FDA Hepatitis Update - Baraclude (entecavir) label revised to expand pediatric indication

[Date Prev][Date Next][Thread Prev][Thread Next][Date Index][Thread Index]

 



Title: FDA Hepatitis Update - Baraclude (entecavir) label revised to expand pediatric indication

You are receiving this message as a subscriber to the FDA hepatitis electronic list serve. The purpose of the list serve is to relay important information about viral hepatitis-related products and issues, including product approvals, significant labeling changes, safety warnings, notices of upcoming public meetings and alerts to proposed regulatory guidances for comment.

Please do not reply to this message.

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.

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:

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.

Ten milliliters of the oral solution provides a 0.5 mg dose and 20 mL provides a 1 mg dose of entecavir.

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.

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.

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)
(CV%)

6.31
(30)

14.48
(31)

AUC(0–24) (ng•h/mL)
(CV%)

18.33
(27)

38.58
(26)

Cmin (ng/mL)
(CV%)

0.28
(22)

0.47
(23)

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.

 

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.

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


This email was sent to list-fda@xxxxxxxxxxx using GovDelivery, on behalf of: U.S. Food & Drug Administration (FDA) · 10903 New Hampshire Ave · Silver Spring, MD 20993 · 800-439-1420 Powered by GovDelivery

[Index of Archives]     [CDC News]     [NIH News]     [USDA News]     [Steve's Art]     [Camping in Yosemite]     [PhotoForum]     [SB Lupus]     [STB]

  Powered by Linux