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Important Drug Warning : Hydrea (hydroxyurea) in combination with Didanosine and/or Stavudine

Date: 2001-03-28

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BGIVD Enquiries

Bristol-Myers Squibb Canada Inc

March 28, 2001

IMPORTANT DRUG SAFETY INFORMATION

Dear Healthcare Professional(s):

RE: Potentially fatal hepatotoxicity and pancreatitis in patients treated for HIV infection with HYDREA (hydroxyurea) in combination with didanosine and/or stavudine, with or without other antiretroviral agents.

Bristol-Myers Squibb would like to bring to your attention reports of hepatotoxicity and pancreatitis that occurred in HIV-infected patients treated with hydroxyurea in combination with antiretroviral agents, in particular, didanosine and/or stavudine. Hydroxyurea is a cytotoxic agent indicated for the treatment of several types of cancers. There have been reports of hepatotoxicity and pancreatitis that occurred in HIV-infected patients treated with hydroxyurea in combination with antiretroviral agents, in particular, didanosine and/or stavudine.

Note: Use of hydroxyurea for the treatment of HIV-1 infection is not approved by Health Canada.

Background

An apparent increase in reports of serious hepatotoxicity, including deaths, in HIV-infected patients treated with hydroxyurea in combination with didanosine and/or stavudine led the US Food and Drug Administration (FDA) to search their spontaneous adverse event reporting system (AERS) for cases of hepatotoxicity associated with hydroxyurea. The search revealed 34 cases reported in 1998-1999 compared to a median of five cases reported per year between 1990 and 1997.

Fifteen of the 34 cases resulted in death. Thirty-one (91%) of the 34 cases were receiving concomitant didanosine, and 56% were also receiving stavudine, reflecting the usage pattern of hydroxyurea in HIV infection. Eleven of 15 (73%) fatal cases and seven of 19 (37%) survivors were taking concomitant didanosine, stavudine, and hydroxyurea.

Reported hepatic events included increased bilirubin, hepatic failure, increases in liver function tests, hepatic steatosis (with and without lactic acidosis), cirrhosis, and cholestatis. The dose of hydroxyurea was not available for most cases, and information about other contributing factors was not mentioned. The proportion of patients with previously documented viral hepatitis was similar among those with and without fatal hepatotoxicity (40% versus 37%, respectively).

The AERS data suggest that there may be an increase in hepatotoxicity and deaths due to hepatic failure when hydroxyurea is part of an antiretroviral regimen, particularly in combination with didanosine and/or stavudine. Although these cases of hepatoxicity were identified retrospectively from a voluntary reporting system, healthcare providers should consider these cases in the context of the results of study ACTG 5025 and the 3-D Study. Both clinical trials were prematurely terminated due to an increased proportion of pancreatitis and peripheral neuropathy in patients treated with hydroxyurea, didanosine, and stavudine with either a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor. HYDREA (hydroxyurea) is not indicated for the treatment of HIV infection; however, if HIV-infected patients are treated with hydroxyurea, and in particular, in combination with didanosine and/or stavudine, they should be closely monitored for signs of liver toxicity, pancreatitis, and peripheral neuropathy.

We appreciate this opportunity to be of service to you in the care of your patients. If you have questions about this information or require additional medical information regarding please contact us at 1-800-267-1088, ext. 2274.

Sincerely,

original signed by

Nacia Faure, MD Medical Director