Baraclude

Keep this medication in the container it came in, tightly closed, and out of reach of children and pets. Store it at room temperature and away from excess heat, light, and moisture (not in the bathroom medicine cabinet or near the kitchen sink).

Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org

Black Box Warnings

Severe acute exacerbations of hepatitis reported following discontinuing drug; monitor hepatic function

Resistance to HIV NRTIs may emerge in patients with chronic hepatitis B in whom HIV infection is unrecognized or untreated

Not for HIV/HBV coinfected patients unless being treated with highly active antiretroviral therapy (HAART)

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, reported

Do not use Epivir HBV tablets or solution to treat HIV

Contraindications

Hypersensitivity

Cautions

Discontinuation may result in acute exacerbation of hepatitis B

Caution in liver transplant recipients or renal impairment

Pregnancy

Risk of HIV resistance: not recommended for HIV/HBV coinfected patients who are not also receiving HAART

Patients with decompensated liver disease may be at greater risk for lactic acidosis

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)-4-hydroxy-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:

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.

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® (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 [see Clinical Studies].
• 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 [see Clinical Studies].

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 In Adults

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.

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 3.

Table 3: Clinical Adverse Reactionsa of Moderate-Severe Intensity (Grades 2–4) Reported in Four Entecavir Clinical Trials Through 2 Years

Frequencies of selected treatment-emergent laboratory abnormalities reported during therapy in four clinical trials of BARACLUDE compared with lamivudine are listed in Table 4.

Table 4: Selected Treatment-Emergenta Laboratory Abnormalities Reported in Four Entecavir Clinical Trials Through 2 Years

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.

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 5 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 WARNINGS AND PRECAUTIONS]

Table 5: Exacerbations of Hepatitis During Off-Treatment Follow-up, Subjects in Studies AI463022, AI463027, and AI463026

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 3 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 × baseline and > 10 × 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.

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].

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.

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.

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.

Tell your healthcare provider if you are breastfeeding or plan to breastfeed.

It is not known if Baraclude crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using Baraclude.

WARNINGS: SEVERE ACUTE EXACERBATIONS OF HEPATITIS B, PATIENTS CO-INFECTED WITH HIV AND HBV, and LACTIC ACIDOSIS AND HEPATOMEGALY

Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including Baraclude. 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.

Limited clinical experience suggests there is a potential for the development of resistance to HIV (human immunodeficiency virus) nucleoside reverse transcriptase inhibitors if Baraclude is used to treat chronic hepatitis B virus (HBV) infection in patients with HIV infection that is not being treated. Therapy with Baraclude is not recommended for HIV/HBV co-infected patients who are not also receiving highly active antiretroviral therapy (HAART).

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.

Chronic Hepatitis B Virus (HBV) Infection

Management of chronic HBV infection in adults and adolescents ≥16 years of age with evidence of active HBV replication and either persistent elevations in serum aminotransaminases (ALT or AST) or histologic evidence of active disease.1 3 5 18 25 26 27 Relationship between treatment response and long-term outcomes such as hepatocellular carcinoma or decompensated cirrhosis not known.1

Has been effective for HBeAg-positive or -negative chronic HBV infection with compensated liver disease in patients who were nucleoside-naive (had not previously received treatment with nucleoside antivirals) or had lamivudine-refractory HBV (history of HBV viremia while receiving lamivudine or HBV strains known to have mutations associated with lamivudine resistance).1 5 25 26 27

Has been effective for treatment of chronic HBV infection in patients coinfected with both HBV and HIV who had recurrence of HBV viremia while receiving a lamivudine-containing antiretroviral regimen.1 2

Should not be used for treatment of HBV infection in HIV-infected patients who are not receiving antiretroviral therapy.1 29 30 31 33 Limited clinical experience in such patients suggests a potential for development of HIV resistance.1 29 30 31 33 (See Individuals Coinfected with HBV and HIV under Cautions.)

Safety and efficacy not established for treatment of chronic HBV infection in liver transplant patients.1 (See Liver Transplant Recipients under Cautions.)

Treatment of chronic HBV infection is complex and rapidly evolving and should be directed by clinicians familiar with the disease; consult a specialist to obtain the most up-to-date information.5 13 14 22

Storage

Oral

Store in outer carton at 25°C (may be exposed to 15–30°C).1 Protect from light.1 After opening, discard by expiration date noted on bottle.1

Tight container at 25°C (may be exposed to 15–30°C).1

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

   Timing of 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 in Adults

The recommended dose of Baraclude for chronic hepatitis B virus infection in nucleoside-inhibitor-treatment-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 substitutions rtM204I/V with or without rtL180M, rtL80I/V, or rtV173L is 1 mg once daily.

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

   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.

   Renal Impairment

In adult subjects with renal impairment, the apparent oral clearance of entecavir decreased as creatinine clearance decreased [see Clinical Pharmacology (12.3)]. 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 2. The once-daily dosing regimens are preferred.

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.

   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.

210 mL NDC 0003-1614-12
Baraclude®
(entecavir)
Oral Solution
0.05 mg/mL
Store Bottle in Carton to Protect from Light
Bristol-Myers Squibb
Rx only

You should not take this medication if you are allergic to entecavir, or if you also have HIV (human immunodeficiency virus) that is not being treated.

If you have certain conditions, you may need a dose adjustment or special tests to safely take this medication. Before you take entecavir, tell your doctor if you are allergic to any drugs, or if you have:

• HIV or AIDS;
• kidney disease;
• liver disease; or
• if you have had a liver transplant.

Some people have developed a life-threatening condition called lactic acidosis while taking entecavir. You may be more likely to develop lactic acidosis if you have liver or kidney disease, congestive heart failure, or if you drink large amounts of alcohol. Talk with your doctor about your individual risk.

FDA pregnancy category C. It is not known whether entecavir is harmful to an unborn baby. Before you take entecavir, tell your doctor if you are pregnant or plan to become pregnant during treatment.

Your name may need to be listed on an antiviral pregnancy registry when you start using this medication.

It is not known whether entecavir passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Taking entecavir will not prevent you from passing hepatitis B to other people through unprotected sex or sharing of needles. Talk with your doctor about safe methods of preventing hepatitis transmission during sex, such as using a condom and spermicide. Sharing drug or medicine needles is never safe, even for a healthy person.

Your pharmacist can provide more information about entecavir.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

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Applies to entecavir: oral solution, oral tablet

Along with its needed effects, entecavir (the active ingredient contained in Baraclude) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking entecavir:

• Abdominal or stomach discomfort
• cough
• decreased appetite
• diarrhea
• difficulty with swallowing
• dizziness
• fast heartbeat
• fast, shallow breathing
• general feeling of discomfort
• hives, itching, or rash
• muscle pain or cramping
• nausea
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• right upper abdominal or stomach pain and fullness
• sleepiness
• tightness in the chest
• unusual tiredness or weakness

Some side effects of entecavir may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Acid or sour stomach
• belching
• headache
• heartburn
• indigestion
• stomach discomfort, upset, or pain

• Trouble sleeping
• Unusual drowsiness

• Hair loss
• thinning of the hair

A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. Excreted into human milk: Unknown Excreted into animal milk: Yes