Drug 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-(2R,5S)-[2-(hydroxymethyl)-1,3oxathiolan-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.

EMTRIVA is available as capsules or as an oral solution.

EMTRIVA Capsules are for oral administration. Each capsule contains 200 mg of emtricitabine and the inactive ingredients, crospovidone, magnesium stearate, microcrystalline cellulose, and povidone.

EMTRIVA Oral Solution is for oral administration. One milliliter (1 mL) of EMTRIVA Oral Solution contains 10 mg of emtricitabine in an aqueous solution with the following inactive ingredients: cotton candy flavor, FD&C yellow No. 6, edetate disodium, methylparaben, and propylparaben (added as preservatives), sodium phosphate (monobasic), propylene glycol, water, and xylitol (added as a sweetener). Sodium hydroxide and hydrochloric acid may be used to adjust pH.

HIV/AIDS-Related Uses

INDICATION AND USAGE

EMTRIVA is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infection.

Additional important information regarding the use of EMTRIVA for the treatment of HIV-1 Infection:

• EMTRIVA should not be coadministered with ATRIPLA^™, TRUVADA^®, or Lamivudine-containing products.
• In treatment-experienced patients, the use of EMTRIVA should be guided by laboratory testing and treatment history.

Description of Clinical Studies:

Treatment-Naive Adult Patients

Study 934: EMTRIVA + VIREAD + Efavirenz Compared with Zidovudine/Lamivudine + Efavirenz
Data through 48 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. 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 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 weeks for those patients who did not have efavirenz resistance at baseline are presented below.

Outcomes of Randomized Treatment at Week 48 (Study 934)

EMTRIVA + TDF + EFV (N=244) – Responder¹: 84%; Virologic failure²: 2% (Rebound: 1%; Never Suppressed: 0%; Change in Antiretroviral Regimen: 1%); Death: <1%; Discontinued Due to Adverse event: 4%; Discontinued for Other Reasons³: 10%.

AZT/3TC + EFV (N=243) – Responder¹: 73%; Virologic failure²: 4% (Rebound: 3%; Never Suppressed: 0%; Change in Antiretroviral Regimen: 1%); Death: 1%; Discontinued Due to Adverse event: 9%; Discontinued for Other Reasons³: 14%.

1. Patients achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Week 48.
2. Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Week 48.
3. Includes lost to follow-up, patient withdrawal, noncompliance, protocol violation and other reasons.

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 + VIREAD group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <50 copies/mL. The mean increase from baseline in CD4 cell count was 190 cells/mm³ in the EMTRIVA + VIREAD group and 158 cells/mm³ in the zidovudine/lamivudine group.

Through 48 weeks, 7 patients in the EMTRIVA + VIREAD group and 5 patients in the zidovudine/lamivudine group experienced a new CDC Class C event.

Study 301A: EMTRIVA QD + Didanosine QD + Efavirenz QD Compared to Stavudine BID + Didanosine QD + Efavirenz QD
Study 301A was a 48 week double-blind, active-controlled multicenter study comparing EMTRIVA (200 mg QD) 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 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 below.

Outcomes of Randomized Treatment at Week 48 (Study 301A)

EMTRIVA + Didanosine + Efavirenz (N=286) – Responder¹: 81% (78%); Virologic failure²: 3%; Death: 0%; Study Discontinuation Due to Adverse Event: 7%; Study Discontinuation for Other Reasons³: 9%.

Stavudine + Didanosine + Efavirenz (N=285) – Responder¹: 68% (59%); Virologic failure²: 11%; Death: <1%; Study Discontinuation Due to Adverse Event: 13%; Study Discontinuation for Other Reasons³: 8%.

1. Patients achieved and maintained confirmed HIV RNA <400 copies/mL (<50 copies/mL) through Week 48.
2. Includes patients who failed to achieve virologic suppression or rebounded after achieving virologic suppression.
3. Includes lost to follow-up, patient withdrawal, non-compliance, protocol violation and other reasons.

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.
 
Treatment-Experienced Adult Patients

Study 303: EMTRIVA QD + Stable Background Therapy (SBT) Compared to Lamivudine BID + SBT
Study 303 was a 48 week, open-label, active-controlled multicenter study comparing EMTRIVA (200 mg QD) to lamivudine, in combination with stavudine or zidovudine and a protease inhibitor or NNRTI in 440 adult patients who were on a lamivudinecontaining 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 BID) or to switch to EMTRIVA (200 mg QD). 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 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 below.

Outcomes of Randomized Treatment at Week 48 (Study 303)

EMTRIVA + ZDV/d4T + NNRTI/PI (N=294) – Responder¹: 77% (67%); Virologic failure²: 7%; Death: 0%; Study Discontinuation Due to Adverse Event: 4%; Study Discontinuation for Other Reasons³: 12%.

Lamivudine + ZDV/d4T + NNRTI/PI (N=146) – Responder¹: 82% (72%); Virologic failure²: 8%; Death: <1%; Study Discontinuation Due to Adverse Event: 0%; Study Discontinuation for Other Reasons³: 10%.

1. Patients achieved and maintained confirmed HIV RNA <400 copies/mL (<50 copies/mL) through Week 48.
2. Includes patients who failed to achieve virologic suppression or rebounded after achieving virologic suppression.
3. Includes lost to follow-up, patient withdrawal, non-compliance, protocol violation and other reasons.

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.

Dosing Information

Mode of Delivery

Oral (capsules, oral solution).

Dosage Form

Capsules containing emtricitabine 200 mg.

Oral solution containing emtricitabine 10 mg/mL.

DOSAGE AND ADMINISTRATION

EMTRIVA may be taken without regard to food.

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.

Pediatric Patients (0–3 months of age):

• EMTRIVA Oral Solution: 3 mg/kg administered once daily orally.

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.

Dose Adjustment in Adult Patients with Renal Impairment:

Significantly increased drug exposures were seen when EMTRIVA was administered to patients with renal impairment. Therefore, the dosing interval of EMTRIVA should be adjusted in patients with baseline creatinine clearance (CLcr) <50 mL/min using the following guidelines (see below). 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.

Dose Adjustment in Adult Patients with Renal Impairment

Capsule (200 mg) – CLcr ≥50 mL/min: 200 mg every 24 hours; CLcr 30–49 mL/min: 200 mg every 48 hours; CLcr 15–29 mL/min: 200 mg every 72 hours; CLcr <15 mL/min or on hemodialysis^*: 200 mg every 96 hours.

Oral Solution (10 mg/mL) – CLcr ≥50 mL/min: 240 mg every 24 hours (24 mL); Clcr 30–49 mL/min: 120 mg every 24 hours (12 mL); CLcr 15–29 mL/min: 80 mg every 24 hours (8 mL); CLcr <15 mL/min or on hemodialysis^*: 60 mg every 24 hours (6 mL).

* Hemodialysis Patients: If dosing on day of dialysis, give dose after dialysis.

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.

Storage

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

Store oral solution 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).

Pharmacology

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 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).

Resistance:
Emtricitabine−resistant isolates of HIV 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 mutation in the HIV 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 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, 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 mutations in the HIV reverse transcriptase gene.

In a clinical study of treatment-naive patients treated with either EMTRIVA, VIREAD^®, and efavirenz or zidovudine/lamivudine and efavirenz, resistance analysis was performed on HIV isolates from all virologic failure patients with >400 copies/mL of HIV-1 RNA at Week 48 or early discontinuations. Development of efavirenz resistance-associated mutations 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 2/12 (17%) analyzed patient isolates in the EMTRIVA + VIREAD group and in 7/22 (32%) analyzed patient isolates in the lamivudine/zidovudine group. Through 48 weeks of Study 934, no patients have developed a detectable K65R mutation in their HIV as analyzed through standard genotypic analysis. Insufficient data are available to assess the development of the K65R mutation upon prolonged exposure to this regimen.

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 mutation, selected in vivo by abacavir, didanosine, tenofovir, and zalcitabine, demonstrated reduced susceptibility to inhibition by emtricitabine. Viruses harboring mutations 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 mutation associated with resistance to NNRTIs was susceptible to emtricitabine.

Pharmacodynamics:
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 QD and 1.7 log₁₀ to 1.9 log₁₀ at a dose of 200 mg QD or BID.

Pharmacokinetics in Adults:
The pharmacokinetics of emtricitabine were evaluated in healthy volunteers and HIV-infected individuals. Emtricitabine pharmacokinetics are similar between these populations. (For additional information, consult the Emtriva complete prescribing information).

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-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 hr•μg/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.

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.

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.

Special Populations:
Race, Gender and Elderly
The pharmacokinetics of emtricitabine were similar in adult male and female patients and no pharmacokinetic differences due to race have been identified. The pharmacokinetics of emtricitabine have not been fully evaluated in the elderly.

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.

Pediatrics
The pharmacokinetics of emtricitabine at steady state were determined in 77 HIV-infected children, and the pharmacokinetic profile was characterized in four age groups (see below). 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-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 QD x 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 (see below).

Mean ± SD Pharmacokinetic Parameters by Age Groups for Pediatric Patients and Neonates Receiving EMTRIVA Capsules or Oral Solution

HIV-exposed Neonates
Age 0–3 mo (N=20¹; formulation: capsule [n=0], oral solution [n=20]) – Dose (mg/kg)²: 3.1 (2.9-3.4); C_max (μg/mL): 1.6 ± 0.6; AUC (hr•μg/mL): 11.0 ± 4.2; T_1/2 (hr): 12.1 ± 3.1.

HIV-infected Pediatric Patients
Age 3–24 mo (N=14; formulation: capsule [n=0], oral solution [n=14]) – Dose (mg/kg)²: 6.1 (5.5−6.8); C_max (μg/mL): 1.9 ± 0.6; AUC (hr•μg/mL): 8.7 ± 3.2; T_1/2 (hr): 8.9 ± 3.2.

Age 25 mo–6 yr (N=19; formulation: capsule [n=0], oral solution [n=19]) – Dose (mg/kg)²: 6.1 (5.6−6.7); C_max (μg/mL): 1.9 ± 0.7; AUC (hr•μg/mL): 9.0 ± 3.0; T_1/2 (hr): 11.3 ± 6.4.

Age 7–12yr (N=17; formulation: capsule [n=10], oral solution [n=7]) – Dose (mg/kg)²: 5.6 (3.1−6.6); C_max (μg/mL): 2.7 ± 0.8; AUC (hr•μg/mL): 12.6 ± 3.5; T_1/2 (hr): 8.2 ± 3.2.

Age 13–17 yr (N=27; formulation: capsule [n=26], oral solution [n=1]) – Dose (mg/kg)²: 4.4 (1.8−7.0); C_max (μg/mL): 2.7 ± 0.9; AUC (hr•μg/mL): 12.6 ± 5.4; T_1/2 (hr): 8.9 ± 3.3.

1. 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.
2. Mean (range)

Renal Impairment
The pharmacokinetics of emtricitabine are altered in patients with renal impairment. In adult patients with creatinine clearance <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 (see below). 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. The effects of renal impairment on emtricitabine pharmacokinetics in pediatric patients are not known.

Mean ± SD Pharmacokinetic Parameters in Adult Patients with Varying Degrees of Renal Function

Creatinine Clearance (mL/min) >80 (N=6) – Baseline creatinine clearance (mL/min): 107 ± 21; C_max (μg/mL): 2.2 ± 0.6; AUC (hr•μg/mL): 11.8 ± 2.9; CL/F (mL/min): 302 ± 94; CLr (mL/min): 213 ± 89.

Creatinine Clearance (mL/min) 50–80 (N=6) – Baseline creatinine clearance (mL/min): 59.8 ± 6.5; C_max (μg/mL): 3.8 ± 0.9; AUC (hr•μg/mL): 19.9 ± 1.2; CL/F (mL/min): 168 ± 10; CLr (mL/min): 121 ± 39.

Creatinine Clearance (mL/min) 30–49 (N=6) – Baseline creatinine clearance (mL/min): 40.9 ± 5.1; C_max (μg/mL): 3.2 ± 0.6; AUC (hr•μg/mL): 25.1 ± 5.7; CL/F (mL/min): 138 ± 28; CLr (mL/min): 69 ± 32.

Creatinine Clearance (mL/min) <30 (N=5) – Baseline creatinine clearance (mL/min): 22.9 ± 5.3; C_max (μg/mL): 2.8 ± 0.7; AUC (hr•μg/mL): 33.7± 2.1; CL/F (mL/min): 99 ± 6; CLr (mL/min): 30 ± 11.

Creatinine Clearance (mL/min) ESRD¹ <30 (N=5) – Baseline creatinine clearance (mL/min): 8.8 ± 1.4; C_max (μg/mL): 2.8 ± 0.5; AUC (hr•μg/mL): 53.2 ± 9.9; CL/F (mL/min 64 ± 12; CLr (mL/min): NA².

1. ESRD patients requiring dialysis
2. NA = Not Applicable

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.

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 450 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 CYP450 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. (For additional information, consult the Emtriva complete prescribing information).

Pregnancy:
Emtricitabine is in FDA 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. To monitor fetal outcomes of pregnant women exposed to emtricitabine, an antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1–800–258–4263.

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

Adverse Events/Toxicity

WARNINGS

• 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. 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).
   
• Patients Co-infected with HIV and Hepatitis B Virus: It is recommended that all patients with HIV 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 co-infected with HBV and HIV. 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 discontinue EMTRIVA and are co-infected with HIV and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

Patients with Impaired Renal Function:
Emtricitabine is principally eliminated by the kidney. Reduction of the dosage of EMTRIVA is recommended for patients with impaired renal function.

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 unknown. A causal relationship has not been established.

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.

The most common treatment emergent adverse events 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 events 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.

The adverse event profile in pediatric patients was generally comparable to that observed in clinical studies of EMTRIVA in adult patients.

Drug and Food Interactions

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.

WARNINGS

• 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, Epivir, Epivir-HBV, Epzicom, or Trizivir.

Drug Interactions:
The potential for drug interactions with EMTRIVA has been studied in combination with zidovudine, indinavir, stavudine, famciclovir, and tenofovir disoproxil fumarate. There were no clinically significant drug interactions for any of these drugs.

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 450 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 CYP450 mediated interactions involving emtricitabine with other medicinal products is low.

Contraindications

EMTRIVA is contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the products. [1]

References

[1] FDA Emtriva Prescribing Information, April 2008. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021500s010,021896s004lbl.pdf. Accessed: 09/09/2011.

Clinical Trials

Click here to search ClinicalTrials.gov for trials that use Emtricitabina.

Chemistry

CAS Name

(2R-cis)-4-Amino-5-fluoro- 1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] -2(1H)-pyrimidinone [1]

CAS Number

143491-57-0 [2]

Molecular Formula

C8-H10-F-N3-O3-S [3]

Molecular Weight

247.24 [4]

Physical Description

White to off-white powder. [5]

Solubility

Approximately 112 mg/mL in water at 25°C (77°F). [6]

References

[1] ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed: 09/09/2011.

[2] ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed: 09/09/2011.

[3] FDA Emtriva Prescribing Information, April 2008. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021500s010,021896s004lbl.pdf. Accessed: 09/09/2011.

[4] FDA Emtriva Prescribing Information, April 2008. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021500s010,021896s004lbl.pdf. Accessed: 09/09/2011.

[5] FDA Emtriva Prescribing Information, April 2008. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021500s010,021896s004lbl.pdf. Accessed: 09/09/2011.

[6] FDA Emtriva Prescribing Information, April 2008. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021500s010,021896s004lbl.pdf. Accessed: 09/09/2011.

Further Reading

Emtriva Prescribing Information from the FDA Web site [PDF] and from the manufacturer's Web site [PDF]. Borroto-Esoda K, Waters JM, Bae AS, Harris JL, Hinkle JE, Quinn JB, Rousseau FS. Baseline genotype as a predictor of virological failure to emtricitabine or stavudine in combination with didanosine and efavirenz. AIDS Res Hum Retroviruses. 2007 Aug;23(8):988-95
Jenny-Avital ER. Tenofovir DF and emtricitabine vs. zidovudine and lamivudine. N Engl J Med. 2006 Jun 8;354(23):2506-8; author reply 2506-8. No abstract available.
McKinney RE Jr, Rodman J, Hu C, Britto P, Hughes M, Smith ME, Serchuck LK, Kraimer J, Ortiz AA, Flynn P, Yogev R, Spector S, Draper L, Tran P, Scites M, Dickover R, Weinberg A, Cunningham C, Abrams E, Blum MR, Chittick GE, Reynolds L, Rathore M; Pediatric AIDS Clinical Trials Group Protocol P1021 Study Team. Long-term safety and efficacy of a once-daily regimen of emtricitabine, didanosine, and efavirenz in HIV-infected, therapy-naive children and adolescents: Pediatric AIDS Clinical Trials Group Protocol P1021. Pediatrics. 2007 Aug;120(2):e416-23. Epub 2007 Jul 23.
Molina JM, Journot V, Furco A, Palmer P, De Castro N, Raffi F, Morlat P, May T, Rancinan C, Chene G; Montana (ANRS 091) Study Group. Five-year follow up of once-daily therapy with emtricitabine, didanosine and efavirenz (Montana ANRS 091 trial). Antivir Ther. 2007;12(3):417-22.
Saag MS. Emtricitabine, a new antiretroviral agent with activity against HIV and hepatitis B virus. Clin Infect Dis. 2006 Jan 1;42(1):126-31. Epub 2005 Nov 23. Review.