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Epivir (Lamivudine) - Indications and Dosage

 


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INDICATIONS AND USAGE

EPIVIR in combination with other antiretroviral agents is indicated for the treatment of HIV infection (see Description of Clinical Studies).

Clinical Studies

The use of EPIVIR is based on the results of clinical studies in HIV-infected patients in combination regimens with other antiretroviral agents. Information from trials with clinical endpoints or a combination of CD4+ cell counts and HIV-1 RNA measurements is included below as documentation of the contribution of lamivudine to a combination regimen in controlled trials.

Clinical Endpoint Study in Adults

B3007 (CAESAR) was a multi-center, double-blind, placebo-controlled study comparing continued current therapy (zidovudine alone [62% of patients] or zidovudine with didanosine or zalcitabine [38% of patients]) to the addition of EPIVIR or EPIVIR plus an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI), randomized 1:2:1. A total of 1,816 HIV-infected adults with 25 to 250 CD4+ cells/mm3 (median = 122 cells/mm3) at baseline were enrolled: median age was 36 years, 87% were male, 84% were nucleoside-experienced, and 16% were therapy-naive. The median duration on study was 12 months. Results are summarized in Table 2.

Table 2. Number of Patients (%) With at Least One HIV Disease Progression Event or Death

Endpoint

Current Therapy

(n = 460)

EPIVIR plus

Current Therapy

(n = 896)

EPIVIR plus an NNRTI* plus Current Therapy

(n = 460)

HIV progression or death

90 (19.6%)

86 (9.6%)

41 (8.9%)

Death

27 (5.9%)

23 (2.6%)

14 (3.0%)

* An investigational non-nucleoside reverse transcriptase inhibitor not approved in the United States.

Surrogate Endpoint Studies in Adults: Dual Nucleoside Analogue Studies

Principal clinical trials in the initial development of lamivudine compared lamivudine/zidovudine combinations against zidovudine monotherapy or against zidovudine plus zalcitabine. These studies demonstrated the antiviral effect of lamivudine in a 2-drug combination. More recent uses of lamivudine in treatment of HIV infection incorporate it into multiple-drug regimens containing at least 3 antiretroviral drugs for enhanced viral suppression.

Dose Regimen Comparison Surrogate Endpoint Studies in Therapy-Naive Adults

EPV20001 was a multi-center, double-blind, controlled study in which patients were randomized 1:1 to receive EPIVIR 300 mg once daily or EPIVIR 150 mg twice daily, in combination with zidovudine 300 mg twice daily and efavirenz 600 mg once daily. A total of 554 antiretroviral treatment-naive HIV-infected adults enrolled: male (79%), Caucasian (50%), median age of 35 years, baseline CD4+ cell counts of 69 to 1,089 cells/mm3 (median = 362 cells/mm3), and median baseline plasma HIV-1 RNA of 4.66 log10 copies/mL. Outcomes of treatment through 48 weeks are summarized in Figure 1 and Table 3.

Figure 1. Virologic Response Through Week 48, EPV20001*†(Intent-to-Treat)

* Roche AMPLICOR HIV-1 MONITOR.

Responders at each visit are patients who had achieved and maintained HIV-1 RNA <400 copies/mL without discontinuation by that visit.

Table 3. Outcomes of Randomized Treatment Through 48 Weeks (Intent-to-Treat)

Outcome

EPIVIR 300 mg

Once Daily

plus RETROVIR®

plus Efavirenz

(n = 278)

EPIVIR 150 mg Twice Daily

plus RETROVIR

plus Efavirenz

(n = 276)

Responder*

67%

65%

Virologic failure

8%

8%

Discontinued due to clinical progression

<1%

0%

Discontinued due to adverse events

6%

12%

Discontinued due to other reasons

18%

14%

* Achieved confirmed plasma HIV-1 RNA <400 copies/mL and maintained through 48 weeks.

† Achieved suppression but rebounded by Week 48, discontinued due to virologic failure, insufficient viral response according to the investigator, or never suppressed through Week 48.

‡ Includes consent withdrawn, lost to followup, protocol violation, data outside the study-defined schedule, and randomized but never initiated treatment.

The proportions of patients with HIV-1 RNA <50 copies/mL (via Roche Ultrasensitive assay) through Week 48 were 61% for patients receiving EPIVIR 300 mg once daily and 63% for patients receiving EPIVIR 150 mg twice daily. Median increases in CD4+ cell counts were 144 cells/mm3 at Week 48 in patients receiving EPIVIR 300 mg once daily and 146 cells/mm3 for patients receiving EPIVIR 150 mg twice daily.

A small, randomized, open-label pilot study, EPV40001, was conducted in Thailand. A total of 159 treatment-naive adult patients (male 32%, Asian 100%, median age 30 years, baseline median CD4+ cell count 380 cells/mm3, median plasma HIV-1 RNA 4.8 log10 copies/mL) were enrolled. Two of the treatment arms in this study provided a comparison between lamivudine 300 mg once daily (n = 54) and lamivudine 150 mg twice daily (n = 52), each in combination with zidovudine 300 mg twice daily and abacavir 300 mg twice daily. In intent-to-treat analyses of 48-week data, the proportions of patients with HIV-1 RNA below 400 copies/mL were 61% (33/54) in the group randomized to once-daily lamivudine and 75% (39/52) in the group randomized to receive all 3 drugs twice daily; the proportions with HIV-1 RNA below 50 copies/mL were 54% (29/54) in the once-daily lamivudine group and 67% (35/52) in the all-twice-daily group; and the median increases in CD4+ cell counts were 166 cells/mm3 in the once-daily lamivudine group and 216 cells/mm3 in the all-twice-daily group.

Clinical Endpoint Study in Pediatric Patients

ACTG300 was a multi-center, randomized, double-blind study that provided for comparison of EPIVIR plus RETROVIR (zidovudine) to didanosine monotherapy. A total of 471 symptomatic, HIV-infected therapy-naive (≤56 days of antiretroviral therapy) pediatric patients were enrolled in these 2 treatment arms. The median age was 2.7 years (range 6 weeks to 14 years), 58% were female, and 86% were non-Caucasian. The mean baseline CD4+ cell count was 868 cells/mm3 (mean: 1,060 cells/mm3 and range:0 to 4,650 cells/mm3 for patients ≤5 years of age; mean 419 cells/mm3 and range: 0 to 1,555 cells/mm3 for patients >5 years of age) and the mean baseline plasma HIV-1 RNA was 5.0 log10 copies/mL. The median duration on study was 10.1 months for the patients receiving EPIVIR plus RETROVIR and 9.2 months for patients receiving didanosine monotherapy. Results are summarized in Table 4.

Table 4. Number of Patients (%) Reaching a Primary Clinical Endpoint (Disease Progression or Death)

Endpoint

EPIVIR plus RETROVIR

(n = 236)

Didanosine

(n = 235)

HIV disease progression or death (total)

15 (6.4%)

37 (15.7%)

Physical growth failure

7 (3.0%)

6 (2.6%)

Central nervous system deterioration

4 (1.7%)

12 (5.1%)

CDC Clinical Category C

2 (0.8%)

8 (3.4%)

Death

2 (0.8%)

11 (4.7%)

DOSAGE AND ADMINISTRATION

Adults

The recommended oral dose of EPIVIR for adults is 300 mg daily, administered as either 150 mg twice daily or 300 mg once daily, in combination with other antiretroviral agents (see DESCRIPTION OF CLINICAL STUDIES, PRECAUTIONS, MICROBIOLOGY, and CLINICAL PHARMACOLOGY). If lamivudine is administered to a patient dually infected with HIV and HBV, the dosage indicated for HIV therapy should be used as part of an appropriate combination regimen (see WARNINGS).

Pediatric Patients

Infants/Children/Adolescents

The recommended oral dose of EPIVIR for HIV-infected pediatric patients 3 months up to 16 years of age is 4 mg/kg twice daily (up to a maximum of 150 mg twice a day), administered in combination with other antiretroviral agents.

Dose Adjustment

It is recommended that doses of EPIVIR be adjusted in accordance with renal function (see Table 9) (see CLINICAL PHARMACOLOGY).

Table 9. Adjustment of Dosage of EPIVIR in Adults and Adolescents in Accordance With Creatinine Clearance

Creatinine Clearance (mL/min)

Recommended Dosage of EPIVIR

≥50

150 mg twice daily or 300 mg once daily

30-49

150 mg once daily

15-29

150 mg first dose, then 100 mg once daily

5-14

150 mg first dose, then 50 mg once daily

<5

50 mg first dose, then 25 mg once daily

No additional dosing of EPIVIR is required after routine (4-hour) hemodialysis or peritoneal dialysis.

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

HOW SUPPLIED

EPIVIR Tablets, 150 mg, are white, modified diamond-shaped, film-coated tablets engraved with “GX CJ7” on one side and plain on the reverse side.

Bottle of 60 tablets (NDC 0173-0470-01) with child-resistant closure.

EPIVIR Tablets, 300 mg, are gray, modified diamond-shaped, film-coated tablets engraved with “GX EJ7” on one side and plain on the reverse side.

Bottle of 30 tablets (NDC 0173-0714-00) with child-resistant closure.

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

EPIVIR Oral Solution, a clear, colorless to pale yellow, strawberry-banana flavored liquid, contains 10 mg of lamivudine in each 1 mL.

Plastic bottle of 240 mL (NDC 0173-0471-00) with child-resistant closure. This product does not require reconstitution.

Store in tightly closed bottles at 25°C (77°F) [see USP Controlled Room Temperature].

GlaxoSmithKline

Research Triangle Park, NC 27709

Manufactured under agreement from

Shire Pharmaceuticals Group plc

Basingstoke, UK

©2006, GlaxoSmithKline. All rights reserved.

October 2006 RL-2317

Page last updated: 2006-10-25

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