Entecavir (Baraclude) is a nucleoside reverse transcriptase inhibitor that is used in the treatment of patients with chronic active hepatitis B infection.

Entecavir (Baraclude) Uses:

• Chronic hepatitis B:

  • Used in the treatment of chronic hepatitis B virus (HBV) infection in adults and pediatric patients 2 years and older with evidence of active viral replication and either evidence of persistent transaminase elevations or histologically-active disease.

Note: In adults, the indication is based on data in patients with compensated and decompensated liver disease; in children, the indication is based on data in patients with compensated liver disease.

• Off Label Use of Entecavir in Adults:

  • HIV/HBV coinfection
  • Hepatitis B virus (HBV) reinfection prophylaxis after liver transplant.

Entecavir (Baraclude) Dose in Adults

Entecavir (Baraclude) Dose in the treatment of Hepatitis B virus (HBV) infection: Oral:

• Nucleoside treatment naive:
  • 0.5 mg once in a day
  • Lamivudine-refractory or -resistant viremia (or known lamivudine- or telbivudine-resistant mutations):
    • 1 mg once in a day.
• Decompensated liver disease:
  • 1 mg once in a day.

Treatment duration (AASLD practice guidelines):

• • Treatment duration for nucleos(t)ide analog-based therapy (eg, entecavir) is variable and influenced by HBeAg status, duration of HBV suppression, and presence of cirrhosis/decompensation:

• Patients without cirrhosis:

  • Hepatitis B e antigen (HBeAg) positive immune-active chronic hepatitis:
    • Treat until HBeAg seroconversion; after seroconversion, prolonged duration of therapy is often required in patients treated with nucleos(t)ide anaglogues,.
    • The optimal duration is unknown; however, consolidation therapy is generally a minimum of 12 months of persistently normal ALT and undetectable serum HBV DNA levels after HBeAg seroconversion
  • HBeAg-negative immune-active chronic hepatitis:
    • treatment discontinuation may be considered in patients with loss of HBsAg;
    • Indefinite antiviral therapy is suggested unless there is a competing rationale for discontinuation (risk/benefit decision); however, there is insufficient evidence to guide decisions in these patients.

• Patients with cirrhosis:

  • HBeAg-positive immune-active chronic hepatitis:
    • In patients who seroconvert on therapy, continue antiviral therapy indefinitely due to concerns with decompensation and death, unless there is a strong competing rationale for discontinuation.
  • HBeAg-negative immune-active chronic hepatitis:
    • Treatment discontinuation is not recommended due to potential for decompensation and death (limited data).

Viral breakthrough (AASLD practice guidelines):

Patients with confirmed viral breakthrough (HBV DNA ≥ 100 IU/mL with previously undetectable levels [<10 IU/mL] or >1 log increase in HBV DNA) should either be switched to an alternative antiviral monotherapy agent with a high genetic barrier to resistance or receive a second antiviral agent with a complementary resistance profile;

Entecavir (Baraclude) Dose in the treatment of HBV reinfection prophylaxis, after liver transplant (with or without HBIG) (off-label):

• Oral: 0.5 mg once in a day or
• 1 mg once in a day (Perrillo 2012)

Entecavir (Baraclude) Dose in the treatment of HIV/HBV coinfection (off-label): Oral:

• Nucleoside treatment-naive:
  • 0.5 mg once in a day.
• Lamivudine refractory or resistant:
  • 1 mg once in a day.

Note:

• Only recommended in patients who cannot take tenofovir;
• must be used in addition to a fully suppressive antiretroviral therapy regimen.

Entecavir (Baraclude) Dose in Children

Note: Oral tablets and solutions may be used interchangeably on an mg: mg basis.

Entecavir (Baraclude) Dose in the treatment of Chronic Hepatitis B infection (HBV): Oral:

Note:

• Optimal duration of treatment not established for nucleoside analogs, a minimum of 12 months and typically longer required;
• consolidation therapy of at least 6 months after seroconversion and complete viral suppression has been suggested.

• Children and Adolescents 2 to <16 years with compensated liver diseases:

  • Treatment naive:

    • 10 to 11 kg: 0.15 mg oral solution once in a day.
    • >11 to 14 kg: 0.2 mg oral solution once in a day.
    • >14 to 17 kg: 0.25 mg oral solution once in a day.
    • >17 to 20 kg: 0.3 mg oral solution once in a day.
    • >20 to 23 kg: 0.35 mg oral solution once in a day.
    • >23 to 26 kg: 0.4 mg oral solution once in a day.
    • >26 to 30 kg: 0.45 mg oral solution once in a day.
    • >30 kg: 0.5 mg oral solution or tablet once in a day.

  • Lamivudine-experienced:

    • 10 to 11 kg: 0.3 mg oral solution once in a day.
    • >11 to 14 kg: 0.4 mg oral solution once in a day.
    • >14 to 17 kg: 0.5 mg oral solution once in a day.
    • >17 to 20 kg: 0.6 mg oral solution once in a day.
    • >20 to 23 kg: 0.7 mg oral solution once in a day.
    • >23 to 26 kg: 0.8 mg oral solution once in a day.
    • >26 to 30 kg: 0.9 mg oral solution once in a day.
    • >30 kg: 1 mg oral solution or tablet once in a day.

• Adolescents ≥16 years:

  • Nucleoside treatment naïve with compensated liver disease:
    • 0.5 mg once daily
  • Lamivudine-refractory or known lamivudine or telbivudine-resistant mutations:
    • 1 mg once daily

Entecavir (Baraclude) Dose in the treatment of HIV/Hepatitis B virus coinfection: Limited data available:

Note: Only recommended in patients who cannot take tenofovir; must be used in addition to a fully suppressive antiretroviral therapy regimen: Oral:

• Nucleoside treatment-naive:

  • Adolescents:5 mg once daily.

• Lamivudine-refractory or -resistant with decompensated liver disease:

  • Children 12 years of age:
    • 5 mg once daily.
  • Adolescents:
    • 1 mg once daily.

Entecavir (Baraclude) Dose in the treatment of HBV reinfection prophylaxis, after liver transplant (with or without HBIG): Limited data available:

• Adolescents ≥16 years:

  • Oral: 1 mg once daily has been reported in an open-label trial of 65 patients (age range: 16 years and older); however, a lower dose of 0.5 mg once daily has also been used in adult patients (age range: 23 to 65 years).

Entecavir (Baraclude) Pregnancy Risk Category: C

• Animal studies have shown that teratogenic effects can be observed.
• Limited information is available on the use of pregnancy.
• For the treatment of chronic liver disease B during pregnancy, other agents might be more suitable.

Entecavir use during breastfeeding:

• It is unknown if breast milk contains entecavir.
• According to the manufacturer breastfeeding during therapy is a decision that should be made after considering the risks to infants and the benefits to mothers.

Entecavir (Baraclude) Dose in Kidney Disease:

• Daily-dosage regimen preferred:

  • CrCl ≥50 mL/minute:
    • No dosage adjustment is necessary.
  • CrCl 30-49 mL/minute:
    • Administer 50% of usual dose daily or administer the normal dose every 48 hours
  • CrCl 10-29 mL/minute:
    • Administer 30% of usual dose daily or administer the normal dose every 72 hours
  • CrCl <10 mL/minute (including hemodialysis and CAPD):
    • Administer 10% of usual dose daily or administer the normal dose every 7 days; administer after hemodialysis

Entecavir (Baraclude) Dose in Liver disease:

No dosage adjustment necessary.

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As reported with adult patients, unless otherwise noted.

Common Side Effects of Entecavir (Baraclude):

• Hepatic:

  • Increased serum alanine aminotransferase

Less Common Side Effects of Entecavir (Baraclude):

• Central Nervous System:

  • Headache
  • Fatigue

• Dermatologic:

  • Skin Rash

• Endocrine & Metabolic:

  • Glycosuria
  • Hyperglycemia

• Gastrointestinal:

  • Increased Serum Lipase
  • Abdominal Pain
  • Diarrhea
  • Nausea
  • Unpleasant Taste
  • Vomiting
  • Dyspepsia

• Genitourinary:

  • Hematuria

• Hepatic:

  • Increased Serum Bilirubin

• Renal:

  • Increased Serum Creatinine

Contraindications to Entecavir (Baraclude):

The US labeling of the manufacturer does not list any contraindications. Canadian labeling: Hypersensitivity of entecavir and any component

Warnings and precautions

• Lactic acidosis/ hepatomegaly: [US Boxed Warning]:

  • With nucleoside analog inhibiters, severe hepatomegaly and lactic acidosis have been reported (including fatal cases).;
  • Patients at high risk for liver disease should be treated with caution.
  • This includes patients who are female, obese, or have had prolonged nucleoside inhibition exposure.
  • It is important to stop treatment if a patient develops laboratory or clinical findings suggesting lactic acidosis, hepatotoxicity, or transaminase elevation.

• Chronic Hepatitis B: [US-Boxed Warning]

  • A severe, acute exacerbation may occur if anti-hepatitis B therapy is stopped, including entecavir.
  • After stopping treatment, monitor liver function. Restarting anti-hepatitis B therapy might be necessary.

• HIV: [US Boxed Warning]

  • HIV resistance may develop in patients with chronic hepatitis B who have untreated or not yet diagnosed HIV infection.
  • Before starting treatment with entecavir, it is important to determine your HIV status.
  • If you are HIV/HBV coinfected, it is not recommended that you also receive antiretroviral treatment.
  • According to the manufacturer's labeling, entecavir doesn't have any clinically relevant activity against human immunodeficiency viruses (HIV type 1)
  • A few cases have reported a decline in virus levels after entecavir treatment.
  • HIV resistance to common HIV drugs has been reported in an HIV/HBV patient who received entecavir monotherapy for HBV.

• Hepatic impairment

  • Adjustment not necessary
  • There are limited data on chronic hepatitis B treatment in patients with decompensated hepatitis B; be aware of increased adverse reactions and hepatorenal dysfunction.

• Renal impairment

  • Patients with kidney impairment and patients who are receiving concomitant therapy that may decrease renal function should be cautious. Dose adjustment is recommended for CrCl less than 50 mL/minute.

Entecavir: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Risk Factor C (Monitor therapy)
Orlistat	May decrease the serum concentration of Antiretroviral Agents.
Risk Factor X (Avoid combination)
Cladribine	Agents that Undergo Intracellular Phosphorylation may diminish the therapeutic effect of Cladribine.

Monitoring parameters:

Manufacturer’s labeling:

• HIV status (prior to initiation of therapy);
• periodic monitoring of hepatic function is recommended during treatment and for at least several months after treatment in patients who discontinue anti-hepatitis B therapy.
• Monitor patients for signs and symptoms of lactic acidosis and hepatotoxicity.

Alternate recommendations:

• Chronic Hepatitis B:
  • HBV DNA and ALT (HBV DNA usually done every 3 months until undetectable and then every 3 to 6 months thereafter);
  • HBeAg;
  • anti-HBe (in patients who are HBeAg-positive to monitor for seroconversion);
  • HBsAg;
  • consider monitoring lactic acid levels (if clinical concern);
  • following discontinuation, monitor for recurrent viremia, ALT flares, seroreversion, and clinical decompensation every 3 months for at least 1 year.
  • As antivirals do not eliminate the risk of hepatocellular carcinoma, continued monitoring for this complication is recommended in at-risk patients.

How to administer Entecavir (Baraclude)?

• Administer on an empty stomach (2 hours before or after a meal).
• Do not dilute or mix the oral solution with water or other beverages; use a calibrated oral dosing syringe.
• Oral solutions and tablets are bioequivalent on an mg-to-mg basis.

Mechanism of action of Entecavir (Baraclude):

• Entecavir is intracellularly phosphorylated as guanosine triphosphate, which competes against natural substrates to inhibit hepatitis B viral Polymerase.
• Enzyme inhibition blocks reverse transcriptase activity, thereby reducing viral genome synthesis.

Notification:

• Pediatric patients with a pharmacokinetic age >=2 years have similar pharmacokinetics to adults.

Absorption:

• Delayed with food; C decreased 44% to 46%, AUC decreased 18% to 20%

Distribution:

• Extensive (V in excess of body water)

Protein binding:

• ~13 percent

Metabolism:

• Minor hepatic glucuronide/sulfate conjugation

Bioavailability:

• Tablet and oral solution are bioequivalent.

Half-life elimination:

• Terminal: ~5-6 days;
• accumulation: ~24 hours

Time to peak, plasma:

• 0.5-1.5 hours

Excretion:

• Urine (60 percent  to 73 percent  as unchanged drug)

International Brand Names of Entecavir:

• Baraclude
• Bacavir
• Baraclude
• Baracross
• Baraenter
• Baraliver
• Baratis Film
• Barcavir
• Caviclude
• Encavir
• APO-Entecavir
• Auro-Entecavir
• JAMP-Entecavir
• PMS-Entecavir
• Agicarvir
• Atevir
• Encavor
• Enped
• Entavir
• Enteca
• Entecabell
• Enteclud
• Entegard
• Enteone
• Entikav
• Hepaclude
• Nulesavir
• Orata
• Tecavir
• Teviral

Entecavir Brand Names in Pakistan:

Entecavir Syrup 0.05 Mg/5ml
Cavidix	Neo Medix

 

Entecavir Suspension 0.05 Mg
Encavir	Selmore Agencies

 

Entecavir Oral Solution 0.05 Mg
Ecavir	Macter International (Pvt) Ltd.

 

Entecavir Oral Solution 0.05 Mg
Ecavir	Macter International (Pvt) Ltd.

 

Entecavir Tablets 1 Mg
Bvir	Bosch Pharmaceuticals (Pvt) Ltd.
Cavira	Brookes Pharmaceutical Laboratories (Pak.) Ltd.
Caviral	Navegal Laboratories
Cure-B	Global Pharmaceuticals
Ecavir	Macter International (Pvt) Ltd.
Entehep	Well & Well Pharma (Pvt) Ltd
Envir	Highnoon Laboratories Ltd.
Envir	Highnoon Laboratories Ltd.
Eteva	S.J. & G. Fazul Ellahie (Pvt) Ltd.
Kavyr	Shawan Pharmaceuticals
Obee	Genome Pharmaceuticals (Pvt) Ltd
Rotavir	Rotex Medica Pakistan (Pvt) Ltd
Ticavir	Shaigan Pharmaceuticals (Pvt) Ltd
Xotivir	Safe Pharmaceutical (Pvt) Ltd.

 

Entecavir Tablets 0.5 Mg]
B-Vir	Danas Pharmaceuticals (Pvt) Ltd
Bvir	Bosch Pharmaceuticals (Pvt) Ltd.
Cavidix	Neo Medix
Cavira	Brookes Pharmaceutical Laboratories (Pak.) Ltd.
Caviral	Navegal Laboratories
Centauru S	Ferozsons Laboratoies Ltd.
Cure-B	Global Pharmaceuticals
Dycavir	Dyson Research Laboratories
Entab	Nova Med Pharmaceuticals
Entaveer	Olive Laboratories
Entawin	Mass Pharma (Private) Limited
Entca	Caraway Pharmaceuticals
Entecavir	Cirin Pharmaceuticals (Pvt) Ltd.
Entegen	Biogen Pharma
Entehep	Well & Well Pharma (Pvt) Ltd
Entevir	Swan Pharmaceuticals(Pvt) Ltd
Entivar	Prays Pharmaceuticals
Entvir	Amson Vaccines & Pharma (Pvt) Ltd.
Entvir	Amson Vaccines & Pharma (Pvt) Ltd.
Envir	Highnoon Laboratories Ltd.
Envir	Highnoon Laboratories Ltd.
Etec	Panacea Pharmaceuticals
Genovirex	Atco Laboratories Limited
Hepavir	Xenon Pharmaceuticals (Pvt) Ltd.
Jecoric	Macter International (Pvt) Ltd.
Kavyr	Shawan Pharmaceuticals
Letecia	Fassgen Pharmaceuticals
Neo-Vir	Linear Pharma
Novir	Gene-Tech Laboratories
Obee	Genome Pharmaceuticals (Pvt) Ltd
Rotavir	Rotex Medica Pakistan (Pvt) Ltd
Tacavir	Consolidated Chemical Laboratories (Pvt) Ltd.
Tecarall	Nimrall Laboratories
Tecarall	Nimrall Laboratories
Ticavir	Shaigan Pharmaceuticals (Pvt) Ltd
Welkavir	Welmark Pharmaceuticals
Xclude	Wns Field Pharmaceuticals
Xotivir	Safe Pharmaceutical (Pvt) Ltd.