First nucleotide analog approved for hepatitis B

October 21, 2002

On September 20, the FDA approved adefovir dipivoxil (Hepsera, Gilead Sciences) for the treatment of chronic hepatitis B virus (HBV) infection in adults with evidence of active liver disease. Adefovir dipivoxil is the first nucleotide analog to be approved for the treatment of chronic infection with hepatitis B. Adefovir dipivoxil is an acyclic analog of deoxyadenosine monophosphate.

 

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First nucleotide analog approved for hepatitis B

Persons infected with hepatitis B virus now have an additional therapeutic option, one that the Food & Drug Administration claims will benefit the approximately 12,000 patients in the United States who are resistant to lamivudine (Epivir HBV, GlaxoSmithKline).

Last month the FDA approved adefovir dipivoxil (Hepsera, Gilead Sciences) for the treatment of chronic hepatitis B virus (HBV) infection in adults with evidence of active liver disease. Chronic active hepatic disease should be assessed by evidence of active viral replication (hepatitis B e antigen [HBeAg] and HBV DNA), active inflammation (increased serum transaminases [alanine aminotransferase or aspartate aminotransferase]), or fibroic and/or inflammatory changes evident on liver biopsy, said Anastasia Rivkin, Pharm.D., assistant professor of clinical pharmacy practice, Arnold and Marie Schwartz College of Pharmacy, Long Island University, Brooklyn, N.Y.

Gilead claims adefovir dipivoxil is the first nucleotide analog to be approved for the treatment of chronic infection with hepatitis B. Adefovir dipivoxil is an acyclic analog of deoxyadenosine monophosphate, explained Rivkin, who is also an internal medicine clinical specialist, St. Luke's-Roosevelt Hospital Center, New York City. Rivkin said that while it is not yet clear why adefovir does not induce viral resistance, as does lamivudine, this capability is its main distinction. It is a potent inhibitor of HBV DNA replication, she said, adding that adefovir dipivoxil is also active against HIV, herpes viruses, and hepadnaviruses.

Adefovir is classified as a pregnancy category C, noted Rivkin. Adequate studies in pregnant women have not been done. Adefovir should be used during pregnancy only if necessary, according to the package insert. A pregnancy registry has been established to monitor fetal outcomes of pregnant women exposed to adefovir. Healthcare providers can register patients at (800) 258-4263. Women should not take adefovir while breast-feeding, according to the PI. Safety and efficacy of adefovir in pediatric patients have not been established. In addition, the PI states that adefovir should be used with caution in older persons.

Ibuprofen may increase adefovir concentrations (33% increase in peak plasma concentration and 23% increase in area under the curve).

The most common adverse effects associated with adefovir therapy in clinical trials were asthenia, headache, abdominal pain, nausea, flatulence, diarrhea, and dyspepsia. Rivkin noted that adefovir was also associated with a slightly higher incidence of mild renal abnormalities (an increase in serum creatinine of >0.3 mg/dl over baseline), compared with placebo, in clinical trials.

The appropriate starting and maintenance dose for adefovir is 10 mg/d by mouth, without regard to food, said Rivkin. The optimal duration of treatment remains to be defined, she continued, although clinical trials that address this issue are ongoing.

The PI states that for patients with renal impairment (creatinine clearance <50 ml/min.), the dosing interval of adefovir should be adjusted as follows: for creatinine clearance of 20-49 ml/min, 10 mg q2d; for creatinine clearance of 10-19 ml/min, 10 mg q3d; and for hemodialysis patients, 10 mg q7d following dialysis.

Future directions for research include the role of adefovir in combination therapy and the treatment of pre- and post-transplant patients with adefovir, said Rivkin. According to a statement released by Gilead, adefovir was to be shipped to wholesalers by the first week of October.

Charlotte LoBuono

TIPS TO REMEMBER: Hepsera

The PI features a black box warning about the following:

  • Hepatic function should be monitored closely in patients who discontinue treatment for hepatitis B, because acute, severe exacerbations have been reported in those who discontinue treatment, including treatment with Hepsera.

  • Chronic administration of Hepsera may result in nephrotoxicity in patients at risk for or having underlying renal dysfunction. The monitoring of renal function is recommended for all patients taking adefovir, but particularly for these patients.

  • HIV resistance may emerge in patients with concurrent hepatitis B and unrecognized or untreated HIV infection who are treated with anti-hepatitis B therapies that have activity against HIV, including adefovir.

  • Lactic acidosis and severe hepatomegaly with steatosis have been reported with the use of nucleoside analogs alone or in combination with other antiretrovirals.

 

Charlotte LoBuono. First nucleotide analog approved for hepatitis B. Drug Topics 2002;20:15.