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NDA 21-798
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B
araclude™
(entecavir)
B
araclude™ (entecavir) Tablets
Baraclude™ (entecavir) Oral Solution
Patient Information Included
WARNINGS
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported
with the use of nucleoside analogues alone or in combination with antiretrovirals.
Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued
anti-hepatitis B therapy, including entecavir. Hepatic function should be monitored closely with
both clinical and laboratory follow-up for at least several months in patients who discontinue
anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted
(see WARNINGS).
DESCRIPTION
BARACLUDE™ is the tradename for entecavir, a guanosine nucleoside analogue with selective activity
against hepatitis B virus (HBV). The chemical name for entecavir is 2-amino-1,9-dihydro-9-[(1S,3R,4S)-
4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one, monohydrate. Its molecular
formula is C
12
H
15
N
5
O
3
•H
2
O, which corresponds to a molecular weight of 295.3. Entecavir has the
following structural formula:
1S
3R
4S
H
2
O
N
HN
N
N
H
2
N
O
OH
OH
CH
2
Rx only
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Entecavir is a white to off-white powder. It is slightly soluble in water (2.4 mg/mL), and the pH of the
saturated solution in water is 7.9 at 25 ± 0.5° C.
BARACLUDE film-coated tablets are available for oral administration in strengths of 0.5 mg and 1 mg
of entecavir. BARACLUDE 0.5-mg and 1-mg film-coated tablets contain the following inactive
ingredients: lactose monohydrate, microcrystalline cellulose, crospovidone, povidone, and magnesium
stearate. The tablet coating contains titanium dioxide, hypromellose, polyethylene glycol 400,
polysorbate 80 (0.5-mg tablet only), and iron oxide red (1-mg tablet only). BARACLUDE Oral
Solution is available for oral administration as a ready-to-use solution containing 0.05 mg of entecavir
per milliliter. BARACLUDE Oral Solution contains the following inactive ingredients: maltitol,
sodium citrate, citric acid, methylparaben, propylparaben, and orange flavor.
MICROBIOLOGY
Mechanism of Action
Entecavir, a guanosine nucleoside analogue with activity against HBV polymerase, is efficiently
phosphorylated to the active triphosphate form, which has an intracellular half-life of 15 hours. By
competing with the natural substrate deoxyguanosine triphosphate, entecavir triphosphate functionally
inhibits all three activities of the HBV polymerase (reverse transcriptase, rt): (1) base priming, (2)
reverse transcription of the negative strand from the pregenomic messenger RNA, and (3) synthesis of
the positive strand of HBV DNA. Entecavir triphosphate has an inhibition constant (K
i
) for HBV DNA
polymerase of 0.0012 µM. Entecavir triphosphate is a weak inhibitor of cellular DNA polymerases α,
ß, and δ and mitochondrial DNA polymerase γ with K
i
values ranging from 18 to >160 µM.
Antiviral Activity
Entecavir inhibited HBV DNA synthesis (50% reduction, EC
50
) at a concentration of 0.004 µM in
human HepG2 cells transfected with wild-type HBV. The median EC
50
value for entecavir against
lamivudine-resistant HBV (rtL180M, rtM204V) was 0.026 µM (range 0.010-0.059 µM). In contrast,
no clinically relevant activity was noted against human immunodeficiency virus (HIV) type 1 (EC
50
value >10 µM) grown in cell culture.
Daily or weekly entecavir treatment significantly reduced viral DNA levels (4 to 8 log
10
) in two
relevant animal models, woodchucks chronically infected with woodchuck hepatitis virus (WHV) and
ducks infected with duck HBV. Long-term studies in woodchucks demonstrated that oral weekly
dosing of 0.5 mg/kg entecavir (equivalent to the 1-mg human dose) maintained viral DNA levels at
undetectable levels (<200 copies/mL by PCR) for up to 3 years in 3 of 5 woodchucks. No entecavir
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resistance changes were detected in the HBV polymerase in any of the treated animals for up to 3 years
of treatment.
The coadministration of HIV nucleoside reverse transcriptase inhibitors (NRTIs) with BARACLUDE
is unlikely to reduce the antiviral efficacy of BARACLUDE against HBV or of any of these agents
against HIV. In HBV combination assays in vitro, abacavir, didanosine, lamivudine, stavudine,
tenofovir, or zidovudine were not antagonistic to the anti-HBV activity of entecavir over a wide range
of concentrations. In HIV antiviral assays, entecavir was not antagonistic to the in vitro anti-HIV
activity of these six NRTIs at >4 times the C
max
of entecavir.
Resistance
In Vitro
In cell-based assays, 8- to 30-fold reductions in entecavir phenotypic susceptibility were observed for
lamivudine-resistant strains. Further reductions (>70-fold) in entecavir phenotypic susceptibility
required the presence of primary lamivudine resistance amino acid substitutions (rtL180M and/or
rtM204V/I) along with additional substitutions at residues rtT184, rtS202, or rtM250, or a combination
of these substitutions with or without an rtI169 substitution in the HBV polymerase.
Clinical Studies
• Nucleoside-naive patients: Eighty-one percent of HBV chronically infected nucleoside-naive
patients receiving entecavir 0.5 mg once daily achieved a reduction in viral load to <300 copies/mL
at 48 weeks. Genotypic analysis of serum HBV DNA from nucleoside-naive HBeAg-positive
(Study AI463022; n=219) or HBeAg-negative (Study AI463027; n=211) patients detected no
genotypic changes in the HBV polymerase associated with phenotypic resistance to entecavir at
Week 48. No genotypic or phenotypic evidence of entecavir resistance was detected in the 2
patients who experienced a confirmed virologic rebound (≥1 log increase from nadir) in Study
AI463022.
Lamivudine-refractory patients: Twenty-two percent of lamivudine-refractory patients with
chronic HBV infection achieved HBV DNA levels <300 copies/mL at Week 48 on entecavir 1 mg
once daily. Genotypic analysis of clinical samples from those patients with detectable viral DNA
identified 7% (13/189) with evidence of emerging entecavir resistance-associated substitutions at
rtI169, rtT184, rtS202, and/or rtM250 by Week 48 when pre-existing lamivudine resistance
mutations rtL180M and/or rtM204V/I were present. Of the 13 patients with genotypic resistance, 3
experienced virologic rebound (≥1 log increase from nadir) by Week 48, with the majority of these
13 patients experiencing virologic rebound beyond Week 48.
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Cross-resistance
Cross-resistance has been observed among HBV nucleoside analogues. In cell-based assays, entecavir
had 8- to 30-fold less inhibition of replication of HBV containing lamivudine resistance mutations
rtL180M and/or rtM204V/I than of wild-type virus. Recombinant HBV genomes encoding adefovir
resistance-associated substitutions at either rtN236T or rtA181V remained susceptible to entecavir.
HBV isolates from lamivudine-refractory patients failing entecavir therapy were susceptible in vitro to
adefovir but retained resistance to lamivudine.
CLINICAL PHARMACOLOGY
Pharmacokinetics
The single- and multiple-dose pharmacokinetics of entecavir were evaluated in healthy subjects and
patients with chronic hepatitis B infection.
Absorption
Following oral administration in healthy subjects, entecavir peak plasma concentrations occurred
between 0.5 and 1.5 hours. Following multiple daily doses ranging from 0.1 to 1.0 mg, C
max
and area
under the concentration-time curve (AUC) at steady state increased in proportion to dose. Steady state
was achieved after 6 to 10 days of once-daily administration with approximately 2-fold accumulation.
For a 0.5-mg oral dose, C
max
at steady state was 4.2 ng/mL and trough plasma concentration (C
trough
)
was 0.3 ng/mL. For a 1-mg oral dose, C
max
was 8.2 ng/mL and C
trough
was 0.5 ng/mL.
In healthy subjects, the bioavailability of the tablet was 100% relative to the oral solution. The oral
solution and tablet may be used interchangeably.
Effects of food on oral absorption: Oral administration of 0.5 mg of entecavir with a standard high-
fat meal (945 kcal, 54.6 g fat) or a light meal (379 kcal, 8.2 g fat) resulted in a delay in absorption (1.0-
1.5 hour fed vs. 0.75 hours fasted), a decrease in C
max
of 44%-46%, and a decrease in AUC of 18%-
20%. Therefore, BARACLUDE should be administered on an empty stomach (at least 2 hours after a
meal and 2 hours before the next meal).
Distribution
Based on the pharmacokinetic profile of entecavir after oral dosing, the estimated apparent volume of
distribution is in excess of total body water, suggesting that entecavir is extensively distributed into
tissues.
Binding of entecavir to human serum proteins in vitro was approximately 13%.
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Metabolism and Elimination
Following administration of
14
C-entecavir in humans and rats, no oxidative or acetylated metabolites
were observed. Minor amounts of phase II metabolites (glucuronide and sulfate conjugates) were
observed. Entecavir is not a substrate, inhibitor, or inducer of the cytochrome P450 (CYP450) enzyme
system (see CLINICAL PHARMACOLOGY: Drug Interactions).
After reaching peak concentration, entecavir plasma concentrations decreased in a bi-exponential
manner with a terminal elimination half-life of approximately 128-149 hours. The observed drug
accumulation index is approximately 2-fold with once-daily dosing, suggesting an effective
accumulation half-life of approximately 24 hours.
Entecavir is predominantly eliminated by the kidney with urinary recovery of unchanged drug at
steady state ranging from 62% to 73% of the administered dose. Renal clearance is independent of
dose and ranges from 360 to 471 mL/min suggesting that entecavir undergoes both glomerular
filtration and net tubular secretion (see PRECAUTIONS: Drug Interactions).
Special Populations
Gender: There are no significant gender differences in entecavir pharmacokinetics.
Race: There are no significant racial differences in entecavir pharmacokinetics.
Elderly: The effect of age on the pharmacokinetics of entecavir was evaluated following
administration of a single 1-mg oral dose in healthy young and elderly volunteers. Entecavir AUC was
29.3% greater in elderly subjects compared to young subjects. The disparity in exposure between
elderly and young subjects was most likely attributable to differences in renal function. Dosage
adjustment of BARACLUDE should be based on the renal function of the patient, rather than age (see
DOSAGE AND ADMINISTRATION: Renal Impairment).
Pediatrics: Pharmacokinetic studies have not been conducted in children.
Renal impairment: The pharmacokinetics of entecavir following a single 1-mg dose were studied in
patients (without chronic hepatitis B infection) with selected degrees of renal impairment, including
patients whose renal impairment was managed by hemodialysis or continuous ambulatory peritoneal
dialysis (CAPD). Results are shown in Table 1.
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Drug Interactions (see also PRECAUTIONS: Drug Interactions)
The metabolism of entecavir was evaluated in in vitro and in vivo studies. Entecavir is not a substrate,
inhibitor, or inducer of the cytochrome P450 (CYP450) enzyme system. At concentrations up to
approximately 10,000-fold higher than those obtained in humans, entecavir inhibited none of the major
human CYP450 enzymes 1A2, 2C9, 2C19, 2D6, 3A4, 2B6, and 2E1. At concentrations up to
approximately 340-fold higher than those observed in humans, entecavir did not induce the human
CYP450 enzymes 1A2, 2C9, 2C19, 3A4, 3A5, and 2B6. (See CLINICAL PHARMACOLOGY:
Metabolism and Elimination.) The pharmacokinetics of entecavir are unlikely to be affected by
coadministration with agents that are either metabolized by, inhibit, or induce the CYP450 system.
Likewise, the pharmacokinetics of known CYP substrates are unlikely to be affected by
coadministration of entecavir.
The steady-state pharmacokinetics of entecavir and coadministered drug were not altered in interaction
studies of entecavir with lamivudine, adefovir dipivoxil, and tenofovir disoproxil fumarate.
INDICATIONS AND USAGE
BARACLUDE (entecavir) is indicated for the treatment of chronic hepatitis B virus infection in adults
with evidence of active viral replication and either evidence of persistent elevations in serum
aminotransferases (ALT or AST) or histologically active disease.
This indication is based on histologic, virologic, biochemical, and serologic responses after one year of
treatment in nucleoside-treatment-naive and lamivudine-resistant adult patients with HBeAg-positive
or HBeAg-negative chronic HBV infection with compensated liver disease and on more limited data in
adult patients with HIV/HBV co-infection who have received prior lamivudine therapy.
Description of Clinical Studies
The safety and efficacy of BARACLUDE were evaluated in three Phase 3 active-controlled trials.
These studies included 1633 patients 16 years of age or older with chronic hepatitis B infection (serum
HBsAg-positive for at least 6 months) accompanied by evidence of viral replication (detectable serum
HBV DNA, as measured by the bDNA hybridization or PCR assay). Patients had persistently elevated
ALT levels ≥1.3 times the upper limit of normal (ULN) and
chronic inflammation on liver biopsy
compatible with a diagnosis of chronic viral hepatitis. The safety and efficacy of BARACLUDE were
also evaluated in a study of 68 patients co-infected with HBV and HIV.
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Nucleoside-Naive Patients With Compensated Liver Disease
HBeAg-positive: Study AI463022 was a multinational, randomized, double-blind study of
BARACLUDE 0.5 mg once daily versus lamivudine 100 mg once daily for 52 weeks in 709 (of 715
randomized) nucleoside-naive patients with chronic hepatitis B infection and detectable HBeAg. The
mean age of patients was 35 years, 75% were male, 57% were Asian, 40% were Caucasian, and 13%
had previously received interferon-α. At baseline, patients had a mean Knodell Necroinflammatory
Score of 7.8, mean serum HBV DNA as measured by Roche COBAS Amplicor
®
PCR assay was 9.66
log
10
copies/mL, and mean serum ALT was 143 U/L. Paired, adequate liver biopsy samples were
available for 89% of patients.
HBeAg-negative (anti-HBe positive/HBV DNA positive): Study AI463027 was a multinational,
randomized, double-blind study of BARACLUDE 0.5 mg once daily versus lamivudine 100 mg once
daily for 52 weeks in 638 (of 648 randomized) nucleoside-naive patients with HBeAg-negative
(HBeAb-positive) chronic hepatitis B infection. The mean age of patients was 44 years, 76% were
male, 39% were Asian, 58% were Caucasian, and 13% had previously received interferon-α. At
baseline, patients had a mean Knodell Necroinflammatory Score of 7.8, mean serum HBV DNA as
measured by Roche COBAS Amplicor PCR assay was 7.58 log
10
copies/mL, and mean serum ALT
level was 142 U/L. Paired, adequate liver biopsy samples were available for 88% of patients.
In Studies AI463022 and AI463027, BARACLUDE was superior to lamivudine on the primary
efficacy endpoint of Histologic Improvement, defined as ≥2-point reduction in Knodell
Necroinflammatory Score with no worsening in Knodell Fibrosis Score at Week 48, and on the
secondary efficacy measures of reduction in viral load and ALT normalization. Histologic
Improvement and change in Ishak Fibrosis Score are shown in Table 2. Selected virologic,
biochemical, and serologic outcome measures are shown in Table 3
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Table 2: Histologic Improvement and Change in Ishak Fibrosis Score at Week 48,
Nucleoside-Naive Patients in Studies AI463022 and AI463027
Study AI463022 (HBeAg-Positive) Study AI463027 (HBeAg-Negative)
BARACLUDE
0.5 mg
Lamivudine
100 mg
BARACLUDE
0.5 mg
Lamivudine
100 mg
n=314
a
n=314
a
n=296
a
n=287
a
Histologic Improvement (Knodell Scores)
Improvement
b
72%* 62% 70%* 61%
No improvement 21% 24% 19% 26%
Ishak Fibrosis Score
Improvement
c
39% 35% 36% 38%
No change 46% 40% 41% 34%
Worsening
c
8% 10% 12% 15%
Missing Week
48 biopsy
7% 14% 10% 13%
a
Patients with evaluable baseline histology (baseline Knodell Necroinflammatory Score ≥2).
b
≥2-point decrease in Knodell Necroinflammatory Score from baseline with no worsening of the Knodell Fibrosis
Score.
c
For Ishak Fibrosis Score, improvement =
≥1-point decrease from baseline and worsening = ≥1-point increase from
baseline.
* p<0.05
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Table 3: Selected Virologic, Biochemical, and Serologic Endpoints at Week 48,
Nucleoside-Naive Patients in Studies AI463022 and AI463027
Study AI463022 (HBeAg-
Positive)
Study AI463027 (HBeAg-Negative)
BARACLUDE
0.5 mg
Lamivudine
100 mg
BARACLUDE
0.5 mg
Lamivudine
100 mg
n=354 n=355 n=325 n=313
HBV DNA
a
Proportion undetectable
(<300 copies/mL)
67%
*
36%
90%* 72%
Mean change from
baseline (log
10
copies/mL)
-6.86
*
-5.39
-5.04
*
-4.53
ALT normalization (≤1
X ULN)
68%* 60% 78%* 71%
HBeAg seroconversion 21% 18% N/A N/A
a
Roche COBAS Amplicor PCR assay (LLOQ = 300 copies/mL).
* p<0.05
Histologic Improvement was independent of baseline levels of HBV DNA or ALT.
Lamivudine-Refractory Patients
Study AI463026 was a multinational, randomized, double-blind study of BARACLUDE in 286 (of
293 randomized) patients with lamivudine-refractory chronic hepatitis B infection. Patients receiving
lamivudine at study entry either switched to BARACLUDE 1 mg once daily (with neither a washout
nor an overlap period) or continued on lamivudine 100 mg for 52 weeks. The mean age of patients was
39 years, 76% were male, 37% were Asian, 62% were Caucasian, and 52% had previously received
interferon-α. The mean duration of prior lamivudine therapy was 2.7 years, and 85% had lamivudine
resistance mutations at baseline by an investigational line probe assay. At baseline, patients had a mean
Knodell Necroinflammatory Score of 6.5, mean serum HBV DNA as measured by Roche COBAS
Amplicor PCR assay was 9.36 log
10
copies/mL, and mean serum ALT level was 128 U/L. Paired,
adequate liver biopsy samples were available for 87% of patients.
BARACLUDE was superior to lamivudine on the coprimary endpoint of Histologic Improvement
(using the Knodell Score at Week 48). These results and change in Ishak Fibrosis Score are shown in
Table 4. Table 5 shows selected virologic, biochemical, and serologic endpoints.
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Table 4: Histologic Improvement and Change in Ishak Fibrosis Score at Week
48, Lamivudine-Refractory Patients in Study AI463026
BARACLUDE
1 mg
Lamivudine
100 mg
n=124
a
n=116
a
Histologic Improvement (Knodell Scores)
Improvement
b
55%
*
28%
No improvement 34% 57%
Ishak Fibrosis Score
Improvement
c
34%* 16%
No change 44% 42%
Worsening
c
11% 26%
Missing Week 48 biopsy 11% 16%
a
Patients with evaluable baseline histology (baseline Knodell Necroinflammatory Score ≥2).
b
≥2-point decrease in Knodell Necroinflammatory Score from baseline with no worsening of the Knodell Fibrosis Score.
c
For Ishak Fibrosis Score, improvement =
≥1-point decrease from baseline and worsening = ≥1-point increase from
baseline.
* p<0.01
Table 5: Selected Virologic, Biochemical, and Serologic Endpoints at Week 48,
Lamivudine-Refractory Patients in Study AI463026
BARACLUDE
1 mg
Lamivudine 100 mg
n=141 n=145
HBV DNA
a
Proportion undetectable
(<300 copies/mL)
19%
*
1%
Mean change from baseline (log
10
copies/mL)
-5.11
*
-0.48
ALT normalization (≤1 X ULN)
61%
*
15%
HBeAg seroconversion 8% 3%
a
Roche COBAS Amplicor PCR assay (LLOQ = 300 copies/mL).
* p<0.0001
Histologic Improvement was independent of baseline levels of HBV DNA or ALT.
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Post-Treatment Follow-up
The optimal duration of therapy with BARACLUDE is unknown. According to protocol-mandated
criteria in the Phase 3 clinical trials, patients discontinued BARACLUDE or lamivudine treatment after
52 weeks according to a definition of response based on HBV virologic suppression (<0.7 MEq/mL by
bDNA assay) and loss of HBeAg (in HBeAg-positive patients) or ALT normalization (<1.25 X ULN,
in HBeAg-negative patients) at Week 48. For the 21% of nucleoside-naive, HBeAg-positive
BARACLUDE-treated patients who met response criteria, response was sustained throughout the 24-
week post-treatment follow-up period in 82%. For the 85% of nucleoside-naive, HBeAg-negative
BARACLUDE-treated patients who met response criteria, response was sustained throughout the 24-
week post-treatment follow-up period in 48%. Few lamivudine-refractory patients met the response
criteria and were eligible to discontinue treatment. These protocol-specified patient management
guidelines are not intended as guidance for clinical practice.
Special Populations
Study AI463038 was a randomized, double-blind, placebo-controlled study of BARACLUDE versus
placebo in 68 patients co-infected with HIV and HBV who experienced recurrence of HBV viremia
while receiving a lamivudine-containing highly active antiretroviral (HAART) regimen. Patients
continued their lamivudine-containing HAART regimen (lamivudine dose 300 mg/day) and were
assigned to add either BARACLUDE 1 mg once daily (51 patients) or placebo (17 patients) for
24 weeks followed by an open-label phase for an additional 24 weeks where all patients received
BARACLUDE. At baseline, patients had a mean serum HBV DNA level by PCR of 9.13
log
10
copies/mL. Ninety-nine percent of patients were HBeAg-positive at baseline, with a mean baseline
ALT level of 71.5 U/L. Median HIV RNA level remained stable at approximately 2 log
10
copies/mL
through 24 weeks of blinded therapy. Virologic and biochemical endpoints at Week 24 are shown in
Table 6. There are no data in patients with HIV/HBV co-infection who have not received prior
lamivudine therapy.
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Table 6: Virologic and Biochemical Endpoints at Week 24, Study AI463038
BARACLUDE 1 mg
a
n=51
Placebo
a
n=17
HBV DNA
b
Proportion undetectable
(<300 copies/mL) 6% 0
Mean change from baseline (log
10
copies/mL)
-3.65
*
+0.11
ALT normalization (≤1 X ULN)
34% 8%
a
All patients also received a lamivudine-containing HAART regimen.
b
Roche COBAS Amplicor PCR assay (LLOQ = 300 copies/mL).
*
p<0.0001
CONTRAINDICATIONS
BARACLUDE is contraindicated in patients with previously demonstrated hypersensitivity to
entecavir or any component of the product.
WARNINGS
Exacerbations of Hepatitis After Discontinuation of Treatment
Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-
hepatitis B therapy, including entecavir. Hepatic function should be monitored closely with both
clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis
B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted (see ADVERSE
REACTIONS: Exacerbations of Hepatitis After Discontinuation of Treatment).
PRECAUTIONS
General
Renal Impairment
Dosage adjustment of BARACLUDE is recommended for patients with a creatinine clearance
<50 mL/min, including patients on hemodialysis or CAPD (see DOSAGE AND
ADMINISTRATION: Renal Impairment).
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Liver Transplant Recipients
The safety and efficacy of BARACLUDE in liver transplant recipients are unknown. If
BARACLUDE treatment is determined to be necessary for a liver transplant recipient who has
received or is receiving an immunosuppressant that may affect renal function, such as cyclosporine or
tracrolimus, renal function must be carefully monitored both before and during treatment with
BARACLUDE (see CLINICAL PHARMACOLOGY: Special Populations and DOSAGE AND
ADMINISTRATION: Renal Impairment).
Information for Patients
A patient package insert (PPI) for BARACLUDE is available for patient information.
Patients should remain under the care of a physician while taking BARACLUDE. They should discuss
any new symptoms or concurrent medications with their physician.
Patients should be advised to take BARACLUDE on an empty stomach (at least 2 hours after a meal
and 2 hours before the next meal).
Patients should be informed that deterioration of liver disease may occur in some cases if treatment is
discontinued, and that they should discuss any change in regimen with their physician.
Patients should be advised that treatment with BARACLUDE has not been shown to reduce the risk of
transmission of HBV to others through sexual contact or blood contamination (see PRECAUTIONS:
Labor and Delivery).
Drug Interactions
Since entecavir is primarily eliminated by the kidneys (see CLINICAL PHARMACOLOGY:
Metabolism and Elimination), coadministration of BARACLUDE with drugs that reduce renal
function or compete for active tubular secretion may increase serum concentrations of either entecavir
or the coadministered drug. Coadministration of entecavir with lamivudine, adefovir dipivoxil, or
tenofovir disoproxil fumarate did not result in significant drug interactions. The effects of
coadministration of BARACLUDE with other drugs that are renally eliminated or are known to affect
renal function have not been evaluated, and patients should be monitored closely for adverse events
when BARACLUDE is coadministered with such drugs.
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Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term oral carcinogenicity studies of entecavir in mice and rats were carried out at exposures up to
approximately 42 times (mice) and 35 times (rats) those observed in humans at the highest
recommended dose of 1 mg/day. In mouse and rat studies, entecavir was positive for carcinogenic
findings.
In mice, lung adenomas were increased in males and females at exposures 3 and 40 times those in
humans. Lung carcinomas in both male and female mice were increased at exposures 40 times those in
humans. Combined lung adenomas and carcinomas were increased in male mice at exposures 3 times
and in female mice at exposures 40 times those in humans. Tumor development was preceded by
pneumocyte proliferation in the lung, which was not observed in rats, dogs, or monkeys administered
entecavir, supporting the conclusion that lung tumors in mice may be a species-specific event.
Hepatocellular carcinomas were increased in males and combined liver adenomas and carcinomas
were also increased at exposures 42 times those in humans. Vascular tumors in female mice
(hemangiomas of ovaries and uterus and hemangiosarcomas of spleen) were increased at exposures 40
times those in humans. In rats, hepatocellular adenomas were increased in females at exposures 24
times those in humans; combined adenomas and carcinomas were also increased in females at
exposures 24 times those in humans. Brain gliomas were induced in both males and females at
exposures 35 and 24 times those in humans. Skin fibromas were induced in females at exposures 4
times those in humans.
It is not known how predictive the results of rodent carcinogenicity studies may be for humans.
Entecavir was clastogenic to human lymphocyte cultures. Entecavir was not mutagenic in the Ames
bacterial reverse mutation assay using S. typhimurium and E. coli strains in the presence or absence of
metabolic activation, a mammalian-cell gene mutation assay, and a transformation assay with Syrian
hamster embryo cells. Entecavir was also negative in an oral micronucleus study and an oral DNA
repair study in rats. In reproductive toxicology studies, in which animals were administered entecavir
at up to 30 mg/kg for up to four weeks, no evidence of impaired fertility was seen in male or female
rats at systemic exposures >90 times those achieved in humans at the highest recommended dose of
1 mg/day. In rodent and dog toxicology studies, seminiferous tubular degeneration was observed at
exposures ≥35 times those achieved in humans. No testicular changes were evident in monkeys.
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Pregnancy
Pregnancy Category C
Reproduction studies have been performed in rats and rabbits at orally administered doses of 200 and
16 mg/kg/day and showed no embryotoxicity or maternal toxicity in rat and rabbit at doses producing
systemic exposures approximately 28 and 212 times those achieved at the highest recommended dose
of 1 mg/day in humans. In rats, maternal toxicity, embryo-fetal toxicity (resorptions), lower fetal body
weights, tail and vertebral malformations, reduced ossification (vertebrae, sternebrae, and phalanges),
and extra lumbar vertebrae and ribs were observed at exposures 3100 times those in humans. In
rabbits, embryo-fetal toxicity (resorptions), reduced ossification (hyoid), and an increased incidence of
13th rib were observed at exposures 883 times those in humans. In a peri-post-natal study, no adverse
effects on offspring were seen with entecavir administered orally to rats at exposures >94 times those
in humans. There are no adequate and well-controlled studies in pregnant women. Because animal
reproduction studies are not always predictive of human response, BARACLUDE should be used
during pregnancy only if clearly needed and after careful consideration of the risks and benefits.
Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to entecavir, a
pregnancy registry has been established. Healthcare providers are encouraged to register patients by
calling 1-800-258-4263.
Labor and Delivery
There are no studies in pregnant women and no data on the effect of BARACLUDE on transmission of
HBV from mother to infant. Therefore, appropriate interventions should be used to prevent neonatal
acquisition of HBV.
Nursing Mothers
Entecavir is excreted in the milk of rats. It is not known whether this drug is excreted in human milk.
Mothers should be instructed not to breast-feed if they are taking BARACLUDE.
Pediatric Use
Safety and effectiveness of entecavir in pediatric patients below the age of 16 years have not been
established.
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Geriatric Use
Clinical studies of BARACLUDE did not include sufficient numbers of subjects aged 65 years and
over to determine whether they respond differently from younger subjects. Entecavir is substantially
excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with
impaired renal function. Because elderly patients are more likely to have decreased renal function, care
should be taken in dose selection, and it may be useful to monitor renal function (see DOSAGE AND
ADMINISTRATION: Renal Impairment).
Use in Racial/Ethnic Groups
Clinical studies of BARACLUDE did not include sufficient numbers of subjects from some
racial/ethnic minorities (black/African American, Hispanic) to determine whether they respond
differently to treatment with the drug. There are no significant racial differences in entecavir
pharmacokinetics.
ADVERSE REACTIONS
Assessment of adverse reactions is based on four studies (AI463014, AI463022, AI463026, and
AI463027) in which 1720 patients with chronic hepatitis B infection received double-blind treatment
with BARACLUDE 0.5 mg/day (n=679), BARACLUDE 1 mg/day (n=183), or lamivudine (n=858)
for up to 107 weeks. Median duration of therapy was 54 weeks for BARACLUDE-treated patients and
53 weeks for lamivudine-treated patients in Studies AI463022 and AI463027 and 69 weeks for
BARACLUDE-treated patients and 52 weeks for lamivudine-treated patients in Studies AI463026 and
AI463014. The safety profiles of BARACLUDE and lamivudine were comparable in these studies.
The safety profile of BARACLUDE 1 mg (n=51) in HIV/HBV co-infected patients enrolled in Study
AI463038 was similar to that of placebo (n=17) through 24 weeks of blinded treatment and similar to
that seen in non-HIV infected patients.
The most common adverse events of any severity with at least a possible relation to study drug for
BARACLUDE-treated patients were headache, fatigue, dizziness, and nausea. The most common
adverse events among lamivudine-treated patients were headache, fatigue, and dizziness. One percent
of BARACLUDE-treated patients in these four studies compared with 4% of lamivudine-treated
patients discontinued for adverse events or abnormal laboratory test results.
Also see WARNINGS
and PRECAUTIONS.
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Clinical Adverse Events
Selected clinical adverse events of moderate-severe intensity and considered at least possibly related to
treatment occurring during therapy in four clinical studies in which BARACLUDE was compared with
lamivudine are presented in Table 7.
Table 7: Selected Clinical Adverse Events
a
of Moderate-Severe Intensity
(Grades 2-4) Reported in Four Entecavir Clinical Trials
Nucleoside-Naive
b
Lamivudine-Refractory
c
Body System/
Adverse Event
BARACLUDE
0.5 mg
n=679
Lamivudine
100 mg
n=668
BARACLUDE
1 mg
n=183
Lamivudine
100 mg
n=190
Gastrointestinal
Diarrhea <1% 0 1% 0
Dyspepsia <1% <1% 1% 0
Nausea <1% <1% <1% 2%
Vomiting <1% <1% <1% 0
General
Fatigue 1% 1% 3% 3%
Nervous System
Headache 2% 2% 4% 1%
Dizziness <1% <1% 0 1%
Somnolence <1% <1% 0 0
Psychiatric
Insomnia <1% <1% 0 <1%
a
Includes events of possible, probable, certain, or unknown relationship to treatment regimen.
b
Studies AI463022 and AI463027.
c
Includes Study AI463026 and the BARACLUDE 1-mg and lamivudine treatment arms of Study AI463014, a Phase 2
multinational, randomized, double-blind study of three doses of BARACLUDE (0.1, 0.5, and 1 mg) once daily versus
continued lamivudine 100 mg once daily for up to 52 weeks in patients who experienced recurrent viremia on lamivudine
therapy.
Laboratory Abnormalities
Frequencies of selected treatment-emergent laboratory abnormalities reported during therapy in four
clinical trials of BARACLUDE compared with lamivudine are listed in Table 8.
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Table 8: Selected Treatment-Emergent
a
Laboratory Abnormalities Reported
in Four Entecavir Clinical Trials
Nucleoside-Naive
b
Lamivudine-Refractory
c
Test
BARACLUDE
0.5 mg
n=679
Lamivudine
100 mg
n=668
BARACLUDE
1 mg
n=183
Lamivudine
100 mg
n=190
ALT >10 X ULN and >2 X
baseline
2% 4% 2% 11%
ALT >5.0 X ULN
11% 16% 12% 24%
AST >5.0 X ULN
5% 8% 5% 17%
Albumin <2.5 g/dL
<1% <1% 0 2%
Total bilirubin >2.5 g/dL
2% 2% 3% 2%
Amylase >2.0 X ULN
2% 2% 3% 3%
Lipase >2.0 X ULN
7% 6% 8% 7%
Creatinine >3.0 X ULN
0 0 0 0
Confirmed creatinine increase
≥0.5 mg/dL
1% 1% 2% 1%
Hyperglycemia, fasting
>250 mg/dL
2% 1% 2% 1%
Glycosuria
d
4% 3% 4% 6%
Hematuria
d
9% 10% 9% 6%
Platelets <50,000/mm
3
<1% <1% <1% <1%
a
On-treatment value worsened from baseline to Grade 3 or Grade 4 for all parameters except albumin (any on-treatment value <2.5
g/dL), confirmed creatinine increase
≥0.5 mg/dL, and ALT >10 X ULN >2 X baseline.
b
Studies AI463022 and AI463027.
c
Includes Study AI463026 and the BARACLUDE 1-mg and lamivudine treatment arms of Study AI463014, a Phase 2 multinational,
randomized, double-blind study of three doses of BARACLUDE (0.1, 0.5, and 1 mg) once daily versus continued lamivudine 100 mg
once daily for up to 52 weeks in patients who experienced recurrent viremia on lamivudine therapy.
d
Grade 3 = 3+, large (also 500, 1000, >1000 and ≥1000 for glycosuria); grade 4 = 4+, 5+, marked, severe (also ++++, 4+:MANY for
hematuria).
Among BARACLUDE-treated patients in these studies, on-treatment ALT elevations >10 X ULN and
>2 X baseline generally resolved with continued treatment. A majority of these exacerbations were
associated with a ≥2 log
10
/mL reduction in viral load that preceded or coincided with the ALT
elevation. Periodic monitoring of hepatic function is recommended during treatment.
Exacerbations of Hepatitis After Discontinuation of Treatment (see also
WARNINGS)
In the Phase 3 studies, a subset of patients was allowed to discontinue treatment at 52 weeks if they
achieved a protocol-defined response to therapy. An exacerbation of hepatitis or ALT flare was
defined as ALT >10 X ULN and >2 X the patient’s baseline level. As demonstrated in Table 9, a
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proportion of patients in the nucleoside-naive studies experienced post-treatment ALT flares. The
number of lamivudine-refractory patients eligible to discontinue treatment was small, and rates of post-
treatment flares in this population could not be determined. If BARACLUDE is discontinued without
regard to treatment response, the rate of post-treatment flares could be higher.
Table 9: Exacerbations of Hepatitis During Off-Treatment Follow-up,
Nucleoside-Naive Patients in Studies AI463022 and AI463027
Patients with ALT Elevations >10 X ULN and >2 X Baseline
BARACLUDE
Lamivudine
Nucleoside-naive 25/431 (6%) 38/392 (10%)
HBeAg-positive
a
2/134 (1%) 9/129 (7%)
HBeAg-negative
b
23/297 (8%) 29/263 (11%)
a
Median time to off-treatment exacerbation was 23 weeks for BARACLUDE-treated patients and 12 weeks for
lamivudine-treated patients.
b
Median time to off-treatment exacerbation was 24 weeks for BARACLUDE-treated patients and 9 weeks for
lamivudine-treated patients
.
OVERDOSAGE
There is no experience of entecavir overdosage reported in patients. Healthy subjects who received
single entecavir doses up to 40 mg or multiple doses up to 20 mg/day for up to 14 days had no increase
in or
unexpected adverse events. If overdose occurs, the patient must be monitored for evidence of
toxicity, and standard supportive treatment applied as necessary.
Following a single 1-mg dose of entecavir, a 4-hour hemodialysis session removed approximately 13%
of the entecavir dose.
DOSAGE AND ADMINISTRATION
Recommended Dosage
The recommended dose of BARACLUDE for chronic hepatitis B virus infection in nucleoside-
treatment-naive adults and adolescents 16 years of age and older is 0.5 mg once daily.
The recommended dose of BARACLUDE in adults and adolescents (≥16 years of age) with a history
of hepatitis B viremia while receiving lamivudine or known lamivudine resistance mutations is 1 mg
once daily.
BARACLUDE should be administered on an empty stomach (at least 2 hours after a meal and 2 hours
before the next meal).
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BARACLUDE Oral Solution contains 0.05 mg of entecavir per milliliter. Therefore, 10 mL of the oral
solution provides a 0.5-mg dose and 20 mL provides a 1-mg dose of entecavir.
Renal Impairment
In patients with renal impairment, the apparent oral clearance of entecavir decreased as creatinine
clearance decreased (see CLINICAL PHARMACOLOGY: Special Populations). Dosage
adjustment is recommended for patients with creatinine clearance <50 mL/min, including patients on
hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), as shown in Table 10.
Table 10: Recommended Dosage of BARACLUDE in Patients with Renal
Impairment
Creatinine Clearance (mL/min) Usual Dose (0.5 mg) Lamivudine-Refractory
(1 mg)
≥50
0.5 mg once daily 1 mg once daily
30 to <50 0.25 mg once daily 0.5 mg once daily
10 to <30 0.15 mg once daily 0.3 mg once daily
<10
Hemodialysis* or CAPD
0.05 mg once daily 0.1 mg once daily
*Administer after hemodialysis.
Hepatic Impairment
No dosage adjustment is necessary for patients with hepatic impairment.
Duration of Therapy
The optimal duration of treatment with BARACLUDE for patients with chronic hepatitis B infection
and the relationship between treatment and long-term outcomes such as cirrhosis and hepatocellular
carcinoma are unknown.
HOW SUPPLIED
BARACLUDE (entecavir) Tablets and Oral Solution are available in the following strengths and
configurations of plastic bottles with child-resistant closures:
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Product Strength and
Dosage Form
Description Quantity NDC Number
30 tablets 0003-1611-12
0.5-mg film-coated tablet
White to off-white, triangular-shaped
tablet, debossed with “BMS” on one side
and “1611” on the other side
30 tablets 0003-1612-12
1.0-mg film-coated tablet
Pink, triangular-shaped tablet, debossed
with “BMS” on one side and “1612” on
the other side.
0.05-mg/mL oral
solution
Ready-to-use orange-flavored, clear,
colorless to pale yellow aqueous solution
in a 260-mL bottle.
210 mL 0003-1614-12
BARACLUDE Oral Solution is a ready-to-use product; dilution or mixing with water or any other
solvent or liquid product is not recommended. Each bottle of the oral solution is accompanied by a
dosing spoon that is calibrated in 1-mL increments up to 10 mL. Patients should be instructed to hold
the spoon in a vertical position and fill it gradually to the mark corresponding to the prescribed dose.
Rinsing of the dosing spoon with water is recommended after each daily dose.
Storage
BARACLUDE Tablets should be stored in a tightly closed container at 25° C (77° F); excursions
permitted between 15-30° C (59-86°F) [see USP Controlled Room Temperature].
BARACLUDE Oral Solution should be stored in the outer carton at 25° C (77° F); excursions
permitted between 15-30° C (59-86° F) [see USP Controlled Room Temperature]. Protect from light.
After opening, the oral solution can be used up to the expiration date on the bottle. The bottle and its
contents should be discarded after the expiration date.
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
Issued _________________
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Patient Information
B
araclude
™
(BEAR
ah klude
)
(generic name = entecavir)
Tablets and Oral Solution
Read the Patient Information that comes with BARACLUDE before you start taking it and each time
you get a refill. There may be new information. This information does not take the place of talking
with your healthcare provider about your medical condition or treatment.
What is the most important information I should know about
BARACLUDE?
1. Some people who have taken medicines like BARACLUDE (a nucleoside analogue) have
developed a serious condition called lactic acidosis (buildup of an acid in the blood). Lactic acidosis
is a medical emergency and must be treated in the hospital. Call your healthcare provider right
away if you get any of the following signs of lactic acidosis.
• You feel very weak or tired.
• You have unusual (not normal) muscle pain.
• You have trouble breathing.
• You have stomach pain with nausea and vomiting.
• You feel cold, especially in your arms and legs.
• You feel dizzy or light-headed.
• You have a fast or irregular heartbeat.
2. Some people who have taken medicines like BARACLUDE have developed serious liver
problems called hepatotoxicity, with liver enlargement (hepatomegaly) and fat in the liver (steatosis).
Call your healthcare provider right away if you get any of the following signs of liver problems.
• Your skin or the white part of your eyes turns yellow (jaundice).
• Your urine turns dark.
• Your bowel movements (stools) turn light in color.
• You don’t feel like eating food for several days or longer.
• You feel sick to your stomach (nausea).
• You have lower stomach pain.
3. Your hepatitis B infection may get worse or become very serious if you stop BARACLUDE.
• Take BARACLUDE exactly as prescribed.
Rx only
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• Do not run out of BARACLUDE.
• Do not stop BARACLUDE without talking to your healthcare provider.
Your healthcare provider will need to monitor your health and do regular blood tests to check
your liver if you stop BARACLUDE. Tell your healthcare provider right away about any new or
unusual symptoms that you notice after you stop taking BARACLUDE.
What is BARACLUDE?
BARACLUDE is a prescription medicine used for chronic infection with hepatitis B virus (HBV) in
adults who also have active liver damage.
• BARACLUDE will not cure HBV.
• BARACLUDE may lower the amount of HBV in the body.
• BARACLUDE may lower the ability of HBV to multiply and infect new liver cells.
• BARACLUDE may improve the condition of your liver.
It is important to stay under your healthcare provider’s care while taking BARACLUDE. Your
healthcare provider will test the level of the hepatitis B virus in your blood regularly.
Does BARACLUDE lower the risk of passing HBV to others?
BARACLUDE does not stop you from spreading HBV to others by sex, sharing needles, or being
exposed to your blood. Talk with your healthcare provider about safe sexual practices that protect
your partner. Never share needles. Do not share personal items that can have blood or body fluids on
them, like toothbrushes or razor blades. A shot (vaccine) is available to protect people at risk from
becoming infected with HBV.
Who should not take BARACLUDE?
Do not take BARACLUDE if you are allergic to any of its ingredients. The active ingredient in
BARACLUDE is entecavir. See the end of this leaflet for a complete list of ingredients in
BARACLUDE. Tell your healthcare provider if you think you have had an allergic reaction to any of
these ingredients.
BARACLUDE has not been studied in children and is not recommended for anyone less than 16 years
old.
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What should I tell my healthcare provider before I take BARACLUDE?
Tell your healthcare provider about all of your medical conditions, including if you:
• have kidney problems. You may need a lower dose of BARACLUDE.
• are pregnant or planning to become pregnant. It is not known if BARACLUDE is safe to use
during pregnancy. It is not known whether BARACLUDE helps prevent a pregnant mother from
passing HBV to her baby. You and your healthcare provider will need to decide if BARACLUDE
is right for you. If you use BARACLUDE while you are pregnant, talk to your healthcare provider
about the BARACLUDE Pregnancy Registry.
• are breast-feeding. It is not known if BARACLUDE can pass into your breast milk or if it can
harm your baby. Do not breast-feed if you are taking BARACLUDE.
Tell your healthcare provider about all the medicines you take including prescription and
nonprescription medicines, vitamins, and herbal supplements. BARACLUDE may interact with other
medicines that leave the body through the kidneys.
Know the medicines you take. Keep a list of your medicines with you to show your healthcare
provider and pharmacist.
How should I take BARACLUDE?
• Take BARACLUDE exactly as prescribed. Your healthcare provider will tell you how much
BARACLUDE to take. Your dose will depend on whether you have been treated for HBV
infection before and what medicine you took. The usual dose of BARACLUDE Tablets is either
0.5 mg (one white tablet) or 1 mg (one pink tablet) once daily by mouth. The usual dose of
BARACLUDE Oral Solution is either 10 mL or 20 mL once daily by mouth. Your dose may be
lower if you have kidney problems.
• Take BARACLUDE once a day on an empty stomach to help it work better. Empty stomach
means at least 2 hours after a meal and at least 2 hours before the next meal. To help you remember
to take your BARACLUDE, try to take it at the same time each day.
• If you are taking BARACLUDE Oral Solution, carefully measure your dose with the spoon
provided, as follows:
1. Hold the spoon in a vertical (upright) position and fill it gradually to the mark corresponding to
the prescribed dose. Holding the spoon with the volume marks facing you, check that it has
been filled to the proper mark.
2. Swallow the medicine directly from the measuring spoon.
3. After each use, rinse the spoon with water and allow it to air dry.
If you lose the spoon, call your pharmacist or healthcare provider for instructions.
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• Do not change your dose or stop taking BARACLUDE without talking to your healthcare provider.
Your hepatitis B symptoms may get worse or become very serious if you stop taking
BARACLUDE. After you stop taking BARACLUDE, it is important to stay under your healthcare
provider’s care. Your healthcare provider will need to do regular blood tests to check your liver.
• If you forget to take BARACLUDE, take it as soon as you remember and then take your next
dose at its regular time. If it is almost time for your next dose, skip the missed dose. Do not take
two doses at the same time. Call your healthcare provider or pharmacist if you are not sure what to
do.
• When your supply of BARACLUDE starts to run low, get more from your healthcare provider or
pharmacy. Do not run out of BARACLUDE.
• If you take more than the prescribed dose of BARACLUDE, call your healthcare provider right
away.
• What are the possible side effects of BARACLUDE?
BARACLUDE may cause the following serious side effects (see “What is the most important
information I should know about BARACLUDE”):
• lactic acidosis and liver problems.
• a worse or very serious heptatisis if you stop taking it.
The most common side effects of BARACLUDE are headache, tiredness, dizziness, and nausea. Less
common side effects include diarrhea, indigestion, vomiting, sleepiness, and trouble sleeping. In some
patients, the results of blood tests that measure how the liver or pancreas is working may worsen.
These are not all the side effects of BARACLUDE. The list of side effects is not complete at this time
because BARACLUDE is still under study. Report any new or continuing symptom to your healthcare
provider. If you have questions about side effects, ask your healthcare provider. Your healthcare
provider may be able to help you manage these side effects.
How should I store BARACLUDE?
• Store BARACLUDE Tablets or Oral Solution at room temperature, 59° to 86° F (15° to 30° C).
They do not require refrigeration. Do not store BARACLUDE Tablets in a damp place such as
a bathroom medicine cabinet or near the kitchen sink.
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• Keep the container tightly closed. BARACLUDE Oral Solution should be stored in the original
carton and protected from light.
• Throw away BARACLUDE when it is outdated or no longer needed by flushing tablets down
the toilet or pouring the oral solution down the sink.
• Keep BARACLUDE and all medicines out of the reach of children and pets.
General information about BARACLUDE: Medicines are sometimes prescribed for conditions
other than those described in patient information leaflets. Do not use BARACLUDE for a condition for
which it was not prescribed. Do not give BARACLUDE to other people, even if they have the same
symptoms you have. It may harm them. This leaflet summarizes the most important information about
BARACLUDE. If you would like more information, talk with your healthcare provider. You can ask
your healthcare provider or pharmacist for information about BARACLUDE that is written for
healthcare professionals. You can also call 1-800-321-1335 or visit the BARACLUDE website at
www.Baraclude.com.
What are the ingredients in BARACLUDE?
Active Ingredient: entecavir
Inactive Ingredients in BARACLUDE Tablets: lactose monohydrate, microcrystalline cellulose,
crospovidone, povidone, magnesium stearate, titanium dioxide, hypromellose, polyethylene glycol
400, polysorbate 80 (0.5-mg tablet only), and iron oxide red (1-mg tablet only).
Inactive Ingredients in BARACLUDE Oral Solution: maltitol, sodium citrate, citric acid,
methylparaben, propylparaben, and orange flavor.
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration.
Issued ______________
Based on package insert dated _________________.
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda