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Drug Details

BARACLUDE Film-Coated Tablets

• Drug Class Description
  Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NNRTI)
• Generic Name
  Entecavir
• Presentation
  0.5 mg filmcoated tablets 1.0 mg filmcoated tablets 0.05 mg/ml oral solution
• Description
  Baraclude®0.5 mg filmcoated tablets Baraclude®1.0 mg filmcoated tablets Baraclude®0.05 mg/ml oral solution
• Indications
  

  Baraclude is indicated for the treatment of chronic hepatitis B virus (HBV) infection in adults with compensated liver disease and evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active inflammation and/or fibrosis.

  This indication is based on clinical trial data in nucleoside naive patients with HBeAg positive and HBeAg negative HBV infection. With respect to patients with lamivudine-refractory hepatitis B.

• Adult Dosage
  

   

  Therapy should be initiated by a physician experienced in the management of chronic hepatitis B infection.

   

  Posology

  Compensated liver disease

  Nucleoside naïve patients: the recommended dose is 0.5 mg once daily, with or without food.

  Lamivudine-refractory patients (i.e. with evidence of viraemia while on lamivudine or the presence of lamivudine resistance [LVDr] mutations): the recommended dose is 1 mg once daily, which must be taken on an empty stomach (more than 2 hours before or more than 2 hours after a meal).

   

  Decompensated liver disease

  The recommended dose for patients with decompensated liver disease is 1 mg once daily, which must be taken on an empty stomach (more than 2 hours before or more than 2 hours after a meal). For patients with lamivudine-refractory hepatitis B.

   

  Duration of therapy

  The optimal duration of treatment is unknown. Treatment discontinuation may be considered as follows:

  • In HBeAg positive patients, treatment should be administered at least until HBe seroconversion (HBeAg loss and HBV DNA loss with anti-HBe detection on two consecutive serum samples at least 3-6 months apart) or until HBs seroconversion or there is loss of efficacy.

  • In HBeAg negative patients, treatment should be administered at least until HBs seroconversion or there is evidence of loss of efficacy. With prolonged treatment for more than 2 years, regular reassessment is recommended to confirm that continuing the selected therapy remains appropriate for the patient.

  In patients with decompensated liver disease or cirrhosis, treatment cessation is not recommended.

  Elderly: no dosage adjustment based on age is required. The dose should be adjusted according to the patient's renal function.

  Gender and race: no dosage adjustment based on gender or race is required.

  Renal impairment: the clearance of entecavir decreases with decreasing creatinine clearance. Dose adjustment is recommended for patients with creatinine clearance < 50 ml/min, including those on haemodialysis or continuous ambulatory peritoneal dialysis (CAPD). A reduction of the daily dose using Baraclude oral solution, as detailed in the table, is recommended. As an alternative, in case the oral solution is not available, the dose can be adjusted by increasing the dosage interval, also shown in the table. The proposed dose modifications are based on extrapolation of limited data, and their safety and effectiveness have not been clinically evaluated. Therefore, virological response should be closely monitored.

   

  	Baraclude dosage*
  Creatinine clearance (ml/min)	Nucleoside naïve patients	Lamivudine-refractory or decompensated liver disease
  50	0.5 mg once daily	1 mg once daily
  30 - 49	0.25 mg once daily* OR 0.5 mg every 48 hours	0.5 mg once daily
  10 - 29	0.15 mg once daily* OR 0.5 mg every 72 hours	0.3 mg once daily* OR 0.5 mg every 48 hours
  < 10   Haemodialysis or CAPD**	0.05 mg once daily* OR 0.5 mg every 5-7 days	0.1 mg once daily* OR 0.5 mg every 72 hours

  * for doses < 0.5 mg Baraclude oral solution is recommended.

  ** on haemodialysis days, administer entecavir after haemodialysis.

  Hepatic impairment: no dose adjustment is required in patients with hepatic impairment.

  Paediatric population: the safety and efficacy of Baraclude in children below 18 years of age have not yet been established. No data are available.

   

  Method of administration

  Baraclude should be taken orally.

   

• Child Dosage
  

  Paediatric population: the safety and efficacy of Baraclude in children below 18 years of age have not yet been established. No data are available.

• Elderly Dosage
  

  Elderly: no dosage adjustment based on age is required. The dose should be adjusted according to the patient's renal function.

• Contra Indications
  

  Hypersensitivity to the active substance or to any of the excipients.

• Special Precautions
  

  Renal impairment: dosage adjustment is recommended for patients with renal impairment. The proposed dose modifications are based on extrapolation of limited data, and their safety and effectiveness have not been clinically evaluated. Therefore, virological response should be closely monitored.

  Exacerbations of hepatitis: spontaneous exacerbations in chronic hepatitis B are relatively common and are characterised by transient increases in serum ALT. After initiating antiviral therapy, serum ALT may increase in some patients as serum HBV DNA levels decline. Among entecavir-treated patients on-treatment exacerbations had a median time of onset of 45 weeks. In patients with compensated liver disease, these increases in serum ALT are generally not accompanied by an increase in serum bilirubin concentrations or hepatic decompensation. Patients with cirrhosis may be at a higher risk for hepatic decompensation following hepatitis exacerbation, and therefore should be monitored closely during therapy.

  Acute exacerbation of hepatitis has also been reported in patients who have discontinued hepatitis B therapy. Post-treatment exacerbations are usually associated with rising HBV DNA, and the majority appears to be selflimited. However, severe exacerbations, including fatalities, have been reported.

  Among entecavir-treated nucleoside naive patients, post-treatment exacerbations had a median time to onset of 2324 weeks, and most were reported in HBeAg negative patients. Hepatic function should be monitored at repeated intervals with both clinical and laboratory follow-up for at least 6 months after discontinuation of hepatitis B therapy. If appropriate, resumption of hepatitis B therapy may be warranted.

  Patients with decompensated cirrhosis: a higher rate of serious hepatic adverse events has been observed in patients with decompensated cirrhosis compared with rates in patients with compensated liver function. This observation is based on limited experience in 45 patients with Child-Pugh score 7 at the start of entecavir treatment. These patients should be regularly monitored for clinical, virological and serological parameters associated with hepatitis B, liver and renal function and antiviral response during treatment, and if treatment is discontinued, for at least 6 months thereafter. Patients experiencing signs of hepatic insufficiency during or post-treatment should be monitored more frequently as appropriate.

  Lactic acidosis and severe hepatomegaly with steatosis: occurrences of lactic acidosis (in the absence of hypoxaemia), sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of nucleoside analogues. As entecavir is a nucleoside analogue, this risk cannot be excluded. Treatment with nucleoside analogues should be discontinued when rapidly elevating aminotransferase levels, progressive hepatomegaly or metabolic/lactic acidosis of unknown aetiology occur. Benign digestive symptoms, such as nausea, vomiting and abdominal pain, might be indicative of lactic acidosis development. Severe cases, sometimes with fatal outcome, were associated with pancreatitis, liver failure/hepatic steatosis, renal failure and higher levels of serum lactate. Caution should be exercised when prescribing nucleoside analogues to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease. These patients should be followed closely.

  To differentiate between elevations in aminotransferases due to response to treatment and increases potentially related to lactic acidosis, physicians should ensure that changes in ALT are associated with improvements in other laboratory markers of chronic hepatitis B.

  Resistance and specific precaution for lamivudine-refractory patients: mutations in the HBV polymerase that encode lamivudine-resistance substitutions may lead to the subsequent emergence of secondary substitutions, including those associated with entecavir associated resistance (ETVr). In a small percentage of lamivudine-refractory patients, ETVr substitutions at residues rtT184, rtS202 or rtM250 were present at baseline. Patients with lamivudine-resistant HBV are at higher risk of developing subsequent entecavir resistance than patients without lamivudine resistance. The cumulative probability of emerging genotypic entecavir resistance after 1, 2, 3, 4 and 5 years treatment in the lamivudine-refractory studies was 6%, 15%, 36%, 47% and 51%, respectively. Virological response should be frequently monitored in the lamivudine-refractory population and appropriate resistance testing should be performed. In patients with a suboptimal virological response after 24 weeks of treatment with entecavir, a modification of treatment should be considered .

  Liver transplant recipients: there are limited data on efficacy and safety of entecavir in liver transplant recipients. Renal function should be carefully evaluated before and during entecavir therapy in liver transplant recipients receiving cyclosporine or tacrolimus.

  Liver transplant recipients: there are limited data on efficacy and safety of entecavir in liver transplant recipients. Renal function should be carefully evaluated before and during entecavir therapy in liver transplant recipients receiving cyclosporine or tacrolimus.

  Co-infection with hepatitis C or D: there are no data on the efficacy of entecavir in patients coinfected with hepatitis C or D virus.

  Human immunodeficiency virus (HIV)/HBV co-infected patients not receiving concomitant antiretroviral therapy: entecavir has not been evaluated in HIV/HBV co-infected patients not concurrently receiving effective HIV treatment. Emergence of HIV resistance has been observed when entecavir was used to treat chronic hepatitis B infection in patients with HIV: no infection not receiving highly active antiretroviral therapy (HAART). Therefore, therapy with entecavir should not be used for HIV/HBV coinfected patients who are not receiving HAART. Entecavir has not been studied as a treatment for HIV infection and is not recommended for this use.

  HIV/HBV co-infected patients receiving concomitant antiretroviral therapy: entecavir has been studied in 68 adults with HIV/HBV co-infection receiving a lamivudine-containing HAART regimen. No data are available on the efficacy of entecavir in HBeAg-negative patients co-infected with HIV. There are limited data on patients co-infected with HIV who have low CD4 cell counts (< 200 cells/mm³).

  General: patients should be advised that therapy with entecavir has not been proven to reduce the risk of transmission of HBV and therefore appropriate precautions should still be taken.

  Lactose:

  0.5 mg filmcoated tablets- this medicinal product contains 120.5 mg of lactose in each 0.5 mg daily dose.

  1.0 mg filmcoated tablets- this medicinal product contains 241 mg of lactose in each 1 mg daily dose

  Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption should not take this medicine. A lactosefree Baraclude oral solution is available for these individuals.

  Maltitol: Baraclude oral solution contains maltitol (13 g maltitol liquid per 20 ml dose). Baraclude may have a mild laxative effect. Calorific value 2.3 kcal/g maltitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine. Baraclude tablets do not contain maltitol and can be taken by patients with fructose intolerance.

  Parahydroxybenzoates: Baraclude oral solution contains the preservatives methylhydroxybenzoate and propylhydroxybenzoate, that may cause allergic reactions (possibly delayed).

• Interactions
  

  Since entecavir is predominantly eliminated by the kidney, coadministration with medicinal products that reduce renal function or compete for active tubular secretion may increase serum concentrations of either medicinal product. Apart from lamivudine, adefovir dipivoxil and tenofovir disoproxil fumarate, the effects of coadministration of entecavir with medicinal products that are excreted renally or affect renal function have not been evaluated. Patients should be monitored closely for adverse reactions when entecavir is coadministered with such medicinal products.

  No pharmacokinetic interactions between entecavir and lamivudine, adefovir or tenofovir were observed.

  Entecavir is not a substrate, an inducer or an inhibitor of cytochrome P450 (CYP450) enzymes. Therefore CYP450 mediated drug interactions are unlikely to occur with entecavir.

• Adverse Drug Reactions
  

  Assessment of adverse reactions is based on four clinical studies in which 1,720 patients with chronic hepatitis B infection received double-blind treatment with entecavir 0.5 mg/day (n = 679), entecavir 1 mg/day (n = 183), or lamivudine (n = 858) for up to 107 weeks. The safety profiles of entecavir and lamivudine, including laboratory test abnormalities, were comparable in these studies.

  The most common adverse reactions of any severity with at least a possible relation to entecavir were headache (9%), fatigue (6%), dizziness (4%) and nausea (3%).

  Adverse reactions considered at least possibly related to treatment with entecavir are listed by body system organ class. Frequency is defined as very common ( 1/10); common ( 1/100, < 1/10). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

  Experience in nucleoside naive patients (HBeAg positive and negative):

  The safety profile is based on treatment exposure to entecavir 0.5 mg once daily for a median of 53 weeks.

  Nervous system disorders:	Common: headache, dizziness, somnolence
  Gastrointestinal disorders:	Common: vomiting, diarrhoea, nausea, dyspepsia
  General disorders and administration site conditions:	Common: fatigue
  Psychiatric disorders:	Common: insomnia

  Laboratory test abnormalities: 2% of patients had ALT elevations both > 10 times upper limit of the normal range (ULN) and > 2 times baseline, 5% had ALT elevations > 3 times baseline, and < 1% had ALT elevations > 2 times baseline together with total bilirubin > 2 times ULN and > 2 times baseline. Albumin levels < 2.5 g/dl occurred in < 1% of patients, amylase levels> 3 times baseline in 2%, lipase levels > 3 times baseline in 11% and platelets < 50,000/mm³ in < 1%.

  Treatment beyond 48 weeks: continued treatment with entecavir for a median duration of 96 weeks did not reveal any new safety signals.

  Experience in lamivudine-refractory patients:

  The safety profile is based on treatment exposure to entecavir 1 mg once daily for a median of 69 weeks.

  Nervous system disorders:	Very common: headache Common: dizziness, somnolence
  Gastrointestinal disorders:	Common: vomiting, diarrhoea, nausea, dyspepsia
  General disorders and administration site conditions:	Common: fatigue
  Psychiatric disorders:	Common: insomnia

  Laboratory test abnormalities: 2% of patients had ALT elevations both > 10 times ULN and > 2 times baseline, 4% had ALT elevations> 3 times baseline, and < 1% had ALT elevations > 2 times baseline together with total bilirubin> 2 times ULN and> 2 times baseline. Amylase levels > 3 times baseline occurred in 2% of patients, lipase levels> 3 times baseline in 18% and platelets < 50,000/mm³ in < 1%.

  Treatment beyond 48 weeks: continued treatment with entecavir for a median duration of 96 weeks did not reveal any new safety signals.

  Exacerbations during treatment: in studies with nucleoside naive patients, on treatment ALT elevations > 10 times ULN and > 2 times baseline occurred in 2% of entecavir treated patients vs 4% of lamivudine treated patients. In studies with lamivudine-refractory patients, on treatment ALT elevations > 10 times ULN and > 2 times baseline occurred in 2% of entecavir treated patients vs 11% of lamivudine treated patients. Among entecavir-treated patients, on-treatment ALT elevations had a median time to onset of 45 weeks, generally resolved with continued treatment, and, in a majority of cases, 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 after discontinuation of treatment: acute exacerbations of hepatitis have been reported in patients who have discontinued anti-hepatitis B virus therapy, including therapy with entecavir (see section 4.4). In studies in nucleoside-naive patients, 6% of entecavirtreated patients and 10% of lamivudinetreated patients experienced ALT elevations (> 10 times ULN and > 2 times reference [minimum of baseline or last end-of-dosing measurement]) during post-treatment follow-up. Among entecavir-treated nucleoside-naive patients, ALT elevations had a median time to onset of 2324 weeks, and 86% (24/28) of ALT elevations occurred in HBeAg negative patients. In studies in lamivudine-refractory patients, with only limited numbers of patients being followed up, 11% of entecavir-treated patients and no lamivudine-treated patients developed ALT elevations during post-treatment follow-up.

  In the clinical trials entecavir treatment was discontinued if patients achieved a prespecified response. If treatment is discontinued without regard to treatment response, the rate of post-treatment ALT flares could be higher.

  Experience in patients coinfected with HIV: the safety profile of entecavir in a limited number of HIV/HBV co-infected patients on lamivudine-containing HAART (highly active antiretroviral therapy) regimens was similar to the safety profile in monoinfected HBV patients (see section 4.4).

  Gender/age: there was no apparent difference in the safety profile of entecavir with respect to gender (≈ 25% women in the clinical trials) or age (≈ 5% of patients > 65 years of age).

  Decompensated cirrhosis: a higher rate of serious hepatic adverse events has been observed in patients with decompensated cirrhosis compared with rates in patients with compensated liver function. This observation is based on limited experience in 45 patients with Child-Pugh score 7 at the start of entecavir treatment.

  Postmarketing experience: in addition to the adverse drug reactions identified from clinical trials, the following adverse reaction has been identified during post-approval use of entecavir.

  Skin and subcutaneous tissue disorders:

  frequency not known: rash