Emtriva (Emtricitabine) - Indications and Dosage

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 in Table 5.

Table 5 Outcomes of Randomized Treatment at Week 48 (Study 934)

Outcome at Week 48	EMTRIVA +TDF + EFV (N=244)	AZT/3TC + EFV (N=243)
	%	%
ResponderPatients achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Week 48.	84%	73%
Virologic FailureIncludes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Week 48.	2%	4%
Rebound	1%	3%
Never Suppressed	0%	0%
Change in Antiretroviral Regimen	1%	1%
Death	<1%	1%
Discontinued Due to Adverse Event	4%	9%
Discontinued for Other ReasonsIncludes lost to follow-up, patient withdrawal, noncompliance, protocol violation and other reasons.	10%	14%

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 in Table 6 below.

Table 6 Outcomes of Randomized Treatment at Week 48 (Study 301A)

Outcome at Week 48	EMTRIVA + Didanosine + Efavirenz (N=286)	Stavudine + Didanosine + Efavirenz (N=285)
ResponderPatients achieved and maintained confirmed HIV RNA <400 copies/mL (<50 copies/mL) through Week 48.	81% (78%)	68% (59%)
Virologic FailureIncludes patients who failed to achieve virologic suppression or rebounded after achieving virologic suppression.	3%	11%
Death	0%	<1%
Study Discontinuation Due to Adverse Event	7%	13%
Study Discontinuation for Other ReasonsIncludes lost to follow-up, patient withdrawal, non-compliance, protocol violation and other reasons.	9%	8%

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

Through 48 weeks in the EMTRIVA group, 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 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 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 in Table 7 below.

Table 7 Outcomes of Randomized Treatment at Week 48 (Study 303)

Outcome at Week 48	EMTRIVA + ZDV/d4T + NNRTI/PI (N=294)	Lamivudine + ZDV/d4T + NNRTI/PI (N=146)
ResponderPatients achieved and maintained confirmed HIV RNA <400 copies/mL (<50 copies/mL) through Week 48.	77% (67%)	82% (72%)
Virologic FailureIncludes patients who failed to achieve virologic suppression or rebounded after achieving virologic suppression.	7%	8%
Death	0%	<1%
Study Discontinuation Due to Adverse Event	4%	0%
Study Discontinuation for Other ReasonsIncludes lost to follow-up, patient withdrawal, non-compliance, protocol violation and other reasons.	12%	10%

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

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

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, Special Populations). Therefore, the dosing interval of EMTRIVA should be adjusted in patients with baseline creatinine clearance <50 mL/min using the following guidelines (see Table 12). The safety and effectiveness of these dose adjustment guidelines have not been clinically evaluated. Therefore, clinical response to treatment and renal function should be closely monitored in these patients.

Table 12 Dose Adjustment in Adult Patients with Renal Impairment

	Creatinine Clearance (mL/min)
Formulation	≥50 mL/min	30–49 mL/min	15–29 mL/min	<15 mL/min or on hemodialysisHemodialysis Patients: If dosing on day of dialysis, give dose after dialysis.
Capsule (200 mg)	200 mg every 24 hours	200 mg every 48 hours	200 mg every 72 hours	200 mg every 96 hours
Oral Solution (10 mg/mL)	240 mg every 24 hours (24 mL)	120 mg every 24 hours (12 mL)	80 mg every 24 hours (8 mL)	60 mg every 24 hours (6 mL)

Although there are insufficient data to recommend 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.