stumbled on [15:<1% 11% 19% Depressive disorders 6% 10% 9% 13% Dizziness 4% 5% 25% 26% Insomnia 7% 3% 16% 21% Neuropathy/peripheral neuritis 4% 3% 4% 13% Paresthesia 5% 7% 6% 12% Respiratory Increased cough 14% 11% 14% 8% Rhinitis 18% 12% 12% 10% Skin Rash event * 17% 14% 30% 33% Studies 301A and 303 Laboratory Abnormalities : Laboratory abnormalities in these trials occurred with similar frequency in the Emtriva and comparator groups. A summary of Grades 3 4 laboratory abnormalities is provided in Table 3. Table 3 Treatment-Emergent Grades 3 4 Laboratory Abnormalities Reported in ≥1% of Emtriva-Treated Subjects in Either Study 301A or 303 303 301A Emtriva + ZDV/d4T + NNRTI/PI (N=294) Lamivudine + ZDV/d4T + NNRTI/PI (N=146) Emtriva + Didanosine + Efavirenz (N=286) Stavudine + Didanosine + Efavirenz (N=285) * ULN = Upper limit of normal Percentage with grade 3 or grade 4 laboratory abnormality 31% 28% 34% 38% ALT (>5.0 ULN * ) 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% Study 934 Treatment Emergent Adverse Reactions: In Study 934, 511 antiretroviral-naïve subjects 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 trial were generally consistent with those seen in previous trials in treatment-experienced or treatment-naïve subjects (Table 4). Table 4 Selected Treatment-Emergent Adverse Reactions * (Grades 2 4) Reported in ≥5% in Any Treatment Group in Study 934 (0 144 Weeks) TDF † + Emtriva + EFV AZT/3TC + EFV N=257 N=254 * Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. † From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of VIREAD + Emtriva with efavirenz. ‡ Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and rash vesicular. Gastrointestinal Disorder Diarrhea 9% 5% Nausea 9% 7% Vomiting 2% 5% General Disorders and Administration Site Condition Fatigue 9% 8% Infections and Infestations Sinusitis 8% 4% Upper respiratory tract infections 8% 5% Nasopharyngitis 5% 3% Nervous System Disorders Headache 6% 5% Dizziness 8% 7% Psychiatric Disorders Depression 9% 7% Insomnia 5% 7% Skin and Subcutaneous Tissue Disorders Rash event ‡ 7% 9% Study 934 Laboratory Abnormalities: Significant laboratory abnormalities observed in this trial are shown in Table 5. Table 5 Significant Laboratory Abnormalities Reported in ≥1% of Subjects in Any Treatment Group in Study 934 (0 144 Weeks) TDF * + Emtriva + EFV AZT/3TC + EFV N=257 N=254 * From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of VIREAD + Emtriva with efavirenz. Any ≥ Grade 3 Laboratory Abnormality 30% 26% Fasting Cholesterol (>240 mg/dL) 22% 24% Creatine Kinase (M: >990 U/L) 9% 7% (F: >845 U/L) Serum Amylase (>175 U/L) 8% 4% Alkaline Phosphatase (>550 U/L) 1% 0% AST (M: >180 U/L) 3% 3% (F: >170 U/L) ALT (M: >215 U/L) 2% 3% (F: >170 U/L) 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% Clinical Trials in Pediatric Subjects Assessment of adverse reactions is based on data from Study 203, an open label, uncontrolled trial of 116 HIV-1 infected pediatric subjects who received emtricitabine 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). Drug Interactions The potential for drug interactions with Emtriva has been studied in combination with zidovudine, indinavir, stavudine, famciclovir, and tenofovir DF. 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) ]. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B The 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 trials 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. Nursing Mothers Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. Samples of breast milk obtained from five HIV-1 infected mothers show that emtricitabine is secreted in human milk. Breastfeeding infants whose mothers are being treated with emtricitabine may be at risk for developing viral resistance to emtricitabine. Other emtricitabine-associated risks in infants breastfed by mothers being treated with emtricitabine are unknown. 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 breastfeed if they are receiving Emtriva . Pediatric Use The safety and efficacy of emtricitabine in patients between 3 months and 21 years of age is supported by data from three open-label, nonrandomized clinical trials in which emtricitabine was administered to 169 HIV-1 infected treatment-naïve and experienced (defined as virologically suppressed on a 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 trial; the efficacy of emtricitabine in preventing or treating HIV-1 could not be determined. 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 . Patients with Impaired Renal Function It is recommended that the dose or dosing interval for Emtriva be modified in patients with creatinine clearance less than 50 mL/min or in patients who require dialysis [See Dosage and Administration (2.5) ] . Overdosage 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 trial, single doses of emtricitabine 1200 mg were administered to 11 subjects. 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 a 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min). It is not known whether emtricitabine can be removed by peritoneal dialysis. Emtriva Description Emtriva is the brand name of emtricitabine, a synthetic nucleoside analog with activity against human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. The chemical name of emtricitabine is 5-fluoro-1-(2 R ,5 S )-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Emtricitabine is the (-) enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5-position. It has a molecular formula of C 8 H 10 FN 3 O 3 S and a molecular weight of 247.24. It has the following structural formula: Emtricitabine is a white to off-white powder with a solubility of approximately 112 mg/mL in water at 25 C. The log P 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, 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 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 a sweetener). Sodium hydroxide and hydrochloric acid may be used to adjust pH. Emtriva - Clinical Pharmacology Mechanism of Action Emtricitabine is an antiviral drug [See Clinical Pharmacology (12.4) ]. Pharmacokinetics Adults The pharmacokinetics of emtricitabine were evaluated in healthy subjects and HIV-1-infected subjects. Emtricitabine pharmacokinetics are similar between these populations. Figure 1 shows the mean steady-state plasma emtricitabine concentration-time profile in 20 HIV-1-infected subjects receiving Emtriva capsules. Figure 1 Mean ( 95% CI) Steady-State Plasma Emtricitabine Concentrations in HIV-1 Infected Adults (N=20) Absorption Emtricitabine is rapidly and extensively absorbed following oral administration, with peak plasma concentrations occurring at 1 2 hours postdose. Following multiple dose oral administration of Emtriva capsules to 20 HIV-1 infected subjects, the (mean SD) steady-state plasma emtricitabine peak concentration (C max ) was 1.8 0.7 µg/mL and the area-under the plasma concentration-time curve over a 24-hour dosing interval (AUC) was 10.0 3.1 µg hr/mL. The mean steady-state plasma trough concentration at 24 hours postdose was 0.09 µg/mL. The mean absolute bioavailability of 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 a dose range of 25 200 mg. Distribution In vitro binding of emtricitabine to human plasma proteins was less than 4% and independent of concentration over the range of 0.02 200 µg/mL. At peak plasma concentration, the mean plasma to blood drug concentration ratio was ~1.0 and the mean semen to plasma drug concentration ratio was ~4.0. Metabolism In vitro studies indicate that emtricitabine is not an inhibitor of human CYP450 enzymes. Following administration of 14 C-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. Elimination The 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 Absorption Emtriva capsules and oral solution may be taken with or without food. Emtricitabine systemic exposure (AUC) was unaffected while C max decreased by 29% when Emtriva capsules were administered with food (an approximately 1000 kcal high-fat meal). Emtricitabine systemic exposure (AUC) and C max were unaffected when 200 mg Emtriva oral solution was administered with either a high-fat or low-fat meal. Specific Populations Race, Gender The pharmacokinetics of emtricitabine were similar in adult male and female subjects, and no pharmacokinetic differences due to race have been identified. Pediatric Patients The pharmacokinetics of emtricitabine 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 emtricitabine exposure achieved in pediatric subjects receiving a daily dose of 6 mg/kg up to a maximum of 240 mg oral solution or a 200 mg capsule is similar to exposures achieved in adult subjects receiving a once-daily dose of 200 mg. 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 6 weeks of zidovudine prophylactically after birth. The neonates were administered two short courses of emtricitabine oral solution (each 3 mg/kg once daily 4 days) during the first 3 months of life. The AUC observed in neonates who received a daily dose of 3 mg/kg of emtricitabine was similar to the AUC observed in pediatric subjects aged 3 months to 17 years who received a daily dose of emtricitabine as a 6 mg/kg oral solution up to 240 mg or as a 200 mg capsule (Table 6). Table 6 Mean SD Pharmacokinetic Parameters by Age Groups for Pediatric Subjects and Neonates Receiving Emtriva Capsules or Oral Solution HIV-1-exposed Neonates HIV-1 Infected Pediatric Subjects Age 0 3 mo (N=20) * 3 24 mo (N=14) 25 mo 6 yr (N=19) 7 12yr (N=17) 13 17 yr (N=27) * Two pharmacokinetic evaluations were conducted in 20 neonates over the first 3 months of life. Median (range) age of infant on day of pharmacokinetic evaluation was 26 (5 81) days. † Mean (range). Formulation Capsule (n) 0 0 0 10 26 Oral Solution (n) 20 14 19 7 1 Dose (mg/kg) † 3.1 (2.9 3.4) 6.1 (5.5 6.8) 6.1 (5.6 6.7) 5.6 (3.1 6.6) 4.4 (1.8 7.0) C max (µg/mL) 1.6 0.6 1.9 0.6 1.9 0.7 2.7 0.8 2.7 0.9 AUC (µg hr/mL) 11.0 4.2 8.7 3.2 9.0 3.0 12.6 3.5 12.6 5.4 T 1/2 (hr) 12.1 3.1 8.9 3.2 11.3 6.4 8.2 3.2 8.9 3.3 Geriatric Patients The pharmacokinetics of emtricitabine have not been fully evaluated in the elderly. Patients with Impaired Renal Function The pharmacokinetics of emtricitabine are altered in subjects with renal impairment [See Warnings and Precautions (5.3) ] . In adult subjects with creatinine clearance less than 50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, C max and AUC of emtricitabine were increased due to a reduction in renal clearance (Table 7). It is recommended that the dosing interval for Emtriva be modified in adult patients with creatinine clearance less than 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 7 Mean SD Pharmacokinetic Parameters in Adult Subjects with Varying Degrees of Renal Function Creatinine Clearance (mL/min) >80 (N=6) 50 80 (N=6) 30 49 (N=6)> <30 (N=5) ESRD *> <30 (N=5) * ESRD subjects requiring dialysis † NA = Not Applicable Baseline creatinine clearance (mL/min) 107 21 59.8 6.5 40.9 5.1 22.9 5.3 8.8 1.4 C max (µg/mL) 2.2 0.6 3.8 0.9 3.2 0.6 2.8 0.7 2.8 0.5 AUC (µg hr/mL) 11.8 2.9 19.9 1.2 25.1 5.7 33.7 2.1 53.2 9.9 CL/F (mL/min) 302 94 168 10 138 28 99 6 64 12 CLr (mL/min) 213 89 121 39 69 32 30 11 NA † Hemodialysis: Hemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min). It is not known whether emtricitabine can be removed by peritoneal dialysis. Patients with Hepatic Impairment The pharmacokinetics of emtricitabine have not been studied in subjects with hepatic impairment; however, emtricitabine is not metabolized by liver enzymes, so the impact of liver impairment should be limited. Assessment of Drug Interactions At concentrations up to 14-fold higher than those observed in vivo, 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 DF, zidovudine, indinavir, famciclovir, and stavudine. Tables 8 and 9 summarize the pharmacokinetic effects of coadministered drug on emtricitabine pharmacokinetics and effects of emtricitabine on the pharmacokinetics of coadministered drug. Table 8 Drug Interactions: Change in Pharmacokinetic Parameters for Emtricitabine in the Presence of the Coadministered Drug * Coadministered Drug Dose of Coadministered Drug (mg) Emtricitabine Dose (mg) N % Change of Emtricitabine Pharmacokinetic Parameters † (90% CI) C max AUC C min * All interaction trials conducted in healthy volunteers. † = Increase; ⇔ = No Effect; NA = Not Applicable Tenofovir DF 300 once daily 7 days 200 once daily 7 days 17 ⇔ ⇔ 20 ( 12 to 29) Zidovudine 300 twice daily 7 days 200 once daily 7 days 27 ⇔ ⇔ ⇔ Indinavir 800 1 200 1 12 ⇔ ⇔ NA Famciclovir 500 1 200 1 12 ⇔ ⇔ NA Stavudine 40 1 200 1 6 ⇔ ⇔ NA Table 9 Drug Interactions: Change in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Emtricitabine * Coadministered Drug Dose of Coadministered Drug (mg) Emtricitabine Dose (mg) N % Change of Coadministered Drug Pharmacokinetic Parameters † (90% CI) C max AUC C min * All interaction trials conducted in healthy volunteers. † = Increase; ⇔ = No Effect; NA = Not Applicable Tenofovir DF 300 once daily 7 days 200 once daily 7 days 17 ⇔ ⇔ ⇔ Zidovudine 300 twice daily 7 days 200 once daily 7 days 27 17 ( 0 to 38) 13 ( 5 to 20) ⇔ Indinavir 800 1 200 1 12 ⇔ ⇔ NA Famciclovir 500 1 200 1 12 ⇔ ⇔ NA Stavudine 40 1 200 1 6 ⇔ ⇔ NA Microbiology Mechanism of Action Emtricitabine, a 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 DNA which results in chain termination. Emtricitabine 5'-triphosphate is a weak inhibitor of mammalian DNA polymerase α, β, ε, and mitochondrial DNA polymerase γ. Antiviral Activity The 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 (EC 50 ) value for emtricitabine was in the range of 0.0013 0.64 µM (0.0003 0.158 µg/mL). In drug combination trials of emtricitabine with nucleoside reverse transcriptase inhibitors (NRTIs) (abacavir, lamivudine, stavudine, tenofovir, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (NNRTIs) (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 G (EC 50 values ranged from 0.007 0.075 µM) and showed strain-specific activity against HIV-2 (EC 50 values ranged from 0.007 1.5 µM). The in vivo activity of emtricitabine was evaluated in two clinical trials in which 101 subjects were administered 25 400 mg a day of Emtriva as monotherapy for 10 14 days. A dose-related antiviral effect was observed, with a median decrease from baseline in plasma HIV-1 RNA of 1.3 log 10 at a dose of 25 mg once daily and 1.7 log 10 to 1.9 log 10 at a dose of 200 mg once daily or twice daily. Resistance Emtricitabine-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 a 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 subjects treated with emtricitabine alone or in combination with other antiretroviral agents. In a clinical trial of treatment-naïve subjects treated with Emtriva, didanosine, and efavirenz [See Clinical Studies (14.1) ] , viral isolates from 37.5% of subjects 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 a clinical trial of treatment-naïve subjects 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 subjects with greater than 400 copies/mL of HIV-1 RNA 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 subject isolates in the Emtriva + VIREAD group and in 10/29 analyzed subject isolates in the lamivudine/zidovudine group. Through 144 weeks of Study 934, no subjects have developed a detectable K65R substitution in their HIV-1 as analyzed through standard genotypic analysis. Cross Resistance Cross-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 Carcinogenesis, 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) 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 Studies Treatment-Naïve Adult Patients Study 934 Data through 144 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter clinical trial comparing Emtriva + tenofovir DF administered in combination with efavirenz versus zidovudine/lamivudine fixed-dose combination administered in combination with efavirenz in 511 antiretroviral- naïve subjects. From Weeks 96 to 144 of the trial, subjects received Emtriva/tenofovir DF fixed-dose combination with efavirenz in place of Emtriva + tenofovir DF with efavirenz. Subjects had a 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 3 (range 2 1191) and median baseline plasma HIV-1 RNA 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 3 and 51% of subjects had baseline viral loads >100,000 copies/mL. Treatment outcomes through 48 and 144 weeks for those subjects 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) Outcomes Week 48 Week 144 Emtriva +TDF +EFV (N=244) AZT/3TC +EFV (N=243) Emtriva +TDF +EFV (N=227) * AZT/3TC +EFV (N=229) * * Subjects who were responders at Week 48 or Week 96 (HIV-1 RNA> <400 copies/mL) but did not consent to continue in the trial after Week 48 or Week 96 were excluded from analysis. † Subjects achieved and maintained confirmed HIV-1 RNA> <400 copies/mL through Weeks 48 and 144. ‡ Includes confirmed viral rebound and failure to achieve confirmed> <400 copies/mL through Weeks 48 and 144. Includes lost to follow-up, subject withdrawal, noncompliance, protocol violation and other reasons. Responder † 84% 73% 71% 58% Virologic failure ‡ 2% 4% 3% 6% Rebound 1% 3% 2% 5% Never suppressed 0% 0% 0% 0% Change in antiretroviral regimen 1% 1% 1% 1% Death> <1% 1% 1% 1% Discontinued due to adverse event 4% 9% 5% 12% Discontinued for other reasons 10% 14% 20% 22% Through Week 48, 84%, and 73% of subjects in the Emtriva + tenofovir DF group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA> <400 copies/mL (71% and 58% through Week 144). The difference in the proportion of subjects who achieved and maintained HIV-1 RNA> <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 trial. In addition, 80% and 70% of subjects in the Emtriva + tenofovir DF group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA> <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 3 in the Emtriva + tenofovir DF group and 158 cells/mm 3 in the zidovudine/lamivudine group at Week 48 (312 and 271 cells/mm 3 at Week 144). Through 48 weeks, 7 subjects in the Emtriva + tenofovir DF group and 5 subjects in the zidovudine/lamivudine group experienced a new CDC Class C event (10 and 6 subjects through 144 weeks). Study 301A Study 301A was a 48-week double-blind, active-controlled, multicenter clinical trial comparing Emtriva (200 mg once daily) administered in combination with didanosine and efavirenz versus stavudine, didanosine, and efavirenz in 571 antiretroviral naïve adult subjects. Subjects had a mean age of 36 years (range 18 69); 85% were male, 52% Caucasian, 16% African-American, and 26% Hispanic. Subjects had a mean baseline CD4+ cell count of 318 cells/mm 3 (range 5 1317) and a median baseline plasma HIV-1 RNA 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. Treatment outcomes are presented in Table 11. Table 11 Outcomes of Randomized Treatment at Week 48 (Study 301A) Outcomes Emtriva + Didanosine + Efavirenz (N=286) Stavudine + Didanosine + Efavirenz (N=285) * Subjects achieved and maintained confirmed HIV RNA> <400 copies/mL (> <50 copies/mL) through Week 48. † Includes subjects who failed to achieve virologic suppression or rebounded after achieving virologic suppression. ‡ Includes lost to follow-up, subject withdrawal, non-compliance, protocol violation, and other reasons. Responder * 81% (78%) 68% (59%) Virologic Failure † 3% 11% Death 0%> <1% Discontinuation Due to Adverse Event 7% 13% Discontinuation for Other Reasons ‡ 9% 8% The mean increase from baseline in CD4+ cell count was 168 cells/mm 3 for the Emtriva arm and 134 cells/mm 3 for the stavudine arm. Through 48 weeks, in the Emtriva group, 5 subjects (1.7%) experienced a new CDC Class C event compared to 7 subjects (2.5%) in the stavudine group. Treatment-Experienced Adult Patients Study 303 Study 303 was a 48 week, open-label, active-controlled, multicenter clinical trial comparing Emtriva (200 mg once daily) to lamivudine, in combination with stavudine or zidovudine and a protease inhibitor or NNRTI in 440 adult subjects who were on a lamivudine-containing triple-antiretroviral drug regimen for at least 12 weeks prior to trial entry and had HIV-1 RNA 400 copies/mL. Subjects were randomized 1:2 to continue therapy with lamivudine (150 mg twice daily) or to switch to Emtriva (200 mg once daily). All subjects were maintained on their stable background regimen. Subjects had a mean age of 42 years (range 22 80); 86% were male, 64% Caucasian, 21% African-American, and 13% Hispanic. Subjects had a mean baseline CD4+ cell count of 527 cells/mm 3 (range 37 1909), and a median baseline plasma HIV-1 RNA of 1.7 log 10 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. Table 12 Outcomes of Randomized Treatment at Week 48 (Study 303) Outcomes Emtriva + ZDV/d4T + NNRTI/PI (N=294) Lamivudine + ZDV/d4T + NN provides you with
abruptly Emtriva is essential
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