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Important Drug Warning - VIRAMUNE - Boehringer Ingelheim (Canada) Ltd.

Date: 2000-11-10

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Boehringer
Ingelheim

November 10, 2000

IMPORTANT DRUG WARNING

Dear Doctor or Pharmacist:

VIRAMUNE® SAFETY UPDATE

Re: Severe, life-threatening and fatal cases of hepatotoxicity with VIRAMUNE^®

Boehringer Ingelheim (Canada) Ltd. would like to inform you of important safety information which is in the process of being added to the Product Monograph for VIRAMUNE^® (nevirapine), a non-nucleoside analog indicated for the treatment of HIV-1 infection in combination with other antiretroviral agents. The existing warnings in the Product Monograph for the risk of hepatotoxicity with VIRAMUNE^® treatment have been strengthened in response to continued reports of severe, life-threatening and in some cases, fatal hepatotoxicity that have been reported from clinical trials and post-marketing use with VIRAMUNE^®.

Based on ongoing analyses of clinical trials and post-marketing safety data, Boehringer Ingelheim (Canada) Ltd. has further characterized hepatic adverse events associated with VIRAMUNE^®. In order to ensure that VIRAMUNE^® is used safely and effectively, Boehringer Ingelheim (Canada) Ltd. is in the process of finalizing the revised Product Monograph with the Therapeutic Products Programme to integrate new clinical data, strengthen warnings, and reinforce the need for careful clinical monitoring of patients during treatment. The revised Product Monograph will be available in the next couple of weeks. In the interim, a summary of the most pertinent safety-related revisions is provided below:

The Product Monograph has been updated to provide additional warning information about the risk of severe, life-threatening and in some cases, fatal hepatotoxicity that have been reported in patients treated with VIRAMUNE^®. Although clinical presentation varied among patients, frequently occurring features included non-specific prodromal signs and symptoms of fatigue, malaise, anorexia and nausea, with or without abnormal serum transaminase levels. In these reports, symptoms progressed to jaundice, hepatomegaly, elevation of transaminase levels and hepatic failure over a period of several days. Patients with signs or symptoms of hepatitis must immediately seek medical evaluation, have liver tests performed, and be advised to discontinue VIRAMUNE^® as soon as possible.

• Based on these reports, the first 12 weeks of VIRAMUNE^® therapy are a critical period during which intensive clinical and laboratory monitoring, including liver function tests, is essential to detect potentially life-threatening hepatotoxicity and skin reactions.
  
  
• Although most serious hepatic events occurred during the first 12 weeks of VIRAMUNE^® therapy, approximately one-third of cases have been reported to occur after this critical period.
  
  
• The optimal frequency of monitoring during the first 12 weeks of therapy with VIRAMUNE^® has not been established. Some experts recommend clinical and laboratory monitoring more often than once per month, and in particular, would include monitoring of liver function tests at baseline, prior to dose escalation and at two weeks post dose escalation. After the initial 12-week period, frequent clinical and laboratory monitoring should continue throughout VIRAMUNE^® treatment.
  
  
• Increased AST or ALT levels and/or a history of chronic hepatitis (B or C) infection are associated with a greater risk of hepatic adverse events.
  
  
• Serious hepatotoxicity, including liver failure requiring transplantation in one instance, has been reported in HIV-uninfected individuals receiving multiple doses of VIRAMUNE^® in the setting of post-exposure prophylaxis, an unapproved use.
  
  
• If clinical hepatotoxicity occurs, VIRAMUNE^® should be permanently discontinued and not restarted after recovery.

In summary, the need for careful clinical and laboratory monitoring of patients receiving VIRAMUNE^® must be emphasized. The diagnosis of hepatotoxicity should be considered for patients presenting with non-specific symptoms of hepatitis even if liver function tests are normal or alternative diagnoses are possible. These considerations are especially critical during the first 12 weeks of therapy, when serious liver toxicity occurs most frequently, but remain important throughout treatment with VIRAMUNE^®.

Boehringer Ingelheim (Canada) Ltd. would additionally like to take this opportunity to inform you that the VIRAMUNE^® Product Monograph is being revised to provide updated safety information regarding the occurrence of serious skin rashes with VIRAMUNE^® therapy. This strengthened information includes a reminder regarding the importance of the 14-day 200 mg lead-in period. It also includes information from a clinical trial in which concomitant prednisone use was associated with an increase in the incidence and severity of rash during the first 6 weeks of VIRAMUNE^® therapy. Therefore, use of prednisone to prevent VIRAMUNE^®-associated rash is not recommended.

Please be aware that the Boehringer-Ingelheim (Canada) Ltd. includes a Patient Package Insert to be dispensed with the drug that provides patients with the most important information they need to know about VIRAMUNE^®.

You can assist us in monitoring the safety of VIRAMUNE^® by reporting adverse reactions to Boehringer Ingelheim (Canada) Ltd. at 905-631-4745.

Sincerely,

original signed by

Dr. Tomasz Uscinowicz
Director, Regulatory Affairs