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.

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

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: