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All about: Epivir

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Generic Name: lamivudine
Dosage Form: Tablets and oral solution

Warning

LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION, INCLUDING LAMIVUDINE AND OTHER ANTIRETROVIRALS (SEE WARNINGS).

Epivir TABLETS AND ORAL SOLUTION (USED TO TREAT HUMAN IMMUNODEFICIENCY VIRUS [HIV] INFECTION) CONTAIN A HIGHER DOSE OF THE ACTIVE INGREDIENT (LAMIVUDINE) THAN Epivir-HBV® TABLETS AND ORAL SOLUTION (USED TO TREAT CHRONIC HEPATITIS B). PATIENTS WITH HIV INFECTION SHOULD RECEIVE ONLY DOSING FORMS APPROPRIATE FOR TREATMENT OF HIV (SEE WARNINGS AND PRECAUTIONS).

SEVERE ACUTE EXACERBATIONS OF HEPATITIS B HAVE BEEN REPORTED IN PATIENTS WHO ARE CO-INFECTED WITH HEPATITIS B VIRUS (HBV) AND HIV AND HAVE DISCONTINUED Epivir. HEPATIC FUNCTION SHOULD BE MONITORED CLOSELY WITH BOTH CLINICAL AND LABORATORY FOLLOW-UP FOR AT LEAST SEVERAL MONTHS IN PATIENTS WHO DISCONTINUE Epivir AND ARE CO-INFECTED WITH HIV AND HBV. IF APPROPRIATE, INITIATION OF ANTI-HEPATITIS B THERAPY MAY BE WARRANTED (SEE WARNINGS).

Epivir Description

Epivir (also known as 3TC) is a brand name for lamivudine, a synthetic nucleoside analogue with activity against HIV-1 and HBV. The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2′,3′-dideoxy, 3′-thiacytidine. It has a molecular formula of C8H11N3O3S and a molecular weight of 229.3. It has the following structural formula:

Lamivudine is a white to off-white crystalline solid with a solubility of approximately 70 mg/mL in water at 20°C.

Epivir Tablets are for oral administration. Each 150-mg film-coated tablet contains 150 mg of lamivudine and the inactive ingredients hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide.

Each 300-mg film-coated tablet contains 300 mg of lamivudine and the inactive ingredients black iron oxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide.

Epivir Oral Solution is for oral administration. One milliliter (1 mL) of Epivir Oral Solution contains 10 mg of lamivudine (10 mg/mL) in an aqueous solution and the inactive ingredients artificial strawberry and banana flavors, citric acid (anhydrous), methylparaben, propylene glycol, propylparaben, sodium citrate (dihydrate), and sucrose (200 mg).

MICROBIOLOGY

Mechanism of Action

Lamivudine is a synthetic nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5′-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is the inhibition of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue into viral DNA. 3TC-TP is a weak inhibitor of mammalian DNA polymerases α, β, and γ.

Antiviral Activity

The in vitro activity of lamivudine against HIV-1 was assessed in a number of cell lines (including monocytes and fresh human peripheral blood lymphocytes) using standard susceptibility assays. IC50 values (50% inhibitory concentrations) were in the range of 0.003 to 15 µM (1 μM = 0.23 mcg/mL). The IC50 values of lamivudine against different HIV-1 clades (A-G) ranged from 0.001 to 0.120 µM, and against HIV-2 isolates from 0.003 to 0.120 μM. Ribavirin (50 μM) decreased the anti-HIV-1 activity of lamivudine by 3.5 fold. In HIV−1-infected MT-4 cells, lamivudine in combination with zidovudine at various ratios exhibited synergistic antiretroviral activity. Please see the Epivir-HBV package insert for information regarding the inhibitory activity of lamivudine against HBV.

Resistance

Lamivudine-resistant variants of HIV-1 have been selected in vitro. Genotypic analysis showed that the resistance was due to a specific amino acid substitution in the HIV-1 reverse transcriptase at codon 184 changing the methionine residue to either isoleucine or valine.

HIV-1 strains resistant to both lamivudine and zidovudine have been isolated from patients. Susceptibility of clinical isolates to lamivudine and zidovudine was monitored in controlled clinical trials. In patients receiving lamivudine monotherapy or combination therapy with lamivudine plus zidovudine, HIV-1 isolates from most patients became phenotypically and genotypically resistant to lamivudine within 12 weeks. In some patients harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine. Combination therapy with lamivudine plus zidovudine delayed the emergence of mutations conferring resistance to zidovudine.

Mutations in the HBV polymerase YMDD motif have been associated with reduced susceptibility of HBV to lamivudine in vitro. In studies of non−HIV-infected patients with chronic hepatitis B, HBV isolates with YMDD mutations were detected in some patients who received lamivudine daily for 6 months or more, and were associated with evidence of diminished treatment response; similar HBV mutants have been reported in HIV-infected patients who received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus (see PRECAUTIONS and Epivir-HBV package insert).

Cross-Resistance

Lamivudine-resistant HIV-1 mutants were cross-resistant to didanosine (ddI) and zalcitabine (ddC). In some patients treated with zidovudine plus didanosine or zalcitabine, isolates resistant to multiple reverse transcriptase inhibitors, including lamivudine, have emerged.

Genotypic and Phenotypic Analysis of On-Therapy HIV-1 Isolates From Patients With Virologic Failure (see INDICATIONS AND USAGE: Description of Clinical Studies)

The clinical relevance of genotypic and phenotypic changes associated with lamivudine therapy has not been fully established.

Study EPV20001

Fifty-three of 554 (10%) patients enrolled in EPV20001 were identified as virological failures (plasma HIV-1 RNA level ≥400 copies/mL) by Week 48. Twenty-eight patients were randomized to the lamivudine once-daily treatment group and 25 to the lamivudine twice-daily treatment group. The median baseline plasma HIV-1 RNA levels of patients in the lamivudine once-daily group and lamivudine twice-daily group were 4.9 log10 copies/mL and 4.6 log10 copies/mL, respectively.

Genotypic analysis of on-therapy isolates from 22 patients identified as virologic failures in the lamivudine once-daily group showed that isolates from 0/22 patients contained treatment-emergent mutations associated with zidovudine resistance (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E), isolates from 10/22 patients contained treatment-emergent mutations associated with efavirenz resistance (L100I, K101E, K103N, V108I, or Y181C), and isolates from 8/22 patients contained a treatment-emergent lamivudine resistance-associated mutation (M184I or M184V).

Genotypic analysis of on-therapy isolates from patients (n = 22) in the lamivudine twice-daily treatment group showed that isolates from 1/22 patients contained treatment-emergent zidovudine resistance mutations, isolates from 7/22 contained treatment-emergent efavirenz resistance mutations, and isolates from 5/22 contained treatment-emergent lamivudine resistance mutations.

Phenotypic analysis of baseline-matched on-therapy HIV-1 isolates from patients (n = 13) receiving lamivudine once daily showed that isolates from 12/13 patients were susceptible to zidovudine; isolates from 8/13 patients exhibited a 25- to 295-fold decrease in susceptibility to efavirenz, and isolates from 7/13 patients showed an 85- to 299-fold decrease in susceptibility to lamivudine.

Phenotypic analysis of baseline-matched on-therapy HIV-1 isolates from patients (n = 13) receiving lamivudine twice daily showed that isolates from all 13 patients were susceptible to zidovudine; isolates from 3/13 patients exhibited a 21- to 342-fold decrease in susceptibility to efavirenz, and isolates from 4/13 patients exhibited a 29- to 159-fold decrease in susceptibility to lamivudine.

Study EPV40001

Fifty patients received zidovudine 300 mg twice daily plus abacavir 300 mg twice daily plus lamivudine 300 mg once daily and 50 patients received zidovudine 300 mg plus abacavir 300 mg plus lamivudine 150 mg all twice daily. The median baseline plasma HIV-1 RNA levels for patients in the 2 groups were 4.79 log10 copies/mL and 4.83 log10 copies/mL, respectively. Fourteen of 50 patients in the lamivudine once-daily treatment group and 9 of 50 patients in the lamivudine twice-daily group were identified as virologic failures.

Genotypic analysis of on-therapy HIV-1 isolates from patients (n = 9) in the lamivudine once-daily treatment group showed that isolates from 6 patients had abacavir and/or lamivudine resistance-associated mutation M184V alone. On-therapy isolates from patients (n = 6) receiving lamivudine twice daily showed that isolates from 2 patients had M184V alone, and isolates from 2 patients harbored the M184V mutation in combination with zidovudine resistance-associated mutations.

Phenotypic analysis of on-therapy isolates from patients (n = 6) receiving lamivudine once daily showed that HIV-1 isolates from 4 patients exhibited a 32- to 53-fold decrease in susceptibility to lamivudine. HIV-1 isolates from these 6 patients were susceptible to zidovudine.

Phenotypic analysis of on-therapy isolates from patients (n = 4) receiving lamivudine twice daily showed that HIV-1 isolates from 1 patient exhibited a 45-fold decrease in susceptibility to lamivudine and a 4.5-fold decrease in susceptibility to zidovudine.

Epivir - Clinical Pharmacology

Pharmacokinetics in Adults

The steady-state pharmacokinetic properties of the Epivir 300-mg tablet once daily for 7 days compared to the Epivir 150-mg tablet twice daily for 7 days were assessed in a crossover study in 60 healthy volunteers. Epivir 300 mg once daily resulted in lamivudine exposures that were similar to Epivir 150 mg twice daily with respect to plasma AUC24,ss; however, Cmax,ss was 66% higher and the trough value was 53% lower compared to the 150-mg twice-daily regimen. Intracellular lamivudine triphosphate exposures in peripheral blood mononuclear cells were also similar with respect to AUC24,ss and Cmax24,ss; however, trough values were lower compared to the 150-mg twice-daily regimen. Inter-subject variability was greater for intracellular lamivudine triphosphate concentrations versus lamivudine plasma trough concentrations. The clinical significance of observed differences for both plasma lamivudine concentrations and intracellular lamivudine triphosphate concentrations is not known.

The pharmacokinetic properties of lamivudine have been studied in asymptomatic, HIV-infected adult patients after administration of single intravenous (IV) doses ranging from 0.25 to 8 mg/kg, as well as single and multiple (twice-daily regimen) oral doses ranging from 0.25 to 10 mg/kg.

The pharmacokinetic properties of lamivudine have also been studied as single and multiple oral doses ranging from 5 mg to 600 mg/day administered to HBV-infected patients.

Absorption and Bioavailability

Lamivudine was rapidly absorbed after oral administration in HIV-infected patients. Absolute bioavailability in 12 adult patients was 86% ± 16% (mean ± SD) for the 150-mg tablet and 87% ± 13% for the oral solution. After oral administration of 2 mg/kg twice a day to 9 adults with HIV, the peak serum lamivudine concentration (Cmax) was 1.5 ± 0.5 mcg/mL (mean ± SD). The area under the plasma concentration versus time curve (AUC) and Cmax increased in proportion to oral dose over the range from 0.25 to 10 mg/kg.

An investigational 25-mg dosage form of lamivudine was administered orally to 12 asymptomatic, HIV-infected patients on 2 occasions, once in the fasted state and once with food (1,099 kcal; 75 grams fat, 34 grams protein, 72 grams carbohydrate). Absorption of lamivudine was slower in the fed state (Tmax: 3.2 ± 1.3 hours) compared with the fasted state (Tmax: 0.9 ± 0.3 hours); Cmax in the fed state was 40% ± 23% (mean ± SD) lower than in the fasted state. There was no significant difference in systemic exposure (AUC∞) in the fed and fasted states; therefore, Epivir Tablets and Oral Solution may be administered with or without food.

The accumulation ratio of lamivudine in HIV-positive asymptomatic adults with normal renal function was 1.50 following 15 days of oral administration of 2 mg/kg twice daily.

Distribution

The apparent volume of distribution after IV administration of lamivudine to 20 patients was 1.3 ± 0.4 L/kg, suggesting that lamivudine distributes into extravascular spaces. Volume of distribution was independent of dose and did not correlate with body weight.

Binding of lamivudine to human plasma proteins is low (<36%). In vitro studies showed that, over the concentration range of 0.1 to 100 mcg/mL, the amount of lamivudine associated with erythrocytes ranged from 53% to 57% and was independent of concentration.

Metabolism

Metabolism of lamivudine is a minor route of elimination. In man, the only known metabolite of lamivudine is the trans-sulfoxide metabolite. Within 12 hours after a single oral dose of lamivudine in 6 HIV-infected adults, 5.2% ± 1.4% (mean ± SD) of the dose was excreted as the trans-sulfoxide metabolite in the urine. Serum concentrations of this metabolite have not been determined.

Elimination

The majority of lamivudine is eliminated unchanged in urine by active organic cationic secretion. In 9 healthy subjects given a single 300-mg oral dose of lamivudine, renal clearance was 199.7 ± 56.9 mL/min (mean ± SD). In 20 HIV-infected patients given a single IV dose, renal clearance was 280.4 ± 75.2 mL/min (mean ± SD), representing 71% ± 16% (mean ± SD) of total clearance of lamivudine.

In most single-dose studies in HIV-infected patients, HBV-infected patients, or healthy subjects with serum sampling for 24 hours after dosing, the observed mean elimination half-life (t½) ranged from 5 to 7 hours. In HIV-infected patients, total clearance was 398.5 ± 69.1 mL/min (mean ± SD). Oral clearance and elimination half-life were independent of dose and body weight over an oral dosing range from 0.25 to 10 mg/kg.

Special Populations

Adults With Impaired Renal Function

The pharmacokinetic properties of lamivudine have been determined in a small group of HIV-infected adults with impaired renal function (Table 1).

Table 1. Pharmacokinetic Parameters (Mean ± SD) After a Single 300-mg Oral Dose of Lamivudine in 3 Groups of Adults With Varying Degrees of Renal Function

Creatinine Clearance Criterion

(Number of Subjects)

Parameter

>60 mL/min

(n = 6)

10-30 mL/min

(n = 4)

<10 mL/min

(n = 6)

Creatinine clearance (mL/min)

111 ± 14

28 ± 8

6 ± 2

Cmax (mcg/mL)

2.6 ± 0.5

3.6 ± 0.8

5.8 ± 1.2

AUC∞ (mcg•hr/mL)

11.0 ± 1.7

48.0 ± 19

157 ± 74

Cl/F (mL/min)

464 ± 76

114 ± 34

36 ± 11

Exposure (AUC∞), Cmax, and half-life increased with diminishing renal function (as expressed by creatinine clearance). Apparent total oral clearance (Cl/F) of lamivudine decreased as creatinine clearance decreased. Tmax was not significantly affected by renal function. Based on these observations, it is recommended that the dosage of lamivudine be modified in patients with renal impairment (see DOSAGE AND ADMINISTRATION).

Based on a study in otherwise healthy subjects with impaired renal function, hemodialysis increased lamivudine clearance from a mean of 64 to 88 mL/min; however, the length of time of hemodialysis (4 hours) was insufficient to significantly alter mean lamivudine exposure after a single-dose administration. Continuous ambulatory peritoneal dialysis and automated peritoneal dialysis have negligible effects on lamivudine clearance. Therefore, it is recommended, following correction of dose for creatinine clearance, that no additional dose modification be made after routine hemodialysis or peritoneal dialysis.

It is not known whether lamivudine can be removed by continuous (24-hour) hemodialysis.

The effects of renal impairment on lamivudine pharmacokinetics in pediatric patients are not known.

Adults With Impaired Hepatic Function

The pharmacokinetic properties of lamivudine have been determined in adults with impaired hepatic function. Pharmacokinetic parameters were not altered by diminishing hepatic function; therefore, no dose adjustment for lamivudine is required for patients with impaired hepatic function. Safety and efficacy of lamivudine have not been established in the presence of decompensated liver disease.

Pediatric Patients

For pharmacokinetic properties of lamivudine in pediatric patients, see PRECAUTIONS: Pediatric Use.

Gender

There are no significant gender differences in lamivudine pharmacokinetics.

Race

There are no significant racial differences in lamivudine pharmacokinetics.

Drug Interactions

No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-infected adult patients given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg q 12 hr).

Lamivudine and trimethoprim/sulfamethoxazole (TMP/SMX) were coadministered to 14 HIV-positive patients in a single-center, open-label, randomized, crossover study. Each patient received treatment with a single 300-mg dose of lamivudine and TMP 160 mg/SMX 800 mg once a day for 5 days with concomitant administration of lamivudine 300 mg with the fifth dose in a crossover design. Coadministration of TMP/SMX with lamivudine resulted in an increase of 43% ± 23% (mean ± SD) in lamivudine AUC∞, a decrease of 29% ± 13% in lamivudine oral clearance, and a decrease of 30% ± 36% in lamivudine renal clearance. The pharmacokinetic properties of TMP and SMX were not altered by coadministration with lamivudine.

Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another. Therefore, use of lamivudine in combination with zalcitabine is not recommended.

There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in a study of 19 healthy male subjects.

Ribavirin

In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HIV/HCV co-infected patients (see WARNINGS).

Indications and Usage for Epivir

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%)

Contraindications

Epivir Tablets and Oral Solution are contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any of the components of the products.

Warnings

In pediatric patients with a history of prior antiretroviral nucleoside exposure, a history of pancreatitis, or other significant risk factors for the development of pancreatitis, Epivir should be used with caution. Treatment with Epivir should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur (see ADVERSE REACTIONS).

Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including lamivudine 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 Epivir to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with Epivir 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).

Important Differences Among Lamivudine-Containing Products

Epivir Tablets and Oral Solution contain a higher dose of the same active ingredient (lamivudine) than in Epivir-HBV Tablets and Oral Solution. Epivir-HBV was developed for patients with chronic hepatitis B. The formulation and dosage of lamivudine in Epivir-HBV are not appropriate for patients dually infected with HIV and HBV. Lamivudine has not been adequately studied for treatment of chronic hepatitis B in patients dually infected with HIV and HBV. If treatment with Epivir-HBV is prescribed for chronic hepatitis B for a patient with unrecognized or untreated HIV infection, rapid emergence of HIV resistance is likely to result because of the subtherapeutic dose and the inappropriateness of monotherapy HIV treatment. If a decision is made to administer lamivudine to patients dually infected with HIV and HBV, Epivir Tablets, Epivir Oral Solution, COMBIVIR® (lamivudine/zidovudine) Tablets, or EPZICOM (abacavir sulfate and lamivudine) Tablets should be used as part of an appropriate combination regimen. COMBIVIR (a fixed-dose combination tablet of lamivudine and zidovudine) should not be administered concomitantly with Epivir, Epivir-HBV, EPZICOM, RETROVIR, or TRIZIVIR®.

Posttreatment Exacerbations of Hepatitis

In clinical trials in non-HIV-infected patients treated with lamivudine for chronic hepatitis B, clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. These exacerbations have been detected primarily by serum ALT elevations in addition to re-emergence of HBV DNA. Although most events appear to have been self-limited, fatalities have been reported in some cases. Similar events have been reported from postmarketing experience after changes from lamivudine-containing HIV treatment regimens to non-lamivudine-containing regimens in patients infected with both HIV and HBV. The causal relationship to discontinuation of lamivudine treatment is unknown. Patients should be closely monitored with both clinical and laboratory followup for at least several months after stopping treatment. There is insufficient evidence to determine whether re-initiation of lamivudine alters the course of posttreatment exacerbations of hepatitis.

Use With Interferon- and Ribavirin-Based Regimens

In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as lamivudine. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine in HIV/HCV co-infected patients (see CLINICAL PHARMACOLOGY: Drug Interactions), hepatic decompensation (some fatal) has occurred in HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and Epivir should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of Epivir should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Childs Pugh >6) (see the complete prescribing information for interferon and ribavirin).

Precautions

Patients With Impaired Renal Function

Reduction of the dosage of Epivir is recommended for patients with impaired renal function (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Patients With HIV and Hepatitis B Virus Co-infection

Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in patients dually infected with HIV and HBV. In non−HIV-infected patients treated with lamivudine for chronic hepatitis B, emergence of lamivudine-resistant HBV has been detected and has been associated with diminished treatment response (see Epivir-HBV package insert for additional information). Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV-infected patients who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. Posttreatment exacerbations of hepatitis have also been reported (see WARNINGS).

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Epivir. 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.

Differences Between Dosing Regimens

Trough levels of lamivudine in plasma and of intracellular lamivudine triphosphate were lower with once-daily dosing than with twice-daily dosing (see CLINICAL PHARMACOLOGY). The clinical significance of this observation is not known.

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.

Information for Patients

Epivir is not a cure for HIV infection and patients may continue to experience illnesses associated with HIV infection, including opportunistic infections. Patients should remain under the care of a physician when using Epivir. Patients should be advised that the use of Epivir has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination.

Patients should be advised that Epivir Tablets and Oral Solution contain a higher dose of the same active ingredient (lamivudine) as Epivir-HBV Tablets and Oral Solution. If a decision is made to include lamivudine in the HIV treatment regimen of a patient dually infected with HIV and HBV, the formulation and dosage of lamivudine in Epivir (not Epivir-HBV) should be used.

Patients co-infected with HIV and HBV should be informed that deterioration of liver disease has occurred in some cases when treatment with lamivudine was discontinued. Patients should be advised to discuss any changes in regimen with their physician.

Patients should be advised that the long-term effects of Epivir are unknown at this time.

Epivir Tablets and Oral Solution are for oral ingestion only.

Patients should be advised of the importance of taking Epivir with combination therapy on a regular dosing schedule and to avoid missing doses.

Parents or guardians should be advised to monitor pediatric patients for signs and symptoms of pancreatitis.

Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time.

Diabetic patients should be advised that each 15-mL dose of Epivir Oral Solution contains 3 grams of sucrose.

Drug Interactions

Lamivudine is predominantly eliminated in the urine by active organic cationic secretion. The possibility of interactions with other drugs administered concurrently should be considered, particularly when their main route of elimination is active renal secretion via the organic cationic transport system (e.g., trimethoprim).

TMP 160 mg/SMX 800 mg once daily has been shown to increase lamivudine exposure (AUC) by 43% (see CLINICAL PHARMACOLOGY). No change in dose of either drug is recommended. There is no information regarding the effect on lamivudine pharmacokinetics of higher doses of TMP/SMX such as those used to treat PCP. No data are available regarding interactions with other drugs that have renal clearance mechanisms similar to that of lamivudine.

Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another. Therefore, use of lamivudine in combination with zalcitabine is not recommended.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) those observed in humans at the recommended therapeutic dose for HIV infection. Lamivudine was not active in a microbial mutagenicity screen or an in vitro cell transformation assay, but showed weak in vitro mutagenic activity in a cytogenetic assay using cultured human lymphocytes and in the mouse lymphoma assay. However, lamivudine showed no evidence of in vivo genotoxic activity in the rat at oral doses of up to 2,000 mg/kg, producing plasma levels of 35 to 45 times those in humans at the recommended dose for HIV infection. In a study of reproductive performance, lamivudine administered to rats at doses up to 4,000 mg/kg/day, producing plasma levels 47 to 70 times those in humans, revealed no evidence of impaired fertility and no effect on the survival, growth, and development to weaning of the offspring.

Pregnancy

Pregnancy Category C. Reproduction studies have been performed in rats and rabbits at orally administered doses up to 4,000 mg/kg/day and 1,000 mg/kg/day, respectively, producing plasma levels up to approximately 35 times that for the adult HIV dose. No evidence of teratogenicity due to lamivudine was observed. Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication of this effect in the rat at exposure levels up to 35 times those in humans. Studies in pregnant rats and rabbits showed that lamivudine is transferred to the fetus through the placenta.

In 2 clinical studies conducted in South Africa, pharmacokinetic measurements were performed on samples from pregnant women who received lamivudine beginning at Week 38 of gestation (10 women who received 150 mg twice daily in combination with zidovudine and 10 who received lamivudine 300 mg twice daily without other antiretrovirals) or beginning at Week 36 of gestation (16 women who received lamivudine 150 mg twice daily in combination with zidovudine). These studies were not designed or powered to provide efficacy information. Lamivudine pharmacokinetics in the pregnant women were similar to those obtained following birth and in non-pregnant adults. Lamivudine concentrations were generally similar in maternal, neonatal, and cord serum samples. In a subset of subjects from whom amniotic fluid specimens were obtained following natural rupture of membranes, amniotic fluid concentrations of lamivudine ranged from 1.2 to 2.5 mcg/mL (150 mg twice daily) and 2.1 to 5.2 mcg/mL (300 mg twice daily) and were typically greater than 2 times the maternal serum levels. See the ADVERSE REACTIONS section for the limited late-pregnancy safety information available from these studies. Lamivudine should be used during pregnancy only if the potential benefits outweigh the risks.

Antiretroviral Pregnancy Registry

To monitor maternal-fetal outcomes of pregnant women exposed to lamivudine, a Pregnancy Registry has been established. Physicians 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 breastfeed their infants to avoid risking postnatal transmission of HIV infection.

A study in lactating rats administered 45 mg/kg of lamivudine showed that lamivudine concentrations in milk were slightly greater than those in plasma. Lamivudine is also excreted in human milk. Samples of breast milk obtained from 20 mothers receiving lamivudine monotherapy (300 mg twice daily) or combination therapy (150 mg lamivudine twice daily and 300 mg zidovudine twice daily) had measurable concentrations of lamivudine.

Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving lamivudine.

Pediatric Use

HIV

Limited, uncontrolled pharmacokinetic and safety data are available from administration of lamivudine (and zidovudine) to 36 infants up to 1 week of age in 2 studies in South Africa. In these studies, lamivudine clearance was substantially reduced in 1-week-old neonates relative to pediatric patients (>3 months of age) studied previously. There is insufficient information to establish the time course of changes in clearance between the immediate neonatal period and the age-ranges >3 months old. See the ADVERSE REACTIONS section for the limited safety information available from these studies.

The safety and effectiveness of twice-daily Epivir in combination with other antiretroviral agents have been established in pediatric patients 3 months of age and older.

In Study A2002, pharmacokinetic properties of lamivudine were assessed in a subset of 57 HIV-infected pediatric patients (age range: 4.8 months to 16 years, weight range: 5 to 66 kg) after oral and IV administration of 1, 2, 4, 8, 12, and 20 mg/kg/day. In the 9 infants and children (range: 5 months to 12 years of age) receiving oral solution 4 mg/kg twice daily (the usual recommended pediatric dose), absolute bioavailability was 66% ± 26% (mean ± SD), which was less than the 86% ± 16% (mean ± SD) observed in adults. The mechanism for the diminished absolute bioavailability of lamivudine in infants and children is unknown.

Systemic clearance decreased with increasing age in pediatric patients, as shown in Figure 2.

Figure 2. Systemic Clearance (L/hr•kg) of Lamivudine in Relation to Age

After oral administration of lamivudine 4 mg/kg twice daily to 11 pediatric patients ranging from 4 months to 14 years of age, Cmax was 1.1 ± 0.6 mcg/mL and half-life was 2.0 ± 0.6 hours. (In adults with similar blood sampling, the half-life was 3.7 ± 1 hours.) Total exposure to lamivudine, as reflected by mean AUC values, was comparable between pediatric patients receiving an 8-mg/kg/day dose and adults receiving a 4-mg/kg/day dose.

Distribution of lamivudine into cerebrospinal fluid (CSF) was assessed in 38 pediatric patients after multiple oral dosing with lamivudine. CSF samples were collected between 2 and 4 hours postdose. At the dose of 8 mg/kg/day, CSF lamivudine concentrations in 8 patients ranged from 5.6% to 30.9% (mean ± SD of 14.2% ± 7.9%) of the concentration in a simultaneous serum sample, with CSF lamivudine concentrations ranging from 0.04 to 0.3 mcg/mL.

The effect of renal impairment on lamivudine pharmacokinetics in pediatric patients is not known.

The safety and pharmacokinetic properties of Epivir in combination with antiretroviral agents other than zidovudine have not been established in pediatric patients.

See INDICATIONS AND USAGE: Description of Clinical Studies, CLINICAL PHARMACOLOGY, WARNINGS, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION.

HBV

See the complete prescribing information for Epivir-HBV Tablets and Oral Solution for additional information on the pharmacokinetics of lamivudine in HBV-infected children.

Geriatric Use

Clinical studies of Epivir did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. In particular, because lamivudine is substantially excreted by the kidney and elderly patients are more likely to have decreased renal function, renal function should be monitored and dosage adjustments should be made accordingly (see PRECAUTIONS: Patients with Impaired Renal Function and DOSAGE AND ADMINISTRATION).

Adverse Reactions

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