Important Safety Information on Trasylol - Bayer Inc.

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Contact : MHPD

Important Safety Information on Trasylol

February, 2006

Subject: IMPORTANT Trasylol^® Safety Information

Dear Health Care Professional,

Bayer HealthCare would like to inform you that Bayer, Health Canada and other regulatory authorities worldwide are evaluating recent reports published in the medical literature concerning Trasylol^® (aprotinin).

A study entitled,"The Risk Associated with Aprotinin in Cardiac Surgery" by Mangano et al., was published in the New England Journal of Medicine, (Mangano D,Tudor J, Dietzel C. N Eng J Med, 2006 (354) :353-65. www.nejm.org). The publication describes the findings from an observational study of 4,374 patients (1,295 treated with aprotinin) scheduled for coronary artery bypass graft (CABG) surgery in multiple centres in multiple countries. Patients received either no therapy for blood loss, or a drug therapy intended to reduce blood loss (aprotinin, aminocaproic acid, tranexamic acid).

The NEJM publication reported an association of Trasylol with increased risk of cardiovascular events (myocardial infarction or heart failure), cerebrovascular events such as stroke, encephalopathy or coma, and renal dysfunction or failure in patients undergoing CABG surgery. Patients were not randomized to these treatments. Instead, choice of study drug (or no treatment) was at physician discretion. Patients receiving Trasylol may have been at a higher risk to begin with for developing renal failure, myocardial infarction, heart failure or stroke compared to patients receiving no treatment or treatment with another drug intended to decrease bleeding. This possibility prevents a direct assessment of whether aprotinin altered the risk for serious adverse events. To try to adjust for known differences between the treatment groups, the study authors used statistical procedures (multivariable logistic regression and propensity score adjustments).

A study entitled,"A propensity score case-control comparison of aprotinin and tranexamic acid in high-transfusion-risk cardiac surgery" by Karkouti et al. has been published in the journal Transfusion (Karkouti K, Beattie W, Dattilo K, McCluskey S, Ghannam M, Hamdy A, et al., Transfusion, on-line edition, 1/20/06. www.blackwellpublishing.com/journal.asp?ref=0041-1132). This was also an observational study that used statistical methodology to compare outcomes from patients undergoing CABG. Like the NEJM study, the patients in this study received, at physician discretion, either Trasylol or another drug intended to decrease the risk for perioperative bleeding.

The study in Transfusion has some of the same limitations as the NEJM publication.The study suggested that Trasylol administration increased the risk for renal dysfunction or failure. Renal dysfunction and renal failure have previously been reported in patients receiving Trasylol. The study by Karkouti et al. did not find an increased rate of cardiovascular or cerebrovascular events in Trasylol-treated patients and reported comparable mortality rates between the control treatment group and the Trasylol group.

In addition to Health Canada, other relevant regulatory authorities have said that they will review these reports, data supplied by Bayer and the authors of the studies, other reports in the literature as well as adverse event reports submitted to regulatory authorities through established processes, to determine if any actions are warranted. Several regulatory authorities have or will issue guidance to physicians and patients in their respective markets. Bayer welcomes and supports both the review and evaluation of these published studies and posting of guidance to physicians and patients in various markets.

Bayer is working with Health Canada and regulatory authorities worldwide to identify appropriate next steps to analyze and evaluate the data reported in the Mangano article and in another recent article (Karkouti et al).This is a complex process that will require review of the reports, data supplied by Bayer and generated by the authors of the studies, other reports in the literature as well as adverse event reports submitted through established regulatory processes. After this analysis is completed, Health Canada and the other regulatory authorities will determine if any action needs to be taken.

Bayer has posted this letter on its website today ( www.bayerhealth.ca).

While the evaluation of these published reports and other relevant data continues, Bayer and various regulatory authorities worldwide are providing guidance for physicians, other health care professionals and patients (e.g. U.S. Food and Drug Administration (FDA) at www.fda.gov). The Swiss and Dutch regulatory authorities and German Institute for Drugs and Medicinal Products have posted information on their respective websites. Bayer has also posted a press statement and letters to Healthcare Professionals on its websites ( www.bayer.com,  www.bayerhealthcare.com, www.bayerpharma.com,  www.pharma.bayer.com, and www.bayervital.de). In the next days Bayer will mail this letter to healthcare providers who use the product e.g. cardiothoracic surgeons, anesthesiologists and hospital pharmacists.

Guidance from regulatory authorities, e.g. the U.S. FDA includes a recommendation that physicians carefully monitor patients receiving Trasylol for the occurrence of adverse events particularly related to the kidneys, heart, or central nervous system and promptly report any events to Bayer or their respective regulatory authorities. The guidance also suggests that while the evaluation continues, physicians should consider limiting Trasylol use to situations where the clinical benefit of reduced blood loss is essential for medical management of the patient and outweighs potential risks.

Bayer supports these actions. We have been working and will continue to work closely with regulatory authorities in countries where Trasylol is marketed to address questions regarding product safety. We share the company's data on Trasylol with regulatory authorities on an ongoing basis and welcome their evaluation of these published reports. Bayer believes that Trasylol is a safe and effective treatment when used in accordance with the product labeling.

If you wish to request further information, please contact Bayer Medical Information at 1-800-265-7382.

Sincerely,

original signed by

Thomas P. Segerson, MD,
Vice President, Medical & Scientific Affairs
Bayer Inc.