The FDA has approved Baraclude (entecavir) from Bristol-Myers Squibb for the treatment of adults with hepatitis B virus (HBV). The drug is indicated for adults with active viral replication and either persistently elevated aminotransferases or histologically active disease. Baraclude is available as 0.5-and 1-mg tablets and as a 0.05-mg/mL oral solution. Baraclude is approved for use in patients 16 years and older.¹

Pharmacology

Baraclude is a guanosine nucleoside analogue that is active against HBV polymerase. When phosphorylated to its active form, Baraclude competes with the natural substrate to inhibit (1) base priming; (2) reverse transcription of the negative strand of messenger RNA; and (3) synthesis of the positive strand of HBV. This action results in the successful inhibition of all 3 activities of the HBV polymerase.¹

Clinical Trials

Baraclude was evaluated for safety and efficacy in 3 phase 3 clinical trials. Each trial was active-controlled and involved patients aged 16 years or older with chronic hepatitis B infection, evidence of viral replication, alanine aminotransferase levels elevated at least 1.3 times above normal, and chronic inflammation as proven by liver biopsy.¹

Two of the 3 studies evaluated patients with compensated liver disease who had not been treated previously with nucleoside agents. Study A1463022 and study A1463027 were multinational, randomized, doubleblind studies that compared Baraclude 0.5 mg daily with lamivudine 100 mg once daily for 52 weeks. At 48 weeks, 67% of the A1463022 patients and 90% of the A1463027 patients displayed a viral load of <300 copies/mL. Resistance to Baraclude was not found in either trial.^1,2

The third clinical trial evaluated the use of Baraclude in patients previously treated with lamivudine. Study A1463026 was a multinational, randomized, double-blind study of Baraclude 1 mg daily or lamivudine 100 mg daily. At 48 weeks, 19% of the Baraclude patients achieved an HBV viral load of <300 copies/mL. Only 1% of the lamivudine patients achieved this value. In this study, genotypic analysis found resistance to Baraclude.^1,2

Safety

Nucleoside analogues, both alone and in conjunction with antiretrovirals, have been associated with lactic acidosis and severe hepatomegaly with steatosis. Lactic acidosis often presents as fatigue, unusual muscle pain, difficulty breathing, severe stomach pain with nausea and vomiting, coldness, dizziness, or irregular heartbeat. Signs of hepatotoxicity may include jaundice, dark urine, pale bowel movements, anorexia, nausea, or lower stomach pain. Patients should be educated to contact a health care professional immediately if they develop any signs of either complication.

Discontinuing Baraclude may be associated with a severe exacerbation of HBV. Hepatic function should be followed closely for several months in patients who stop taking the drug. Patients with a history of hypersensitivity to Baraclude should not take it.

Baraclude was not found to be altered or metabolized by the cytochrome P-450 (CYP450) enzyme system. Concomitant administration of Baraclude with medications that alter renal function or compete for active tubular secretion may result in a need for a dosing adjustment.

Baraclude is in pregnancy category C. It should not be used in women who are lactating, because its safety in breast-feeding has not been determined.¹

The most commonly reported adverse effects included headache, fatigue, dizziness, and nausea. Additional adverse effects included diarrhea, indigestion, vomiting, and insomnia.^1,3

Outlook

The usual starting dose for nucleoside- naïve patients is 0.5 mg daily. Patients who have failed lamivudine may require 1 mg daily.² Baraclude is cleared renally; patients with a creatinine clearance of <50 mL/min will require a lower dose of Baraclude. When the drug is administered to elderly patients, dosing should be based on renal function instead of age. No dose adjustment is necessary in hepatic impairment. Baraclude has not been studied in liver transplant patients. The drug should be taken daily on an empty stomach, 2 hours before or after a meal.¹

Dr. Holmberg is a pharmacist with Phoenix Children's Hospital, Phoenix, Ariz.

For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. A. Stahl, Pharmacy Times, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mail request to: astahl@ascendmedia.com.