Association of Ezetrol (ezetimibe) with myalgia, rhabdomyolysis, hepatitis, pancreatitis, and thrombocytopenia - Merck Frosst/Schering Pharmaceuticals

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Contact : MHPD DPSC

Health Canada Endorsed Important Safety Information on EZETROL^® (ezetimibe)

February 1, 2005

Subject: Association of Ezetrol^® (ezetimibe) with myalgia, rhabdomyolysis, hepatitis, pancreatitis, and thrombocytopenia

Dear Health Care Professional,

Merck Frosst/Schering Pharmaceuticals, following discussions with Health Canada, would like to inform you of new safety data for Ezetrol^® (ezetimibe), used alone or in combination with a statin. Ezetimibe is a cholesterol absorption inhibitor that is classified as a systemic drug, because of the enterohepatic recirculation of one of its metabolites¹.

The Product Monograph for Ezetrol^® (ezetimibe) has been updated to include information from international post-marketing reports of rare, and in some cases serious, adverse events. The Patient Information section is being updated to inform patients of the signs and symptoms of hepatic, muscle, and pancreatic adverse events, for which early consultation with a physician is recommended.

Additional reports of myalgia, many accompanied by elevated creatine phosphokinase (CK) values, have been reviewed by Health Canada.

While it is not possible to definitively establish a causal relationship between these adverse events and the use of Ezetrol^® (ezetimibe), the Product Monograph changes and the following recommendations are based on the potentially serious nature of these events.

Adverse muscle events:

     Myalgia

Myalgia has been reported in patients treated with Ezetrol^® (ezetimibe).

Importantly, a number of patients treated with Ezetrol^® (ezetimibe) in whom myalgia occurred, had previously experienced myalgia (with or without elevated CK levels) with statin therapy. Patients with a history of statin intolerance (myalgia with or without elevated CK levels) should be closely monitored for adverse muscle events during treatment with Ezetrol^® (ezetimibe).

     Rhabdomyolysis

Patients treated with Ezetrol^® (ezetimibe), who experience persistent muscle pain, should be instructed to contact their physicians for evaluation of the possibility of rhabdomyolysis. In most reported cases, rhabdomyolysis resolved when the drugs were discontinued.

Adverse hepatic events:

Elevations of liver transaminases and cases of hepatitis have been reported in patients treated with Ezetrol^® (ezetimibe). Liver function monitoring is recommended when therapy with Ezetrol^® (ezetimibe) is initiated in patients treated or about to begin treatment with a statin.

Health care professionals should be aware that the use of Ezetrol^® (ezetimibe) in combination with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations of liver transaminases.

Care should be exercised in the use of Ezetrol^® (ezetimibe) in patients with active liver disease or unexplained persistent elevations of liver transaminases.

Adverse pancreatic events:

Physicians should consider the diagnosis of pancreatitis in patients who develop sudden acute abdominal pain during therapy with Ezetrol^® (ezetimibe).

Suspected interaction between Ezetrol^® (ezetimibe) and warfarin:

Additional International Normalized Ratio (INR) measurements are recommended in patients treated with warfarin, and in whom Ezetrol^® (ezetimibe) is initiated.

The identification, characterization, and management of marketed health product-related adverse reactions are dependent on the active participation of health care professionals in adverse reaction reporting programmes. Any occurrences of muscle, hepatic, pancreatic, hematologic, suspected interaction with warfarin or other serious and/or unexpected adverse reactions in patients receiving Ezetrol^® (ezetimibe) should be reported to Merck Frosst/Schering Pharmaceuticals or Health Canada at the following addresses:

Your professional commitment to the informed use of Ezetrol^® (ezetimibe) represents an important contribution to the protection of patients' well-being through the early recognition of potentially serious adverse events by patients.

Patient safety is of paramount importance to Merck Frosst/Schering Pharmaceuticals. We routinely review data from completed studies and clinical use of our products.

Should you have any questions or require additional information concerning the use of Ezetrol^® (ezetimibe), please contact Merck Frosst/Schering Pharmaceuticals at 1-800-567-2594 from 8:30 am to 5:30 pm, Eastern Standard Time, Monday to Friday.

Sincerely,

original signed by

François Bertrand, M.D.
Executive Director, Medical Research

^® Registered Trademark used under license by Merck Frosst-Schering Pharma, G.P.

References:

¹ Simard D, Turgeon J. The pharmacokinetics of ezetimibe. Can J Clin Pharmacol 2003;10 suppl A: 13A.