Entecavir (Monograph)

Brand name: Baraclude
Drug class: Nucleosides and Nucleotides
VA class: AM800
Chemical name: 6H-purin-6-one, 2- amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-monohydrate.
Molecular formula: C₁₂H₁₅N₅O₃•H2O
CAS number: 209216-23-9

Medically reviewed by Drugs.com on Oct 13, 2022. Written by ASHP.

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-naive (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-naive 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. (See HBV-infected Individuals Coinfected with HIV under Cautions.)

Only limited efficacy and safety data available regarding use for treatment of chronic HBV infection in liver transplant patients. (See Liver Transplant Recipients under Cautions.)

Treatment of chronic HBV infection is complex and evolving; consult specialized references and experts. Information from the American Association for the Study of Liver Diseases (AASLD) regarding management of HBV infection, including recommendations for initial treatment, is available at [Web].

Entecavir Dosage and Administration

Administration

Oral Administration

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

Administer oral solution using oral dosing spoon according to manufacturer’s instructions. Do not dilute or mix oral solution with water or any other liquid.

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-naive pediatric patients weighing >30 kg may receive 0.5 mg (10 mL) of entecavir oral solution containing 0.05 mg/mL once daily or one 0.5-mg tablet once daily.

Lamivudine-experienced pediatric patients weighing >30 kg may receive 1 mg (20 mL) of entecavir oral solution containing 0.05 mg/mL once daily or one 1-mg tablet once daily.

Adolescents ≥16 years of age (nucleoside-naive): 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.

Adults

Chronic HBV Infection

Compensated Liver Disease

Oral

Nucleoside-naive: 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.

Decompensated Liver Disease

Oral

1 mg once daily.

Optimal duration of treatment 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, entecavir oral solution should be used.

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

Pediatric patients ≥2 years of age with renal impairment: Manufacturer states data insufficient to recommend specific dosage adjustments; consider reducing dose or increased dosing intervals similar to recommendations for adults with renal impairment.

Geriatric Patients

Select dosage with caution because of possible age-related decreases in renal impairment; monitor closely. (See Geriatric Use under Cautions.)

Cautions for Entecavir

Contraindications

• Manufacturers state none known.

Warnings/Precautions

Warnings

Exacerbation of Hepatitis

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

Exacerbations of hepatitis or ALT flare (e.g. ALT elevations ≥10 times ULN and ≥2 times baseline) reported in 2, 8, or 12% of nucleoside-naive HBeAg-positive patients, nucleoside-naive 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, but generally resolved with continued therapy.

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

HBV-infected Individuals Coinfected with HIV

Use of entecavir for treatment of chronic HBV infection in patients with unrecognized or untreated HIV infection may result in emergence of HIV isolates resistant to HIV NRTIs.

Offer HIV testing to all patients prior to entecavir therapy.

Has not been systematically evaluated in HBV-infected patients coinfected with HIV who were not receiving concomitant antiretroviral therapy.

Because of possible risk of emergence of NRTI-resistant HIV, do not use entecavir for treatment of HBV in HIV-infected patients not receiving antiretroviral therapy.

Has not been systematically evaluated for treatment of HIV infection and such use not recommended.

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 have 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 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).

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. (See Specific Drugs under Interactions.)

Specific Populations

Pregnancy

Category C.

Pregnancy registry at 800-258-4263.

No adequate, well-controlled studies in pregnant women. Use during pregnancy only if potential benefits justify potential risks to fetus.

Data not available regarding effect of entecavir therapy during pregnancy on transmission of HBV to the infant. Routine screening for HBV infection recommended for all pregnant women. For prevention of perinatal transmission of HBV, US Public Health Service Advisory Committee on Immunization Practices (ACIP), AAP, and others state that infants born to hepatitis B surface antigen (HBsAg)-positive women should receive first dose of hepatitis B vaccine and a dose of hepatitis B immune globulin (HBIG) within 12 hours of birth.

Lactation

Distributed into milk in rats; not known whether distributed into human milk.

Discontinue nursing or the drug, taking into account the importance of the drug to the women.

Pediatric Use

Safety and efficacy not established in children <2 years of age.

Only limited data available on use in lamivudine-experienced pediatric patients; use in such 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.

Geriatric Use

Experience in those ≥65 years of age insufficient to determine whether they respond differently than younger adults.

Use with caution. Because of age-related decreases in renal function, select dosage based on degree of renal impairment; monitor renal function in such patients. (See Renal Impairment under Dosage and Administration.)

Renal Impairment

Dosage adjustments recommended in patients with Cl_cr <50 mL/minute, including those undergoing hemodialysis or CAPD. (See Renal Impairment under Dosage and Administration.)

Hispanic Patients

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

Race

No substantial race-related differences in entecavir pharmacokinetics.

Common Adverse Effects

Compensated liver disease: Headache, fatigue, dizziness, nausea. Elevated ALT concentrations, hyperbilirubinemia, elevated lipase concentrations, hematuria, glycosuria, hyperglycemia, elevated creatinine concentrations.

Decompensated liver disease: Peripheral edema, ascites, pyrexia, hepatic encephalopathy, upper respiratory infection.

Interactions for Entecavir

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

Pharmacokinetic interactions with drugs metabolized by CYP isoenzymes unlikely.

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 excreted renally or with drugs known to affect renal function. (See Specific Drugs under Interactions)

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.

Food

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

Distribution

Extent

Extensively distributed into tissues.

Distributed into milk in rats; not known whether distributed into human milk.

Plasma Protein Binding

Approximately 13% in vitro.

Elimination

Metabolism

Undergoes phosphorylation by cellular enzymes to form active metabolite, entecavir triphosphate.

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

Impaired hepatic function: Pharmacokinetics not affected.

Impaired renal function: Decreased clearance and increased plasma concentrations and AUC.

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

Pediatric patients 2 years to <18 years of age with compensated liver disease: Exposures in those who are nucleoside-naive receiving oral solution in a dosage of 0.015 mg/kg (up to 0.5 mg) once daily similar to exposures observed in adults receiving 0.5-mg tablet once daily. Exposures in those who are lamivudine-experienced receiving oral solution in a dosage of 0.03 mg/kg (up to 1 mg) once daily similar to exposures observed in adults receiving 1-mg tablet once daily.

Stability

Storage

Oral

Solution

Store in outer carton at 25°C (may be exposed to 15–30°C). Protect from light. After opening, discard by expiration date noted on bottle.

Tablets

Tight container at 25°C (may be exposed to 15–30°C).

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 HIV-1 and HSV-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-naive 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

• Importance of providing a copy of the manufacturer’s patient information.

• Importance of taking entecavir exactly as prescribed and not discontinuing or interrupting therapy unless instructed by a clinician; importance of regular medical follow-up.

• Advise patients that deterioration of liver disease has occurred when entecavir therapy is discontinued and that any change in treatment should be discussed with the clinician.

• Importance of taking entecavir on an empty stomach (at least 2 hours before or 2 hours after meals), preferably at the same time each day.

• Importance of protecting oral solution from light. When using the oral solution, importance of using the calibrated dosing spoon provided, holding the spoon in a vertical position and filling it gradually to the mark corresponding to the prescribed dose, and rinsing it well after each use.

• Importance of liver function test monitoring and immediate reporting of potential exacerbations of hepatitis following discontinuance of entecavir therapy.

• Importance of immediately reporting 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) or any other new symptoms.

• Importance of HBV therapy compliance. Entecavir is not a cure for HBV infection. HBV transmission via sexual contact, sharing needles, or blood contamination is not prevented by entecavir therapy.

• Patients should be advised of available measures to prevent spread of HBV infection to close contacts.

• Importance of testing 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 HIV resistance.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, and any concomitant illnesses (e.g., renal disease).

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

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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