Entecavir (Monograph)

Brand name: Baraclude
Drug class: Nucleosides and Nucleotides

Medically reviewed by Drugs.com on Dec 16, 2023. Written by ASHP.

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Introduction

Antiviral; purine nucleoside analog derived from guanine.

Uses for Entecavir

Chronic HBV Infection

Treatment of chronic HBV infection in adults and pediatric patients ≥2 years of age with evidence of active HBV replication and either persistent elevations in serum aminotransaminases (ALT or AST) or histologic evidence of active disease.

Has been effective in adults and adolescents ≥16 years of age with hepatitis B e antigen (HBeAg)-positive or HBeAg-negative chronic HBV infection with compensated liver disease who were nucleoside-naïve (had not previously received treatment with nucleoside antivirals) or had lamivudine-refractory HBV; most had compensated liver disease, a limited number had decompensated liver disease.

Has been effective in pediatric patients ≥2 years of age with HBeAg-positive chronic HBV infection who were nucleoside-naïve or lamivudine-experienced with compensated liver disease.

Has not been evaluated for treatment of chronic HBV infection in HIV-infected patients not receiving antiretroviral therapy; do not use for treatment of HBV infection in such patients.

Only limited efficacy and safety data available regarding use for treatment of chronic HBV infection in liver transplant recipients.

Entecavir is one of several preferred initial treatment options in adults and pediatric patients when chronic HBV treatment is indicated; choice of antiviral medication should be individualized based on patient characteristics and comorbidities, treatment tolerability, and cost.

Entecavir Dosage and Administration

General

Pretreatment Screening

• Offer human immunodeficiency virus (HIV) antibody testing to all patients prior to initiating entecavir therapy.

• Carefully monitor renal function before initiating entecavir therapy in liver transplant recipients who have received or are receiving an immunosuppressant that may affect renal function (e.g., cyclosporine, tacrolimus).

Patient Monitoring

• Carefully monitor renal function during treatment with entecavir in elderly patients and in liver transplant recipients who have received or are receiving an immunosuppressant that may affect renal function (e.g., cyclosporine, tacrolimus).

• Closely monitor hepatic function with both clinical and laboratory follow-up for at least several months after discontinuing treatment with entecavir.

• Monitor hepatic function periodically during treatment.

• Monitor for adverse events if entecavir is coadministered with other drugs that are renally eliminated or are known to affect renal function.

Dispensing and Administration Precautions

• Handling and Disposal: Entecavir meets the National Institute for Occupational Safety and Health (NIOSH) definition of a hazardous drug, but does not have manufacturer’s safe handling instructions or is not classified as a known or probable carcinogen by the National Toxicology Program or International Agency for Research on Cancer. Use appropriate precautions for receiving, handling, administration, and disposal.

Administration

Oral Administration

Available as tablets and oral solution.

Administer orally on an empty stomach at least 2 hours before or 2 hours after meals.

Administer oral solution using supplied oral dosing spoon according to manufacturer’s patient instructions. Do not dilute or mix oral solution with water or any other liquid. Refer to full prescribing information for specific instructions for administration of the oral solution.

Dosage

Pediatric Patients

Chronic HBV Infection

Oral

Pediatric patients ≥2 years of age weighing ≥10 kg: Dosage based on weight. (See Table 1.) For those weighing ≤30 kg, use oral solution.

Treatment-naïve pediatric patients weighing >30 kg should receive 0.5 mg (10 mL) of entecavir oral solution once daily or one 0.5-mg tablet once daily.

Lamivudine-experienced pediatric patients weighing >30 kg should receive 1 mg (20 mL) of entecavir oral solution once daily or one 1-mg tablet once daily.

Adolescents ≥16 years of age (nucleoside-naïve): 0.5 mg once daily.

Adolescents ≥16 years of age (lamivudine-refractory HBV or known lamivudine- or telbivudine-associated resistance mutations): 1 mg once daily.

Optimal duration of treatment unknown. Relationship between treatment and long-term outcomes (e.g., cirrhosis, hepatocellular carcinoma) unknown.

Adults

Chronic HBV Infection

Compensated Liver Disease

Oral

Nucleoside-naïve: 0.5 mg once daily.

Lamivudine-refractory HBV or known lamivudine- or telbivudine-associated resistance mutations: 1 mg once daily.

Optimal duration of treatment unknown. Relationship between treatment and long-term outcomes (e.g., cirrhosis, hepatocellular carcinoma) unknown.

Decompensated Liver Disease

Oral

1 mg once daily.

Optimal duration of treatment unknown. Relationship between treatment and long-term outcomes (e.g., cirrhosis, hepatocellular carcinoma) unknown.

Special Populations

Hepatic Impairment

Dosage adjustments not needed.

Renal Impairment

Adults with Cl_cr <50 mL/minute, including those undergoing hemodialysis or CAPD: Adjust dosage. (See Table 2.) Manufacturer states once-daily regimens preferred.

For doses <0.5 mg, use entecavir oral solution.

When a dose is indicated on a hemodialysis day, administer dose after the hemodialysis session.

Insufficient data in pediatric patients with renal impairment; consider dose reduction or increase in dosing interval similar to adjustments for adults.

Geriatric Use

Select dosage with caution due to possible age-related decreases in renal function; may be helpful to also monitor renal function.

Cautions for Entecavir

Contraindications

• None.

Warnings/Precautions

Warnings

Severe Acute Exacerbations of HBV Infection

Severe acute exacerbations of HBV reported following discontinuance of anti-HBV therapy, including entecavir.

Exacerbations of hepatitis or ALT flare (e.g., ALT elevations >10 times ULN and >2 times reference level [minimum of the baseline concentration or last measurement at the end of dosing]) reported in 2, 8, or 12% of nucleoside-naïve HBeAg-positive patients, nucleoside-naïve HBeAg-negative patients, or lamivudine-refractory patients, respectively, following discontinuance of entecavir. Median time to exacerbations of hepatitis was 23 weeks.

Exacerbations of hepatitis also reported during entecavir treatment of HBV, but generally resolved with continued therapy.

Closely monitor hepatic function with both clinical and laboratory follow-up for at least several months after entecavir is discontinued. If appropriate, resumption of anti-HBV therapy may be warranted. (See Boxed Warning.)

Coinfection with HIV

Has not been systematically evaluated in HBV-infected patients coinfected with HIV who are not receiving concomitant antiretroviral therapy. Use of entecavir is not recommended for treatment of HBV/HIV coinfection in patients who are not receiving highly active antiretroviral therapy, since limited clinical evidence suggests there is potential for development of resistance to HIV nucleoside reverse transcriptase inhibitors if entecavir is used to treat chronic HBV infection in patients with untreated HIV infection.

Offer HIV testing to all patients prior to initiating entecavir therapy.

Has not been systematically evaluated for treatment of HIV infection and such use not recommended. (See Boxed Warning.)

Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis (including some fatalities) reported in patients receiving nucleoside analogs alone or in conjunction with antiretrovirals. Most reported cases involved women; obesity and long-term therapy with NRTIs also may be risk factors.

Use nucleoside analogs with particular caution in patients with known risk factors for liver disease; however, lactic acidosis and severe hepatomegaly with steatosis have also been reported in patients with no known risk factors.

Lactic acidosis in patients receiving entecavir often is reported in association with hepatic decompensation, other serious medical conditions, or drug exposures. Patients with decompensated liver disease may be at higher risk of lactic acidosis.

Discontinue entecavir in any patient with clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked aminotransferase elevations). (See Boxed Warning.)

Specific Populations

Pregnancy

A pregnancy exposure registry (Antiretroviral Pregnancy Registry [APR]) monitors maternal-fetal outcomes of pregnant women exposed to entecavir; clinicians encouraged to enroll patients in the pregnancy registry at 800-258-4263.

Prospective data from the APR insufficient to adequately evaluate the risk of birth defects, miscarriage, or adverse maternal or fetal outcomes. The limited number of entecavir exposures reported to the APR is insufficient to inform a risk assessment in comparison to a reference population. Rate of miscarriage not reported in the APR.

In animal reproduction studies, no evidence of developmental toxicities observed in rats or rabbits at systemic entecavir exposures approximately 28 or 212 times, respectively, human exposures achieved at the maximum recommended human dosage (MRHD) of 1 mg daily.

Lactation

Not known whether entecavir is distributed into human milk, affects human milk production, or has effects on the breast-fed infant. Distributed into milk in rats.

Consider benefits of breast-feeding and importance of entecavir to the mother along with the potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.

Pediatric Use

Safety and efficacy of entecavir confirmed in clinical trials of pediatric patients ≥2 years of age with HBeAg-positive chronic HBV infection and compensated liver disease.

Steady-state pharmacokinetics of entecavir evaluated in pediatric patients 2 to <18 years of age with compensated liver disease. Exposures in nucleoside-naïve children receiving oral solution in a dosage of 0.015 mg/kg (≤0.5 mg) once daily similar to exposures observed in adults receiving a 0.5-mg tablet once daily. Exposures in lamivudine-experienced children receiving oral solution in a dosage of 0.03 mg/kg (≤1 mg) once daily similar to exposures observed in adults receiving a 1-mg tablet once daily.

Only limited data available on use in lamivudine-experienced pediatric patients; use entecavir in these patients only if potential benefits justify potential risks. Since some pediatric patients may require long-term or lifetime management of chronic active HBV infection, consider impact of entecavir use on future treatment options.

Efficacy and safety not established in pediatric patients <2 years of age.

Geriatric Use

Clinical studies did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently to entecavir than younger adults.

Increased AUC compared with younger adults, possibly as the result of age-related changes in renal function.

Since geriatric patients may be more likely to have decreased renal function, select dosage with caution; it also may be useful to monitor renal function in geriatric patients.

Hepatic Impairment

Entecavir pharmacokinetics similar between adults (without chronic HBV infection) with moderate or severe hepatic impairment (Child-Pugh class B or C) and adults without hepatic impairment. No dosage adjustments recommended for patients with hepatic impairment. Pharmacokinetics not studied in pediatric patients with hepatic impairment.

Renal Impairment

Decreased clearance and increased plasma concentrations and AUC in adults with impaired renal function (without HBV infection) compared with adults without renal impairment. Dosage adjustments recommended in patients with Cl_cr <50 mL/minute, including those on hemodialysis or CAPD. See Table 2 for dosing strategies.

Hispanic Patients

Safety and efficacy not established in the US Hispanic population because of low enrollment of such patients in clinical trials.

Liver Transplant Recipients

Only limited data on safety and efficacy in liver transplant recipients. In a small, open-label post-liver transplant trial, frequency and nature of adverse events were consistent with those expected in liver transplant recipients and the known safety profile of entecavir.

If considered necessary in liver transplant recipients who have received or are receiving an immunosuppressive agent that may affect renal function (e.g., cyclosporine, tacrolimus), monitor renal function prior to and during entecavir treatment.

Common Adverse Effects

Most common adverse effects (≥3%) in adults were headache, fatigue, dizziness, nausea. Adverse effects observed in pediatric patients were consistent with those observed in adults.

Drug Interactions

Entecavir is not a substrate, inducer, or inhibitor of the CYP isoenzymes. Entecavir does not inhibit or induce CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 3A4, or 2B6, and does not inhibit 2E1 or induce 3A5.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetics of entecavir are unlikely to be affected by coadministration of drugs that are metabolized by, inhibit, or induce the CYP isoenzymes. Pharmacokinetics of known CYP substrates are unlikely to be affected by coadministration of entecavir.

Nephrotoxic Drugs or Drugs Eliminated by Renal Excretion

Concomitant use with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of entecavir and/or the other drug. Monitor closely for adverse effects if used concomitantly with drugs that are excreted renally or that affect renal function.

Specific Drugs

Entecavir Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration.

Peak plasma concentrations attained within 0.5–1.5 hours after a dose. Steady-state concentrations achieved after 6–10 days of once-daily administration with approximately 2-fold accumulation.

Commercially available tablets and oral solution are bioequivalent and may be used interchangeably.

Food

Food delays absorption, decreases peak plasma concentrations, and decreases AUC.

Distribution

Extent

Extensively distributed into tissues.

Plasma Protein Binding

Approximately 13% in vitro.

Elimination

Metabolism

Undergoes phosphorylation by cellular enzymes to form active metabolite, entecavir triphosphate, which has an intracellular half-life of 15 hours.

Partially metabolized to glucuronide and sulfate conjugates.

Elimination Route

Excreted principally in urine by both glomerular filtration and tubular secretion. Approximately 62–73% of an oral dose eliminated unchanged in urine.

Hemodialysis removes approximately 13% of a dose in 4 hours; CAPD removes approximately 0.3% of a dose over 7 days.

Half-life

Biphasic; terminal half-life approximately 128–149 hours.

Special Populations

No significant gender or racial differences in the pharmacokinetics of entecavir.

Stability

Storage

Oral

Solution

Store in outer carton at 25°C (excursions permitted between 15–30°C). Protect from light. After opening, discard by expiration date noted on bottle.

Tablets

Store in tightly-closed container at 25°C (excursions permitted between 15–30°C). Store in outer carton to protect from light.

Actions and Spectrum

• Purine nucleoside analog antiviral agent active in vitro and in vivo against HBV, including some strains of lamivudine-resistant HBV.

• Undergoes phosphorylation by cellular enzymes to form the active metabolite, entecavir triphosphate. Inhibits activities of HBV DNA polymerase (reverse transcriptase).

• Has some limited in vitro activity against herpes simplex virus types 1 and 2, varicella zoster virus, and cytomegalovirus, but has not been shown to be effective in clinical infections caused by these viruses.

• HBV with reduced susceptibility to entecavir can develop slowly in some patients during long-term use. At week 96, viral rebound due to entecavir resistance reported in <1% of patients who were nucleoside-naïve prior to entecavir therapy. Viral rebound due to entecavir resistance reported in 1% of lamivudine-refractory patients after 1 year of entecavir therapy and in 9% during the second year of therapy.

• Cross-resistance can occur among the nucleoside and nucleotide antivirals used for treatment of HBV. Lamivudine- and telbivudine-resistant HBV with reduced susceptibility to entecavir reported. Adefovir-resistant HBV with changes in susceptibility to entecavir reported; efficacy of entecavir against such HBV not established. HBV resistant to entecavir and lamivudine may retain susceptibility to adefovir.

Advice to Patients

• Inform patients to take entecavir on a regular dosing schedule on an empty stomach at least 2 hours before or 2 hours after meals, and to avoid missing doses in order to prevent development of resistance. Advise patients of the importance of regular medical follow-up during treatment with entecavir.

• Inform patients that if they miss a dose of their medicine, take the dose as soon as they remember. If it is almost time for the next dose, skip the missed dose and take the dose that is due. Patients should not take two doses at a time.

• Inform patients that severe acute exacerbations of hepatitis B virus (HBV) infection have been reported following discontinuance of HBV treatment, including entecavir. Advise patients to not discontinue entecavir without first informing a clinician.

• Advise patients that lactic acidosis and severe hepatomegaly with steatosis, including fatalities, have occurred in patients receiving drugs similar to entecavir. Inform patients to contact their clinician immediately if they experience any signs or symptoms of lactic acidosis (e.g., weakness/fatigue, unusual muscle pain, trouble breathing, stomach pain with nausea and vomiting, feeling cold especially in arms and legs, dizziness or feeling light-headed, fast or irregular heart beat) or hepatotoxicity (e.g., jaundice, dark urine, bowel movements light in color, anorexia, nausea, stomach pain). Inform patients that the clinician may discontinue entecavir therapy if such signs and symptoms occur.

• Inform patients that it is important to test for HIV prior to initiation of entecavir therapy. Advise patients that, if they have HIV infection and are not receiving effective HIV treatment, entecavir may increase the risk of resistance to HIV treatment.

• Inform patients using entecavir oral solution to measure the prescribed dose using the calibrated dosing spoon provided by the manufacturer, and to refer to the patient information for specific instructions for use.

• Advise patients that the optimal duration of entecavir therapy for the treatment of chronic hepatitis B and the relationship between response to treatment and long-term prevention of outcomes such as hepatocellular carcinoma are unknown.

• Inform patients that entecavir is not a cure for HBV infection, and that HBV transmission via sexual contact, sharing needles, or blood contamination is not prevented by entecavir therapy. Inform patients of available measures to prevent spread of HBV infection to close contacts.

• Advise patients to inform their clinician if they are or plan to become pregnant or plan to breastfeed. Inform patients that there is a registry to monitor fetal outcomes of pregnant women exposed to entecavir.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, and any concomitant illnesses (e.g., renal disease).

• Advise patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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