Entecavir - Drug Monograph

Introduction

Entecavir is a potent nucleoside analogue antiviral medication specifically designed for the treatment of chronic hepatitis B virus (HBV) infection. Approved by the FDA in 2005, entecavir represents a cornerstone in the management of HBV, offering high genetic barrier to resistance and potent viral suppression. It belongs to the guanosine nucleoside analogue class and has demonstrated superior efficacy compared to earlier antiviral agents like lamivudine in clinical trials.

Mechanism of Action

Entecavir exerts its antiviral effect through selective inhibition of HBV replication. The drug is phosphorylated intracellularly to its active triphosphate form, which competes with the natural substrate deoxyguanosine triphosphate. This active metabolite inhibits all three functions of the HBV polymerase: (1) base priming, (2) reverse transcription of the negative strand from the pregenomic RNA, and (3) synthesis of the positive strand of HBV DNA. Entecavir triphosphate has a half-life of 15 hours, allowing for once-daily dosing, and is approximately 1000-fold more potent against HBV polymerase than human DNA polymerases.

Indications

Entecavir is indicated for the treatment of chronic hepatitis B virus infection in adults and children 2 years of age and older with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. It is approved for both nucleoside-naïve patients and those with lamivudine-refractory HBV (with higher dosing). Entecavir is not indicated for the treatment of HIV infection and may promote HIV resistance if used in dually infected patients without adequate HIV suppression.

Dosage and Administration

• Nucleoside-naïve adults and adolescents (≥16 years): 0.5 mg once daily
• Lamivudine-refractory or known resistance: 1.0 mg once daily
• Pediatric patients (2 to <16 years): Weight-based dosing (0.015 mg/kg up to maximum 0.5 mg daily)

• Administer on an empty stomach (at least 2 hours before or after food)
• Available as 0.5 mg and 1.0 mg tablets and oral solution (0.05 mg/mL)
• Renal impairment requires dosage adjustment:

- CrCl 30-49 mL/min: 0.25 mg daily or 0.5 mg every 48 hours - CrCl 10-29 mL/min: 0.15 mg daily or 0.5 mg every 72 hours - CrCl <10 mL/min: 0.05 mg daily or 0.5 mg every 7 days - Hemodialysis: Administer after dialysis

Pharmacokinetics

Contraindications

• Hypersensitivity to entecavir or any component of the formulation
• Use in HIV/HBV co-infected patients not receiving HAART (due to risk of HIV resistance)
• Severe hepatic impairment without close monitoring (limited data)

Warnings and Precautions

• Severe acute exacerbations of hepatitis B have been reported following discontinuation of antiviral therapy
• Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with nucleoside analogues

• Renal impairment: Requires dosage adjustment; monitor renal function during treatment
• Hepatic impairment: Limited data in Child-Pugh class B or C; use with caution
• Pregnancy: Category C; use only if potential benefit justifies potential risk
• Lactation: Not recommended during breastfeeding
• Elderly patients: Increased likelihood of decreased renal function requiring dose adjustment

Drug Interactions

• Drugs affecting renal function: May alter entecavir clearance (e.g., aminoglycosides, vancomycin, NSAIDs)
• HIV medications: Entecavir is not recommended with antiretroviral regimens containing lamivudine
• No clinically significant interactions with CYP450 substrates, inhibitors, or inducers
• Limited data with immunosuppressants; monitor appropriately

Adverse Effects

• Headache (2-4%)
• Fatigue (1-3%)
• Dizziness (1-2%)
• Nausea (1-2%)
• Diarrhea (1-2%)
• Dyspepsia (1-2%)

• Lactic acidosis/hepatic steatosis (<1%)
• Severe acute exacerbation of hepatitis after discontinuation (2-8%)
• Myopathy (rare)
• Peripheral neuropathy (rare)
• Rash (<1%)

Monitoring Parameters

• HBV DNA levels
• Liver function tests (ALT, AST, bilirubin, albumin, INR)
• Renal function (serum creatinine, calculated CrCl)
• HIV status (must be documented)
• Complete blood count

• HBV DNA every 3 months until undetectable, then every 3-6 months
• LFTs every 3 months
• Renal function every 3-6 months
• Signs/symptoms of lactic acidosis
• Clinical assessment for hepatic decompensation

• Monitor for at least 6 months for hepatitis flare

Patient Education

• Take on empty stomach (2 hours before or after food)
• Complete full course as prescribed; do not discontinue without medical supervision
• Regular monitoring is essential for treatment success and safety
• Report any new symptoms, especially nausea, vomiting, abdominal pain, or muscle pain
• Notify all healthcare providers of entecavir use
• Use effective contraception during treatment
• Do not breastfeed while taking entecavir
• Store at room temperature; oral solution should be used within expiration date after opening

References

1. FDA Prescribing Information: Baraclude (entecavir) 2. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50(3):661-662. 3. Chang TT, et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2006;354(10):1011-1020. 4. Lai CL, et al. Entecavir versus lamivudine for patients with HBeAg-positive chronic hepatitis B. N Engl J Med. 2006;354(10):1001-1010. 5. AASLD Guidelines: Hepatitis B Guidance Update. Hepatology. 2018;67(4):1560-1599. 6. European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67(2):370-398.