2.1 Recommended Dose

EMTRIVA may be taken without regard to food.

2.2 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.

2.3 Pediatric Patients (0–3 months of age)

• EMTRIVA oral solution: 3 mg/kg administered once daily orally.

2.4 Pediatric Patients (3 months through 17 years)

• EMTRIVA oral solution: 6 mg/kg up to a maximum of 240 mg (24 mL) administered once daily orally.
• EMTRIVA capsules: for children weighing more than 33 kg who can swallow an intact capsule, one 200 mg capsule administered once daily orally.

2.5 Dose Adjustment in Adult Patients with Renal Impairment

Significantly increased drug exposures were seen when EMTRIVA was administered to patients with renal impairment [See Clinical Pharmacology (12.3)]. Therefore, the dosing interval or dose of EMTRIVA should be adjusted in patients with baseline creatinine clearance <50 mL/min using the following guidelines (see Table 1). The safety and effectiveness of these dose adjustment guidelines have not been clinically evaluated. Therefore, clinical response to treatment and renal function should be closely monitored in these patients.

Although there are insufficient data to recommend a specific dose adjustment of EMTRIVA in pediatric patients with renal impairment, a reduction in the dose and/or an increase in the dosing interval similar to adjustments for adults should be considered.

5.1 Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination, including emtricitabine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver diseases; however, cases have also been reported in patients with no known risk factors. Treatment with EMTRIVA should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

5.2 Patients Coinfected with HIV-1 and HBV

It is recommended that all patients with HIV-1 be tested for the presence of chronic Hepatitis B virus (HBV) before initiating antiretroviral therapy. EMTRIVA is not approved for the treatment of chronic HBV infection and the safety and efficacy of EMTRIVA have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of Hepatitis B have been reported in patients after the discontinuation of EMTRIVA. In some patients infected with HBV and treated with EMTRIVA, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue EMTRIVA. If appropriate, initiation of anti-Hepatitis B therapy may be warranted.

5.3 Coadministration with Related Products

EMTRIVA is a component of TRUVADA (a fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate) and ATRIPLA (a fixed-dose combination of efavirenz, emtricitabine, and tenofovir disoproxil fumarate). EMTRIVA should not be coadministered with TRUVADA or ATRIPLA. Due to similarities between emtricitabine and lamivudine, EMTRIVA should not be coadministered with other drugs containing lamivudine, including Combivir (lamivudine/zidovudine), Epivir or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), or Trizivir (abacavir sulfate/lamivudine/zidovudine).

5.4 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 (2.5) and Clinical Pharmacology (12.3)].

5.5 Fat Redistribution

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

5.6 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including EMTRIVA. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment.

6.1 Adverse Reactions from Clinical Trials Experience

Adult Patients

More than 2,000 adult patients with HIV-1 infection have been treated with EMTRIVA alone or in combination with other antiretroviral agents for periods of 10 days to 200 weeks in clinical trials.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most common adverse reactions (incidence ≥10%, any severity) identified from any of the 3 large controlled clinical trials include headache, diarrhea nausea, fatigue, dizziness, depression, insomnia, abnormal dreams, rash, abdominal pain, asthenia, increased cough, and rhinitis.

Studies 301A and 303 - Treatment Emergent Adverse Reactions: The most common adverse reactions that occurred in patients receiving EMTRIVA with other antiretroviral agents in clinical studies 301A and 303 were headache, diarrhea, nausea, and rash, which were generally of mild to moderate severity. Approximately 1% of patients discontinued participation in the clinical studies due to these events. All adverse reactions were reported with similar frequency in EMTRIVA and control treatment groups with the exception of skin discoloration which was reported with higher frequency in the EMTRIVA treated group.

Skin discoloration, manifested by hyperpigmentation on the palms and/or soles was generally mild and asymptomatic. The mechanism and clinical significance are unknown.

A summary of EMTRIVA treatment emergent clinical adverse reactions in studies 301A and 303 is provided in Table 2.

Studies 301A and 303 - Laboratory Abnormalities:

Laboratory abnormalities in these studies occurred with similar frequency in the EMTRIVA and comparator groups. A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 3 below.

Study 934 - Treatment Emergent Adverse Reactions: In Study 934, 511 antiretroviral-naïve patients received either VIREAD + EMTRIVA administered in combination with efavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz (N=254). Adverse reactions observed in this study were generally consistent with those seen in previous studies in treatment-experienced or treatment-naïve patients (Table 4).

Study 934 – Laboratory Abnormalities: Significant laboratory abnormalities observed in this study are shown in Table 5.

Pediatric Patients

Assessment of adverse reactions is based on data from Study 203, an open label, uncontrolled study of 116 HIV-1-infected pediatric patients who received emtricitabine through 48 weeks. The adverse reaction profile in pediatric patients was generally comparable to that observed in clinical studies of EMTRIVA in adult patients [See Adverse Reactions (6.1)]. Hyperpigmentation was more frequent in children. Additional adverse reactions identified from this study include anemia.

Selected treatment-emergent adverse events, regardless of causality, reported in patients during 48 weeks of treatment were the following: infection (44%), hyperpigmentation (32%), increased cough (28%), vomiting (23%), otitis media (23%), rash (21%), rhinitis (20%), diarrhea (20%), fever (18%), pneumonia (15%), gastroenteritis (11%), abdominal pain (10%), and anemia (7%). Treatment-emergent grade 3/4 laboratory abnormalities were experienced by 9% of pediatric patients, including amylase >2.0 × ULN (n=4), neutrophils <750/mm3 (n=3), ALT >5 × ULN (n=2), elevated CPK (>4 × ULN) (n=2) and one patient each with elevated bilirubin (>3.0 × ULN), elevated GGT (>10 × ULN), elevated lipase (>2.5 × ULN), decreased hemoglobin (<7 g/dL), and decreased glucose (<40 mg/dL).

8.1 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 studies in pregnant women. Because animal reproduction studies are not always predictive of human response, EMTRIVA should be used during pregnancy only if clearly needed.

Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to EMTRIVA, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1–800–258–4263.

8.3 Nursing Mothers

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

8.4 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, non-randomized clinical studies in which emtricitabine was administered to 169 HIV-1 infected treatment-naive 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 study; the efficacy of emtricitabine in preventing or treating HIV-1 could not be determined.

8.5 Geriatric Use

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

8.6 Patients with Impaired Renal Function

It is recommended that the dose or dosing interval for EMTRIVA be modified in patients with creatinine clearance <50 mL/min or in patients who require dialysis [See Dosage and Administration (2.5)].

12.1 Mechanism of Action

Emtricitabine is an antiviral drug. [See Clinical Pharmacology (12.4)]

12.3 Pharmacokinetics

Adult Subjects

The pharmacokinetics of emtricitabine were evaluated in healthy volunteers and HIV-1-infected individuals. 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 post-dose. Following multiple dose oral administration of EMTRIVA capsules to 20 HIV-1-infected subjects, the (mean ± SD) steady-state plasma emtricitabine peak concentration (Cmax) was 1.8 ± 0.7 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 post-dose 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 <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 14C-emtricitabine, complete recovery of the dose was achieved in urine (~86%) and feces (~14%). Thirteen percent (13%) of the dose was recovered in urine as three putative metabolites. The biotransformation of emtricitabine includes oxidation of the thiol moiety to form the 3'-sulfoxide diastereomers (~9% of dose) and conjugation with glucuronic acid to form 2'-O-glucuronide (~4% of dose). No other metabolites were identifiable.

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 Cmax decreased by 29% when EMTRIVA capsules were administered with food (an approximately 1000 kcal high-fat meal). Emtricitabine systemic exposure (AUC) and Cmax were unaffected when 200 mg EMTRIVA oral solution was administered with either a high-fat or low-fat meal.

Special Populations

Race, Gender

The pharmacokinetics of emtricitabine were similar in adult male and female patients 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 children, and the pharmacokinetic profile was characterized in four age groups (Table 6). The emtricitabine exposure achieved in children 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 adults 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 patients ≥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).

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 patients with renal impairment [See Warnings and Precautions (5.4)]. In adult patients with creatinine clearance <50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, Cmax and AUC of emtricitabine were increased due to a reduction in renal clearance (Table 7). It is recommended that the dosing interval for EMTRIVA be modified in adult patients with creatinine clearance <50 mL/min or in adult patients with ESRD who require dialysis [See Dosage and Administration (2.5)]. The effects of renal impairment on emtricitabine pharmacokinetics in pediatric patients are not known.

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 patients 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 disoproxil fumarate (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)
				Cmax	AUC	Cmin
* All interaction studies conducted in healthy volunteers. † ↑ = Increase; ↓ = Decrease; = No Effect; NA = Not Applicable
Tenofovir DF	300 once daily x 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)
				Cmax	AUC	Cmin
* All interaction studies conducted in healthy volunteers. † ↑ = Increase; ↓ = Decrease; = 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

12.4 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 (EC50) value for emtricitabine was in the range of 0.0013–0.64 µM (0.0003–0.158 µg/mL). In drug combination studies of emtricitabine with nucleoside reverse transcriptase inhibitors (abacavir, lamivudine, stavudine, tenofovir, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0.007–0.075 µM) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007–1.5 µM).

The in vivo activity of emtricitabine was evaluated in two clinical trials in which 101 patients 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 log10 at a dose of 25 mg once daily and 1.7 log10 to 1.9 log10 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 patients treated with emtricitabine alone or in combination with other antiretroviral agents. In a clinical study of treatment-naive patients treated with EMTRIVA, didanosine, and efavirenz [See Clinical Studies (14.1)], viral isolates from 37.5% of patients with virologic failure showed reduced susceptibility to emtricitabine. Genotypic analysis of these isolates showed that the resistance was due to M184V/I substitutions in the HIV-1 reverse transcriptase gene.

In a clinical study of treatment-naive patients treated with either EMTRIVA, VIREAD, and efavirenz or zidovudine/lamivudine and efavirenz [See Clinical Studies (14.1)], resistance analysis was performed on HIV-1 isolates from all confirmed virologic failure patients with >400 copies/mL of HIV-1 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 patient isolates in the EMTRIVA + VIREAD group and in 10/29 analyzed patient isolates in the lamivudine/zidovudine group. Through 144 weeks of Study 934, no patients have developed 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.

13.1 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), 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.

14.1 Treatment-Naive Adult Patients

Study 934

Data through 144 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter study comparing EMTRIVA + VIREAD administered in combination with efavirenz versus zidovudine/lamivudine fixed-dose combination administered in combination with efavirenz in 511 antiretroviral-naive patients. From Weeks 96 to 144 of the study, patients received emtricitabine + tenofovir disoproxil fumarate (tenofovir DF) with efavirenz in place of EMTRIVA + tenofovir DF with efavirenz. Patients had 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/mm3 (range 2–1191) and median baseline plasma HIV-1 RNA was 5.01 log10 copies/mL (range 3.56–6.54). Patients were stratified by baseline CD4+ cell count (< or ≥200 cells/mm3); 41% had CD4+ cell counts <200 cells/mm3 and 51% of patients had baseline viral loads >100,000 copies/mL. Treatment outcomes through 48 and 144 weeks for those patients who did not have efavirenz resistance at baseline are presented in Table 10.

Through Week 48, 84% and 73% of patients in the EMTRIVA + tenofovir DF group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <400 copies/mL (71% and 58% through Week 144). The difference in the proportion of patients 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 study. In addition, 80% and 70% of patients in the EMTRIVA + tenofovir DF group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 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/mm3 in the EMTRIVA + tenofovir DF group and 158 cells/mm3 in the zidovudine/lamivudine group at Week 48 (312 and 271 cells/mm3 at Week 144).

Through 48 weeks, 7 patients in the EMTRIVA + tenofovir DF group and 5 patients in the zidovudine/lamivudine group experienced a new CDC Class C event (10 and 6 patients through 144 weeks).

Study 301A

Study 301A was a 48 week double-blind, active-controlled multicenter study comparing EMTRIVA (200 mg once daily) administered in combination with didanosine and efavirenz versus stavudine, didanosine and efavirenz in 571 antiretroviral naive adult patients. Patients had a mean age of 36 years (range 18–69), 85% were male, 52% Caucasian, 16% African-American and 26% Hispanic. Patients had a mean baseline CD4+ cell count of 318 cells/mm3 (range 5–1317) and a median baseline plasma HIV-1 RNA of 4.9 log10 copies/mL (range 2.6–7.0). Thirty-eight percent of patients had baseline viral loads >100,000 copies/mL and 31% had CD4+ cell counts <200 cells/mL. Treatment outcomes are presented in Table 11 below.

The mean increase from baseline in CD4+ cell count was 168 cells/mm3 for the EMTRIVA arm and 134 cells/mm3 for the stavudine arm.

Through 48 weeks in the EMTRIVA group, 5 patients (1.7%) experienced a new CDC Class C event, compared to 7 patients (2.5%) in the stavudine group.

14.2 Treatment-Experienced Adult Patients

Study 303

Study 303 was a 48 week, open-label, active-controlled multicenter study comparing EMTRIVA (200 mg once daily) to lamivudine, in combination with stavudine or zidovudine and a protease inhibitor or NNRTI in 440 adult patients who were on a lamivudine-containing triple-antiretroviral drug regimen for at least 12 weeks prior to study entry and had HIV-1 RNA ≤400 copies/mL.

Patients were randomized 1:2 to continue therapy with lamivudine (150 mg twice daily) or to switch to EMTRIVA (200 mg once daily). All patients were maintained on their stable background regimen. Patients had a mean age of 42 years (range 22–80), 86% were male, 64% Caucasian, 21% African-American and 13% Hispanic. Patients had a mean baseline CD4+ cell count of 527 cells/mm3 (range 37–1909), and a median baseline plasma HIV-1 RNA of 1.7 log10 copies/mL (range 1.7–4.0).

The median duration of prior antiretroviral therapy was 27.6 months. Treatment outcomes are presented in Table 12 below.

The mean increase from baseline in CD4+ cell count was 29 cells/mm3 for the EMTRIVA arm and 61 cells/mm3 for the lamivudine arm.

Through 48 weeks, in the EMTRIVA group 2 patients (0.7%) experienced a new CDC Class C event, compared to 2 patients (1.4%) in the lamivudine group.

14.3 Pediatric Patients

In three open-label, non-randomized clinical studies, emtricitabine was administered to 169 HIV-1 infected treatment-naive and experienced (defined as virologically suppressed on a lamivudine containing regimen for which emtricitabine was substituted for lamivudine) patients between 3 months and 21 years of age. Patients received once-daily EMTRIVA oral solution (6 mg/kg to a maximum of 240 mg/day) or EMTRIVA capsules (a single 200 mg capsule once daily) in combination with at least two other antiretroviral agents.

Patients had a mean age of 7.9 years (range 0.3–21), 49% were male, 15% Caucasian, 61% Black and 24% Hispanic. Patients had a median baseline HIV-1 RNA of 4.6 log10 copies/mL (range 1.7–6.4) and a mean baseline CD4+ cell count of 745 cells/mm3 (range 2–2650). Through 48 weeks of therapy, the overall proportion of patients who achieved and sustained an HIV-1 RNA <400 copies/mL was 86%, and <50 copies/mL was 73%. The mean increase from baseline in CD4+ cell count was 232 cells/mm3 (-945, +1512). The adverse reaction profile observed during these clinical trials was similar to that of adult patients, with the exception of the occurrence of anemia and higher frequency of hyperpigmentation in children [See Adverse Reactions (6)].

The pharmacokinetics of emtricitabine were studied in 20 neonates born to HIV-1-positive mothers. Each mother received prenatal and intrapartum combination antiretroviral therapy. Neonates received up to 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. Emtricitabine exposures in neonates were similar to the exposures achieved in patients >3 months to 17 years [See Clinical Pharmacology (12.3)]. During the two short dosing periods on emtricitabine there were no safety issues identified in the treated neonates. All neonates were HIV-1 negative at the end of the study; the efficacy of emtricitabine in preventing or treating HIV-1 could not be determined.

Capsules

The size 1 hard gelatin capsules with a blue cap and white body contain 200 mg of emtricitabine, are printed with "200 mg" in black on the cap and "GILEAD" and the corporate logo in black on the body.

They are supplied by State of Florida DOH Central Pharmacy as follows:

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

Oral Solution

The oral solution is a clear, orange to dark orange liquid, contains 10 mg/mL of emtricitabine.

Store refrigerated, 2–8 °C (36–46 °F). Emtriva oral solution should be used within 3 months if stored by the patient at 25 °C (77 °F); excursions permitted to 15–30 °C (59–86 °F).

17.1 Information for Patients

Patients should be advised that:

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

17.2 FDA-Approved Patient Labeling