###### PRODUCT INFORMATION

**EPIVIR-HBV^®^**

**(lamivudine)**

### Tablets

**EPIVIR-HBV^®^**

**(lamivudine)**

### 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).**

**HUMAN IMMUNODEFICIENCY VIRUS (HIV) COUNSELING AND TESTING SHOULD BE
OFFERED TO ALL PATIENTS BEFORE BEGINNING EPIVIR‑HBV AND PERIODICALLY
DURING TREATMENT (SEE WARNINGS), BECAUSE EPIVIR‑HBV TABLETS AND ORAL
SOLUTION CONTAIN A LOWER DOSE OF THE SAME ACTIVE INGREDIENT (LAMIVUDINE)
AS EPIVIR^®^ TABLETS AND ORAL SOLUTION USED TO TREAT HIV INFECTION. 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 BECAUSE OF SUBTHERAPEUTIC DOSE AND
INAPPROPRIATE MONOTHERAPY.**

**DESCRIPTION:** EPIVIR‑HBV is a brand name for lamivudine, a synthetic
nucleoside analogue with activity against HBV and HIV. Lamivudine was
initially developed for the treatment of HIV infection as EPIVIR^®^.
Please see the complete prescribing information for EPIVIR Tablets and
Oral Solution for additional information. 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 C~8~H~11~N~3~O~3~S and a
molecular weight of 229.3. It has the following structural formula:

![](media/image1.wmf){width="1.475in" height="1.5in"}

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

**EPIVIR‑HBV Tablets** are for oral administration. Each tablet contains
100 mg of lamivudine and the inactive ingredients magnesium stearate,
microcrystalline cellulose, and sodium starch glycolate. Opadry
YS‑1‑17307‑A Butterscotch is the coloring agent in the tablet coating.

**EPIVIR‑HBV Oral Solution** is for oral administration. One milliliter
(1 mL) of EPIVIR‑HBV Oral Solution contains 5 mg of lamivudine (5 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.

**MICROBIOLOGY:**

**Mechanism of Action:** Lamivudine is a synthetic nucleoside analogue.
Lamivudine is phosphorylated intracellularly to lamivudine triphosphate,
L‑TP. Incorporation of the monophosphate form into viral DNA by
hepatitis B virus (HBV) polymerase results in DNA chain termination.
L‑TP also inhibits the RNA- and DNA‑dependent DNA polymerase activities
of HIV‑1 reverse transcriptase (RT). L‑TP is a weak inhibitor of
mammalian alpha-, beta-, and gamma‑DNA polymerases.

**Antiviral Activity:** In Vitro**:** *In vitro* activity of lamivudine
against HBV was assessed in HBV DNA‑transfected 2.2.15 cells, HB611
cells, and infected human primary hepatocytes. IC~50~ values (the
concentration of drug needed to reduce the level of extracellular HBV
DNA by 50%) varied from 0.01 μM (2.3 ng/mL) to 5.6 μM (1.3 μg/mL)
depending upon the duration of exposure of cells to lamivudine, the cell
model system, and the protocol used*.* See the EPIVIR package insert for
information regarding activity of lamivudine against HIV.

**Drug Resistance:** HBV: Genotypic analysis of viral isolates obtained
from patients who show renewed evidence of replication of HBV while
receiving lamivudine suggests that a reduction in sensitivity of HBV to
lamivudine is associated with mutations resulting in a methionine to
valine or isoleucine substitution in the YMDD motif of the catalytic
domain of HBV polymerase (position 552) and a leucine to methionine
substitution at position 528. It is not known whether other HBV
mutations may be associated with reduced lamivudine susceptibility *in
vitro*.

In 4 controlled clinical trials in adults, YMDD‑mutant HBV were detected
in 81 of 335 patients receiving lamivudine 100 mg once daily for
52 weeks. The prevalence of YMDD mutations was less than 10% in each of
these trials for patients studied at 24 weeks and increased to an
average of 24% (range in four studies: 16% to 32%) at 52 weeks. In
limited data from a long‑term follow‑up trial in patients who continued
100 mg/day lamivudine after one of these studies, YMDD mutations further
increased from 16% at 1 year to 42% at 2 years. In small numbers of
patients receiving lamivudine for longer periods, further increases in
the appearance of YMDD mutations were observed.

In a controlled trial in pediatric patients, YMDD‑mutant HBV were
detected in 31 of 166 (19%) patients receiving lamivudine for 52 weeks.
For a subgroup who remained on lamivudine therapy in a follow-up study,
YMDD mutations increased from 24% at 12 months to 45% (53 of 118) at
18 months of lamivudine treatment.

Mutant viruses were associated with evidence of diminished treatment
response at 52 weeks relative to lamivudine‑treated patients without
evidence of YMDD mutations in both adult and pediatric studies (see
PRECAUTIONS). The long‑term clinical significance of YMDD‑mutant HBV is
not known.

HIV: In studies of HIV-1‑infected patients who received lamivudine
monotherapy or combination therapy with lamivudine plus zidovudine for
at least 12 weeks, HIV‑1 isolates with reduced *in vitro* susceptibility
to lamivudine were detected in most patients (see WARNINGS).

**CLINICAL PHARMACOLOGY:**

**Pharmacokinetics in Adults:** The pharmacokinetic properties of
lamivudine have been studied as single and multiple oral doses ranging
from 5 to 600 mg per day administered to HBV‑infected patients.

The pharmacokinetic properties of lamivudine have also 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.

Absorption and Bioavailability: Lamivudine was rapidly absorbed after
oral administration in HBV‑infected patients and in healthy subjects.
Following single oral doses of 100 mg, the peak serum lamivudine
concentration (C~max~) in HBV‑infected patients (steady state) and
healthy subjects (single dose) was 1.28 ± 0.56 μg/mL and
1.05 ± 0.32 μg/mL (mean ± SD), respectively, which occurred between 0.5
and 2 hours after administration. The area under the plasma
concentration versus time curve (AUC~\[0‑24 h\]~) following 100 mg
lamivudine oral single and repeated daily doses to steady state was
4.3 ± 1.4 (mean ± SD) and 4.7 ± 1.7 μg•h/mL, respectively. The relative
bioavailability of the tablet and solution were then demonstrated in
healthy subjects. Although the solution demonstrated a slightly higher
peak serum concentration (C~max~), there was no significant difference
in systemic exposure (AUC∞) between the solution and the tablet.
Therefore, the solution and the tablet may be used interchangeably.

After oral administration of lamivudine once daily to HBV‑infected
adults, the AUC and peak serum levels (C~max~) increased in proportion
to dose over the range from 5 mg to 600 mg once daily.

The 100‑mg tablet was administered orally to 24 healthy subjects on two
occasions, once in the fasted state and once with food (standard meal:
967 kcal; 67 grams fat, 33 grams protein, 58 grams carbohydrate). There
was no significant difference in systemic exposure (AUC∞) in the fed and
fasted states; therefore, EPIVIR‑HBV Tablets and Oral Solution may be
administered with or without food.

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
10‑mg/mL oral solution.

Distribution: The apparent volume of distribution after IV
administration of lamivudine to 20 asymptomatic HIV‑infected 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%) and
independent of dose. *In vitro* studies showed that, over the
concentration range of 0.1 to 100 µg/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. In nine healthy subjects receiving 300 mg of lamivudine as
single oral doses, a total of 4.2% (range 1.5% to 7.5%) of the dose was
excreted as the trans‑sulfoxide metabolite in the urine, the majority of
which was excreted in the first 12 hours.

Serum concentrations of the trans‑sulfoxide metabolite have not been
determined.

Elimination: The majority of lamivudine is eliminated unchanged in
urine. In nine 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- or 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 healthy
subjects and in subjects with impaired renal function, with and without
hemodialysis (Table 1):

**Table 1: Pharmacokinetic Parameters (Mean ** SD) Dose‑Normalized to a
Single 100‑mg Oral Dose of Lamivudine in Patients With Varying Degrees
of Renal Function

+--------------------+---------------+---------------+---------------+
|                    | Creatinine    |               |               |
|                    | Clearance     |               |               |
|                    | Criterion     |               |               |
|                    |               |               |               |
|                    | (Number of    |               |               |
|                    | Subjects)     |               |               |
+--------------------+---------------+---------------+---------------+
| Parameter          | ≥80 mL/min    | 20‑59 mL/min  | \<20 mL/min   |
|                    |               |               |               |
|                    | (n = 9)       | (n = 8)       | (n = 6)       |
+--------------------+---------------+---------------+---------------+
| Creatinine         | 97            | 39            | 15            |
| clearance (mL/min) |               |               |               |
|                    | (range        | (range 25-49) | (range 13-19) |
|                    | 82-117)       |               |               |
+--------------------+---------------+---------------+---------------+
| C~max~ (μg/mL)     | 1.31 ± 0.35   | 1.85 ± 0.40   | 1.55 ± 0.31   |
+--------------------+---------------+---------------+---------------+
| AUC∞ (μg•h/mL)     | 5.28 ± 1.01   | 14.67 ± 3.74  | 27.33 ± 6.56  |
+--------------------+---------------+---------------+---------------+
| CI/F (mL/min)      | 326.4 ± 63.8  | 120.1 ± 29.5  | 64.5 ± 18.3   |
+--------------------+---------------+---------------+---------------+

Exposure (AUC∞), C~max~, 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. T~max~ 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).

Hemodialysis increases 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. Therefore, it is recommended, following
correction of dose for creatinine clearance, that no additional dose
modification is made after routine hemodialysis.

It is not known whether lamivudine can be removed by peritoneal dialysis
or continuous (24‑hour) hemodialysis.

The effect of renal impairment on lamivudine pharmacokinetics in
pediatric patients with chronic hepatitis B is not known.

Adults With Impaired Hepatic Function: The pharmacokinetic properties of
lamivudine have been determined in adults with impaired hepatic function
(Table 2). Patients were stratified by severity of hepatic functional
impairment.

**Table 2: Pharmacokinetic Parameters (Mean ** SD) Dose‑Normalized to a
Single 100‑mg Dose of Lamivudine in Three Groups of Subjects With Normal
or Impaired Hepatic Function

+----------------------+---------------+---------------+--------------+
|                      | #             | Impairment\*  |              |
+----------------------+---------------+---------------+--------------+
|                      | # Normal      | Moderate      | Severe       |
+----------------------+---------------+---------------+--------------+
| Parameter            | (n = 8)       | (n = 8)       | (n = 8)      |
+----------------------+---------------+---------------+--------------+
| C~max~ (μg/mL)       | 0.92 ± 0.31   | 1.06 ± 0.58   | 1.08 ± 0.27  |
+----------------------+---------------+---------------+--------------+
| AUC∞ (μg•h/mL)       | 3.96 ± 0.58   | 3.97 ± 1.36   | 4.30 ± 0.63  |
+----------------------+---------------+---------------+--------------+
| T~max~ (h)           | 1.3 ± 0.8     | 1.4 ± 0.8     | 1.4 ± 1.2    |
+----------------------+---------------+---------------+--------------+
| CI/F (mL/min)        | 424.7 ± 61.9  | 456.9 ± 129.8 | 395.2 ± 51.8 |
+----------------------+---------------+---------------+--------------+
| Clr (mL/min)         | 279.2 ± 79.2  | 323.5 ± 100.9 | 216.1 ± 58.0 |
+----------------------+---------------+---------------+--------------+

\*Hepatic impairment assessed by aminopyrine breath test.

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
EPIVIR‑HBV have not been established in the presence of decompensated
liver disease (see PRECAUTIONS).

Post‑Hepatic Transplant: Fourteen HBV‑infected patients received liver
transplant following lamivudine therapy and completed pharmacokinetic
assessments at enrollment, 2 weeks after 100‑mg once‑daily dosing
(pre‑transplant), and 3 months following transplant; there were no
significant differences in pharmacokinetic parameters. The overall
exposure of lamivudine is primarily affected by renal dysfunction;
consequently, transplant patients with reduced renal function had
generally higher exposure than patients with normal renal function.
Safety and efficacy of EPIVIR‑HBV have not been established in this
population (see PRECAUTIONS).

Pediatric Patients: Lamivudine pharmacokinetics were evaluated in a
28‑day dose‑ranging study in 53 pediatric patients with chronic
hepatitis B. Patients aged 2 to 12 years were randomized to receive
lamivudine 0.35 mg/kg twice daily, 3 mg/kg once daily, 1.5 mg/kg twice
daily, or 4 mg/kg twice daily. Patients aged 13 to 17 years received
lamivudine 100 mg once daily. Lamivudine was rapidly absorbed (T~max~
0.5 to 1 hour). In general, both C~max~ and exposure (AUC) showed dose
proportionality in the dosing range studied. Weight‑corrected oral
clearance was highest at age 2 and declined from 2 to 12 years, where
values were then similar to those seen in adults. A dose of 3 mg/kg
given once daily produced a steady‑state lamivudine AUC (mean
5953 ng·h/mL ± 1562 SD) similar to that associated with a dose of
100 mg/day in adults.

Gender: There are no significant gender differences in lamivudine
pharmacokinetics.

Race: There are no significant racial differences in lamivudine
pharmacokinetics.

**Drug Interactions:** Multiple doses of lamivudine and a single dose of
interferon were coadministered to 19 healthy male subjects in a
pharmacokinetics study. Results indicated a small (10%) reduction in
lamivudine AUC, but no change in interferon pharmacokinetic parameters
when the two drugs were given in combination. All other pharmacokinetic
parameters (C~max~, T~max~, and t~½~) were unchanged. There was no
significant pharmacokinetic interaction between lamivudine and
interferon alfa in this study.

Lamivudine and zidovudine were coadministered to 12 asymptomatic
HIV‑positive adult patients in a single‑center, open‑label, randomized,
crossover study. No significant differences were observed in AUC∞ or
total clearance for lamivudine or zidovudine when the two drugs were
administered together. Coadministration of lamivudine with zidovudine
resulted in an increase of 39% ± 62% (mean ± SD) in C~max~ of
zidovudine.

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 44% ± 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 (see PRECAUTIONS: Drug Interactions).

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

**INDICATIONS AND USAGE:** EPIVIR‑HBV is indicated for the treatment of
chronic hepatitis B associated with evidence of hepatitis B viral
replication and active liver inflammation. This indication is based on
1‑year histologic and serologic responses in adult patients with
compensated chronic hepatitis B, and more limited information from a
study in pediatric patients ages 2 to 17 years (see Description of
Clinical Studies below).

**Description of Clinical Studies:** Adults: The safety and efficacy of
EPIVIR‑HBV were evaluated in four controlled studies in 967 patients
with compensated chronic hepatitis B. All patients were 16 years of age
or older and had chronic hepatitis B virus infection (serum HBsAg
positive for at least 6 months) accompanied by evidence of HBV
replication (serum HBeAg positive and positive for serum HBV DNA, as
measured by a research solution‑hybridization assay) and persistently
elevated ALT levels and/or chronic inflammation on liver biopsy
compatible with a diagnosis of chronic viral hepatitis. Three of these
studies provided comparisons of EPIVIR‑HBV 100 mg once daily versus
placebo, and results of these comparisons are summarized below.

-   Study 1 was a randomized, double‑blind study of EPIVIR-HBV 100 mg
    once daily versus placebo for 52 weeks, followed by a 16‑week
    no‑treatment period, in treatment‑naive US patients.

-   Study 2 was a randomized, double‑blind, three‑arm study that
    compared EPIVIR‑HBV 25 mg once daily versus EPIVIR‑HBV 100 mg once
    daily versus placebo for 52 weeks in Asian patients.

-   Study 3 was a randomized, partially‑blind, three‑arm study conducted
    primarily in North America and Europe in patients who had ongoing
    evidence of active chronic hepatitis B despite previous treatment
    with interferon alfa. The study compared EPIVIR‑HBV 100 mg once
    daily for 52 weeks, followed by either EPIVIR‑HBV 100 mg or matching
    placebo once daily for 16 weeks (Arm 1), versus placebo once daily
    for 68 weeks (Arm 2). (A third arm using a combination of interferon
    and lamivudine is not presented here because there was not
    sufficient information to evaluate this regimen.)

Principal endpoint comparisons for the histologic and serologic outcomes
in lamivudine (100 mg daily) and placebo recipients in
placebo‑controlled studies are shown in the following tables.

**Table 3: Histologic Response at Week 52 Among Adult Patients
Receiving**

EPIVIR‑HBV 100 mg Once Daily or Placebo

+------------+----------+------+---+----------+------+---+----------+------+
|            | Study 1  |      |   | Study 2  |      |   | Study 3  |      |
+------------+----------+------+---+----------+------+---+----------+------+
| Assessment | EP       | Pla  | E |          | Pla  | E |          | Pla  |
|            | IVIR‑HBV | cebo | P |          | cebo | P |          | cebo |
|            |          |      | I |          |      | I |          |      |
|            | (n = 62) | (n = | V |          | (n = | V |          | (n = |
|            |          |  63) | I |          | 68)  | I |          | 54)  |
|            |          |      | R |          |      | R |          |      |
|            |          |      | ‑ |          |      | ‑ |          |      |
|            |          |      | H |          |      | H |          |      |
|            |          |      | B |          |      | B |          |      |
|            |          |      | V |          |      | V |          |      |
|            |          |      |   |          |      |   |          |      |
|            |          |      | ( |          |      | ( |          |      |
|            |          |      | n |          |      | n |          |      |
|            |          |      |   |          |      | = |          |      |
|            |          |      | = |          |      | 1 |          |      |
|            |          |      |   |          |      | 1 |          |      |
|            |          |      | 1 |          |      | 0 |          |      |
|            |          |      | 3 |          |      | ) |          |      |
|            |          |      | 1 |          |      |   |          |      |
|            |          |      | ) |          |      |   |          |      |
+------------+----------+------+---+----------+------+---+----------+------+
| Imp        | 55%      | 25%  | 5 |          | 26%  | 5 |          | 26%  |
| rovement\* |          |      | 6 |          |      | 6 |          |      |
|            |          |      | % |          |      | % |          |      |
+------------+----------+------+---+----------+------+---+----------+------+
| No         | 27%      | 59%  | 3 |          | 62%  | 2 |          | 54%  |
| I          |          |      | 6 |          |      | 5 |          |      |
| mprovement |          |      | % |          |      | % |          |      |
+------------+----------+------+---+----------+------+---+----------+------+
| Missing    | 18%      | 16%  | 8 |          | 12%  | 1 |          | 20%  |
| Data       |          |      | % |          |      | 9 |          |      |
|            |          |      |   |          |      | % |          |      |
+------------+----------+------+---+----------+------+---+----------+------+

\* Improvement was defined as a ≥2‑point decrease in the Knodell
Histologic Activity Index (HAI)^1^ at Week 52 compared with pretreatment
HAI. Patients with missing data at baseline were excluded.

**Table 4: HBeAg Seroconversion\* at Week 52 Among Adult Patients
Receiving**

EPIVIR‑HBV 100 mg Once Daily or Placebo

+------------+----------+------+---+----------+-------+---+----------+------+
| Sero       | Study 1  |      |   | Study 2  |       |   | Study 3  |      |
| conversion |          |      |   |          |       |   |          |      |
+------------+----------+------+---+----------+-------+---+----------+------+
|            | EP       | Pla  | E |          | Pl    | E |          | Pla  |
|            | IVIR‑HBV | cebo | P |          | acebo | P |          | cebo |
|            |          |      | I |          |       | I |          |      |
|            | (n = 63) | (n = | V |          | (n    | V |          | (n = |
|            |          |  69) | I |          | = 70) | I |          |  53) |
|            |          |      | R |          |       | R |          |      |
|            |          |      | ‑ |          |       | ‑ |          |      |
|            |          |      | H |          |       | H |          |      |
|            |          |      | B |          |       | B |          |      |
|            |          |      | V |          |       | V |          |      |
|            |          |      |   |          |       |   |          |      |
|            |          |      | ( |          |       | ( |          |      |
|            |          |      | n |          |       | n |          |      |
|            |          |      |   |          |       |   |          |      |
|            |          |      | = |          |       | = |          |      |
|            |          |      |   |          |       |   |          |      |
|            |          |      | 1 |          |       | 1 |          |      |
|            |          |      | 4 |          |       | 0 |          |      |
|            |          |      | 0 |          |       | 8 |          |      |
|            |          |      | ) |          |       | ) |          |      |
+------------+----------+------+---+----------+-------+---+----------+------+
| Responder  | 17%      | 6%   | 1 |          | 4%    | 1 |          | 13%  |
|            |          |      | 6 |          |       | 5 |          |      |
|            |          |      | % |          |       | % |          |      |
+------------+----------+------+---+----------+-------+---+----------+------+
| No         | 67%      | 78%  | 8 |          | 91%   | 6 |          | 68%  |
| nresponder |          |      | 0 |          |       | 9 |          |      |
|            |          |      | % |          |       | % |          |      |
+------------+----------+------+---+----------+-------+---+----------+------+
| Missing    | 16%      | 16%  | 4 |          | 4%    | 1 |          | 19%  |
| Data       |          |      | % |          |       | 7 |          |      |
|            |          |      |   |          |       | % |          |      |
+------------+----------+------+---+----------+-------+---+----------+------+

\* Three‑component seroconversion was defined as Week 52 values showing
loss of HBeAg, gain of HBeAb, and reduction of HBV DNA to below the
solution hybridization assay limit. Subjects with negative baseline
HBeAg or HBV DNA assay were excluded from the analysis.

Normalization of serum ALT levels was more frequent with lamivudine
treatment compared with placebo in Studies 1-3.

The majority of lamivudine‑treated patients showed a decrease of HBV DNA
to below the assay limit early in the course of therapy. However,
reappearance of assay‑detectable HBV DNA during lamivudine treatment was
observed in approximately one third of patients after this initial
response.

Pediatrics: The safety and efficacy of EPIVIR‑HBV were evaluated in a
double‑blind clinical trial in 286 patients ranging from 2 to 17 years
of age, who were randomized (2:1) to receive 52 weeks of lamivudine
(3 mg/kg once daily to a maximum of 100 mg once daily) or placebo. All
patients had compensated chronic hepatitis B accompanied by evidence of
hepatitis B virus replication (positive serum HBeAg and positive for
serum HBV DNA by a research branched‑chain DNA assay) and persistently
elevated serum ALT levels. The combination of loss of HBeAg and
reduction of HBV DNA to below the assay limit of the research assay,
evaluated at Week 52, was observed in 23% of lamivudine subjects and 13%
of placebo subjects. Normalization of serum ALT was achieved and
maintained to Week 52 more frequently in patients treated with
EPIVIR‑HBV compared with placebo (55% versus 13%). As in the adult
controlled trials, most lamivudine‑treated subjects had decreases in HBV
DNA below the assay limit early in treatment, but about one third of
subjects with this initial response had reappearance of assay‑detectable
HBV DNA during treatment. Adolescents (ages 13 to 17 years) showed less
evidence of treatment effect than younger children.

**CONTRAINDICATIONS:** EPIVIR‑HBV Tablets and EPIVIR‑HBV Oral Solution
are contraindicated in patients with previously demonstrated clinically
significant hypersensitivity to any of the components of the products.

**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 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. Most of these reports have described patients receiving
nucleoside analogues for treatment of HIV infection, but there have been
reports of lactic acidosis in patients receiving lamivudine for
hepatitis B. Particular caution should be exercised when administering
EPIVIR or EPIVIR‑HBV 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 or EPIVIR‑HBV 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 Between Lamivudine‑Containing Products, HIV
Testing, and Risk of Emergence of Resistant HIV:** EPIVIR‑HBV Tablets
and Oral Solution contain a lower dose of the same active ingredient
(lamivudine) as EPIVIR Tablets and Oral Solution, COMBIVIR^®^
(lamivudine/zidovudine) Tablets, and TRIZIVIR^®^ (abacavir, lamivudine,
and zidovudine) Tablets used to treat HIV infection. The formulation and
dosage of lamivudine in EPIVIR‑HBV are not appropriate for patients
dually infected with HBV and HIV. If a decision is made to administer
lamivudine to such patients, the higher dosage indicated for HIV therapy
should be used as part of an appropriate combination regimen, and the
prescribing information for EPIVIR , COMBIVIR, or TRIZIVIR as well as
for EPIVIR‑HBV should be consulted. HIV counseling and testing should be
offered to all patients before beginning EPIVIR‑HBV and periodically
during treatment because of the risk of rapid emergence of resistant HIV
and limitation of treatment options if EPIVIR‑HBV is prescribed to treat
chronic hepatitis B in a patient who has unrecognized or untreated HIV
infection or acquires HIV infection during treatment.

**Posttreatment Exacerbations of Hepatitis:** Clinical and laboratory
evidence of exacerbations of hepatitis have occurred after
discontinuation of EPIVIR‑HBV (these have been primarily detected by
serum ALT elevations, in addition to the re‑emergence of HBV DNA
commonly observed after stopping treatment; see Table 7 for more
information regarding frequency of posttreatment ALT elevations).
Although most events appear to have been self‑limited, fatalities have
been reported in some cases. The causal relationship to discontinuation
of lamivudine treatment is unknown. Patients should be closely monitored
with both clinical and laboratory follow‑up for at least several months
after stopping treatment. There is insufficient evidence to determine
whether re‑initiation of therapy alters the course of posttreatment
exacerbations of hepatitis.

**Pancreatitis:** Pancreatitis has been reported in patients receiving
lamivudine, particularly in HIV‑infected pediatric patients with prior
nucleoside exposure.

**PRECAUTIONS:**

**General:** Patients should be assessed before beginning treatment with
EPIVIR‑HBV by a physician experienced in the management of chronic
hepatitis B.

**Emergence of Resistance‑Associated HBV Mutations:** In controlled
clinical trials, YMDD‑mutant HBV were detected in patients with
on‑lamivudine re‑appearance of HBV DNA after an initial decline below
the solution hybridization assay limit (see MICROBIOLOGY: Drug
Resistance). These mutations can be detected by a research assay and
have been associated with reduced susceptibility to lamivudine *in
vitro*. Lamivudine‑treated patients (adult and pediatric) with
YMDD‑mutant HBV at 52 weeks showed diminished treatment responses in
comparison to lamivudine‑treated patients without evidence of YMDD
mutations, including lower rates of HBeAg seroconversion and HBeAg loss
(no greater than placebo recipients), more frequent return of positive
HBV DNA by solution hybridization or branched‑chain DNA assay, and more
frequent ALT elevations. In the controlled trials, when patients
developed YMDD‑mutant HBV, they had a rise in HBV DNA and ALT from their
own previous on‑treatment levels. Progression of hepatitis B, including
death, has been reported in some patients with YMDD‑mutant HBV,
including patients from the liver transplant setting and from other
clinical trials. The long‑term clinical significance of YMDD‑mutant HBV
is not known. Increased clinical and laboratory monitoring may aid in
treatment decisions if emergence of viral mutants is suspected.

**Limitations of Populations Studied:** Safety and efficacy of
EPIVIR‑HBV have not been established in patients with decompensated
liver disease or organ transplants; pediatric patients \<2 years of age;
patients dually infected with HBV and HCV, hepatitis delta, or HIV; or
other populations not included in the principal phase III controlled
studies. There are no studies in pregnant women and no data regarding
effect on vertical transmission, and appropriate infant immunizations
should be used to prevent neonatal acquisition of HBV.

**Assessing Patients During Treatment:** Patients should be monitored
regularly during treatment by a physician experienced in the management
of chronic hepatitis B. The safety and effectiveness of treatment with
EPIVIR‑HBV beyond 1 year have not been established. During treatment,
combinations of such events such as return of persistently elevated ALT,
increasing levels of HBV DNA over time after an initial decline below
assay limit, progression of clinical signs or symptoms of hepatic
disease, and/or worsening of hepatic necroinflammatory findings may be
considered as potentially reflecting loss of therapeutic response. Such
observations should be taken into consideration when determining the
advisability of continuing therapy with EPIVIR‑HBV.

The optimal duration of treatment, the durability of HBeAg
seroconversions occurring during treatment, and the relationship between
treatment response and long‑term outcomes such as hepatocellular
carcinoma or decompensated cirrhosis are not known.

**Patients with Impaired Renal Function:** Reduction of the dosage of
EPIVIR‑HBV is recommended for patients with impaired renal function (see
CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

**Information for Patients:** A Patient Package Insert (PPI) for
EPIVIR‑HBV is available for patient information.

Patients should remain under the care of a physician while taking
EPIVIR‑HBV. They should discuss any new symptoms or concurrent
medications with their physician.

Patients should be advised that EPIVIR‑HBV is not a cure for hepatitis
B, that the long‑term treatment benefits of EPIVIR‑HBV are unknown at
this time, and, in particular, that the relationship of initial
treatment response to outcomes such as hepatocellular carcinoma and
decompensated cirrhosis is unknown. Patients should be informed that
deterioration of liver disease has occurred in some cases if treatment
was discontinued, and that they should discuss any change in regimen
with their physician. Patients should be informed that emergence of
resistant hepatitis B virus and worsening of disease can occur during
treatment, and they should promptly report any new symptoms to their
physician.

Patients should be counseled on the importance of testing for HIV to
avoid inappropriate therapy and development of resistant HIV, and HIV
counseling and testing should be offered before starting EPIVIR‑HBV and
periodically during therapy. Patients should be advised that EPIVIR‑HBV
Tablets and EPIVIR‑HBV Oral Solution contain a lower dose of the same
active ingredient (lamivudine) as EPIVIR Tablets, EPIVIR Oral Solution,
COMBIVIR Tablets, and TRIZIVIR Tablets. EPIVIR‑HBV should not be taken
concurrently with EPIVIR, COMBIVIR, or TRIZIVIR (see WARNINGS). Patients
infected with both HBV and HIV who are planning to change their HIV
treatment regimen to a regimen that does not include EPIVIR, COMBIVIR,
or TRIZIVIR should discuss continued therapy for hepatitis B with their
physician.

Patients should be advised that treatment with EPIVIR‑HBV has not been
shown to reduce the risk of transmission of HBV to others through sexual
contact or blood contamination (see Pregnancy section).

**Drug Interactions:** TMP 160 mg/SMX 800 mg once daily has been shown
to increase lamivudine exposure (AUC) by 44% (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 *Pneumocystis
carinii* pneumonia. No data are available regarding the potential for
interaction 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:** Lamivudine
long‑term carcinogenicity studies in mice and rats showed no evidence of
carcinogenic potential at exposures up to 34 times (mice) and 200 times
(rats) those observed in humans at the recommended therapeutic dose for
chronic hepatitis B. 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 2000 mg/kg producing plasma levels of 60 to
70 times those in humans at the recommended dose for chronic hepatitis
B. In a study of reproductive performance, lamivudine administered to
rats at doses up to 4000 mg/kg per day, producing plasma levels 80 to
120 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
4000 mg/kg per day and 1000 mg/kg per day, respectively, producing
plasma levels up to approximately 60 times that for the adult HBV 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 exposures up to 60 times that in humans. Studies in
pregnant rats and rabbits showed that lamivudine is transferred to the
fetus through the placenta. There are no adequate and well‑controlled
studies in pregnant women. Because animal reproductive toxicity studies
are not always predictive of human response, lamivudine should be used
during pregnancy only if the potential benefits outweigh the risks.

Lamivudine has not been shown to affect the transmission of HBV from
mother to infant, and appropriate infant immunizations should be used to
prevent neonatal acquisition of HBV.

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:** A study in lactating rats showed that lamivudine
concentrations in milk were similar to those in plasma. Although it is
not known if lamivudine is excreted in human milk, there is the
potential for adverse effects from lamivudine in nursing infants.
Mothers should be instructed not to breastfeed if they are receiving
lamivudine.

**Pediatric Use:** HBV: Safety and efficacy of lamivudine for treatment
of chronic hepatitis B in children have been studied in pediatric
patients from 2 to 17 years of age in a controlled clinical trial (see
CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE, and DOSAGE AND
ADMINISTRATION).

Safety and efficacy in pediatric patients \<2 years of age have not been
established.

HIV: See the complete prescribing information for EPIVIR Tablets and
Oral Solution for additional information on pharmacokinetics of
lamivudine in HIV‑infected children.

**Geriatric Use:** Clinical studies of EPIVIR‑HBV 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:** Several serious adverse events reported with
lamivudine (lactic acidosis and severe hepatomegaly with steatosis,
posttreatment exacerbations of hepatitis B, pancreatitis, and emergence
of viral mutants associated with reduced drug susceptibility and
diminished treatment response) are also described in WARNINGS and
PRECAUTIONS.

**Clinical Trials In Chronic Hepatitis B:** Adults: Selected clinical
adverse events observed with a ≥5% frequency during therapy with
EPIVIR‑HBV compared with placebo are listed in Table 5. Frequencies of
specified laboratory abnormalities during therapy with EPIVIR‑HBV
compared with placebo are listed in Table 6.

######## Table 5: Selected Clinical Adverse Events (≥5% Frequency) in Three Placebo‑Controlled Clinical Trials in Adults During Treatment\* (Studies 1-3) 

+--------------------------+---------------------+---------------------+
| Adverse Event            | EPIVIR‑HBV          | Placebo             |
|                          |                     |                     |
|                          | (n = 332)           | (n = 200)           |
+--------------------------+---------------------+---------------------+
| **Non‑site specific**    | 24%                 | 28%                 |
|                          |                     |                     |
| Malaise and fatigue      | 7%                  | 9%                  |
|                          |                     |                     |
| Fever or chills          |                     |                     |
+--------------------------+---------------------+---------------------+
| **Ear, nose, and         | 25%                 | 21%                 |
| throat**                 |                     |                     |
|                          | 13%                 | 8%                  |
| Ear, nose, and throat    |                     |                     |
| infections               |                     |                     |
|                          |                     |                     |
| Sore throat              |                     |                     |
+--------------------------+---------------------+---------------------+
| **Gastrointestinal**     | 15%                 | 17%                 |
|                          |                     |                     |
| Nausea and vomiting      | 16%                 | 17%                 |
|                          |                     |                     |
| Abdominal discomfort and | 14%                 | 12%                 |
| pain                     |                     |                     |
|                          |                     |                     |
| Diarrhea                 |                     |                     |
+--------------------------+---------------------+---------------------+
| **Musculoskeletal**      | 14%                 | 17%                 |
|                          |                     |                     |
| Myalgia                  | 7%                  | 5%                  |
|                          |                     |                     |
| Arthralgia               |                     |                     |
+--------------------------+---------------------+---------------------+
| ######### Neurological   | 21%                 | 21%                 |
|                          |                     |                     |
| Headache                 |                     |                     |
+--------------------------+---------------------+---------------------+
| **Skin**                 | 5%                  | 5%                  |
|                          |                     |                     |
| Skin rashes              |                     |                     |
+--------------------------+---------------------+---------------------+

\*Includes patients treated for 52 to 68 weeks.

**Table 6: Frequencies of Specified Laboratory Abnormalities in Three
Placebo‑Controlled Trials in Adults During Treatment\* (Studies 1-3)**

  -------------------------- ---------------------- ----------------------
  Test                       Patients with          
                             Abnormality/Patients   
                             with Observations      

  (Abnormal Level)           EPIVIR‑HBV             Placebo

  ALT \>3 x baseline^†^      37/331 (11%)           26/199 (13%)

  Albumin \<2.5 g/dL         0/331 (0%)             2/199 (1%)

  Amylase \>3 x baseline     2/259 (\<1%)           4/167 (2%)

  Serum Lipase ≥2.5 x ULN^‡^ 19/189 (10%)           9/127 (7%)

  CPK ≥7 x baseline          31/329 (9%)            9/198 (5%)

  Neutrophils \<750/mm^3^    0/331 (0%)             1/199 (\<1%)

  Platelets \<50,000/mm^3^   10/272 (4%)            5/168 (3%)
  -------------------------- ---------------------- ----------------------

\* Includes patients treated for 52 to 68 weeks.

^†^ See Table 7 for posttreatment ALT values.

^‡^ Includes observations during and after treatment in the two
placebo‑controlled trials that collected this information.

ULN = Upper limit of normal.

In patients followed for up to 16 weeks after discontinuation of
treatment, posttreatment ALT elevations were observed more frequently in
patients who had received EPIVIR‑HBV than in patients who had received
placebo. A comparison of ALT elevations between weeks 52 and 68 in
patients who discontinued EPIVIR‑HBV at week 52 and patients in the same
studies who received placebo throughout the treatment course is shown in
Table 7.

**Table 7: Posttreatment ALT Elevations in Two Placebo‑Controlled
Studies in Adults With No‑Active‑Treatment Follow‑up (Studies 1 and 3)**

+-----------------------------------+----------------+----------------+
|                                   | Patients with  |                |
|                                   | ALT Elevation/ |                |
|                                   |                |                |
|                                   | Patients with  |                |
|                                   | Observations\* |                |
+-----------------------------------+----------------+----------------+
| Abnormal Value                    | EPIVIR‑HBV     | Placebo        |
+-----------------------------------+----------------+----------------+
| ALT ≥2 x baseline value           | 37/137 (27%)   | 22/116 (19%)   |
+-----------------------------------+----------------+----------------+
| ALT ≥3 x baseline value^†^        | 29/137 (21%)   | 9/116 (8%)     |
+-----------------------------------+----------------+----------------+
| ALT ≥2 x baseline value and       | 21/137 (15%)   | 8/116 (7%)     |
| absolute ALT \>500 IU/L           |                |                |
+-----------------------------------+----------------+----------------+
| ALT ≥2 x baseline value; and      | 1/137 (0.7%)   | 1/116 (0.9%)   |
| bilirubin \>2 x ULN and ≥2 x      |                |                |
| baseline value                    |                |                |
+-----------------------------------+----------------+----------------+

\*Each patient may be represented in one or more category.

^†^Comparable to a Grade 3 toxicity in accordance with modified WHO
criteria.

ULN = Upper limit of normal.

**Lamivudine in Patients with HIV:** In HIV‑infected patients, safety
information reflects a higher dose of lamivudine (150 mg b.i.d.) than
the dose used to treat chronic hepatitis B in HIV‑negative patients. In
clinical trials using lamivudine as part of a combination regimen for
treatment of HIV infection, several clinical adverse events occurred
more often in lamivudine‑containing treatment arms than in comparator
arms. These included nasal signs and symptoms (20% vs 11%), dizziness
(10% vs 4%), and depressive disorders (9% vs 4%). Pancreatitis was
observed in three of the 656 adult patients (\<0.5%) who received EPIVIR
in controlled clinical trials. Laboratory abnormalities reported more
often in lamivudine‑containing arms included neutropenia and elevations
of liver function tests (also more frequent in lamivudine‑containing
arms for a retrospective analysis of HIV/HBV dually infected patients in
one study), and amylase elevations. Please see the complete prescribing
information for EPIVIR Tablets and Oral Solution for more information.

**Pediatric Patients with Hepatitis B:** Most commonly observed adverse
events in the pediatric trials were similar to those in adult trials; in
addition, respiratory symptoms (cough, bronchitis, and viral respiratory
infections) were reported in both lamivudine and placebo recipients.
Posttreatment transaminase elevations were observed in some patients
followed after cessation of lamivudine.

**Pediatric Patients with HIV Infection:** In early open‑label studies
of lamivudine in children with HIV, peripheral neuropathy and
neutropenia were reported, and pancreatitis was observed in 14% to 15%
of patients.

**Observed During Clinical Practice:** The following events have been
identified during post‑approval use of lamivudine in clinical practice.
Because they are reported voluntarily from a population of unknown size,
estimates of frequency cannot be made. These events have been chosen for
inclusion due to either their seriousness, frequency of reporting,
potential causal connection to lamivudine, or a combination of these
factors. Post‑marketing experience with lamivudine at this time is
largely limited to use in HIV‑infected patients. Digestive: Stomatitis.

Endocrine and Metabolic***:*** Hyperglycemia.

General: Weakness.

Hemic and Lymphatic: Anemia, pure red cell aplasia, lymphadenopathy,
splenomegaly.

Hepatic and Pancreatic: Lactic acidosis and steatosis, pancreatitis,
posttreatment exacerbation of hepatitis (see WARNINGS and PRECAUTIONS).

Hypersensitivity: Anaphylaxis, urticaria.

Musculoskeletal: Rhabdomyolysis.

Nervous: Paresthesia, peripheral neuropathy.

Respiratory: Abnormal breath sounds/wheezing.

Skin: Alopecia, pruritus, rash.

**OVERDOSAGE:** There is no known antidote for EPIVIR‑HBV. One case of
an adult ingesting 6 g of EPIVIR was reported; there were no clinical
signs or symptoms noted and hematologic tests remained normal. It is not
known whether lamivudine can be removed by peritoneal dialysis or
hemodialysis.

**DOSAGE AND ADMINISTRATION:**

**Adults:** The recommended oral dose of EPIVIR‑HBV for treatment of
chronic hepatitis B in adults is 100 mg once daily (see paragraph below
and WARNINGS). Safety and effectiveness of treatment beyond 1 year have
not been established and the optimum duration of treatment is not known
(see PRECAUTIONS).

**The formulation and dosage of lamivudine in EPIVIR‑HBV are not
appropriate for patients dually infected with HBV and HIV. If lamivudine
is administered to such patients, the higher dosage indicated for HIV
therapy should be used as part of an appropriate combination regimen,
and the prescribing information for EPIVIR as well as EPIVIR‑HBV should
be consulted.**

**Pediatric Patients:** The recommended oral dose of EPIVIR‑HBV for
pediatric patients 2 to 17 years of age with chronic hepatitis B is
3 mg/kg once daily up to a maximum daily dose of 100 mg. Safety and
effectiveness of treatment beyond 1 year have not been established and
the optimum duration of treatment is not known (see PRECAUTIONS).

EPIVIR‑HBV is available in a 5‑mg/mL oral solution when a liquid
formulation is needed. (Please see information above regarding
distinctions between different lamivudine‑containing products.)

**Dose Adjustment:** It is recommended that doses of EPIVIR‑HBV be
adjusted in accordance with renal function (Table 8) (see CLINICAL
PHARMACOLOGY: Special Populations).

Table 8: Adjustment of Adult Dosage of EPIVIR‑HBV in Accordance With
Creatinine Clearance

+-----------------------------+----------------------------------------+
| Creatinine Clearance        | Recommended Dosage                     |
|                             |                                        |
| (mL/min)                    | of EPIVIR‑HBV                          |
+-----------------------------+----------------------------------------+
| ≥50                         | 100 mg once daily                      |
+-----------------------------+----------------------------------------+
| 30‑49                       | 100 mg first dose, then 50 mg once     |
|                             | daily                                  |
+-----------------------------+----------------------------------------+
| 15‑29                       | 100 mg first dose, then 25 mg once     |
|                             | daily                                  |
+-----------------------------+----------------------------------------+
| 5‑14                        | 35 mg first dose, then 15 mg once      |
|                             | daily                                  |
+-----------------------------+----------------------------------------+
| \<5                         | 35 mg first dose, then 10 mg once      |
|                             | daily                                  |
+-----------------------------+----------------------------------------+

Although there are insufficient data to recommend a specific dose
adjustment of EPIVIR‑HBV in pediatric patients with renal impairment, a
dose reduction should be considered.

No additional dosing of EPIVIR‑HBV is required after routine (4‑hour)
hemodialysis. Insufficient data are available to recommend a dosage of
EPIVIR‑HBV in patients undergoing peritoneal dialysis (see CLINICAL
PHARMACOLOGY: Special Populations).

**HOW SUPPLIED:** EPIVIR‑HBV Tablets, 100 mg, are butterscotch‑colored,
film‑coated, biconvex, capsule‑shaped tablets imprinted with "GX CG5" on
one side.

Bottles of 60 tablets (NDC 0173-0662-00) with child‑resistant closures.

**Store at controlled room temperature of 20° to 25°C (68° to 77°F) (see
USP) in tightly closed bottles.**

EPIVIR‑HBV Oral Solution, a clear, colorless to pale yellow,
strawberry‑banana flavored liquid, contains 5 mg of lamivudine in each
1 mL in plastic bottles of 240 mL.

Bottles of 240 mL (NDC 0173-0663-00) with child‑resistant closures. This
product does not require reconstitution.

**Store at controlled room temperature of 20° to 25°C (68° to 77°F) (see
USP) in tightly closed bottles.**

**REFERENCES:**

1.  Knodell RG, Ishak KG, Black WC, et al. Formulation and application
    of a numerical scoring system for assessing histological activity in
    asymptomatic chronic active hepatitis. *Hepatology*. 1982;1:431-435.

![](media/image2.wmf){width="1.9965277777777777in" height="0.2375in"}

Glaxo Wellcome Inc.

Research Triangle Park, NC 27709

Manufactured under agreement from

Shire PLC

Basing Stoke, UK

©Copyright 2001, Glaxo Wellcome Inc. All rights reserved.

Date of Issue RL-no.

PHARMACIST‑DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT

\_ \_ \_ \_ \_ \_ \_ \_ \_ \_ \_ \_ \_ \_ \_ \_ \_ \_ \_ \_ \_ \_ \_ \_
\_ \_ \_ \_ \_ \_ \_ \_ \_ \_ \_ \_ \_ \_ \_ \_ \_ \_ \_\_ \_ \_ \_ \_
\_ \_ \_ \_

PATIENT INFORMATION

**EPIVIR ‑HBV® (lamivudine) Tablets**

**EPIVIR‑HBV® (lamivudine) Oral Solution**

Please read this information before you start taking EPIVIR‑HBV
(pronounced EP-i-veer h-b-v). Re-read it each time you get your
prescription, in case some information has changed. **This information
does not take the place of careful discussions with your doctor when you
start this medication and at checkups. Stay under a doctor's care when
you take EPIVIR‑HBV and do not change or stop treatment without first
talking with your doctor.**

**[What is EPIVIR‑HBV?]{.underline}**

EPIVIR‑HBV is the brand name of a product that contains lamivudine, a
drug used to treat chronic hepatitis B in patients with actively growing
virus and liver inflammation. Hepatitis B can cause damage to cells in
the liver. Eventually, this can scar the liver.

The lamivudine in EPIVIR‑HBV can reduce the ability of the hepatitis B
virus to multiply and infect new liver cells. It may help to lower the
amount of hepatitis B virus in your body. EPIVIR‑HBV contains a lower
dose of lamivudine than the dose in EPIVIR^®^, COMBIVIR^®^, and
TRIZIVIR^®^.

**[Why should I consider HIV testing before starting treatment with
EPIVIR‑HBV?]{.underline}**

Your doctor or healthcare provider should offer you counseling and
testing for HIV infection (sometimes called the AIDS virus) before
treatment for hepatitis B is started with EPIVIR‑HBV, and periodically
during treatment. EPIVIR‑HBV Tablets and EPIVIR‑HBV Oral Solution
contain a lower dose of the medicine than other lamivudine‑containing
drugs, such as EPIVIR, COMBIVIR, and TRIZIVIR which are used to treat
HIV. Treatment with EPIVIR‑HBV in HIV‑infected patients may cause the
HIV virus to be less treatable with lamivudine and some other drugs.

**[If I am HIV‑positive, can I take EPIVIR‑HBV?]{.underline}**

People who have both chronic hepatitis B and HIV should not take
EPIVIR‑HBV. EPIVIR‑HBV Tablets and EPIVIR‑HBV Oral Solution contain a
lower dose of the same drug (lamivudine) as EPIVIR Tablets, EPIVIR Oral
Solution, COMBIVIR Tablets, and TRIZIVIR Tablets. If you have both
hepatitis B and HIV, make sure that your doctor or healthcare provider
is aware that you have both infections. If you are prescribed lamivudine
as part of your combination treatment for HIV, you should use only the
products and doses that are intended for treatment of HIV infection,
because the lower dose of lamivudine in EPIVIR‑HBV could cause the HIV
virus to be less responsive to treatment. If you are planning to change
your HIV treatment to a regimen that does not include EPIVIR, COMBIVIR,
or TRIZIVIR, you should first discuss this change with your doctor or
healthcare provider.

**[Does EPIVIR‑HBV cure hepatitis B infection?]{.underline}**

EPIVIR‑HBV is not a cure for hepatitis B. In studies comparing
EPIVIR‑HBV with placebo (an inactive sugar pill) for 1 year, more people
treated with EPIVIR-HBV had reductions in liver inflammation. It is not
known whether EPIVIR‑HBV will reduce the risk of getting liver cancer or
cirrhosis that may be caused by the hepatitis B virus.

In studies, some patients developed hepatitis B viruses that are
resistant to EPIVIR‑HBV. These patients generally had less benefit from
treatment with EPIVIR‑HBV. Some patients have had worsening of hepatitis
after resistant virus appears. The long‑term importance of a resistant
virus is not known.

**[What happens if I stop taking EPIVIR‑HBV?]{.underline}**

After stopping treatment with EPIVIR‑HBV, some patients have had
symptoms or blood tests showing that their hepatitis has gotten worse.
Therefore, your doctor should check your health, which may include blood
tests, for at least several months after stopping treatment with
EPIVIR‑HBV. Tell your doctor right away about any new or unusual
symptoms that you notice after stopping treatment.

**[Who should not take EPIVIR‑HBV?]{.underline}**

You should not take EPIVIR‑HBV if you have or may have HIV infection
(sometimes called the AIDS virus). EPIVIR‑HBV does not contain an
appropriate dose of lamivudine for treatment of HIV infection, and using
EPIVIR‑HBV could cause the HIV virus to become less treatable with
lamivudine and some other drugs.

You should not take EPIVIR‑HBV if you are also taking EPIVIR, COMBIVIR,
or TRIZIVIR. These drugs all contain lamivudine.

You should not take EPIVIR‑HBV if you have had an allergic reaction to
lamivudine.

EPIVIR‑HBV has not been studied in children less than 2 years old.

**[Can pregnant women and nursing mothers take
EPIVIR‑HBV?]{.underline}**

There are no studies of EPIVIR‑HBV in pregnant women. If you are
pregnant or if you become pregnant while taking EPIVIR‑HBV, notify your
doctor or healthcare provider immediately.

EPIVIR‑HBV has not been shown to prevent the spread of the hepatitis B
virus from mother to infant.

It is not known whether lamivudine is passed to the infant in breast
milk. If there is lamivudine in the breast milk, this could cause side
effects in nursing infants. Mothers should not breastfeed while taking
EPIVIR‑HBV or other forms of lamivudine.

**[How should I take EPIVIR‑HBV?]{.underline}**

Your doctor will tell you how much EPIVIR‑HBV to take. The usual dose is
one EPIVIR‑HBV Tablet orally (by mouth) once a day. Your doctor may
prescribe a lower dose if you have problems with your kidneys.
EPIVIR‑HBV may be taken with food or on an empty stomach. To help you
remember to take your EPIVIR‑HBV as prescribed, you should try to take
EPIVIR‑HBV at the same time each day. You must not skip doses or stop
treatment without first talking with your doctor or healthcare provider.
A strawberry‑banana-flavored liquid of EPIVIR‑HBV is available for
patients who need a liquid.

If you miss your regular time for taking your dose, but then remember it
during that same day, take your missed dose immediately. Then, take your
next dose at the regularly scheduled time the following day. Do **not**
take two doses of EPIVIR‑HBV at once to make up for missing a dose. If
you are not sure what to do if you miss taking your medication, check
with your doctor or healthcare provider for further instructions.

EPIVIR‑HBV can usually be taken with many other medications; however, be
sure to tell your doctor or healthcare provider about all medications
(including over-the-counter and prescription drugs) that you are taking.
EPIVIR‑HBV Tablets and EPIVIR‑HBV Oral Solution contain a lower dose of
the same drug (lamivudine) as EPIVIR Tablets, EPIVIR Oral Solution,
COMBIVIR Tablets, and TRIZIVIR Tablets; therefore, EPIVIR‑HBV should not
be taken together with EPIVIR, COMBIVIR, or TRIZIVIR.

You should talk to your doctor about any changes in your treatment.

**[What are the possible side effects of EPIVIR‑HBV?]{.underline}**

You should stay under the care of a doctor during treatment so you can
be checked for possible serious side effects. Serious side effects such
as inflammation of the pancreas can occur with EPIVIR‑HBV. Lactic acid
buildup in the body and an enlarged liver have been reported with
EPIVIR‑HBV; this is not common but can result in death.

Hepatitis B virus sometimes becomes resistant to EPIVIR‑HBV during
treatment, and some people have had tests showing that their hepatitis
was getting worse around the time the virus became resistant. Some
people also have worsening of hepatitis after stopping EPIVIR‑HBV. You
should discuss any change in treatment with your doctor.

In studies, the most common side effects seen during treatment with
EPIVIR‑HBV were ear, nose, and throat infections; malaise and fatigue
(feeling tired and run down); headache; abdominal discomfort and pain;
nausea and vomiting; diarrhea; muscle pain; sore throat; joint pain;
fever or chills; and skin rash.

This list of possible side effects is not complete. Your doctor or
pharmacist can discuss with you a more complete list of possible side
effects with EPIVIR‑HBV. Talk to your doctor right away about any side
effects or other unusual symptoms that occur when taking EPIVIR‑HBV.

**[Does EPIVIR‑HBV reduce the risk of passing hepatitis B to
others?]{.underline}**

No, EPIVIR‑HBV has not been shown to reduce the risk of passing
hepatitis B to others through sexual contact or exposure to infected
blood. EPIVIR‑HBV also has not been shown to reduce the risk of a mother
passing hepatitis B to her baby.

**[What previous or current medical problems or conditions should I
discuss with my doctor or healthcare provider?]{.underline}**

Talk to your doctor or healthcare provider if:

-   You have HIV infection.

-   You are pregnant or if you become pregnant while taking EPIVIR‑HBV.

-   You are breastfeeding.

Also talk to your doctor or healthcare provider about:

-   Problems with your blood counts.

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-   Problems with your muscles.

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-   Problems with your kidneys.

-   Problems with your pancreas.

-   Any side effects or unusual symptoms during treatment.

**[How should I store EPIVIR‑HBV Tablets and Oral
Solution?]{.underline}**

EPIVIR‑HBV Tablets and Oral Solution should be stored at room
temperature. They do not require refrigeration. **Keep EPIVIR‑HBV and
all medicines out of the reach of children.**

**[Other Information]{.underline}**

This medication is prescribed for a particular condition. Do not use it
for any other condition or give it to anybody else.

For more complete information about EPIVIR‑HBV ask your doctor or
pharmacist. You can also ask to read the longer information leaflet that
is written for health professionals.

Keep EPIVIR‑HBV and all medicines out of the reach of children. In case
of overdose, get medical help or contact a Poison Control Center right
away.

![](media/image2.wmf){width="2.0375in" height="0.24375in"}

Glaxo Wellcome Inc.

Research Triangle Park, NC 27709

Manufactured under agreement from

####### Shire PLC

Basing Stoke, UK

©Copyright 2001, Glaxo Wellcome Inc. All rights reserved.

Date of Issue RL-no.