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On March 20, 2014, FDA approved new labeling for BARACKUDE (entecavir) to expand the patient population for treatment to include pediatric subjects two years of age and older with chronic hepatitis B virus infection.
- The revised INDICATIONS AND USAGE is as follows:
BARACLUDE (entecavir) is indicated for the treatment of chronic hepatitis B virus infection in adults and pediatric patients 2 years of age and older 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:
- In adult patients, this indication is based on clinical trial data in nucleoside-inhibitor-treatment-naïve and lamivudine-resistant subjects with HBeAg-positive and HBeAg-negative HBV infection and compensated liver disease and a more limited number of subjects with decompensated liver disease.
- In pediatric patients 2 years of age and older, this indication is based on clinical trial data in nucleoside-inhibitor-treatment-naïve and in a limited number of lamivudine-experienced subjects with HBeAg-positive chronic HBV infection and compensated liver disease.
- The DOSAGE AND ADMINISTRATION section was updated to include the recommend dosage in pediatric patients:
Recommended Dosage in Pediatric Patients
Table 1 describes the recommended dose of BARACLUDE for pediatric patients 2 years of age or older and weighing at least 10 kg. The oral solution should be used for patients with body weight up to 30 kg.
|
Table 1: Dosing Schedule for Pediatric Patients |
||
|---|---|---|
|
|
Recommended Once-Daily Dose of Oral Solution (mL) |
|
|
Body Weight (kg) |
Treatment-Naïve Patientsa |
Lamivudine-Experienced Patientsb |
|
10 to 11 |
3 |
6 |
|
greater than 11 to 14 |
4 |
8 |
|
greater than 14 to 17 |
5 |
10 |
|
greater than 17 to 20 |
6 |
12 |
|
greater than 20 to 23 |
7 |
14 |
|
greater than 23 to 26 |
8 |
16 |
|
greater than 26 to 30 |
9 |
18 |
|
greater than 30 |
10 |
20 |
|
a Children with body weight greater than 30 kg should receive 10 mL (0.5 mg) of oral solution or one 0.5 mg tablet once daily. b Children with body weight greater than 30 kg should receive 20 mL (1 mg) of oral solution or one 1 mg tablet once daily. |
||
Although there are insufficient data to recommend a specific dose adjustment of BARACLUDE in pediatric patients with renal impairment, a reduction in the dose or an increase in the dosing interval similar to adjustments for adults should be considered.
- Section 3 DOSAGE FORMS AND STRENGTHS was updated as follows:
Ten milliliters of the oral solution provides a 0.5 mg dose and 20 mL provides a 1 mg dose of entecavir.
- The ADVERSE REACTION section was updated to include clinical trial experience in pediatric subjects
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.
The safety of BARACLUDE in pediatric subjects 2 to less than 18 years of age is based on two ongoing clinical trials in subjects with chronic HBV infection (one Phase 2 pharmacokinetic trial [AI463028] and one Phase 3 trial [AI463189]). These trials provide experience in 168 HBeAg-positive subjects treated with BARACLUDE for a median duration of 72 weeks. The adverse reactions observed in pediatric subjects who received treatment with BARACLUDE were consistent with those observed in clinical trials of BARACLUDE in adults. Adverse drug reactions reported in greater than 1% of pediatric subjects included abdominal pain, rash events, poor palatability (“product taste abnormal”), nausea, diarrhea, and vomiting.
- Section 8.4 Pediatric Use section was revised to include the following:
BARACLUDE was evaluated in two clinical trials of pediatric subjects 2 years of age and older with HBeAg-positive chronic HBV infection and compensated liver disease. The exposure of BARACLUDE in nucleoside-inhibitor-treatment-naïve and lamivudine-experienced pediatric subjects 2 years of age and older with HBeAg-positive chronic HBV infection and compensated liver disease receiving 0.015 mg/kg (up to 0.5 mg once daily) or 0.03 mg/kg (up to 1 mg once daily), respectively, was evaluated in Study AI463028. Safety and efficacy of the selected dose in treatment-naïve pediatric subjects were confirmed in Study AI463189, a randomized, placebo-controlled treatment trial [see Indications and Usage (1), Dosage and Administration (2.3), Adverse Reactions (6.2), Clinical Pharmacology (12.3), and Clinical Studies (14.2)].
There are limited data available on the use of BARACLUDE in lamivudine-experienced pediatric patients; BARACLUDE should be used in these patients only if the potential benefit justifies the potential risk to the child. Since some pediatric patients may require long-term or even lifetime management of chronic active hepatitis B, consideration should be given to the impact of BARACLUDE on future treatment options [see Microbiology (12.4)].
The efficacy and safety of BARACLUDE have not been established in patients less than 2 years of age. Use of BARACLUDE in this age group has not been evaluated because treatment of HBV in this age group is rarely required.
- Section 12 CLINICIAL PHARMACOLOGY was updated to include data in pediatrics as follows:
Pediatrics: The steady-state pharmacokinetics of entecavir were evaluated in nucleoside-inhibitor-naïve and lamivudine-experienced HBeAg-positive pediatric subjects 2 to less than 18 years of age with compensated liver disease. Results are shown in Table 6. Entecavir exposure among nucleoside-inhibitor-naïve subjects was similar to the exposure achieved in adults receiving once-daily doses of 0.5 mg. Entecavir exposure among lamivudine-experienced subjects was similar to the exposure achieved in adults receiving once-daily doses of 1 mg.
|
Table 6: Pharmacokinetic Parameters in Pediatric Subjects |
||
|---|---|---|
|
|
Nucleoside-Inhibitor-Naïvea |
Lamivudine-Experiencedb |
|
|
n=24 |
n=19 |
|
Cmax (ng/mL) |
6.31 |
14.48 |
|
AUC(0–24) (ng•h/mL) |
18.33 |
38.58 |
|
Cmin (ng/mL) |
0.28 |
0.47 |
|
a Subjects received once-daily doses of 0.015 mg/kg up to a maximum of 0.5 mg. b Subjects received once-daily doses of 0.030 mg/kg up to a maximum of 1 mg. |
||
- Section 14 CLINICAL STUDIES was updated to include trial results in pediatric subjects as follows:
14.2 Outcomes in Pediatric Subjects
The pharmacokinetics, safety and antiviral activity of BARACLUDE in pediatric subjects were initially assessed in Study AI463028. Twenty-four treatment-naïve and 19 lamivudine-experienced HBeAg-positive pediatric subjects 2 to less than 18 years of age with compensated CHB and elevated ALT were treated with BARACLUDE 0.015 mg/kg (up to 0.5 mg) or 0.03 mg/kg (up to 1 mg) once daily. Fifty-eight percent (14/24) of treatment-naïve subjects and 47% (9/19) of lamivudine-experienced subjects achieved HBV DNA <50 IU/mL at Week 48 and ALT normalized in 83% (20/24) of treatment-naïve and 95% (18/19) of lamivudine-experienced subjects.
Safety and antiviral efficacy were confirmed in Study AI463189, an ongoing study of BARACLUDE among 180 nucleoside-inhibitor-treatment-naïve pediatric subjects 2 to less than 18 years of age with HBeAg-positive chronic hepatitis B infection, compensated liver disease, and elevated ALT. Subjects were randomized 2:1 to receive blinded treatment with BARACLUDE 0.015 mg/kg up to 0.5 mg/day (N=120) or placebo (N=60). The randomization was stratified by age group (2 to 6 years; >6 to 12 years; and >12 to <18 years). Baseline demographics and HBV disease characteristics were comparable between the 2 treatment arms and across age cohorts. At study entry, the mean HBV DNA was 8.1 log10 IU/mL and mean ALT was 103 U/L. The primary efficacy endpoint was a composite of HBeAg seroconversion and serum HBV DNA <50 IU/mL at Week 48.assessed in the first 123 subjects reaching 48 weeks of blinded treatment. Twenty-four percent (20/82) of subjects in the BARACLUDE-treated group and 2% (1/41) of subjects in the placebo-treated group met the primary endpoint. Forty-six percent (38/82) of BARACLUDE-treated subjects and 2% (1/41) of placebo-treated subjects achieved HBV DNA <50 IU/mL at Week 48. ALT normalization occurred in 67% (55/82) of BARACLUDE-treated subjects and 22% (9/41) of placebo-treated subjects; 24% (20/82) of BARACLUDE-treated subjects and 12% (5/41) of placebo-treated subjects had HBeAg seroconversion.
- Section 17 PATIENT COUNSELING INFORMATION section was updated to state the following. Additionally, the Patient Package Insert was updated to include detailed instructions on how to administerusing a dosing spoon.
Some patients may find it difficult to accurately measure the prescribed dose using the provided dosing spoon; therefore, patients/caregivers should refer to the steps in the Patient Information section that demonstrate the correct technique of using the provided dosing spoon to measure the prescribed BARACLUDE dose.
The complete revised label will be posted on Drugs@FDA.
Baraclude is a product of Bristol-Myers Squibb Company.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
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