October 19, 2005

Talecris Biotherapeutics, Inc., in collaboration with Health Canada, is informing health care professionals of the receipt of spontaneous adverse event reports of suspected hemolytic anemia, hemolysis, or hemolytic reaction temporally associated with the use of Gamunex^®. Gamunex^® is indicated for the treatment of primary humoral immunodeficiency, idiopathic thrombocytopenic purpura, allogeneic bone marrow transplantation and pediatric Human Immunodeficiency Virus infection. Reactions have been reported when the product was used in approved indications and other medical conditions.

Hemolytic anemia has been reported in the medical literature in association with diverse Immune Globulin Intravenous (Human) (IGIV) products, particularly with high-dose therapy^1-5. IGIV products can contain blood group antibodies which may act as hemolysins and result in coating of red blood cells in vivo with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis, from enhanced red blood cell (RBC) sequestration. In most reports from the literature, there is objective evidence for hemolytic anemia (demonstration of a hemoglobin drop ≥ 4 gm/dL, increase of bilirubin or LDH, decrease or negative haptoglobin within hours or days of receiving IGIV treatment), plus evidence of elutable blood group isoantibodies^1-12. Since September 1, 2003, 26 cases of suspected hemolytic reactions in association with Gamunex^® have been reported globally (20 in Canada), with a reporting rate of 0.04% in a total exposure of 58949 patient years. Analysis of suspected hemolytic anemia events, hemolysis, and hemolytic reactions reported in association with Gamunex^® indicates that the etiology may include a combination of different factors. The reported cases reveal that some of these patients received doses exceeding recommended package instructions. The information from many of these reports identified the presence of other risk factors for hemolytic anemia, including use of antibiotic treatment, renal transplant rejection, multiple blood transfusions, history of idiopathic hemolytic anemia, hereditary spherocytosis, history of incompatible blood transfusion, and history of autoimmune disorder. For those cases in which this information was reported, the time between Gamunex^® infusion and reported hemolytic reactions was predominantly within 3 days of Gamunex^® infusion. In all reports wherein Gamunex^® lot numbers were provided, corresponding isoantibody titers were within specifications established in the European Pharmacopoeia for IGIV products.

In about half of all reported cases, there was no mention of the treatment of anemia. The remaining cases were treated by blood transfusion, corticosteroids, or plasmapheresis.

Patients with laboratory or clinical findings suggesting hemolytic anemia should be properly tested to confirm the diagnosis. Appropriate testing would include unconjugated serum bilirubin, serum haptoglobin, Direct Antiglobulin Test (DAT), and serum LDH. Twelve of 26 cases (46%) did not have data confirming a diagnosis of hemolytic anemia. Appropriate treatment should be determined according to the individual patient's clinical condition.

Reporting rates determined on the basis of spontaneously reported post-marketing adverse events are generally presumed to underestimate the risks associated with drug treatments.

Talecris and Health Canada depend on health care professionals to report any cases of hemolytic anemia and/or other serious and/or unexpected adverse reactions in patients receiving Gamunex^® to Bayer Inc., Canadian distributor and importer of the product, or Health Canada at the following addresses:

Your professional commitment in this regard has an important role in protecting the well-being of your patients by contributing to early signal detection and informed use of drugs. Comprehensive information is important to our ability to evaluate the significance of the reported event in association with Gamunex^®.

Talecris, in consultation with Health Canada, has updated the Product Monograph for Gamunex^®. The full copy of the Gamunex^® Product Monograph will be posted at http://www.gamunex.ca.

If you require any further information on Gamunex^®, please contact Bayer Medical Information at 1-800-265-7382.

Sincerely,

TALECRIS BIOTHERAPEUTICS, INC.

original signed by

Gerald L. Klein, MD
Vice President, Medical and Clinical Affairs

References:

1. Comenzo RL, Malachowski ME, Meissner HC, Fulton DR, Berkman EM. Immune hemolysis, disseminated intravascular coagulation, and serum sickness after large doses of immune globulin given intravenously for Kawasaki disease. J Pediatr 1992;120(6):926-8.
2. Kluge A, Dopfer R, Pfeiffer-Wolf I, Roelcke D. Immunoglobulin high-dose therapy: RBC-alloantibodies in commercial preparations and haemolytic anaemia: a case report. Beitr Infusionsther Transfusionsmed 1994;32:474-5.
3. Nakamura S, Yoshida T, Ohtake S, Matsuda T. Hemolysis due to high-dose intravenous gammaglobulin treatment for patients with idiopathic thrombocytopenic purpura. Acta Haematol 1986;76(2-3):115-8.
4. Okubo S, Ishida T, Yasunaga K. Hemolysis after intravenous immune globulin therapy: relation to IgG subclasses of red cell antibody. Transfusion 1990;30(5):436-8.
5. Salama A, Mueller-Eckhardt C, Kiefel V. Effect of intravenous immunoglobulin in immune thrombocytopenia. Lancet 1983;2(8343):193-5.
6. Brox AG, Cournoyer D, Sternbach M, Spurll G. Hemolytic anemia following intravenous gamma globulin administration. Am J Med 1987;82(3 Spec No):633-5.
7. Copelan EA, Strohm PL, Kennedy MS, Tutschka PJ. Hemolysis following intravenous immune globulin therapy. Transfusion 1986;26(5):410-2.
8. Nakagawa M, Watanabe N, Okuno M, Kondo M, Okagawa H, Taga T. Severe hemolytic anemia following high-dose intravenous immunoglobulin administration in a patient with Kawasaki disease. Am J Hematol 2000;63(3):160-1.
9. Nicholls MD, Cummins JC, Davies VJ, Greenwood JK. Haemolysis induced by intravenously-administered immunoglobulin. Med J Aust 1989;150(7):404-6.
10. Robertson VM, Dickson LG, Romond EH, Ash RC. Positive antiglobulin tests due to intravenous immunoglobulin in patients who received bone marrow transplant. Transfusion 1987;27(1):28-31.
11. Strobel E, Wullenweber J, Peters J. [Detection and side effects of isoantibodies in intravenously administered immunoglobulin preparations]. Infusionsther Transfusionsmed 1995;22(1):31-5.
12. Wilson JR, Bhoopalam H, Fisher M. Hemolytic anemia associated with intravenous immunoglobulin. Muscle Nerve 1997;20(9):1142-5.