Baraclude

Baraclude information, interactions and side effects, 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.

BARACLUDE® is the tradename for entecavir, a guanosine nucleoside analogue with selective activity against HBV. The chemical name for entecavir is 2-amino-1,9-dihydro-9-[(1S,3R,4S)-4hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one, monohydrate. Its molecular formula is C12H15N5O3•H2O, which corresponds to a molecular weight of 295.3. Entecavir has the following structural formula:

baraclude1

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° C ± 0.5° C.

INDICATIONS

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.

The following points should be considered when initiating therapy with BARACLUDE:

  • This indication is based on histologic, virologic, biochemical, and serologic responses in nucleoside-treatment-naïve and lamivudine-resistant adult subjects with HBeAg-positive or HBeAg-negative chronic HBV infection and compensated liver disease [see Clinical Studies].
  • Virologic, biochemical, serologic, and safety data are available from a controlled study in adult subjects with chronic HBV infection and decompensated liver disease [see ADVERSE REACTIONS and Clinical Studies].
  • Virologic, biochemical, serologic, and safety data are available for a limited number of adult subjects with HIV/HBV co-infection who have received prior lamivudine therapy [see WARNINGS AND PRECAUTIONS and Clinical Studies].

DOSAGE AND ADMINISTRATION

BARACLUDE should be administered on an empty stomach (at least 2 hours after a meal and 2 hours before the next meal).

Recommended Dosage

Compensated Liver Disease

The recommended dose of BARACLUDE for chronic hepatitis B virus infection in nucleosidetreatment-naïve adults and adolescents 16 years of age and older is 0.5 mg once daily.

The recommended dose of BARACLUDE in adults and adolescents (at least 16 years of age) with a history of hepatitis B viremia while receiving lamivudine or known lamivudine or telbivudine resistance mutations rtM204I/V with or without rtL180M, rtL80I/V, or rtV173L is 1 mg once daily.

Decompensated Liver Disease

The recommended dose of BARACLUDE for chronic hepatitis B virus infection in adults with decompensated liver disease is 1 mg once daily.

Oral Solution

BARACLUDE (entecavir) 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 subjects with renal impairment, the apparent oral clearance of entecavir decreased as creatinine clearance decreased [see CLINICAL PHARMACOLOGY]. Dosage adjustment is recommended for patients with creatinine clearance less than 50 mL/min, including patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), as shown in Table 1. The once-daily dosing regimens are preferred.

Table 1: Recommended Dosage Of BARACLUDE In Patients With Renal Impairment

 

Creatinine Clearance (mL/min) Usual Dose (0.5 mg) Lamivudine-Refractory or Decompensated Liver Disease (1 mg)
≥ 50 0.5 mg once daily 1 mg once daily
30 to < 50 0.25 mg once dailya OR 0.5 mg every 48 hours 0.5 mg once daily OR 1 mg every 48 hours
10 to < 30 0.15 mg once dailya OR 0.5 mg every 72 hours 0.3 mg once dailya OR 1 mg every 72 hours
< 10 Hemodialysisb or CAPD 0.05 mg once dailya OR 0.5 mg every 7 days 0.1 mg once dailya OR 1 mg every 7 days
a For doses less than 0.5 mg, BARACLUDE Oral Solution is recommended.
b If administered on a hemodialysis day, administer BARACLUDE after the hemodialysis session.

 

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 virus infection and the relationship between treatment and long-term outcomes such as cirrhosis and hepatocellular carcinoma are unknown.

HOW SUPPLIED

Dosage Forms And Strengths

  • BARACLUDE 0.5 mg film-coated tablets are white to off-white, triangular-shaped, and debossed with “BMS” on one side and “1611” on the other side.
  • BARACLUDE 1 mg film-coated tablets are pink, triangular-shaped, and debossed with “BMS” on one side and “1612” on the other side.
  • BARACLUDE oral solution, 0.05 mg/mL, is a ready-to-use, orange-flavored, clear, colorless to pale yellow, aqueous solution.

Storage And Handling

BARACLUDE® (entecavir) Tablets and Oral Solution are available in the following strengths and configurations of plastic bottles with child-resistant closures:

 

Product Strength and Dosage Form Description Quantity NDC Number
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 0003-1611-12
90 tablets 0003-1611-13
1.0 mg film-coated tablet Pink, triangular-shaped tablet, debossed with “BMS” on one side and “1612” on the other side. 30 tablets 0003-1612-12
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 [see PATIENT INFORMATION].

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]. Store in the outer carton to protect from light.

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.

SIDE EFFECTS

The following adverse reactions are discussed in other sections of the labeling:

  • Exacerbations of hepatitis after discontinuation of treatment [see BOXED WARNING, WARNINGS AND PRECAUTIONS].
  • Lactic acidosis and severe hepatomegaly with steatosis [see BOXED WARNING, WARNINGS AND PRECAUTIONS].

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Compensated Liver Disease

Assessment of adverse reactions is based on four studies (AI463014, AI463022, AI463026, and AI463027) in which 1720 subjects with chronic hepatitis B virus infection and compensated liver disease 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 2 years. Median duration of therapy was 69 weeks for BARACLUDE-treated subjects and 63 weeks for lamivudine-treated subjects in Studies AI463022 and AI463027 and 73 weeks for BARACLUDE-treated subjects and 51 weeks for lamivudine-treated subjects in Studies AI463026 and AI463014. The safety profiles of BARACLUDE and lamivudine were comparable in these studies.

The most common adverse reactions of any severity ( ≥ 3%) with at least a possible relation to study drug for BARACLUDE-treated subjects were headache, fatigue, dizziness, and nausea. The most common adverse reactions among lamivudine-treated subjects were headache, fatigue, and dizziness. One percent of BARACLUDE-treated subjects in these four studies compared with 4% of lamivudine-treated subjects discontinued for adverse events or abnormal laboratory test results.

Clinical adverse reactions 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 2.

Table 2: Clinical Adverse Reactionsa of Moderate-Severe Intensity (Grades 2–4) Reported in Four Entecavir Clinical Trials Through 2 Years

 

Body System/ Adverse Reaction Nucleoside-Naiveb Lamivudine-Refractoryc
BARACLUDE 0.5 mg
n=679
Lamivudine 100 mg
n=668
BARACLUDE 1 mg
n=183
Lamivudine 100 mg
n=190
Any Grade 2-4 adverse reactiona 15% 18% 22% 23%
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 subjects 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 3.

Table 3: Selected Treatment-Emergenta Laboratory Abnormalities Reported in Four Entecavir Clinical Trials Through 2 Years

 

Test Nucleoside–Naiveb Lamivudine-Refractoryc
BARACLUDE 0.5 mg
n=679
Lamivudine 100 mg
n=668
BARACLUDE 1 mg
n=183
Lamivudine 100 mg
n=190
Any Grade 3-4 laboratory abnormalityd 35% 36% 37% 45%
ALT > 10 x ULN and > 2 x baseline 2% 4% 2% 11%
ALT > 5.0 x ULN 11% 16% 12% 24%
Albumin < 2.5 g/dL < 1% < 1% 0 2%
Total bilirubin > 2.5 x ULN 2% 2% 3% 2%
Lipase ≥ 2.1 x ULN 7% 6% 7% 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% 3% 1%
Glycosuriae 4% 3% 4% 6%
Hematuriaf 9% 10% 9% 6%
3 Platelets < 50,000/mm < 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 and > 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 subjects who experienced recurrent viremia on lamivudine therapy.
d Includes hematology, routine chemistries, renal and liver function tests, pancreatic enzymes, and urinalysis.
e Grade 3 = 3+, large, ≥ 500 mg/dL; Grade 4 = 4+, marked, severe.
f Grade 3 = 3+, large; Grade 4 = ≥ 4+, marked, severe, many.
ULN=upper limit of normal.

Among BARACLUDE-treated subjects in these studies, on-treatment ALT elevations greater than 10 times the upper limit of normal (ULN) and greater than 2 times baseline generally resolved with continued treatment. A majority of these exacerbations were associated with a ≥ 2 log10/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

An exacerbation of hepatitis or ALT flare was defined as ALT greater than 10 times ULN and greater than 2 times the subject’s reference level (minimum of the baseline or last measurement at end of dosing). For all subjects who discontinued treatment (regardless of reason), Table 4 presents the proportion of subjects in each study who experienced post-treatment ALT flares. In these studies, a subset of subjects was allowed to discontinue treatment at or after 52 weeks if they achieved a protocol-defined response to therapy. If BARACLUDE is discontinued without regard to treatment response, the rate of post-treatment flares could be higher. [See also WARNINGS AND PRECAUTIONS]

Table 4: Exacerbations of Hepatitis During Off-Treatment Follow-up, Subjects in Studies AI463022, AI463027, and AI463026

 

Subjects with ALT Elevations > 10 x ULN and > 2 x Referencea
BARACLUDE Lamivudine
Nucleoside-naive
  HBeAg-positive 4/174 (2%) 13/147 (9%)
  HBeAg-negative 24/302 (8%) 30/270 (11%)
Lamivudine-refractory 6/52 (12%) 0/16
a Reference is the minimum of the baseline or last measurement at end of dosing. Median time to off-treatment exacerbation was 23 weeks for BARACLUDE-treated subjects and 10 weeks for lamivudine-treated subjects.

 

Decompensated Liver Disease

Study AI463048 was a randomized, open-label study of BARACLUDE 1 mg once daily versus adefovir dipivoxil 10 mg once daily given for up to 48 weeks in adult subjects with chronic HBV infection and evidence of hepatic decompensation, defined as a Child-Turcotte-Pugh (CTP) score of 7 or higher [see Clinical Studies]. Among the 102 subjects receiving BARACLUDE, the most common treatment-emergent adverse events of any severity, regardless of causality, occurring through Week 48 were peripheral edema (16%), ascites (15%), pyrexia (14%), hepatic encephalopathy (10%), and upper respiratory infection (10%). Clinical adverse reactions not listed in Table 2 that were observed through Week 48 include blood bicarbonate decreased (2%) and renal failure ( < 1%).

Eighteen of 102 (18%) subjects treated with BARACLUDE and 18/89 (20%) subjects treated with adefovir dipivoxil died during the first 48 weeks of therapy. The majority of deaths (11 in the BARACLUDE group and 16 in the adefovir dipivoxil group) were due to liver-related causes such as hepatic failure, hepatic encephalopathy, hepatorenal syndrome, and upper gastrointestinal hemorrhage. The rate of hepatocellular carcinoma (HCC) through Week 48 was 6% (6/102) for subjects treated with BARACLUDE and 8% (7/89) for subjects treated with adefovir dipivoxil. Five percent of subjects in either treatment arm discontinued therapy due to an adverse event through Week 48.

No subject in either treatment arm experienced an on-treatment hepatic flare (ALT > 2 x baseline and > 10 x ULN) through Week 48. Eleven of 102 (11%) subjects treated with BARACLUDE and 11/89 (13%) subjects treated with adefovir dipivoxil had a confirmed increase in serum creatinine of 0.5 mg/dL through Week 48.

HIV/HBV Co-Infected

The safety profile of BARACLUDE 1 mg (n=51) in HIV/HBV co-infected subjects 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 subjects [see WARNINGS AND PRECAUTIONS].

Liver Transplant Recipients

Among 65 subjects receiving BARACLUDE in an open-label, post-liver transplant trial [see Use In Specific Populations], the frequency and nature of adverse events were consistent with those expected in patients who have received a liver transplant and the known safety profile of BARACLUDE.

Postmarketing Experience

The following adverse reactions have been reported during postmarketing use of BARACLUDE. Because these reactions were reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or establish a causal relationship to BARACLUDE exposure.

Immune system disorders: Anaphylactoid reaction.

Metabolism and nutrition disorders: Lactic acidosis.

Hepatobiliary disorders: Increased transaminases.

Skin and subcutaneous tissue disorders: Alopecia, rash.

DRUG INTERACTIONS

Since entecavir is primarily eliminated by the kidneys [see CLINICAL PHARMACOLOGY], 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.

PRECAUTIONS

Severe Acute Exacerbations Of Hepatitis B

Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including entecavir [see ADVERSE REACTIONS]. 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.

Patients Co-Infected With HIV And HBV

BARACLUDE has not been evaluated in HIV/HBV co-infected patients who were not simultaneously receiving effective HIV treatment. Limited clinical experience suggests there is a potential for the development of resistance to HIV nucleoside reverse transcriptase inhibitors if BARACLUDE is used to treat chronic hepatitis B virus infection in patients with HIV infection that is not being treated [see Microbiology]. Therefore, therapy with BARACLUDE is not recommended for HIV/HBV co-infected patients who are not also receiving HAART. Before initiating BARACLUDE therapy, HIV antibody testing should be offered to all patients. BARACLUDE has not been studied as a treatment for HIV infection and is not recommended for this use.

Lactic Acidosis And Severe Hepatomegaly With Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including BARACLUDE, alone or in combination with antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogues to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors.

Lactic acidosis with BARACLUDE use has been reported, often in association with hepatic decompensation, other serious medical conditions, or drug exposures. Patients with decompensated liver disease may be at higher risk for lactic acidosis. Treatment with BARACLUDE 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).

Patient Counseling Information

See FDA-approved patient labeling (PATIENT INFORMATION).

Information about Treatment

Physicians should inform their patients of the following important points when initiating BARACLUDE treatment:

  • 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 that treatment with BARACLUDE has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination.
  • 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 using the oral solution should be instructed to hold the dosing 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.
  • Patients should be advised to take a missed dose as soon as remembered unless it is almost time for the next dose. Patients should not take two doses at the same time.
  • Patients should be advised that treatment with BARACLUDE will not cure HBV.
  • Patients should be informed that BARACLUDE may lower the amount of HBV in the body, may lower the ability of HBV to multiply and infect new liver cells, and may improve the condition of the liver.
  • Patients should be informed that it is not known whether BARACLUDE will reduce their chances of getting liver cancer or cirrhosis.
Post-treatment Exacerbation Of Hepatitis

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.

HIV/HBV Co-infection

Patients should be offered HIV antibody testing before starting BARACLUDE therapy. They should be informed that if they have HIV infection and are not receiving effective HIV treatment, BARACLUDE may increase the chance of HIV resistance to HIV medication.

Nonclinical Toxicology

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 4 weeks, no evidence of impaired fertility was seen in male or female rats at systemic exposures greater than 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 or greater than those achieved in humans. No testicular changes were evident in monkeys.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of BARACLUDE in pregnant women. When pregnant rats and rabbits received entecavir at 28 and 212 times the human exposure at the highest human dose, there were no signs of embryofetal toxicity. 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.

Developmental toxicity studies were performed in rats and rabbits. There were no signs of embryofetal or maternal toxicity when pregnant animals received oral entecavir at approximately 28 (rat) and 212 (rabbit) times the human exposure achieved at the highest recommended human dose of 1 mg/day. In rats, maternal toxicity, embryofetal 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, embryofetal toxicity (resorptions), reduced ossification (hyoid), and an increased incidence of 13th rib were observed at exposures 883 times those in humans. In a peripostnatal study, no adverse effects on offspring occurred when rats received oral entecavir at exposures greater than 94 times those in humans.

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

It is not known whether BARACLUDE is excreted into human milk; however, entecavir is excreted into the milk of rats. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from BARACLUDE, a decision should be made to discontinue nursing or to discontinue BARACLUDE taking into consideration the importance of continued hepatitis B therapy to the mother and the known benefits of breastfeeding.

Pediatric Use

Safety and effectiveness of entecavir in pediatric patients below the age of 16 years have not been established.

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].

Racial/Ethnic Groups

There are no significant racial differences in entecavir pharmacokinetics. The safety and efficacy of BARACLUDE 0.5 mg once daily were assessed in a single-arm, open-label trial of HBeAgpositive or -negative, nucleoside-naïve, Black/African American (n=40) and Hispanic (n=6) subjects with chronic HBV infection. In this trial, 76% of subjects were male, the mean age was 42 years, 57% were HBeAg-positive, the mean baseline HBV DNA was 7.0 log10 IU/mL, and the mean baseline ALT was 162 U/L. At Week 48 of treatment, 32 of 46 (70%) subjects had HBV DNA < 50 IU/mL (approximately 300 copies/mL), 31 of 46 (67%) subjects had ALT normalization ( ≤ 1 x ULN), and 12 of 26 (46%) HBeAg-positive subjects had HBe seroconversion. Safety data were similar to those observed in the larger controlled clinical trials.

Because of low enrollment, safety and efficacy have not been established in the US Hispanic population.

Renal Impairment

Dosage adjustment of BARACLUDE is recommended for patients with creatinine clearance less than 50 mL/min, including patients on hemodialysis or CAPD [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

Liver Transplant Recipients

The safety and efficacy of BARACLUDE were assessed in a single-arm, open-label trial in 65 subjects who received a liver transplant for complications of chronic HBV infection. Eligible subjects who had HBV DNA less than 172 IU/mL (approximately 1000 copies/mL) at the time of transplant were treated with BARACLUDE 1 mg once daily in addition to usual post-transplantation management, including hepatitis B immune globulin. The trial population was 82% male, 39% Caucasian, and 37% Asian, with a mean age of 49 years; 89% of subjects had HBeAg-negative disease at the time of transplant.

Four of the 65 subjects received 4 weeks or less of BARACLUDE (2 deaths, 1 retransplantation, and 1 protocol violation) and were not considered evaluable. Of the 61 subjects who received more than 4 weeks of BARACLUDE, 60 received hepatitis B immune globulin post-transplant. Fifty-three subjects (82% of all 65 subjects treated) completed the trial and had HBV DNA measurements at or after 72 weeks treatment post-transplant. All 53 subjects had HBV DNA < 50 IU/mL (approximately 300 copies/mL). Eight evaluable subjects did not have HBV DNA data available at 72 weeks, including 3 subjects who died prior to study completion. No subjects had HBV DNA values ≥ 50 IU/mL while receiving BARACLUDE (plus hepatitis B immune globulin). All 61 evaluable subjects lost HBsAg post-transplant; 2 of these subjects experienced recurrence of measurable HBsAg without recurrence of HBV viremia. This trial was not designed to determine whether addition of BARACLUDE to hepatitis B immune globulin decreased the proportion of subjects with measurable HBV DNA post-transplant compared to hepatitis B immune globulin alone.

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 tacrolimus, renal function must be carefully monitored both before and during treatment with BARACLUDE [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

OVERDOSE

There is limited 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.

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