NEW INFORMATION: HEPATITIS "FLARES" AFTER CESSATION OF
LAMIVUDINE IN PATIENTS CHRONICALLY INFECTED WITH HEPATITIS B

September 8, 1997

Dear Doctor:

Epivir (lamivudine) 150 mg Tablets and Epivir Oral Solution (10 mg/mL) are approved in the United States for use in combination with zidovudine and other antiretroviral drugs for the treatment of patients with human immunodeficiency virus (HIV) infection when therapy is warranted. Because 8%-10% of U.S. patients infected with HIV may be chronic carriers of hepatitis B virus (HBV)¹, patients who are dually infected with HIV and HBV may be exposed to Epivir. Therefore, it is important for physicians who treat HIV-infected persons to be aware of recent experience with recurrences of hepatitis manifestations in HBV-infected patients after cessation of lamivudine.

New Information - Resumption of HBV Replication and Recurrence of Hepatitis Following Discontinuation of Lamivudine:

The package insert for Epivir Tablets and Epivir Oral Solution has been changed to add the following new information to the section on precautions:

"Patients with HIV and Hepatitis B Virus Coinfection: In clinical trials, some patients with HIV infection who have chronic liver disease due to hepatitis B virus infection experienced clinical or laboratory evidence of recurrent hepatitis upon discontinuation of EPIVIR."

The following paragraphs explain the basis for this new information.

Lamivudine is not indicated for the treatment of chronic hepatitis B. Clinical studies are being conducted to evaluate whether it is safe and effective in patients with hepatitis B virus infection.

• In the Phase II clinical studies utilizing up to 6 months of lamivudine treatment, most patients with hepatitis B who had decreases in HBV DNA while on lamivudine have experienced a resumption of viral replication following discontinuation of lamivudine. Typically, this is associated with a return of HBV DNA levels and ALT levels towards pre-treatment levels, and with mild ALT flares (> or = 2 times patient's baseline ALT value) in approximately 20% of patients. A smaller percentage (2%-4%) of hepatitis B patients discontinuing lamivudine have had clinically notable post-treatment recurrences of hepatitis, defined as peak serum ALT levels exceeding 500 IU/mL and/or elevation of serum bilirubin levels.

• In clinical trials in Japan as of February 1997, 11 hepatitis B patients had clinically noted recurrent hepatitis after discontinuation of lamivudine (100 mg daily). Recurrent hepatitis was usually noted within 3 months after discontinuation of lamivudine. In 4 of the Japanese patients, the post-treatment aminotransferase elevations were associated with evidence of hepatic insufficiency. All 11 patients required hospitalization. One patient died.

• In the Phase III clinical studies in hepatitis B patients in the United States and Europe (ongoing), two US patients have experienced clincially notable post-treatment hepatitis, with ALT values exceeding 500 IU/mL. The post-treatment ALT elevations resolved in both patients without signs of hepatic insufficiency.

  We will continue to monitor all aspects of the safety of lamivudine therapy in the ongoing clinical programs. If you have any questions regarding this information, please contact Glaxo Wellcome's Medical Services Department at (800) 334-0089. Thank you.

  Sincerely,

  Marc Rubin, M.D.
  Vice President, Clinical Research

  Reference:
  

  1. Rustgi VK, Hoofnagle JH, Gerin JL, et al. Hepatitis B virus infection in the acquired immunodeficiency syndrome. Ann. Intern. Med. 1984; 101:795-797.

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