Entecavir

Pronunciation: (en-TEK-a-vir)
Class: Antiviral agent

Trade Names

Baraclude
- Tablets, oral 0.5 mg
- Tablets, oral 1 mg
- Solution, oral 0.05 mg/mL

Pharmacology

Inhibits hepatitis B virus (HBV) polymerase (reverse transcriptase) by competing with the natural substrate deoxyguanosine triphosphate.

Pharmacokinetics

Absorption

Bioavailability of tablet is 100% relative to oral solution. T _max is between 0.5 and 1.5 h. Steady state is achieved after 6 to 10 days. For 0.5 mg dose, C _max was 4.2 ng/mL and C _trough was 0.3 ng/mL; for 1 mg dose, C _max was 8.2 ng/mL and C _trough was 0.5 ng/mL. Administration with food decreases C _max by 44% to 46% and AUC by 18% to 20%.

Distribution

Approximately 13% protein bound. Vd is in excess of total body water, suggesting extensive distribution into tissues.

Metabolism

No oxidative or acetylated metabolites found. Minor amounts of phase 2 metabolites (glucuronide, sulfate conjugates) noted.

Elimination

Terminal elimination half-life is 128 to 149 h; accumulation half-life approximately 24 h. Eliminated predominantly by kidney (both glomerular filtration and tubular secretion), with 62% to 73% of dose recovered in the urine.

Special Populations

Renal Function Impairment

C _max and AUC increased in patients with renal impairment or with ESRD. Dose reduction recommended for patients with CrCl less than 50 mL/min.

Hepatic Function Impairment

Pharmacokinetics are similar between hepatically impaired and healthy patients.

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.

Children

Pharmacokinetic studies have not been conducted.

Gender

No significant gender differences in entecavir pharmacokinetics.

Race

No significant racial differences in entecavir pharmacokinetics.

Indications and Usage

Treatment of chronic HBV in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.

Contraindications

None well documented.

Dosage and Administration

Compensated Liver Disease
History of Hepatitis B Viremia While Receiving Lamivudine or With Known Lamivudine- or Telbivudine-Resistant Mutations (rtM204I/V With or Without rtL180M, rtL80I/V, or rtV173L) Adults and children 16 y of age and older

PO 1 mg daily.

Nucleoside Treatment–Naive Patients Adults and children 16 y of age and older

PO 0.5 mg daily.

Decompensated Liver Disease
Adults and children 16 y of age and older

PO 1 mg daily.

Renal Impairment
Adults and Children 16 y of age and older PO CrCl 30 to 49 mL/min Nucleoside-naive patients

0.25 mg once daily or 0.5 mg every 48 h.

Lamivudine-refractory or decompensated liver disease patients

0.5 mg once daily or 1 mg every 48 h.

CrCl 10 to 29 mL/min Nucleoside-naive patients

0.15 mg once daily or 0.5 mg every 72 h.

Lamivudine-refractory or decompensated liver disease patients

0.3 mg once daily or 1 mg every 72 h.

CrCl less than 10 mL/min or hemodialysis or chronic peritoneal dialysis patients

If administered on a hemodialysis day, give entecavir after the hemodialysis session.

Nucleoside-naive patients

0.05 mg once daily or 0.5 mg every 7 days.

Lamivudine-refractory or decompensated liver disease patients

0.1 mg once daily or 1 mg every 7 days.

General Advice

Administer on an empty stomach, at least 2 h after a meal or 2 h before the next meal.
Oral solution and tablets may be used interchangeably on a mg-to-mg basis.
Oral solution contains entecavir 0.05 mg/mL. 10 mL of oral solution provides a 0.5 mg dose and 20 mL provides a 1 mg dose.
Oral solution is a ready-to-use product; dilution or mixing with water or any other liquid product is not recommended.
Oral solution is supplied with dosing spoon calibrated in 1 mL increments up to 10 mL. Hold spoon in vertical position and fill gradually to prescribed dose. Administer dose directly from dosing spoon. Rinse dosing spoon with water after each use.

Storage/Stability

Store at controlled room temperature (59° to 86°F). Protect oral solution from light. After opening, the oral solution can be used up to the expiration date on the bottle.

Drug Interactions

Drugs that reduce renal function or compete for active tubular secretion

Serum concentrations of entecavir or the coadministered drug may be elevated, possibly increasing pharmacologic and adverse effects. Monitor patients closely for adverse reactions when entecavir is coadministered with such drugs.

Food

Oral administration of entecavir with a standard high- or low-fat meal may delay absorption and decrease the entecavir C _max and AUC. Entecavir should be taken on an empty stomach, at least 2 h after a meal and 2 h before the next meal.

Adverse Reactions

CNS

Headache (4%); dizziness, fatigue (at least 3%).

Dermatologic

Alopecia, rash (postmarketing).

GI

Nausea (at least 3%); diarrhea, dyspepsia (1%).

Hepatic

Exacerbation of hepatitis (12%).

Hypersensitivity

Anaphylactoid reaction (postmarketing).

Lab Tests

Elevated ALT (12%); hematuria (9%); increased lipase (7%); glucosuria (4%); fasting hyperglycemia, increased total bilirubin (3%); decreased blood bicarbonate, increased creatinine (2%).

Precautions

Warnings

Coinfected with HIV and HBV

There is a potential for development of resistance to HIV nucleoside reverse transcriptase inhibitors if entecavir is used to treat chronic hepatitis B infection in patients with HIV infection who are not being treated with highly active antiretroviral therapy.

Hepatitis B exacerbation

Severe acute exacerbations have occurred in patients who have discontinued anti–hepatitis B therapy, including entecavir. Monitor hepatic function closely with clinical and laboratory follow-up for at least several months in patients who discontinue anti–hepatitis B therapy. Resumption of anti–hepatitis B therapy may be warranted.

Lactic acidosis/severe hepatomegaly

Lactic acidosis and severe hepatomegaly with steatosis (including fatal cases) have been reported with use of nucleoside analogues alone or in combination with other antiretrovirals.

Monitor

Monitor patients for evidence of lactic acidosis and hepatitis. Monitor closely for adverse reactions when entecavir is coadministered with drugs that are excreted renally or with drugs known to affect renal function (eg, cyclosporine). Monitor hepatic function for several months after discontinuing therapy. Monitor renal function carefully in liver transplant patients who have received or are receiving an immunosuppressant that may affect renal function (eg, cyclosporine, tacrolimus).

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy in children younger than 16 y of age not established.

Elderly

Select dose with caution, reflecting greater frequency of decreased renal function.

Renal Function

Dosage adjustments are recommended for patients with CrCl less than 50 mL/min, including patients on hemodialysis.

Overdosage

Symptoms

No experience reported.

Patient Information

Advise patient to review the patient information leaflet carefully before starting therapy and to read and check for new information each time the medication is refilled.
Review dosing schedule with patient.
Advise patient that each dose must be taken on an empty stomach, 2 h after a meal or 2 h before the next meal.
Advise patient or caregiver using oral solution to measure prescribed dose using supplied dosing spoon. Instruct patient or caregiver to hold spoon in upright position and gradually fill it to the mark corresponding to prescribed dose, and then to swallow medication directly from the spoon, rinse the spoon with water, and allow it to air dry. Caution patient or caregiver not to dilute or mix oral solution with any other liquid.
Advise patient that if a dose is missed to take it as soon as remembered on that day unless it is nearing time for the next dose, in which case the dose should be skipped and the next dose taken at the scheduled time. Caution patient not to take more than 1 dose of entecavir in a day and not to take 2 doses at the same time to catch up.
Caution patient not to change the dose or stop taking unless advised by health care provider. Advise patient that stopping therapy may result in severe exacerbation of the hepatitis.
Advise patient to get an HIV test before starting therapy and any time after that when there is a chance of exposure to HIV.
Advise patient that medication will not cure hepatitis B infection nor any other viral infection (eg, HIV) and to continue to take other antiviral medications as prescribed.
Advise patient that this therapy will not prevent transmission of hepatitis B to others and to avoid things that could spread hepatitis B to others: do not share needles or injection equipment; do not share personal items that have blood or body fluids on them (eg, toothbrushes, razor blades); do not have any kind of sex without protection (eg, condoms, dental dams).
Advise patient that it is not known if entecavir can prevent cirrhosis, liver failure, or liver cancer that may develop as a result of hepatitis B infection.
Instruct patient to immediately report any of the following to health care provider: appetite loss; bowel movements turn light in color; cold feeling, especially in arms and legs; difficulty breathing; dizziness; fast or irregular heartbeat; generalized body discomfort; light-headedness; stomach pain with nausea and vomiting; unexplained drowsiness; unusual muscle pain; urine turns very dark in color; yellowing of the skin or eyes.