Archived – Thrombotic Events and Immune Globulin Intravenous (IGIV) – Baxter

Important Drug Safety Information

April 12, 2002

Dear Health Care Provider:

Subject: Thrombotic Events and Immune Globulin Intravenous (IGIV)

There are many articles in the literature that describe the occurrence of thrombotic events in patients receiving immune globulin intravenous (1-28*). In view of the serious nature of these reported thrombotic events, we wish to draw your attention to the package insert for Gammagard S/D, which includes a statement to this effect under the 'Precautions' section of the document. The precautionary statement is as follows:

There is clinical evidence of a possible association between Immune Globulin Intravenous (Human) (IGIV) administration and thrombotic events. The exact cause of this is unknown; therefore, caution should be exercised in the prescribing and infusion of IGIV in patients with a history of cardiovascular disease or thrombotic episodes.

From both the medical literature and our internal pharmacovigilance/quality assurance program, we continue to receive reports describing serious thrombotic (vascular occlusive) events possibly associated with the infusion of immune globulin intravenous (IGIV). Analysis of these events indicates that the etiology is complex and multi-variant and the cause of this association is not clearly understood.

However, our own recent analysis of serious adverse events reported via pharmacovigilance, has identified rapid infusion of immune globulin intravenous as a possible risk factor. For example,

Grillo and co-workers report on the use of rapid infusion of immune globulin intravenous in patients with neuromuscular disorders in the November 2001 issue of the journal Neurology, Vol. 57 (pages 1699 - 1701). Their abstract and discussion claim safety and convenience of this practice in their population of patients and the final sentence of their abstract states "Rapid infusion IVIg can be given safely and conveniently in many patients with neuromuscular disorders." While this is accurate for the majority of their patients, the authors report 89 adverse events in 341 rapid infusions in 50 patients, 3.5% of which were considered "major." This amounted to a "major" event in 11 out of 50 patients (22%).

It is these "major" events, and their frequency, which is of concern to us as these events included chest pain, myocardial infarction, congestive cardiac failure, severe headache requiring hospitalization, pulmonary embolism and "transfusion related acute lung injury." These are serious events almost certainly directly related to the rapid infusion protocol (reaching as high as 800 ml/hour) in what is essentially an at-risk population.

It is strongly recommended that clinicians and other health care workers such as pharmacists and nurses, who may be associated with the therapeutic administration of immune globulin intravenous, read and follow the package insert.

In the event where there is a possible risk of a thrombotic event, we strongly recommend that the infusion concentration should be no more than 5%, and the infusion rate should be initiated no faster than 0.5 milliliter per kilogram body weight per hour and advanced slowly only if well tolerated to a maximum rate of 4 milliliter per kilogram body weight per hour. In other words, the rate of infusion and percent of the solution concentration should be flexible and targeted to the safety of the patient rather than convenience.

Please refer to the enclosed package insert for more complete prescribing information. If you have any further questions or concerns regarding this letter, please call Baxter BioScience Medical Affairs Department at (800) 423-2862.

Sincerely,

original signed by

Edward Gomperts, MD

Vice President, Medical Affairs

Baxter BioScience

* References:

1. Woodruff RK, Grigg AP, Firkin FC, Smith IL: Fatal thrombotic events during treatment of autoimmune throm bocytopenia with intravenous immunoglobulin in elderly patients. Lancet 2(8500): 217-218, 1986.
2. Frame WD, and Crawford RJ: Thrombotic Events after Intravenous Immunoglobulin. Lancet 2(8504): 468, 1986.
3. Comenzo RL, Malachowski ME, Meissner HC , Berkman EM , Fulton DR: Immune hemolysis, disseminated intravascular coagulation, and serum sickness after large doses of immune globulin given intravenously for Kawasaki disease. Journal of Pediatrics 120(6): 926-928, 1992.
4. Reinhart WH, Berchtold P E: Effect of high -dose intravenous immunoglobulin therapy on blood rheology. Lancet 339(8794): 662-664, 1992.
5. Silbert PL, Knezevic WV, Bridge DT: Cerebral infarction complicating intravenous immunoglobulin therapy for polyneuritis cranialis. Neurology 42(1): 257-258, 1992.
6. Madl C, Koppeensteiner R, Wendelin B, Lenz K, Kramer L, Grimm G, Kranz A, Schneeweiss B, Ehringer H: Effect of Immunoglobulin Administration on Blood R heology in P atients with Septic Shock. Circulatory Shock 40(4): 264-267, 1993.
7. Durand JM, Lefevre P, Kaplanski G, Retornaz F, Cretel E, Soubeyrand J: Deleterious Effects of Intravenous Immunoglobulin in a Patient with Thrombotic Thrombocytopenic Purpura. American Journal of Hematology 44(3): 214-215, 1993.
8. Steg RE, Lefkowitz DM. Cerebral infarction following intravenous immunoglobulin therapy for myasthenia gravis. Neurology 44 (6): 1180-1181, 1994.
9. Dalakas MC: High-dose intravenous immunoglobulin and serum viscosity: Risk of precipitating thromboembolic events. Neurology 44(2): 223-226, 1994.
10. Duhem C, Dicato MA, Ries F: Side effects of intravenous immune globulins. Clinical & Experimental Immunology 97 (Suppl 1): 79-83, 1994.
11. Harkness K, Howell SJL, Davies-Jones GAB: Encephalopathy associated with intravenous immunoglobulin treatment for Guillain-Barre syndrome. Journal of Neurology, Neurosurgery, Psychiatry 60(5): 586-598, 1996.
12. Hashkes PJ, Lovell D J: Vasculitis in systemic lupus erythematosus following intravenous immunoglobulin therapy. Clinical & Experimental Rheumatology 14(6): 673-675, 1996.
13. Brannagan TH 3rd, Nagle KJ, Lange DJ, Rowland LP: Complications of intravenous immune globulin treatment in neurologic disease. Neurology 47(3): 674-677, 1996.
14. Bertorini TE, Nance AM, Horner LH, Greene W, Gelfand M S, Jaster JH: Complications of Intravenous Gammaglobulin in Neuromuscular and other diseases. Muscle & Nerve 19(3): 388-391, 1996.
15. Oh KT, Boldt HC, Danis RP: Iatrogenic central retinal vein occlusion and hyperviscosity associated with high-dose intravenous immunoglobulin administration. American Journal of Ophthalmology 124 (3): 416-418, 1997.
16. Fisman DN, Smilovitch M : Intravenous Immunoglobulin, Blood Viscosity and Myocardial Infarction. Canadian Journal of Cardiology 13(8): 775-777, 1997
17. Rosenbaum JT: M yocardial Infarction as a complication of immunoglobulin therapy. Arthritis Rheumatology 40(9): 1732-1733, 1997.
18. Stangel M , Hartung HP, Marx P, Gold R: Review: Side effects of High-Dose Intravenous Immunoglobulins. Clinical Neuropharmacology 20(5): 385-393, 1997.
19. Haplea SS, Farrar JT, Gibson GA, Laskin M, Pizzi LT, Ashbury AK: Thromboembolic Events Associated with Intravenous Immunoglobulin Therapy: Neurology 48: A54, 1997.
20. Chatot-Henry C, Smadja D, Mehdaoui H, Fournerie P, Drault JN, Brebion A, Sobesky G: Acute renal insufficiency and cerebral infarction during high-dose intravenous immunoglobulin therapy.(French) Revue de Medecine Interne 19 (12): 914-916, 1998.
21. Sztajzel R, Le Floch-Rohr J, Eggimann P: High-Dose Intravenous Immunoglobulin Treatment and Cerebral Vasospasm: A Possible Mechanism of Ischemic Encephalopathy? European Neurology 41(3): 153-158 1999.
22. Kwan T, and K eith P: Stroke Following Intravenous Immunoglobulin Infusion in a 28-Year-Old Male with Comm on Variable Immune Deficiency: A Case Report and Literature Review. Canadian Journal of Allergy & Clinical Immunology 4:250-253, 1999.
23. Go RS, Call TG: Deep Venous Thrombosis of the Arm After Intravenous Immunoglobulin Infusion: Case Report and Literature Review of Intravenous Immunoglobulin-Related Thrombotic Complications. Mayo Clinical Proceedings 75(1): 83-85, 2000.
24. Elkayam O, Paran D, M ilo R, Davidovitz Y, Almoznino-Sarafian D, Zeltser D, Yaron M, Caspi D: Acute Myocardial Infarction Associated with High Dose Intravenous Immunoglobulin Infusion for Autoimmune Disorders. A study of four cases. Annals of Rheumatic Diseases 59(1): 77-80 2000.
25. Paolini R, Fabris F, Cella G: Acute myocardial infarction during treatment with intravenous immunoglobulin for idiopathic thrombocytopenic purpura (ITP). American Journal of Hematology 65(2): 177-178, 2000.
26. Alliot C, Rapin JP, Besson M , Bedjaoui F, Messouak D: Pulmonary embolism after intravenous immunoglobulin. Journal of the Royal Society of Medicine 94(4): 187-188, 2001.
27. Grillo JA, Gorson KC, Ropper AH, Lewis J, Weinstein R: Rapid infusion of intravenous immune globulin in patients with neuromuscular disorders. Neurology 57(9): 1699-1701, 2001.
28. Gomperts ED, Darr F: Letter to the Editor: Reference article - Rapid infusion of intravenous immune globulin in patients with neuromuscular disorders. Neurology, 2002. In Press.

Any suspected adverse reactions can also be reported to:

Canadian Adverse Drug Reaction Monitoring Program (CADRMP)

Marketed Health Products Directorate

Health Canada

Address Locator: 0201C2

Ottawa, Ontario, K1A 1B9

Tel: (613) 957-0337 or Fax: (613) 957-0335

Toll free for consumers and health professionals:

Tel: 866 234-2345, Fax: 866 678-6789

cadrmp@hc-sc.gc.ca

The ADR Reporting Form can be found in The Canadian Compendium of Pharmaceuticals and Specialties, or on the TPD website, along with the ADR Guidelines.