(en TE ka veer)
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Baraclude: 0.05 mg/mL (210 mL) [contains methylparaben, propylparaben; orange flavor]
Baraclude: 0.5 mg, 1 mg
Generic: 0.5 mg, 1 mg
Brand Names: U.S.
- Antihepadnaviral, Reverse Transcriptase Inhibitor, Nucleoside (Anti-HBV)
Entecavir is intracellularly phosphorylated to guanosine triphosphate which competes with natural substrates to effectively inhibit hepatitis B viral polymerase; enzyme inhibition blocks reverse transcriptase activity thereby reducing viral DNA synthesis.
Delayed with food; Cmax decreased 44% to 46%, AUC decreased 18% to 20%
Extensive (Vd in excess of body water)
Minor hepatic glucuronide/sulfate conjugation
Urine (60% to 73% as unchanged drug)
Time to Peak
Terminal: ~5-6 days; accumulation: ~24 hours
Special Populations: Renal Function Impairment
Apparent oral clearance of entecavir decreased as CrCl decreased. Cmax and AUC increased. Hemodialysis removed about 13% of the entecavir dose over 4 hours; continuous ambulatory peritoneal dialysis (CAPD) removed about 0.3% of the dose during 7 days.
Special Populations: Elderly
AUC was 29.3% greater in elderly subjects, most likely because of differences in renal function. Base dose adjustment of entecavir on renal function of patient, not on age.
Use: Labeled Indications
Chronic hepatitis B: 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, indication is based on data in patients with compensated and decompensated liver disease; in children, indication is based on data in patients with compensated liver disease.
Off Label Uses
Hepatitis B virus (HBV) reinfection prophylaxis, post liver transplant
Data from an open-label, prospective study supports the use of entecavir for the prophylaxis of HBV reinfection after liver transplantation [Fung 2011]. Another phase IIIb, single-arm, open-label study in patients undergoing orthotopic liver transplantation for chronic hepatitis B infection with HBV DNA <172 IU/mL at time of transplant supports the use of entecavir in this setting [Perillo 2012]. Additional trials may be necessary to further define the role of entecavir in this setting.
Based on the Department of Health and Human Services (DHHS) Panel on Antiretroviral Guidelines for Adults and Adolescents, entecavir (in combination with a fully suppressive antiretroviral regimen) is effective and recommended in the management of HIV/HBV coinfected patients.
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Hypersensitivity to entecavir or any component of the formulation
Hepatitis B virus (HBV) infection, treatment: Oral:
Nucleoside treatment naive: 0.5 mg once daily
Lamivudine-refractory or -resistant viremia (or known lamivudine- or telbivudine-resistant mutations): 1 mg once daily
Decompensated liver disease: 1 mg once daily
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 (AASLD [Terrault 2016]):
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,. 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: Indefinite antiviral therapy is suggested unless there is competing rationale for discontinuation (risk/benefit decision); treatment discontinuation may be considered in patients with loss of HBsAg; 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; consult current clinical practice guidelines for recommended agents (AASLD [Terrault 2016]).
HBV reinfection prophylaxis, post liver transplant (with or without HBIG) (off-label use): Oral: 0.5 mg once daily (Fung, 2011) or 1 mg once daily (Perrillo 2012)
HIV/HBV coinfection (off-label use): Oral:
Nucleoside treatment naive: 0.5 mg once daily
Lamivudine refractory or resistant: 1 mg once daily
Note: Only recommended in patients who cannot take tenofovir; must be used in addition to a fully suppressive antiretroviral therapy regimen (DHHS, 2013).
Refer to adult dosing.
Hepatitis B virus (HBV) infection, treatment (nucleoside treatment naïve or lamivudine-refractory or -resistant viremia [or known lamivudine- or telbivudine-resistance mutations]):
Children ≥2 years and Adolescents: Oral: Note: Oral solution should be used for patients weighing ≤30 kg.
10 to 11 kg: 0.15 mg once daily (oral solution)
>11 to 14 kg: 0.2 mg once daily (oral solution)
>14 to 17 kg: 0.25 mg once daily (oral solution)
>17 to 20 kg: 0.3 mg once daily (oral solution)
>20 to 23 kg: 0.35 mg once daily (oral solution)
>23 to 26 kg: 0.4 mg once daily (oral solution)
>26 to 30 kg: 0.45 mg once daily (oral solution)
>30 kg: 0.5 mg once daily (oral solution or tablet)
10 to 11 kg: 0.3 mg once daily (oral solution)
>11 to 14 kg: 0.4 mg once daily (oral solution)
>14 to 17 kg: 0.5 mg once daily (oral solution)
>17 to 20 kg: 0.6 mg once daily (oral solution)
>20 to 23 kg: 0.7 mg once daily (oral solution)
>23 to 26 kg: 0.8 mg once daily (oral solution)
>26 to 30 kg: 0.9 mg once daily (oral solution)
>30 kg: 1 mg once daily (oral solution or tablet)
Dosing: Renal Impairment
Adults: Daily-dosage regimen preferred:
CrCl ≥50 mL/minute: No dosage adjustment 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
Children >2 years and Adolescents: Insufficient data to recommend a specific dose adjustment in pediatric patients with renal impairment; consider a reduction in the dose or an increase in the dosing interval similar to adjustments for adults.
Dosing: Hepatic Impairment
Adults: No dosage adjustment necessary.
Children >2 years and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Administer on an empty stomach (2 hours before or after a meal). Do not dilute or mix oral solution with water or other beverages; use calibrated oral dosing syringe. Oral solution and tablet are bioequivalent on a mg-to-mg basis.
Take on an empty stomach (2 hours before or after a meal).
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light. After opening, oral solution can be used up to expiration date on the bottle.
Orlistat: May decrease the serum concentration of Antiretroviral Agents. Monitor therapy
Adverse reactions are generally similar in adult and pediatric patients.
Cardiovascular: Peripheral edema (16% with decompensated liver disease)
Hepatic: Ascites (15% with decompensated liver disease), increased serum ALT (>5 x ULN: 11% to 12%; post-treatment flare [lamivudine refractory]: >10 x ULN and >2 x baseline: 12%)
Renal: Increased serum creatinine (11% with decompensated liver disease; 1% to 2% with compensated liver disease)
Miscellaneous: Fever (14% with decompensated liver disease)
1% to 10%:
Central nervous system: Headache (2% to 4%), fatigue (1% to 3%), dizziness
Dermatologic: Skin rash
Endocrine & metabolic: Glycosuria (4%), hyperglycemia (2% to 3%), decreased serum bicarbonate (2% with decompensated liver disease)
Gastrointestinal: Increased serum lipase (7%), increased serum amylase (2% to 3%), abdominal pain (children and adolescents >1%), diarrhea (children and adolescents >1%; adults ≤1%), unpleasant taste (children and adolescents >1%), vomiting (children and adolescents >1%; adults <1%), dyspepsia (≤1%), nausea
Genitourinary: Hematuria (9%)
Hematologic & oncologic: Hepatic carcinoma (6% with decompensated liver disease)
Hepatic: Hepatic encephalopathy (10% with decompensated liver disease), increased serum bilirubin (2% to 3%), increased serum ALT (>10 x ULN and >2 x baseline: 2%; post-treatment flare [nucleoside-naive]: >10 x ULN and >2 x baseline: 2% to 8%)
Respiratory: Upper respiratory tract infection (10% with decompensated liver disease)
<1% (Limited to important or life-threatening): Alopecia, anaphylactoid reaction, hepatomegaly, insomnia, lactic acidosis, macular edema (Muqit, 2011), renal failure, thrombocytopenia
Concerns related to adverse effects:
• Lactic acidosis/hepatomegaly: [US Boxed Warning]: Lactic acidosis and severe hepatomegaly with steatosis (including fatal cases) have been reported with nucleoside analogue inhibitors; use with caution in patients with risk factors for liver disease (risk may be increased with female gender, decompensated liver disease, obesity, or prolonged nucleoside inhibitor exposure) and suspend treatment in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity (transaminase elevation may/may not accompany hepatomegaly and steatosis).
• Chronic hepatitis B: [US Boxed Warning]: Severe, acute exacerbation of hepatitis B may occur upon discontinuation of antihepatitis B therapy, including entecavir. Monitor liver function for at least several months after stopping treatment; reinitiation of antihepatitis B therapy may be required.
• HIV: [US Boxed Warning]: May cause the development of HIV resistance in chronic hepatitis B patients with unrecognized or untreated HIV infection. Determine HIV status prior to initiating treatment with entecavir. Not recommended for HIV/HBV coinfected patients unless also receiving antiretroviral therapy. The manufacturer's labeling states that entecavir does not exhibit any clinically-relevant activity against human immunodeficiency virus (HIV type 1). However, a small number of case reports have indicated declines in virus levels during entecavir therapy. HIV resistance to a common HIV drug has been reported in an HIV/HBV-infected patient receiving entecavir as monotherapy for HBV.
• Hepatic impairment: Dose adjustment not required. Limited data supporting treatment of chronic hepatitis B in patients with decompensated liver disease; observe for increased adverse reactions, including hepatorenal dysfunction.
• Renal impairment: Use with caution in patients with renal impairment or patients receiving concomitant therapy which may reduce renal function; dose adjustment recommended for CrCl <50 mL/minute.
• Children: There are limited data available on the use of entecavir in lamivudine-experienced pediatric patients; use in these patients only if the potential benefit justifies the potential risk to the child.
Dosage form specific issues:
• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson, 2002; Lucente 2000; Shelley, 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade, 1986; CDC, 1984). See manufacturer’s labeling.
• Resistance: Cross-resistance may develop in patients failing previous therapy with lamivudine.
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 (AASLD [Terrault 2016]). As antivirals do not eliminate the risk of hepatocellular carcinoma, continued monitoring for this complication is recommended in at-risk patients.
Pregnancy Risk Factor
Teratogenic effects have been observed in animal studies. Information related to use in pregnancy is limited; use only if other options are inappropriate (DHHS [OI], 2013). Pregnant women taking entecavir should enroll in the pregnancy registry by calling 1-800-258-4263.
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience headache, dizziness, nausea, or loss of strength and energy. Have patient report immediately to prescriber signs of lactic acidosis (fast breathing, tachycardia, abnormal heartbeat, vomiting, fatigue, shortness of breath, severe loss of strength and energy, severe dizziness, feeling cold, or muscle pain or cramps), or signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice) (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
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- Drug class: nucleoside reverse transcriptase inhibitors (NRTIs)
Other brands: Baraclude