Drug Criteria & Outcomes
Entecavir (Baraclude) Formulary Evaluation
Mechanism of action, Pharmacokinetics, Dosage, Clinical studies, Strengths, Weaknesses, Drug interactions, Adverse reactions, Warnings/precautions, Monitoring, Cost comparison, Summary and recommendations
By Summer Johnson Beard, PharmD Candidate
McWhorter School of Pharmacy
Samford University
Birmingham, AL
Entecavir (Baraclude) is a guanosine nucleoside analog.
Mechanism of action
Entecavir inhibits all three activities of hepatitis B virus (HBV) polymerase:
- Base priming.
- Reverse transcription of the negative strand from the pre-genomic mRNA.
- Synthesis of the positive strand of HBV DNA.
Pharmacokinetics
Absorption: Absorption occurs rapidly after oral administration with a bioavailability of 100%.
Distribution: The volume of distribution is greater than total body water. Entecavir has a low percentage of protein binding.
Metabolism: Metabolism occurs via CYP450, although it is not a substrate, inducer, or inhibitor. Small amounts of sulfate and glucuronide metabolites have been observed. Accumulation half-life is approximately 24 hours, allowing once-daily dosing.
Elimination: Entecavir is primarily eliminated unchanged in the urine. Renal clearance occurs via filtration and net tubular secretion.
Indications: Entecavir is indicated for the treatment of chronic HBV infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.
Dosage
Oral
- If the patient is HBeAg-positive and nucleoside-naïve, starting dose is recommended at 0.5 mg once daily.
- If the patient is lamivudine refractory, the recommended dose is 1 mg once daily.
- Entecavir should be administered at least two hours after a meal or two hours before the next meal.
Clinical studies
Lai CL, Rosmawati M, Lao J, et al. Entecavir is superior to lamivudine in reducing hepatitis B virus DNA in patients with chronic hepatitis B infection. Gastroenterology 2002;123:1,831-1,838.
Purpose: To evaluate the safety and antiviral activity of entecavir as compared to lamivudine in the treatment of adults with chronic hepatitis B infection.
Study design: Twenty-four-week, Phase II, randomized, double-blind, dose-ranging multicenter trial.
Methods: Amplicor PCR Assay and Quantiplex Assay were used to determine viral load and to monitor reductions that occurred over the course of therapy. Cochran-Mantel-Haenszel statistical test and a t-test also were used by the investigators.
Results
Virologic response
- 169 patients.
- Entecavir at doses of 0.1 mg daily and 0.5 mg daily were found to be superior to lamivudine at a dose of 100 mg daily in viral load reduction.
Serologic response: No significant differences were found between comparison groups. Some patients did achieve loss of HBeAg and seroconversion.
Biochemical response
- A trend was found among the two higher doses of entecavir to normalize ALT levels when compared to lamivudine.
- Due to the low population size, this comparison did not relate a significant conclusion.
- Post-treatment follow-up found an increased incidence of elevated ALT in patients discontinuing entecavir when compared to the patients discontinuing lamivudine.
Histologic response: Only a small population size (15%) was able to be evaluated using the Knodell system.
Adverse events: Most common events were headache, abdominal pain, rhinitis, fatigue, fever, diarrhea, nausea, dizziness, cough, and myalgia. These adverse events were mild to moderate in severity and comparative among study groups. The incidence of these adverse events did not reveal a significant drug or dose relationship.
Conclusion: The authors concluded that entecavir is a potent antiviral agent that is effective as monotherapy for the treatment of chronic HBV. The 0.5 mg and 0.1 mg dose of entecavir were found to be superior to lamivudine 100 mg in reducing serum HBV-DNA levels.
Strengths
- Trial included a power analysis of >85%.
- Statistical tests.
- Randomized, double-blind study.
- An extremely small number of participants (four) had to drop out due to adverse events, and only one participant was lost due to noncompliance.
Weaknesses
- The trial was funded by Bristol-Myers Squibb so bias must be considered.
- Length of the clinical trial was too short.
- Confidence intervals were not included.
Drug interaction
Since entecavir is eliminated by the kidneys, coadministration of this drug with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either entecavir or the coadministered drug. Coadministration of entecavir with lamivudine, adefovir dipivoxil, or tenofovir disoproxil fumarate did not result in significant drug interactions.
Adverse reactions
The most common adverse events were headache, fatigue, dizziness, and nausea. Other reported side effects included diarrhea, dyspepsia, vomiting, somnolence, and insomnia.
Warnings/precautions
Boxed warnings: Lactic acidosis and severe hepatomegaly, and severe acute exacerbations of hepatitis B have been reported in patients that have discontinued therapy.
Precautions: The safety and efficacy of entecavir in liver transplant recipients are unknown. Liver function must be closely monitored before and during therapy. Dosage reductions are necessary for patients whose creatinine clearance is less than 50 mL/min.
Pregnancy Category C
Monitoring
Regular monitoring of liver function is needed to make sure that further decompensation is not occurring. If entecavir is being coadministered with a drug that reduces kidney or liver function, the serum concentrations of both drugs should be monitored for toxicity.
Cost comparison
Entecavir costs $592.02 for a month’s supply of 30 tablets of the 0.5 mg and the 0.1 mg dosage formulations.
Other agents used to treat HBV: Adefovir dipivoxil (Hepsera) costs $492.26 for a month supply of 30 tablets of the 10 mg dosage formulation.
Summary and recommendations
We recommend that entecavir become a nonformulary medication, and that a small quantity may be made available if absolutely necessary. This recommendation is based on the fact that more clinical experience is needed with this agent and its high cost. Entecavir has been studied and has shown to be effective in the treatment of chronic HBV infection; however, drug resistance already has been reported, and this agent has only been on the market since early 2005.
Mechanism of action, Pharmacokinetics, Dosage, Clinical studies, Strengths, Weaknesses, Drug interactions, Adverse reactions, Warnings/precautions, Monitoring, Cost comparison, Summary and recommendationsYou have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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