25%26% Neuropathy/peripheral neuritis4%3%4%13% Abnormal dreams2%<1%11%19%Respiratory Rhinitis18%12%12%10% Increased cough14%11%14%8%Skin Rash event Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, pustular rash, and allergic reaction. 17%14%30%33%. Laboratory Abnormalities Laboratory abnormalities in these trials occurred with similar frequency in the EMTRIVA and comparator groups. summary of Grades 3-4 laboratory abnormalities is provided in Table 3. Table Treatment-Emergent Grades 3-4 Laboratory Abnormalities Reported in >=1% of EMTRIVA-Treated Subjects in Either Trial 301A or 303303301AEMTRIVA AZT/d4T NNRTI/PI (N=294) 3TC AZT/d4T NNRTI/PI (N=146) EMTRIVA Didanosine EFV (N=286) d4T Didanosine EFV (N=285) Any >= Grade Laboratory Abnormality31%28%34%38%ALT (>5.0 ULN ULN Upper limit of normal) 2%1%5%6%AST (>5.0 ULN)3%<1%6%9%Bilirubin (>2.5 ULN)1%2%<1%<1%Creatine kinase (>4.0 ULN) 11%14%12%11%Neutrophils (<750 mm 3) 5%3%5%7%Pancreatic amylase (>2.0 ULN) 2%2%<1%1%Serum amylase (>2.0 ULN) 2%2%5%10%Serum glucose <40 or >250 mg/dL) 3%3%2%3%Serum lipase (>2.0 ULN) <1%<1%1%2%Triglycerides (>750 mg/dL) 10%8%9%6%In Trial 934, 511 antiretroviral-naive subjects received efavirenz (EFV) administered in combination with either EMTRIVA tenofovir disoproxil fumarate (TDF) (N=257) or AZT/3TC (N=254) for 144 weeks. The most common adverse reactions (incidence greater than or equal to 10%, all grades) included diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. Table provides the treatment-emergent adverse reactions (Grades 2-4) occurring in greater than or equal to 5% of subjects treated in any treatment group.Table 4Selected Adverse Reactions Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. (Grades 2-4) Reported in >=5% in Any Treatment Group in Trial 934 (0-144 Weeks) EMTRIVA TDF EFV From Weeks 96 to 144 of the trial, subjects received TRUVADA (R) with EFV in place of EMTRIVA TDF with EFV. AZT/3TC EFVN=257N=254Fatigue9%8%Depression9%7%Nausea9%7%Diarrhea9%5%Dizziness8%7%Upper respiratory tract infections8%5%Sinusitis8%4%Rash event Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and rash vesicular. 7%9%Headache6%5%Insomnia5%7%Nasopharyngitis5%3%Vomiting2%5%. Laboratory Abnormalities: Laboratory abnormalities observed in Trial 934 were generally consistent with those seen in previous trials (Table 5). Table 5Significant Laboratory Abnormalities Reported in >=1% of Subjects in Any Treatment Group in Trial 934 (0-144 Weeks)EMTRIVA TDF EFV From Weeks 96 to 144 of the trial, subjects received TRUVADA with EFV in place of EMTRIVA TDF with EFV. AZT/3TC 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/mm 3) 3%5%Fasting Triglycerides (>750 mg/dL)4%2%. Adverse Reactions from Clinical Trials Experience in Pediatric SubjectsAssessment of adverse reactions in pediatric subjects is based on data from Trial 203, an open label, uncontrolled trial of 116 HIV-1 infected subjects who received FTC through 48 weeks. The adverse reaction profile in pediatric subjects was generally comparable to that observed in clinical trials of EMTRIVA in adult subjects [see Adverse Reactions (6.1)] Hyperpigmentation was more frequent in children. Additional adverse reactions identified from this trial include anemia. Selected treatment-emergent adverse events, regardless of causality, reported in subjects during 48 weeks of treatment were the following: infection (44%), hyperpigmentation (32%), increased cough (28%), vomiting (23%), otitis media (23%), rash (21%), rhinitis (20%), diarrhea (20%), fever (18%), pneumonia (15%), gastroenteritis (11%), abdominal pain (10%), and anemia (7%). Treatment-emergent Grades 3-4 laboratory abnormalities were experienced by 9% of pediatric subjects, including elevated amylase (>2.0 ULN) (n=4), decreased neutrophils (<750/mm 3) (n=3), elevated ALT (>5 ULN) (n=2), elevated CPK (>4 ULN) (n=2) and one subject 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.


WARNING: POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS B. Severe acute exacerbations of hepatitis (HBV) have been reported in patients who are coinfected with HIV-1 and HBV and 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 (5.1)]. WARNING: POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS BSee full prescribing information for complete boxed warning. Severe acute exacerbations of Hepatitis (HBV) have been reported in patients coinfected with HIV-1 and HBV who have discontinued EMTRIVA. Hepatic function should be monitored closely in patients coinfected with HIV-1 and HBV who discontinue EMTRIVA. If appropriate, initiation of anti-hepatitis therapy may be warranted. 5.1).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. In long-term oral carcinogenicity studies of FTC, 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) or 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.


12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Emtricitabine is an antiretroviral drug [see Microbiology (12.4)]. 12.3 Pharmacokinetics. Adults The pharmacokinetic properties of FTC were evaluated in healthy subjects and HIV-1-infected subjects. Emtricitabine pharmacokinetics are similar between these populations.Figure shows the mean steady-state plasma FTC concentration-time profile in 20 HIV-1-infected subjects receiving EMTRIVA capsules.Figure Mean (+- 95% CI) Steady-State Plasma FTC Concentrations in HIV-1 Infected Adults (N=20). Figure 1. AbsorptionEmtricitabine is rapidly and extensively absorbed following oral administration, with peak plasma concentrations occurring at 1-2 hours postdose. Following multiple dose oral administration of EMTRIVA capsules to 20 HIV-1 infected subjects, the (mean +- SD) steady-state plasma FTC peak concentration (C max) 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 ug hr/mL. The mean steady-state plasma trough concentration at 24 hours postdose 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 FTC are dose proportional over dose range of 25-200 mg.. DistributionIn vitro binding of FTC to human plasma proteins was less than 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.. MetabolismFollowing administration of radiolabelled FTC, complete recovery of the dose was achieved in urine (~86%) and feces (~14%). Thirteen percent (13%) of the dose was recovered in urine as three putative metabolites. The biotransformation of FTC includes oxidation of the thiol moiety to form the 3-sulfoxide diastereomers (~9% of dose) and conjugation with glucuronic acid to form 2-O-glucuronide (~4% of dose). No other metabolites were identifiable.. EliminationThe plasma FTC half-life is approximately 10 hours. The renal clearance of FTC is greater than the estimated creatinine clearance, suggesting elimination by both glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also renally eliminated.. Effects of Food on Oral AbsorptionEMTRIVA capsules and oral solution may be taken with or without food. Emtricitabine systemic exposure (AUC) was unaffected while max decreased by 29% when EMTRIVA capsules were administered with food (an approximately 1000 kcal high-fat meal). Emtricitabine systemic exposure (AUC) and max were unaffected when 200 mg EMTRIVA oral solution was administered with either high-fat or low-fat meal. Specific Populations. Geriatric PatientsThe pharmacokinetics of FTC have not been fully evaluated in the elderly (65 years of age and older).. Pediatric PatientsThe pharmacokinetics of FTC at steady state were determined in 77 HIV-1 infected pediatric subjects, and the pharmacokinetic profile was characterized in four age groups (Table 6). The FTC exposure achieved in pediatric subjects receiving daily dose of mg/kg up to maximum of 240 mg oral solution or 200-mg capsule is similar to exposures achieved in adult subjects receiving once-daily dose of 200 mg.The pharmacokinetics of FTC 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 AZT prophylactically after birth. The neonates were administered two short courses of FTC 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 FTC was similar to the AUC observed in pediatric subjects aged months to 17 years who received daily dose of FTC as 6 mg/kg oral solution up to 240 mg or as 200-mg capsule (Table 6).Table 6Mean +- SD Pharmacokinetic Parameters by Age Groups for Pediatric Subjects and Neonates Receiving EMTRIVA Capsules or Oral SolutionHIV-1-exposed NeonatesHIV-1 Infected Pediatric SubjectsAge0-3 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)C max (ug/mL) 1.6 +- 0.61.9 +- 0.61.9 +- 0.72.7 +- 0.82.7 +- 0.9AUC (ug hr/mL) 11.0 +- 4.28.7 +- 3.29.0 +- 3.012.6 +- 3.512.6 +- 5.4T 1/2 (hr) 12.1 +- 3.18.9 +- 3.211.3 +- 6.48.2 +- 3.28.9 +- 3.3. GenderFTC pharmacokinetics are similar in adult male and female subjects.. RaceNo pharmacokinetic differences due to race have been identified.. Patients with Renal ImpairmentThe pharmacokinetics of FTC are altered in subjects with renal impairment [see Warnings and Precautions (5.4)] In adult subjects with creatinine clearance below 50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, max and AUC of FTC were increased (Table 7). The effects of renal impairment on FTC pharmacokinetics in pediatric patients are not known. Table 7Pharmacokinetic Parameters (Mean +- SD) of FTC in Adult Subjects with Varying Degrees of Renal FunctionCreatinine Clearance (mL/min)>80 (N=6) 50-80 (N=6) 30-49 (N=6) <30 (N=5) ESRD ESRD subjects requiring dialysis <30 (N=5) Baseline creatinine clearance (mL/min)107 +- 2159.8 +- 6.540.9 +- 5.122.9 +- 5.38.8 +- 1.4C max (ug/mL) 2.2 +- 0.63.8 +- 0.93.2 +- 0.62.8 +- 0.72.8 +- 0.5AUC (ug hr/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 +- 11NULL NULL Not Applicable Patients with Hepatic ImpairmentThe pharmacokinetics of FTC have not been studied in subjects with hepatic impairment; however, FTC is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.. Assessment of Drug InteractionsAt concentrations up to 14-fold higher than those observed in vivo, FTC did not inhibit in vitro drug metabolism mediated by any of the following human CYP isoforms: CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. FTC did not inhibit the enzyme responsible for glucuronidation (uridine-5-disphosphoglucuronyl transferase). Based on the results of these in vitro experiments and the known elimination pathways of FTC, the potential for CYP-mediated interactions involving FTC with other medicinal products is low.EMTRIVA has been evaluated in healthy volunteers in combination with TDF, AZT, indinavir, famciclovir, and d4T. Tables and summarize the pharmacokinetic effects of coadministered drug on FTC pharmacokinetics and effects of FTC on the pharmacokinetics of coadministered drug.Table 8Drug Interactions: Change in Pharmacokinetic Parameters for FTC in the Presence of the Coadministered Drug All interaction trials conducted in healthy volunteers. Coadministered DrugDose of Coadministered Drug (mg)FTC Dose (mg)N% Change of FTC Pharmacokinetic Parameters Increase; <=> No Effect; NULL Not Applicable (90% CI) max AUCC min Famciclovir500 1200 112<=><=>NULLIndinavir800 1200 112<=><=>NULLStavudine40 1200 16<=><=>NULLTenofovir DF300 once daily 7 days200 once daily 7 days17<=><=>- 20 (- 12 to 29) Zidovudine300 twice daily 7 days200 once daily 7 days27<=><=><=>Table 9Drug Interactions: Change in Pharmacokinetic Parameters for Coadministered Drug in the Presence of FTC All interaction trials conducted in healthy volunteers. Coadministered DrugDose of Coadministered Drug (mg)FTC Dose (mg)N% Change of Coadministered Drug Pharmacokinetic Parameters Increase; <=> No Effect; NULL Not Applicable (90% CI) max AUCC min Famciclovir500 1200 112<=><=>NULLIndinavir800 1200 112<=><=>NULLStavudine40 1200 16<=><=>NULLTenofovir DF300 once daily 7 days200 once daily 7 days17<=><=><=>Zidovudine300 twice daily 7 days200 once daily 7 days27- 17 (- to 38) 13 (- to- 20) <=>. 12.4 Microbiology. Mechanism of ActionFTC, synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5-triphosphate (FTC-TP), which inhibits the activity of the HIV-1 reverse transcriptase (RT) by competing with the natural substrate deoxycytidine 5-triphosphate and by being incorporated into nascent viral DNULL resulting in chain termination. FTC-TP is weak inhibitor of mammalian DNULL polymerases , and mitochondrial DNULL polymerase .. Antiviral ActivityThe antiviral activity of FTC 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 (EC 50) values for FTC were in the range of 0.0013-0.64 uM (0.0003-0.158 ug/mL). The median EC 50, range, and number of isolates for the laboratory isolates were 0.07, 0.009-0.62, 10; 0.011, 0.002-0.03, 12; 0.055, 0.0015-0.09, respectively for lymphoblastoid, PBMC, and reporter cells. The median EC 50, range, and number of isolates for the clinical isolates were 0.05, 0.0105-0.64, 15; 0.015, 0.004-0.028, respectively for lymphoblastoid cells and PBMCs. No antagonism was observed in drug combination studies of emtricitabine with nucleoside reverse transcriptase inhibitors (NRTIs) (abacavir, lamivudine, stavudine, tenofovir, zidovudine), non-nucleoside reverse transcriptase inhibitors (NNRTIs) (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, nelfinavir, ritonavir, saquinavir). FTC displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and (EC 50 values ranged from 0.007-0.075 uM) and showed strain-specific activity against HIV-2 (EC 50 values ranged from 0.007-1.5 uM in PBMCs and MAGI cells). ResistanceFTC-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 FTC was associated with valine or isoleucine (M184V/I) substitution in the HIV-1 RT.FTC-resistant isolates of HIV-1 have been recovered from some subjects treated with FTC alone or in combination with other antiretroviral agents. In clinical trial of treatment-naive subjects treated with EMTRIVA, didanosine, and efavirenz (EFV) [see Clinical Studies (14.2)] viral isolates from 37.5% of subjects with virologic failure showed reduced susceptibility to FTC. Genotypic analysis of these isolates showed that the resistance was due to M184V/I substitutions in the HIV-1 RT. In clinical trial of treatment-naive subjects treated with either EMTRIVA, TDF, and EFV or AZT/3TC and EFV [see Clinical Studies (14.2)], resistance analysis was performed on HIV-1 isolates from all confirmed virologic failure subjects with greater than 400 copies/mL of HIV-1 RNULL at Week 144 or early discontinuation. Development of EFV resistance-associated substitutions occurred most frequently and was similar between the treatment arms. The M184V amino acid substitution, associated with resistance to EMTRIVA and 3TC, was observed in 2/19 analyzed subject isolates in the EMTRIVA TDF group and in 10/29 analyzed subject isolates in the AZT/3TC group. Through 144 weeks of Trial 934, no subjects have developed detectable K65R substitution in their HIV-1 as analyzed through standard genotypic analysis. Cross ResistanceCross-resistance among certain NRTIs has been recognized. FTC-resistant isolates (M184V/I) were cross-resistant to 3TC but retained susceptibility in cell culture to AZT, didanosine, d4T, and tenofovir, and to NNRTIs (delavirdine, EFV, and nevirapine). HIV-1 isolates containing the K65R substitution, selected in vivo by abacavir, didanosine, and tenofovir, demonstrated reduced susceptibility to inhibition by FTC. Viruses harboring substitutions conferring reduced susceptibility to AZT and d4T (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) or didanosine (L74V) remained sensitive to FTC. HIV-1 containing the K103N substitution associated with resistance to NNRTIs was susceptible to FTC.

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES. 14.1Overview of Clinical Trials. The efficacy and safety of EMTRIVA were evaluated in the trials summarized in Table 10.Table 10Trials Conducted with EMTRIVA in Adult and Pediatric SubjectsTrialPopulationTrial Arms (N) Randomized and dosed. Timepoint (Weeks) Trial 934 Randomized, open-label, active-controlled trial. (NCT00112047) HIV-1 treatment-naive adultsEMTRIVA+TDF+EFV (227) AZT/3TC+EFV (229) 144Trial 301A Randomized, double-blind, active-controlled trial. (NCT00006208) EMTRIVA+didanosine+EFV (286) d4T+didanosine+EFV (285) 48Trial 303 (NCT00002416) HIV-1 treatment-experienced adultsEMTRIVA+AZT/d4T+NNRTI/PI (294) 3TC+AZT/d4T+NNRTI/PI (146) 48Trial 202 Nonrandomized, open-label trial. (NCT00016718) HIV-1 treatment-naive and experienced pediatricsEMTRIVA+didanosine+EFV (43)48Trial 203 (NCT00743340) EMTRIVA+d4T+lopinavir/ritonavir (116)48Trial 211 (NCT00642291) EMTRIVA+didanosine+EFV (16)48. 14.2Clinical Trial Results in Treatment-Naive Adults. Trial 934Data through 144 weeks are reported for Trial 934, randomized, open-label, active-controlled multicenter clinical trial comparing EMTRIVA TDF administered in combination with EFV versus AZT/3TC fixed-dose combination administered in combination with EFV in 511 antiretroviral-naive subjects. From Weeks 96 to 144 of the trial, subjects received FTC/TDF fixed-dose combination with EFV in place of EMTRIVA TDF with EFV. Subjects 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/mm (range 2-1191) and median baseline plasma HIV-1 RNULL was 5.01 log 10 copies/mL (range 3.56-6.54). Subjects were stratified by baseline CD4+ cell count (< or >=200 cells/mm 3); 41% had CD4+ cell counts <200 cells/mm and 51% of subjects had baseline viral loads >100,000 copies/mL. Table 11 provides treatment outcomes through 48 and 144 weeks for those subjects who did not have EFV resistance at baseline. Table 11Virologic Outcomes of Randomized Treatment at Week 48 and 144 (Trial 934)OutcomesWeek 48Week 144EMTRIVA+TDF+EFV (N=244) AZT/3TC+EFV (N=243) EMTRIVA+TDF+EFV (N=227) Subjects who were responders at Week 48 or Week 96 (HIV-1 RNULL <400 copies/mL) but did not consent to continue in the trial after Week 48 or Week 96 were excluded from analysis. AZT/3TC+EFV (N=229) Responder Subjects achieved and maintained confirmed HIV-1 RNULL <400 copies/mL through Weeks 48 and 144. 84%73%71%58%Virologic failure Includes 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 reasons Includes lost to follow-up, subject withdrawal, noncompliance, protocol violation and other reasons. 10%14%20%22%Through Week 48, 84%, and 73% of subjects in the EMTRIVA TDF group and the AZT/3TC group, respectively, achieved and maintained HIV-1 RNULL <400 copies/mL (71% and 58% through Week 144). The difference in the proportion of subjects 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 AZT/3TC group in this open-label trial. In addition, 80% and 70% of subjects in the EMTRIVA TDF group and the AZT/3TC 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/mm in the EMTRIVA TDF group and 158 cells/mm in the AZT/3TC group at Week 48 (312 and 271 cells/mm at Week 144). Through 48 weeks, subjects in the EMTRIVA TDF group and subjects in the AZT/3TC group experienced new CDC Class event (10 and subjects through 144 weeks).. Trial 301ATrial 301A was 48-week double-blind, active-controlled, multicenter clinical trial comparing EMTRIVA (200 mg once daily) administered in combination with didanosine and EFV versus d4T, didanosine, and EFV in 571 antiretroviral naive adult subjects. Subjects had mean age of 36 years (range 18-69); 85% were male, 52% Caucasian, 16% African-American, and 26% Hispanic. Subjects had mean baseline CD4+ cell count of 318 cells/mm (range 5-1317) and median baseline plasma HIV-1 RNULL of 4.9 log 10 copies/mL (range 2.6-7.0). Thirty-eight percent of subjects had baseline viral loads >100,000 copies/mL and 31% had CD4+ cell counts <200 cells/mL. Table 12 provides treatment outcomes through 48 weeks. Table 12Virologic Outcomes of Randomized Treatment at Week 48 (Trial 301A)OutcomesEMTRIVA+ Didanosine+ EFV (N=286) d4T+ Didanosine+ EFV (N=285) Responder Subjects achieved and maintained confirmed HIV RNULL <400 copies/mL (<50 copies/mL) through Week 48. 81% (78%)68% (59%)Virologic Failure Includes subjects who failed to achieve virologic suppression or rebounded after achieving virologic suppression. 3%11%Death0%<1%Discontinuation Due to Adverse Event7%13%Discontinuation for Other Reasons Includes lost to follow-up, subject withdrawal, non-compliance, protocol violation, and other reasons. 9%8%The mean increase from baseline in CD4+ cell count was 168 cells/mm for the EMTRIVA arm and 134 cells/mm for the d4T arm. Through 48 weeks, subjects (1.7%) in the EMTRIVA group experienced new CDC Class event compared to subjects (2.5%) in the d4T group.. 14.3Clinical Trial Results in Treatment-Experienced Adults. Trial 303Trial 303 was 48-week, open-label, active-controlled, multicenter clinical trial comparing EMTRIVA (200 mg once daily) to 3TC, in combination with d4T or AZT and protease inhibitor or NNRTI in 440 adult subjects who were on 3TC-containing triple-antiretroviral drug regimen for at least 12 weeks prior to trial entry and had HIV-1 RNULL <=400 copies/mL.Subjects were randomized 1:2 to continue therapy with 3TC (150 mg twice daily) or to switch to EMTRIVA (200 mg once daily). All subjects were maintained on their stable background regimen. Subjects had mean age of 42 years (range 22-80); 86% were male, 64% Caucasian, 21% African-American, and 13% Hispanic. Subjects had mean baseline CD4+ cell count of 527 cells/mm (range 37-1909), and median baseline plasma HIV-1 RNULL of 1.7 log 10 copies/mL (range 1.7-4.0). The median duration of prior antiretroviral therapy was 27.6 months. Table 13 provides treatment outcomes through 48 weeks.Table 13Virologic Outcomes of Randomized Treatment at Week 48 (Trial 303)OutcomesEMTRIVA+ AZT/d4T+ NNRTI/PI (N=294) 3TC+ AZT/d4T+ NNRTI/PI (N=146) Responder Subjects achieved and maintained confirmed HIV RNULL <400 copies/mL (<50 copies/mL) through Week 48. 77% (67%)82% (72%)Virologic Failure Includes subjects who failed to achieve virologic suppression or rebounded after achieving virologic suppression. 7%8%Death0%<1%Discontinuation Due to Adverse Event4%0%Discontinuation for Other Reasons Includes lost to follow-up, subject withdrawal, non-compliance, protocol violation, and other reasons. 12%10%The mean increase from baseline in CD4+ cell count was 29 cells/mm for the EMTRIVA arm and 61 cells/mm for the 3TC arm. Through 48 weeks, in the EMTRIVA group subjects (0.7%) experienced new CDC Class event compared to subjects (1.4%) in the 3TC group.. 14.4Clinical Trial Results in Pediatrics. In three open-label, nonrandomized clinical trials, FTC was administered to 169 HIV-1 infected treatment-naive and experienced (defined as virologically suppressed on 3TC-containing regimen for which FTC was substituted for 3TC) subjects between months and 21 years of age. Subjects 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.Subjects had mean age of 7.9 years (range 0.3-21); 49% were male, 15% Caucasian, 61% Black, and 24% Hispanic. Subjects had median baseline HIV-1 RNULL of 4.6 log 10 copies/mL (range 1.7-6.4) and mean baseline CD4+ cell count of 745 cells/mm (range 2-2650). Through 48 weeks of therapy, the overall proportion of subjects 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/mm (-945, +1512). The adverse reaction profile observed during these clinical trials was similar to that of adult subjects, with the exception of the occurrence of anemia and higher frequency of hyperpigmentation in children [see Adverse Reactions (6.1)]. The pharmacokinetics of FTC 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 AZT prophylactically after birth. The neonates were administered two short courses of FTC oral solution (each mg/kg once daily 4 days) during the first months of life. FTC exposures in neonates were similar to the exposures achieved in subjects aged months to 17 years [see Clinical Pharmacology (12.3)]. During the two short dosing periods on FTC, there were no safety issues identified in the treated neonates. All neonates were HIV-1 negative at the end of the trial; the efficacy of FTC in preventing or treating HIV-1 could not be determined.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS. 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.


11 DESCRIPTION. EMTRIVA is the brand name of emtricitabine (FTC), synthetic nucleoside analog with activity against human immunodeficiency virus type (HIV-1) reverse transcriptase.The chemical name of FTC is 5-fluoro-1-(2 R,5 S)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Emtricitabine is the (-) enantiomer of thio analog of cytidine, which differs from other cytidine analogs in that it has fluorine in the 5-position. It has molecular formula of 8H 10FN 3O 3S 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 partition coefficient (log P) for FTC 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 FTC and the inactive ingredients crospovidone, magnesium stearate, microcrystalline cellulose, povidone, titanium dioxide, gelatin, and FD&C blue No. 2.EMTRIVA oral solution is for oral administration. One milliliter (1 mL) of EMTRIVA oral solution contains 10 mg of FTC 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.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION. Testing: Prior to or when initiating EMTRIVA test for hepatitis virus infection. 2.1) EMTRIVA may be taken without regard to food. 2.2) Adult Patients (18 years of age and older) 2.3): 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) 2.4): EMTRIVA oral solution: mg/kg administered once daily orally. Pediatric Patients (3 months through 17 years of age) 2.5): 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. Dose interval adjustment in adult patients with renal impairment 2.6): Creatinine Clearance (mL/min)Formulation>=50 mL/min30-49 mL/min15-29 mL/min<15 mL/min or on hemodialysis Hemodialysis 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) Testing: Prior to or when initiating EMTRIVA test for hepatitis virus infection. 2.1) EMTRIVA may be taken without regard to food. 2.2) Adult Patients (18 years of age and older) 2.3): 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) 2.4): 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 of age) 2.5): 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.. EMTRIVA oral solution: mg/kg up to maximum of 240 mg (24 mL) administered once daily orally.. Dose interval adjustment in adult patients with renal impairment 2.6): 2.1 Testing Prior to Initiation of Treatment with EMTRIVA. Prior to or when initiating EMTRIVA, test patients for hepatitis virus infection [see Warnings and Precautions (5.1)]. 2.2 Recommended Dosage. EMTRIVA is taken by mouth once daily and may be taken without regard to food [see Clinical Pharmacology (12.3)] . 2.3Recommended Dosage in Adult 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.. 2.4Recommended Dosage in Pediatric Patients (0-3 months of age). EMTRIVA oral solution: mg per kg administered once daily orally.. 2.5Recommended Dosage in Pediatric Patients (3 months through 17 years of age). EMTRIVA oral solution: mg per kg up to maximum of 240 mg (24 mL) administered once daily orally.EMTRIVA capsules: For pediatric patients weighing more than 33 kg who can swallow an intact capsule, one 200 mg capsule administered once daily orally.. 2.6Dosage Adjustment in Patients with Renal Impairment. Table provides dosage interval adjustment for patients with renal impairment. No dosage adjustment is necessary for patients with mild renal impairment (creatinine clearance 50-80 mL/min). The safety and effectiveness of dose adjustment recommendations in patients with moderate to severe renal impairment (creatinine clearance below 50 mL/min) have not been clinically evaluated. Therefore, clinical response to treatment and renal function should be closely monitored in these patients [see Warnings and Precautions (5.4), Use in Specific Populations (8.6)] Table Dose Interval Adjustment for Adult Patients with Altered Creatinine ClearanceCreatinine Clearance (mL/min)Formulation>=50 mL/min30-49 mL/min15-29 mL/min<15 mL/min or on hemodialysis Hemodialysis 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) There are insufficient data available to make dosage recommendations in pediatric patients with renal impairment.

DOSAGE FORMS & STRENGTHS SECTION.


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

DRUG INTERACTIONS SECTION.


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

GERIATRIC USE SECTION.


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

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING. EMTRIVA capsules are available in bottles containing 30 capsules with child-resistant closure as follows:200 mg of FTC capsules are size hard gelatin capsules with blue cap and white body and printed with 200 mg in black on the cap and with GILEAD and the corporate logo in black on the body (NDC 61958-0601-1).Store EMTRIVA capsules at 25 (77 F); excursions permitted to 15-30 (59-86 F).Dispense only in original container. Keep container tightly closed.EMTRIVA oral solution is clear, orange to dark orange liquid containing 10 mg/mL of FTC and is available in unit of use plastic, amber bottles containing 170 mL of oral solution closed with child resistant closure, and packaged with marked dosing cup (NDC 61958-0602-1).. Store EMTRIVA capsules at 25 (77 F); excursions permitted to 15-30 (59-86 F).. Dispense only in original container. Keep container tightly closed.. Store EMTRIVA oral solution refrigerated at 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).Keep container tightly closed.. Keep container tightly closed.

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE. EMTRIVA (R) is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. 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.


17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information) . Severe Acute Exacerbation of Hepatitis in Patients Coinfected with HIV-1 and HBVInform patients that severe acute exacerbations of hepatitis have been reported in patients who are coinfected with HIV-1 and hepatitis virus (HBV) who have discontinued EMTRIVA. Advise patients not to discontinue EMTRIVA without first informing their healthcare provider. All patients should be tested for HBV infection before or when starting EMTRIVA and those who are infected with HBV need close medical follow-up for several months after stopping EMTRIVA to monitor for exacerbations of hepatitis [see Warnings and Precautions (5.1)]. Immune Reconstitution SyndromeInform patients that in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the bodys immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Advise patients to inform their healthcare provider immediately of any symptoms of infection [see Warnings and Precautions (5.2)]. Lactic Acidosis and Severe HepatomegalyInform patients that 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 [see Warnings and Precautions (5.3)]. Pregnancy RegistryInform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant women exposed to EMTRIVA [see Use in Specific Populations (8.1)]. LactationInstruct mothers not to breastfeed if they are taking EMTRIVA because of the risk of passing the HIV-1 virus to the baby [see Use in Specific Populations (8.2)].

LACTATION SECTION.


8.2 Lactation. Risk SummaryThe Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1.Based on published data, FTC has been shown to be present in human breast milk. It is not known if FTC affects milk production or has effects on the breastfed child.Because of the potential for: (1) HIV transmission (in HIV-negative infants); (2) developing viral resistance (in HIV-positive infants); and (3) adverse reactions in breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are taking EMTRIVA.

MECHANISM OF ACTION SECTION.


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

MICROBIOLOGY SECTION.


12.4 Microbiology. Mechanism of ActionFTC, synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5-triphosphate (FTC-TP), which inhibits the activity of the HIV-1 reverse transcriptase (RT) by competing with the natural substrate deoxycytidine 5-triphosphate and by being incorporated into nascent viral DNULL resulting in chain termination. FTC-TP is weak inhibitor of mammalian DNULL polymerases , and mitochondrial DNULL polymerase .. Antiviral ActivityThe antiviral activity of FTC 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 (EC 50) values for FTC were in the range of 0.0013-0.64 uM (0.0003-0.158 ug/mL). The median EC 50, range, and number of isolates for the laboratory isolates were 0.07, 0.009-0.62, 10; 0.011, 0.002-0.03, 12; 0.055, 0.0015-0.09, respectively for lymphoblastoid, PBMC, and reporter cells. The median EC 50, range, and number of isolates for the clinical isolates were 0.05, 0.0105-0.64, 15; 0.015, 0.004-0.028, respectively for lymphoblastoid cells and PBMCs. No antagonism was observed in drug combination studies of emtricitabine with nucleoside reverse transcriptase inhibitors (NRTIs) (abacavir, lamivudine, stavudine, tenofovir, zidovudine), non-nucleoside reverse transcriptase inhibitors (NNRTIs) (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, nelfinavir, ritonavir, saquinavir). FTC displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and (EC 50 values ranged from 0.007-0.075 uM) and showed strain-specific activity against HIV-2 (EC 50 values ranged from 0.007-1.5 uM in PBMCs and MAGI cells). ResistanceFTC-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 FTC was associated with valine or isoleucine (M184V/I) substitution in the HIV-1 RT.FTC-resistant isolates of HIV-1 have been recovered from some subjects treated with FTC alone or in combination with other antiretroviral agents. In clinical trial of treatment-naive subjects treated with EMTRIVA, didanosine, and efavirenz (EFV) [see Clinical Studies (14.2)] viral isolates from 37.5% of subjects with virologic failure showed reduced susceptibility to FTC. Genotypic analysis of these isolates showed that the resistance was due to M184V/I substitutions in the HIV-1 RT. In clinical trial of treatment-naive subjects treated with either EMTRIVA, TDF, and EFV or AZT/3TC and EFV [see Clinical Studies (14.2)], resistance analysis was performed on HIV-1 isolates from all confirmed virologic failure subjects with greater than 400 copies/mL of HIV-1 RNULL at Week 144 or early discontinuation. Development of EFV resistance-associated substitutions occurred most frequently and was similar between the treatment arms. The M184V amino acid substitution, associated with resistance to EMTRIVA and 3TC, was observed in 2/19 analyzed subject isolates in the EMTRIVA TDF group and in 10/29 analyzed subject isolates in the AZT/3TC group. Through 144 weeks of Trial 934, no subjects have developed detectable K65R substitution in their HIV-1 as analyzed through standard genotypic analysis. Cross ResistanceCross-resistance among certain NRTIs has been recognized. FTC-resistant isolates (M184V/I) were cross-resistant to 3TC but retained susceptibility in cell culture to AZT, didanosine, d4T, and tenofovir, and to NNRTIs (delavirdine, EFV, and nevirapine). HIV-1 isolates containing the K65R substitution, selected in vivo by abacavir, didanosine, and tenofovir, demonstrated reduced susceptibility to inhibition by FTC. Viruses harboring substitutions conferring reduced susceptibility to AZT and d4T (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) or didanosine (L74V) remained sensitive to FTC. HIV-1 containing the K103N substitution associated with resistance to NNRTIs was susceptible to FTC.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. In long-term oral carcinogenicity studies of FTC, 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) or 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.

OVERDOSAGE SECTION.


10 OVERDOSAGE. If overdose occurs, the patient should be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.Hemodialysis treatment removes approximately 30% of the FTC dose over 3-hour dialysis period starting within 1.5 hours of FTC dosing (blood flow rate of 400 mL/min and dialysate flow rate of 600 mL/min). It is not known whether FTC can be removed by peritoneal dialysis.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL Representative Bottle LabelNDC 61958-0601-1Emtriva (R) (emtricitabine) Capsules, 200 mg 30 capsulesRx only. emtriva-03.jpg.

PEDIATRIC USE SECTION.


8.4 Pediatric Use. The safety and efficacy of FTC in patients between months and 21 years of age is supported by data from three open-label, nonrandomized clinical trials in which FTC was administered to 169 HIV-1 infected treatment-naive and experienced (defined as virologically suppressed on 3TC containing regimen for which FTC was substituted for 3TC) subjects [see Clinical Studies (14.4)] The pharmacokinetics of FTC were studied in 20 neonates born to HIV-1 positive mothers [see Clinical Studies (14.4)] All neonates were HIV-1 negative at the end of the trial; the efficacy of FTC in preventing or treating HIV-1 could not be determined.

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics. Adults The pharmacokinetic properties of FTC were evaluated in healthy subjects and HIV-1-infected subjects. Emtricitabine pharmacokinetics are similar between these populations.Figure shows the mean steady-state plasma FTC concentration-time profile in 20 HIV-1-infected subjects receiving EMTRIVA capsules.Figure Mean (+- 95% CI) Steady-State Plasma FTC Concentrations in HIV-1 Infected Adults (N=20). Figure 1. AbsorptionEmtricitabine is rapidly and extensively absorbed following oral administration, with peak plasma concentrations occurring at 1-2 hours postdose. Following multiple dose oral administration of EMTRIVA capsules to 20 HIV-1 infected subjects, the (mean +- SD) steady-state plasma FTC peak concentration (C max) 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 ug hr/mL. The mean steady-state plasma trough concentration at 24 hours postdose 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 FTC are dose proportional over dose range of 25-200 mg.. DistributionIn vitro binding of FTC to human plasma proteins was less than 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.. MetabolismFollowing administration of radiolabelled FTC, complete recovery of the dose was achieved in urine (~86%) and feces (~14%). Thirteen percent (13%) of the dose was recovered in urine as three putative metabolites. The biotransformation of FTC includes oxidation of the thiol moiety to form the 3-sulfoxide diastereomers (~9% of dose) and conjugation with glucuronic acid to form 2-O-glucuronide (~4% of dose). No other metabolites were identifiable.. EliminationThe plasma FTC half-life is approximately 10 hours. The renal clearance of FTC is greater than the estimated creatinine clearance, suggesting elimination by both glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also renally eliminated.. Effects of Food on Oral AbsorptionEMTRIVA capsules and oral solution may be taken with or without food. Emtricitabine systemic exposure (AUC) was unaffected while max decreased by 29% when EMTRIVA capsules were administered with food (an approximately 1000 kcal high-fat meal). Emtricitabine systemic exposure (AUC) and max were unaffected when 200 mg EMTRIVA oral solution was administered with either high-fat or low-fat meal. Specific Populations. Geriatric PatientsThe pharmacokinetics of FTC have not been fully evaluated in the elderly (65 years of age and older).. Pediatric PatientsThe pharmacokinetics of FTC at steady state were determined in 77 HIV-1 infected pediatric subjects, and the pharmacokinetic profile was characterized in four age groups (Table 6). The FTC exposure achieved in pediatric subjects receiving daily dose of mg/kg up to maximum of 240 mg oral solution or 200-mg capsule is similar to exposures achieved in adult subjects receiving once-daily dose of 200 mg.The pharmacokinetics of FTC 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 AZT prophylactically after birth. The neonates were administered two short courses of FTC 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 FTC was similar to the AUC observed in pediatric subjects aged months to 17 years who received daily dose of FTC as 6 mg/kg oral solution up to 240 mg or as 200-mg capsule (Table 6).Table 6Mean +- SD Pharmacokinetic Parameters by Age Groups for Pediatric Subjects and Neonates Receiving EMTRIVA Capsules or Oral SolutionHIV-1-exposed NeonatesHIV-1 Infected Pediatric SubjectsAge0-3 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)C max (ug/mL) 1.6 +- 0.61.9 +- 0.61.9 +- 0.72.7 +- 0.82.7 +- 0.9AUC (ug hr/mL) 11.0 +- 4.28.7 +- 3.29.0 +- 3.012.6 +- 3.512.6 +- 5.4T 1/2 (hr) 12.1 +- 3.18.9 +- 3.211.3 +- 6.48.2 +- 3.28.9 +- 3.3. GenderFTC pharmacokinetics are similar in adult male and female subjects.. RaceNo pharmacokinetic differences due to race have been identified.. Patients with Renal ImpairmentThe pharmacokinetics of FTC are altered in subjects with renal impairment [see Warnings and Precautions (5.4)] In adult subjects with creatinine clearance below 50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, max and AUC of FTC were increased (Table 7). The effects of renal impairment on FTC pharmacokinetics in pediatric patients are not known. Table 7Pharmacokinetic Parameters (Mean +- SD) of FTC in Adult Subjects with Varying Degrees of Renal FunctionCreatinine Clearance (mL/min)>80 (N=6) 50-80 (N=6) 30-49 (N=6) <30 (N=5) ESRD ESRD subjects requiring dialysis <30 (N=5) Baseline creatinine clearance (mL/min)107 +- 2159.8 +- 6.540.9 +- 5.122.9 +- 5.38.8 +- 1.4C max (ug/mL) 2.2 +- 0.63.8 +- 0.93.2 +- 0.62.8 +- 0.72.8 +- 0.5AUC (ug hr/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 +- 11NULL NULL Not Applicable Patients with Hepatic ImpairmentThe pharmacokinetics of FTC have not been studied in subjects with hepatic impairment; however, FTC is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.. Assessment of Drug InteractionsAt concentrations up to 14-fold higher than those observed in vivo, FTC did not inhibit in vitro drug metabolism mediated by any of the following human CYP isoforms: CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. FTC did not inhibit the enzyme responsible for glucuronidation (uridine-5-disphosphoglucuronyl transferase). Based on the results of these in vitro experiments and the known elimination pathways of FTC, the potential for CYP-mediated interactions involving FTC with other medicinal products is low.EMTRIVA has been evaluated in healthy volunteers in combination with TDF, AZT, indinavir, famciclovir, and d4T. Tables and summarize the pharmacokinetic effects of coadministered drug on FTC pharmacokinetics and effects of FTC on the pharmacokinetics of coadministered drug.Table 8Drug Interactions: Change in Pharmacokinetic Parameters for FTC in the Presence of the Coadministered Drug All interaction trials conducted in healthy volunteers. Coadministered DrugDose of Coadministered Drug (mg)FTC Dose (mg)N% Change of FTC Pharmacokinetic Parameters Increase; <=> No Effect; NULL Not Applicable (90% CI) max AUCC min Famciclovir500 1200 112<=><=>NULLIndinavir800 1200 112<=><=>NULLStavudine40 1200 16<=><=>NULLTenofovir DF300 once daily 7 days200 once daily 7 days17<=><=>- 20 (- 12 to 29) Zidovudine300 twice daily 7 days200 once daily 7 days27<=><=><=>Table 9Drug Interactions: Change in Pharmacokinetic Parameters for Coadministered Drug in the Presence of FTC All interaction trials conducted in healthy volunteers. Coadministered DrugDose of Coadministered Drug (mg)FTC Dose (mg)N% Change of Coadministered Drug Pharmacokinetic Parameters Increase; <=> No Effect; NULL Not Applicable (90% CI) max AUCC min Famciclovir500 1200 112<=><=>NULLIndinavir800 1200 112<=><=>NULLStavudine40 1200 16<=><=>NULLTenofovir DF300 once daily 7 days200 once daily 7 days17<=><=><=>Zidovudine300 twice daily 7 days200 once daily 7 days27- 17 (- to 38) 13 (- to- 20) <=>.

PREGNULLNCY SECTION.


8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to EMTRIVA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.. Risk SummaryAvailable data from the APR show no increase in the overall risk of major birth defects with first trimester exposure for emtricitabine (FTC) (2.3%) compared with the background rate for major birth defects of 2.7% in U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data) The rate of miscarriage for individual drugs is not reported in the APR. In the U.S. general population, the estimated background risk of miscarriage in clinically recognized pregnancies is 15-20%. In animal reproduction studies, no adverse developmental effects were observed when FTC was administered at exposures >=60 times that of the recommended daily dose of EMTRIVA (see Data) . Data. Human DataBased on prospective reports to the APR of exposures to FTC-containing regimens during pregnancy resulting in live births (including over 2,700 exposed in the first trimester and over 1,200 exposed in the second/third trimester), there was no increase between FTC and overall birth defects compared with the background birth defect rate of 2.7% in U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.4% (95% CI: 1.9% to 3.1%) with first trimester exposure to FTC-containing regimens and 2.3% (95% CI: 1.5% to 3.3%) with the second/third trimester exposure to FTC-containing regimens.Prospective reports from the APR of overall major birth defects in pregnancies exposed to FTC are compared with U.S. background major birth defect rate. Methodologic limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease.Additionally, published observational studies on FTC exposure in pregnancy have not shown an increased risk for major malformations.. Animal DataFTC was administered orally to pregnant mice (at 0, 250, 500, or 1,000 mg/kg/day), and rabbits (at 0, 100, 300, or 1,000 mg/kg/day) through organogenesis (on gestation days through 15, and through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with FTC in mice at exposures (AUC) approximately 60 times higher and in rabbits at approximately 120 times higher than human exposures at the recommended daily dose. In pre/postnatal development study in mice, FTC was administered orally at doses up to 1,000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60 times higher than human exposures at the recommended daily dose.

RECENT MAJOR CHANGES SECTION.


Dosage and Administration Testing Prior to Initiation of Treatment with EMTRIVA 2.1) 12/2018Warnings and Precautions Severe Acute Exacerbation of Hepatitis in Patients Coinfected with HIV-1 and HBV 5.1) 12/2018 Coadministration with Related ProductsRemoved 12/2018.

RENULLL IMPAIRMENT SUBSECTION.


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

SPL PATIENT PACKAGE INSERT SECTION.


This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: December/2018Patient Information EMTRIVA (R) (em-treev-ah) (emtricitabine) capsules and oral solution What is the most important information should know about EMTRIVAEMTRIVA can cause serious side effects, including:Worsening of Hepatitis virus infection (HBV). Your healthcare provider will test you for HBV before starting treatment with EMTRIVA. If you have HBV infection and take EMTRIVA, your HBV may get worse (flare-up) if you stop taking EMTRIVA. flare-up is when your HBV infection suddenly returns in worse way than before. Do not stop taking EMTRIVA without first talking to your healthcare provider.Do not run out of EMTRIVA. Refill your prescription or talk to your healthcare provider before your EMTRIVA is all gone.If you stop taking EMTRIVA, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your HBV infection, or give you medication to treat hepatitis B. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking EMTRIVA. For more information about side effects, see the section What are the possible side effects of EMTRIVA What is EMTRIVAEMTRIVA is prescription medicine used in combination with other antiretroviral medicines to treat Human Immunodeficiency Virus-1 (HIV-1) infection.HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS).Who should not take EMTRIVADo not take EMTRIVA if you are allergic to emtricitabine or any of the ingredients in EMTRIVA. See the end of this leaflet for complete list of ingredients in EMTRIVA. What should tell my healthcare provider before taking EMTRIVABefore taking EMTRIVA, tell your healthcare provider about all of your medical conditions, including if you:have liver problems, including HBV infectionhave kidney problems or receive kidney dialysis treatmentare pregnant or planning to become pregnant. It is not known if EMTRIVA can harm your unborn baby. Tell your healthcare provider if you become pregnant during treatment with EMTRIVA. Pregnancy Registry: There is pregnancy registry for women who take EMTRIVA during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry. are breastfeeding or plan to breastfeed. EMTRIVA can pass to your baby in your breast milk. Do not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. Talk with your healthcare provider about the best way to feed your baby.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines may interact with EMTRIVA. Keep list of your medicines and show it to your healthcare provider and pharmacist when you get new medicine.You can ask your healthcare provider or pharmacist for list of medicines that interact with EMTRIVA. Do not start new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take EMTRIVA with other medicines.How should take EMTRIVATake EMTRIVA exactly as your healthcare provider tells you to take it.Dosing in adults: Take EMTRIVA by mouth time each day. Dosing in children: Take EMTRIVA by mouth time each day. The childs healthcare provider will calculate the right dose of EMTRIVA (oral solution or capsule) based on the childs weight. EMTRIVA may be taken with or without food.Do not miss dose of EMTRIVA. Missing dose lowers the amount of medicine in your blood. Refill your EMTRIVA prescription before you run out of medicine. Do not change your dose or stop taking EMTRIVA without first talking with your healthcare provider. Stay under healthcare providers care when taking EMTRIVA.If you take too much EMTRIVA, call your healthcare provider or go to the nearest hospital emergency room right away.What are the possible side effects of EMTRIVAEMTRIVA may cause serious side effects, including:See What is the most important information should know about EMTRIVA Changes in your immune system (Immune Reconstitution Syndrome) can happen when an HIV-infected person starts taking antiretroviral medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for long time. Tell your healthcare provider right away if you start having any new symptoms after starting EMTRIVA. Too much lactic acid in your blood (lactic acidosis). Too much lactic acid is serious but rare medical emergency that can lead to death. Tell your healthcare provider right away if you develop any of these symptoms: weakness or being more tired than usualbeing short of breath or fast breathingcold or blue hands and feetfast or abnormal heartbeatunusual muscle painstomach pain with nausea and vomitingfeel dizzy or lightheadedSevere liver problems. In rare cases, severe liver problems can happen that can lead to death. Your healthcare provider may tell you to stop taking EMTRIVA if you develop new or worse liver problems during treatment with EMTRIVA. Tell your healthcare provider right away if you develop any of these symptoms: fatigueweaknessyellowing of your skin or the white part of your eyes (jaundice)light colored stoolsnausea and vomitingconfusiondark tea-colored urineloss of appetite for several days or longerstomach-area (abdominal) swelling and painThe most common side effects of EMTRIVA include:headachediarrheanauseatirednessdizzinessdepressionproblems sleepingabnormal dreamsrashabdominal painweaknesscoughrunny noseSkin discoloration in children may also happen with EMTRIVA.These are not all the possible side effects of EMTRIVA.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store EMTRIVAStore EMTRIVA capsules at room temperature between 68F to 77F (20C to 25C) .Store EMTRIVA oral solution in the refrigerator between 36F to 46F (2C to 8C). Do not freeze.You may also store EMTRIVA oral solution at room temperature between 68F to 77F (20C to 25C) for up to months. Throw away any unused EMTRIVA oral solution after months.Keep EMTRIVA in its original container and keep the container tightly closed.Do not use EMTRIVA if seal over bottle opening is broken or missing.Keep EMTRIVA and all other medicines out of reach of children.General information about the safe and effective use of EMTRIVA.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. 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. You can ask your healthcare provider or pharmacist for information about EMTRIVA that is written for health professionals.What are the ingredients of EMTRIVAActive Ingredient: emtricitabine Inactive Ingredients:EMTRIVA capsules: crospovidone, magnesium stearate, microcrystalline cellulose, povidone, titanium dioxide, gelatin, and FD&C blue No. 2.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.Manufactured for and distributed by: Gilead Sciences, Inc. Foster City, CA 94404 EMTRIVA is trademark of Gilead Sciences, Inc., or its related companies. (C) 2018 Gilead Sciences, Inc. All rights reserved. For more information, call 1-800-GILEAD-5 (1-800-445-3235). 21-500-896-GS-019 Worsening of Hepatitis virus infection (HBV). Your healthcare provider will test you for HBV before starting treatment with EMTRIVA. If you have HBV infection and take EMTRIVA, your HBV may get worse (flare-up) if you stop taking EMTRIVA. flare-up is when your HBV infection suddenly returns in worse way than before. Do not stop taking EMTRIVA without first talking to your healthcare provider.Do not run out of EMTRIVA. Refill your prescription or talk to your healthcare provider before your EMTRIVA is all gone.If you stop taking EMTRIVA, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your HBV infection, or give you medication to treat hepatitis B. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking EMTRIVA. Do not stop taking EMTRIVA without first talking to your healthcare provider.. Do not run out of EMTRIVA. Refill your prescription or talk to your healthcare provider before your EMTRIVA is all gone.. If you stop taking EMTRIVA, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your HBV infection, or give you medication to treat hepatitis B. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking EMTRIVA.. have liver problems, including HBV infection. have kidney problems or receive kidney dialysis treatment. are pregnant or planning to become pregnant. It is not known if EMTRIVA can harm your unborn baby. Tell your healthcare provider if you become pregnant during treatment with EMTRIVA. Pregnancy Registry: There is pregnancy registry for women who take EMTRIVA during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry. are breastfeeding or plan to breastfeed. EMTRIVA can pass to your baby in your breast milk. Do not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. Talk with your healthcare provider about the best way to feed your baby.. Take EMTRIVA exactly as your healthcare provider tells you to take it.. Dosing in adults: Take EMTRIVA by mouth time each day. Dosing in children: Take EMTRIVA by mouth time each day. The childs healthcare provider will calculate the right dose of EMTRIVA (oral solution or capsule) based on the childs weight. EMTRIVA may be taken with or without food.. Do not miss dose of EMTRIVA. Missing dose lowers the amount of medicine in your blood. Refill your EMTRIVA prescription before you run out of medicine. Do not change your dose or stop taking EMTRIVA without first talking with your healthcare provider. Stay under healthcare providers care when taking EMTRIVA.. If you take too much EMTRIVA, call your healthcare provider or go to the nearest hospital emergency room right away.. See What is the most important information should know about EMTRIVA Changes in your immune system (Immune Reconstitution Syndrome) can happen when an HIV-infected person starts taking antiretroviral medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for long time. Tell your healthcare provider right away if you start having any new symptoms after starting EMTRIVA. Too much lactic acid in your blood (lactic acidosis). Too much lactic acid is serious but rare medical emergency that can lead to death. Tell your healthcare provider right away if you develop any of these symptoms: weakness or being more tired than usual. being short of breath or fast breathing. cold or blue hands and feet. fast or abnormal heartbeat. unusual muscle pain. stomach pain with nausea and vomiting. feel dizzy or lightheaded. Severe liver problems. In rare cases, severe liver problems can happen that can lead to death. Your healthcare provider may tell you to stop taking EMTRIVA if you develop new or worse liver problems during treatment with EMTRIVA. Tell your healthcare provider right away if you develop any of these symptoms: fatigue. weakness. yellowing of your skin or the white part of your eyes (jaundice). light colored stools. nausea and vomiting. confusion. dark tea-colored urine. loss of appetite for several days or longer. stomach-area (abdominal) swelling and pain. headache. diarrhea. nausea. tiredness. dizziness. depression. problems sleeping. abnormal dreams. rash. abdominal pain. weakness. cough. runny nose. Store EMTRIVA capsules at room temperature between 68F to 77F (20C to 25C) .. Store EMTRIVA oral solution in the refrigerator between 36F to 46F (2C to 8C). Do not freeze.. You may also store EMTRIVA oral solution at room temperature between 68F to 77F (20C to 25C) for up to months. Throw away any unused EMTRIVA oral solution after months.. Keep EMTRIVA in its original container and keep the container tightly closed.. Do not use EMTRIVA if seal over bottle opening is broken or missing.

SPL UNCLASSIFIED SECTION.


2.1 Testing Prior to Initiation of Treatment with EMTRIVA. Prior to or when initiating EMTRIVA, test patients for hepatitis virus infection [see Warnings and Precautions (5.1)].

STORAGE AND HANDLING SECTION.


Store EMTRIVA oral solution refrigerated at 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).Keep container tightly closed.. Keep container tightly closed.

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS. Lactation: Breastfeeding is not recommended. 8.2) Pediatrics: Dose adjustment based on age and weight. 2.4, 2.5, 12.3) Lactation: Breastfeeding is not recommended. 8.2) Pediatrics: Dose adjustment based on age and weight. 2.4, 2.5, 12.3) 8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to EMTRIVA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.. Risk SummaryAvailable data from the APR show no increase in the overall risk of major birth defects with first trimester exposure for emtricitabine (FTC) (2.3%) compared with the background rate for major birth defects of 2.7% in U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data) The rate of miscarriage for individual drugs is not reported in the APR. In the U.S. general population, the estimated background risk of miscarriage in clinically recognized pregnancies is 15-20%. In animal reproduction studies, no adverse developmental effects were observed when FTC was administered at exposures >=60 times that of the recommended daily dose of EMTRIVA (see Data) . Data. Human DataBased on prospective reports to the APR of exposures to FTC-containing regimens during pregnancy resulting in live births (including over 2,700 exposed in the first trimester and over 1,200 exposed in the second/third trimester), there was no increase between FTC and overall birth defects compared with the background birth defect rate of 2.7% in U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.4% (95% CI: 1.9% to 3.1%) with first trimester exposure to FTC-containing regimens and 2.3% (95% CI: 1.5% to 3.3%) with the second/third trimester exposure to FTC-containing regimens.Prospective reports from the APR of overall major birth defects in pregnancies exposed to FTC are compared with U.S. background major birth defect rate. Methodologic limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease.Additionally, published observational studies on FTC exposure in pregnancy have not shown an increased risk for major malformations.. Animal DataFTC was administered orally to pregnant mice (at 0, 250, 500, or 1,000 mg/kg/day), and rabbits (at 0, 100, 300, or 1,000 mg/kg/day) through organogenesis (on gestation days through 15, and through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with FTC in mice at exposures (AUC) approximately 60 times higher and in rabbits at approximately 120 times higher than human exposures at the recommended daily dose. In pre/postnatal development study in mice, FTC was administered orally at doses up to 1,000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60 times higher than human exposures at the recommended daily dose.. 8.2 Lactation. Risk SummaryThe Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1.Based on published data, FTC has been shown to be present in human breast milk. It is not known if FTC affects milk production or has effects on the breastfed child.Because of the potential for: (1) HIV transmission (in HIV-negative infants); (2) developing viral resistance (in HIV-positive infants); and (3) adverse reactions in breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are taking EMTRIVA.. 8.4 Pediatric Use. The safety and efficacy of FTC in patients between months and 21 years of age is supported by data from three open-label, nonrandomized clinical trials in which FTC was administered to 169 HIV-1 infected treatment-naive and experienced (defined as virologically suppressed on 3TC containing regimen for which FTC was substituted for 3TC) subjects [see Clinical Studies (14.4)] The pharmacokinetics of FTC were studied in 20 neonates born to HIV-1 positive mothers [see Clinical Studies (14.4)] All neonates were HIV-1 negative at the end of the trial; the efficacy of FTC in preventing or treating HIV-1 could not be determined. 8.5 Geriatric Use. Clinical trials of EMTRIVA did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. In general, dose selection for the elderly patient should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy . 8.6Renal Impairment. Modify the dose or dosing interval for EMTRIVA in patients with creatinine clearance below 50 mL/min or in patients with end stage renal disease requiring dialysis [see Dosage and Administration (2.6)].

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS. Immune reconstitution syndrome: May necessitate further evaluation and treatment. 5.2) Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. 5.3) Immune reconstitution syndrome: May necessitate further evaluation and treatment. 5.2) Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. 5.3) 5.1 Severe Acute Exacerbation of Hepatitis in Patients Coinfected with HIV-1 and HBV. All patients should be tested for the presence of chronic Hepatitis virus (HBV) before or when initiating EMTRIVA [see Dosage and Administration (2.1)] Severe acute exacerbations of hepatitis (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued EMTRIVA. Patients who are coinfected with HIV-1 and HBV who discontinue EMTRIVA should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, initiation of anti-hepatitis therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.. 5.2Immune 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.. 5.3Lactic Acidosis/Severe Hepatomegaly with Steatosis. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including FTC, alone or in combination with other antiretrovirals. Treatment with EMTRIVA should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).. 5.4Dose Adjustment in Patients with New Onset or Worsening Renal Impairment. Emtricitabine is principally eliminated by the kidney. Reduction of the dosage of EMTRIVA is recommended for patients with impaired renal function [see Dosage and Administration (2.6), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].