Trasylol (aprotinin) - Important New Safety Information - Notice to Hospitals

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This is duplicated text of a letter from Bayer Inc.
Contact the company for a copy of any references, attachments or enclosures.

NOTICE TO HOSPITALS
Health Canada Endorsed Important Safety Information on TRASYLOL (aprotinin)

September 19, 2011

To: Hospital Chief of Medical Staff

Please distribute to relevant Departments of Thoracic Surgery, Cardiology, Cardiothoracic Surgery, Anesthesiology, Critical Care, Nephrology, Internal Medicine, Hospital Pharmacy, and/or other Departments as required and post this Notice in an appropriate location in your institution.

Subject: Important new safety information on TRASYLOL^®

Bayer is pleased to announce that the temporary market authorization suspension of TRASYLOL^® (aprotinin) is lifted effective immediately. In November 2007, Bayer, after consultation with Health Canada, announced the temporary suspension of marketing for TRASYLOL^® due to safety concerns based on increased mortality in the TRASYLOL^® arm of a clinical trial. TRASYLOL^® was subsequently made available through a limited access program.

After review of the available information, in consultation with Health Canada, Bayer would like to inform you of important safety information regarding TRASYLOL^®. A Public Communication will also be issued to inform patients.

The indication for TRASYLOL^® is clarified to specify use in isolated coronary artery bypass graft (CABG) surgery:

TRASYLOL^® is indicated for prophylactic use to reduce perioperative blood loss and the need for blood transfusion in those patients undergoing cardiopulmonary bypass in the course of isolated coronary artery bypass graft (CABG) surgery who are at risk for blood loss and blood transfusion requirement.

An association between TRASYLOL^® use and increased mortality has been reported in some nonrandomized observational studies while other non-randomized studies have not reported such an association. In these studies, TRASYLOL^® was usually administered to patients who had more risk factors for increased mortality before surgery than patients in the other treatment groups. Most of the studies did not adequately account for these baseline differences in risk factors and the influence of these risk factors on the results is not known. Therefore interpretation of these observational studies is limited and an association between TRASYLOL^® use and increased mortality can neither be established nor refuted. Thus, TRASYLOL^® should only be used as authorized in isolated CABG surgery, after careful consideration of the potential risks and benefits.

A publication by Fergusson et al 2008 analyzed data from a randomized controlled trial, Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART), and reported a higher mortality trend in TRASYLOL^®-treated patients compared to those treated with tranexamic acid or aminocaproic acid. However, the BART study was not adequately powered for the secondary endpoint of all-cause mortality, and, thus, given the small numbers of deaths, the mortality results reported by Fergusson et al 2008 could be due to statistical chance. Also, further analysis of the data has revealed that the PTT was significantly longer in the TRASYLOL^® treatment group than in the comparator groups. Less heparin was used in the TRASYLOL^® arm, but the reasons for this are unclear. Therefore, the available BART data on mortality do not establish nor refute an association between TRASYLOL^® use and increased mortality.

In patients undergoing cardiopulmonary bypass with TRASYLOL^® therapy, one of two methods is recommended to manage adequate anticoagulation: Fixed Heparin Dosing, or Heparin Titration. Activated Clotting Time (ACT) should be used to monitor anticoagulation.

DRUG INTERACTIONS

Drug-Laboratory Interactions

Significant elevations in the partial thromboplastin time (PTT) and celite Activated Clotting Time (Celite ACT) are expected in TRASYLOL^®-treated patients during surgery, and in the hours after surgery due to circulating concentrations of TRASYLOL^®, which are known to inhibit activation of the intrinsic clotting system by contact with a foreign material (eg, celite), a method used in these tests. These increases may lead to an overestimation of the degree of anticoagulation, thereby leading to inadequate anticoagulation which may be associated with an increased risk of graft closure.

Partial thromboplastin time (PTT) - The PTT alone should not be used to monitor adequate anticoagulation with heparin in patients receiving TRASYLOL^®.

In patients undergoing cardiopulmonary bypass with TRASYLOL^® therapy, one of two methods is recommended to manage adequate anticoagulation: Fixed Heparin Dosing or Heparin Titration.

1. Fixed Heparin Dosing - A standard loading dose of heparin, administered prior to cannulation of the heart, plus the quantity of heparin added to the prime volume of the cardiopulmonary bypass circuit, should total at least 350 IU/kg. Additional heparin should be administered in a fixed dose regimen based on patient weight and duration of cardiopulmonary bypass.
2. Heparin Titration - Protamine titration, a method that is not affected by aprotinin, can be used to measure heparin levels. A heparin dose response, assessed by protamine titration, should be performed prior to administration of aprotinin to determine the heparin loading dose. Additional heparin should be administered on the basis of heparin levels measured by protamine titration. Heparin levels during bypass should not be allowed to drop below 2.7 IU/mL (2.0 mg/kg) or below the level indicated by heparin dose-response testing performed prior to administration of aprotinin.

Activated Clotting Time (ACT) should be used to monitor anticoagulation.

Activated Clotting Time (ACT) - While protocols vary, a minimal celite-ACT of 750 seconds or kaolin-ACT of 480 seconds, independent of the effects of hemodilution and hypothermia, is recommended in the presence of aprotinin. During extended extracorporeal circulation, patients may require additional heparin, even in the presence of ACT levels that appear adequate. The manufacturer of the ACT test should be consulted regarding interpretation of the assay in the presence of TRASYLOL^®.

In TRASYLOL^® treated patients the neutralisation of heparin by protamine after discontinuation of cardiopulmonary bypass should either be based on a fixed ratio to the amount of heparin administered or be guided by a protamine titration method.

TRASYLOL^® is not a heparin-sparing agent.

Additional safety information and information regarding the proper use of TRASYLOL^® can be found in the revised Canadian Product Monograph (CPM). The CPM as well as this Notice to Hospitals can be found on the Canadian  Bayer website. In addition, this Notice to Hospitals can be found on the Health Canada website.

Managing marketed health product-related adverse reactions depends on health care professionals and consumers reporting them. Any case of serious and/or unexpected adverse reactions in patients receiving TRASYLOL^® should be reported to Bayer Inc. or Health Canada at the following addresses:

Sincerely,

original signed by

Shurjeel H. Choudhri, MD, FRCPC
Senior Vice President and Head, Medical & Scientific Affairs
Bayer Inc. Canada