Version May 2024
Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued antihepatitis B therapy, including entecavir. Closely monitor hepatic function with clinical and laboratory follow-up for at least several months in patients who discontinue antihepatitis B therapy. If appropriate, initiation of antihepatitis B therapy may be warranted.
Limited clinical experience suggests there is a potential for the development of resistance to HIV nucleoside reverse transcriptase inhibitors if entecavir is used to treat chronic hepatitis B virus (HBV) infection in patients with HIV infection not being treated. Therapy with entecavir is not recommended for HIV/HBV coinfected patients who are not also receiving antiretroviral therapy.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogue inhibitors alone or in combination with antiretrovirals.
Hepatitis B virus infection, treatment: Oral:
Nucleoside-treatment naive, compensated liver disease: 0.5 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 hepatitis B virus (HBV) suppression, and presence of cirrhosis/decompensation (Ref).
Patients without cirrhosis:
Hepatitis B e antigen (HBeAg) positive immune-active chronic hepatitis: Treat until HBeAg seroconversion; after seroconversion, prolonged consolidation therapy is often required in patients treated with nucleos(t)ide analogues to prevent hepatitis flares. 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 compensated 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).
Patients with decompensated cirrhosis: Individuals with decompensated cirrhosis should receive indefinite therapy regardless of HBV DNA level, HBeAg status, or ALT level.
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 (Ref).
Hepatitis B virus reactivation prophylaxis, immunocompromised patients (off-label use): Oral: 0.5 mg once daily (Ref).
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function: Note: Daily-dosage regimen preferred.
CrCl ≥50 mL/minute: No dosage adjustment necessary.
CrCl 30 to <50 mL/minute: Administer 50% of usual indication-specific dose daily. Alternatively, administer the usual indication-specific dose every 48 hours.
CrCl 10 to <30 mL/minute: Administer 30% of usual indication-specific dose daily. Alternatively, administer the usual indication-specific dose every 72 hours.
CrCl <10 mL/minute: Administer 10% of usual indication-specific dose daily. Alternatively, administer the usual indication-specific dose every 7 days.
Hemodialysis, intermittent (thrice weekly): Not significantly dialyzed (13%): Administer 10% of usual indication-specific dose daily. Alternatively, administer usual indication-specific dose every 7 days (Ref). When scheduled dose falls on a dialysis day, administer after hemodialysis.
Peritoneal dialysis: Not significantly dialyzed (0.3% over 7 days): Administer 10% of usual indication-specific dose daily. Alternatively, administer usual indication-specific dose every 7 days (Ref).
CRRT: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and effluent flow rates of 20 to 25 mL/kg/hour (or ~1,500 to 3,000 mL/hour) unless otherwise noted. Close monitoring of response and adverse reactions due to drug accumulation is important.
No data available in patients on CRRT; because significant clearance is unlikely (large Vd, low intermittent dialysis clearance), may consider administering 10% of usual indication-specific dose daily. Alternatively, administer usual indication-specific dose every 7 days (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Close monitoring of response and adverse reactions due to drug accumulation is important.
No data available in patients on PIRRT; because significant clearance is unlikely (large Vd, low intermittent dialysis clearance), may consider administering 10% of usual indication-specific dose daily. Alternatively, administer usual indication-specific dose every 7 days. When scheduled dose falls on a PIRRT session day, administer after PIRRT (Ref).
No dosage adjustment necessary.
Refer to adult dosing.
(For additional information see "Entecavir: Pediatric drug information")
Note: Oral tablets and solution may be used interchangeably on a mg:mg basis.
Chronic hepatitis B (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 (Ref).
Children and Adolescents 2 to <16 years with compensated liver diseases:
Treatment naive:
10 to 11 kg: 0.15 mg oral solution once daily.
>11 to 14 kg: 0.2 mg oral solution once daily.
>14 to 17 kg: 0.25 mg oral solution once daily.
>17 to 20 kg: 0.3 mg oral solution once daily.
>20 to 23 kg: 0.35 mg oral solution once daily.
>23 to 26 kg: 0.4 mg oral solution once daily.
>26 to 30 kg: 0.45 mg oral solution once daily.
>30 kg: 0.5 mg oral solution or tablet once daily.
Lamivudine-experienced (ie, >12 weeks of prior lamivudine therapy):
10 to 11 kg: 0.3 mg oral solution once daily.
>11 to 14 kg: 0.4 mg oral solution once daily.
>14 to 17 kg: 0.5 mg oral solution once daily.
>17 to 20 kg: 0.6 mg oral solution once daily.
>20 to 23 kg: 0.7 mg oral solution once daily.
>23 to 26 kg: 0.8 mg oral solution once daily.
>26 to 30 kg: 0.9 mg oral solution once daily.
>30 kg: 1 mg oral solution or tablet once daily.
Adolescents ≥16 years:
Nucleoside treatment naive with compensated liver disease: 0.5 mg once daily.
Lamivudine-refractory or known lamivudine or telbivudine-resistant mutations: 1 mg once daily.
Hepatitis B virus reinfection prophylaxis, post 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) (Ref).
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 (Ref): Oral:
Nucleoside treatment naive: Adolescents: 0.5 mg once daily (Ref).
Lamivudine-refractory or -resistant with decompensated liver disease:
Children 12 years of age: 0.5 mg once daily (Ref).
Adolescents: 1 mg once daily (Ref).
Children and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling; insufficient data to recommend a specific dose adjustment 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.
Children ≥ 2 years and Adolescents: No adjustment necessary.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. As reported with adult patients, unless otherwise noted.
>10%: Hepatic: Increased serum alanine aminotransferase (>5 x ULN: 11% to 12%; >10 x ULN and >2 x baseline: 2%)
1% to 10%:
Dermatologic: Skin rash (children and adolescents: >1%)
Endocrine & metabolic: Glycosuria (4%), hyperglycemia (2% to 3%)
Gastrointestinal: Abdominal pain (children and adolescents: >1%), diarrhea (children and adolescents: >1%; adults: ≤1%), dyspepsia (≤1%), increased serum lipase (7%), nausea (children and adolescents: >1%; adults: <1%), vomiting (children and adolescents: >1%; adults: <1%)
Genitourinary: Hematuria (9%)
Hepatic: Increased serum bilirubin (2% to 3%)
Nervous system: Fatigue (1% to 3%), headache (2% to 4%)
Renal: Increased serum creatinine (1% to 2%)
<1%:
Endocrine & metabolic: Decreased serum albumin
Hematologic & oncologic: Thrombocytopenia
Nervous system: Dizziness, drowsiness, insomnia
Frequency not defined: Hepatic: Exacerbation of hepatitis B (severe, acute, with discontinuation)
Postmarketing:
Dermatologic: Alopecia
Endocrine & metabolic: Lactic acidosis
Hematologic & oncologic: Malignant neoplasm
Hepatic: Hepatocellular neoplasm, hepatomegaly with steatosis, increased serum transaminases
Hypersensitivity: Nonimmune anaphylaxis
Ophthalmic: Macular edema (Muqit 2011)
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Hypersensitivity to entecavir or any component of the formulation
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).
Disease-related concerns:
• 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.
Special populations:
• 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.
Other warnings/precautions:
• Resistance: Cross-resistance may develop in patients failing previous therapy with lamivudine.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Oral:
Baraclude: 0.05 mg/mL (210 mL) [contains methylparaben, propylparaben; orange flavor]
Tablet, Oral:
Baraclude: 0.5 mg, 1 mg
Generic: 0.5 mg, 1 mg
May be product dependent
Solution (Baraclude Oral)
0.05 mg/mL (per mL): $5.49
Tablets (Baraclude Oral)
0.5 mg (per each): $54.90
1 mg (per each): $54.90
Tablets (Entecavir Oral)
0.5 mg (per each): $2.60 - $60.00
1 mg (per each): $2.60 - $60.00
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Baraclude: 0.5 mg [contains polysorbate 80]
Generic: 0.5 mg, 1 mg
Oral: 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.
Oral: Administer on an empty stomach (2 hours before or after a meal).
Oral solution: Do not dilute or mix oral solution with water or other beverages; use calibrated oral dosing syringe.
Hazardous agent (NIOSH 2016 [group 2]).
Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage.
NIOSH recommends single gloving for administration of intact tablets or capsules. NIOSH recommends double gloving, a protective gown, and (if there is a potential for vomit or spit up) eye/face protection for administration of an oral liquid/feeding tube administration (NIOSH 2016). Assess risk to determine appropriate containment strategy (USP-NF 2017).
Chronic hepatitis B: Treatment of chronic hepatitis B virus (HBV) infection in adults and pediatric patients ≥2 years of age 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, HBeAg-positive liver disease.
Hepatitis B virus reactivation prophylaxis, immunocompromised patients; Hepatitis B virus reinfection prophylaxis, post liver transplant
Substrate of OCT2
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Cladribine: Agents that Undergo Intracellular Phosphorylation may diminish the therapeutic effect of Cladribine. Risk X: Avoid combination
Orlistat: May decrease the serum concentration of Antiretroviral Agents. Risk C: Monitor therapy
Food delays absorption and reduces AUC by 18% to 20%. Management: Administer on an empty stomach 2 hours before or after a meal.
Treatment for hepatitis B should be evaluated prior to pregnancy. Entecavir is not recommended for use in pregnant patients (AASLD [Terrault 2018]; EASL 2017).
Outcome data following maternal use of entecavir during pregnancy are available (Gao 2022; Kakiuchi 2021; Tavakolpour 2018; Yang 2022). Agents other than entecavir are recommended when hepatitis B treatment is needed in pregnant patients. Patients who become pregnant while taking entecavir should be switched to the preferred agent (AASLD [Terrault 2018]; EASL 2017).
Data collection to monitor pregnancy and infant outcomes following exposure to entecavir are ongoing. Health care providers are encouraged to enroll patients exposed to entecavir during pregnancy in the antiretroviral pregnancy registry (1-800-258-4263).
It is not known if entecavir is present in breast milk.
Patients requiring antivirals for hepatitis B may breastfeed if the infant received immunoprophylaxis at birth; however, recommendations are not specific to entecavir, and other agents may be preferred (AASLD [Terrault 2018]; EASL 2017; SMFM [Dionne-Odom 2016]). According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.
Take on an empty stomach (2 hours before or after a meal).
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 (AASLD [Terrault 2018]). Renal function at baseline and at least annually; monitor renal function more frequently in patients at high risk of renal dysfunction (WHO 2015).
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.
Note: The pharmacokinetics of pediatric patients ≥2 years are similar to adult values.
Absorption: Delayed with food; Cmax decreased 44% to 46%, AUC decreased 18% to 20%
Distribution: Extensive (Vd in excess of body water)
Protein binding: ~13%
Metabolism: Minor hepatic glucuronide/sulfate conjugation
Bioavailability: Tablet and oral solution are bioequivalent.
Half-life elimination: Terminal: ~5 to 6 days; accumulation: ~24 hours
Time to peak, plasma: 0.5 to 1.5 hours
Excretion: Urine (60% to 73% as unchanged drug)
Altered kidney function: 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.
Older adult: 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.
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