Independent research teams based at Northwestern University in the U.S. and at the McGill University Health Centre (MUHC) in Canada are reporting similar findings about a rare and potentially life-threatening form of anemia known as antibody-associated pure red-cell aplasia (PRCA). This disorder is associated with recombinant human erythropoietin (epoetin), a widely used product for anemia that occurs among cancer patients or persons undergoing dialysis.
Epoetin has allowed hundreds of thousands of patients suffering from chronic renal failure and other medical conditions to avoid blood transfusions. It is the most successful biotechnology product marketed today. The predominant formulation associated with this rare but serious toxicity was Eprex®, a formulation of epoetin that is sold in Canada, Europe, Asia and Australia, but not in the United States. Almost 200 patients with chronic kidney disease worldwide have developed an unusual form of PRCA in which antibodies to recombinant erythropoietin develop and attack a natural hormone in the body that is responsible for producing red blood cells. The resultant anemia is severe and requires almost weekly blood transfusions.
In a study published in the October 1, 2004 issue of the Journal of the American Society of Nephrology, MUHC researcher Dr. Denis Cournoyer (Division of Hematology and Research Ethics Office) and his colleagues from the Canadian PRCA Focus Group estimated the risk of erythropoietin-associated PRCA among patients with chronic kidney disease for the time period between January 1998 and March 2003. They found that Eprex lacking human serum albumin and administered subcutaneously was associated with the greatest risk of PRCA (26.9 cases per 100,000 patient-years of exposure). The Canadian PRCA Focus Group concluded that Eprex lacking human serum albumin should not be administered subcutaneously to patients with chronic kidney disease due to increased risk of PRCA.
Although the subcutaneous administration of Eprex formulation with human serum albumin and NeoRecormon were found to present slightly higher risk than some erythropoietin products administered intravenously, there is currently no evidence that other products administered subcutaneously are safer than these two products. Therefore no recommendation can be made regarding the use of specific erythropoietin products other than avoiding the use of Eprex lacking human serum albumin for patients with chronic kidney disease who lack an intravenous access device (for instance, in the context of pre-dialysis or home dialysis).
The Canadian PRCA Focus Group investigators noted that the results of their analysis should be considered in light of the limitations of pharmacovigilance data. Risk analysis for antibody positive PRCA was performed on data generated by self-reporting and marketing rather than through a prospective study.
In another study, published in the September 30, 2004 issue of the New England Journal of Medicine, researcher Dr. Charles L. Bennett and colleagues from Northwestern University, the Jesse Brown Veterans Administration Hospital and institutions in Italy and France reported that national health agencies in Europe and Canada collaborated with pharmaceutical manufacturers of epoetin to find the cause of pure red-cell aplasia associated with use of the drug and reduce its incidence.
Worldwide, there were 191 reports of epoetin-associated pure red-cell aplasia; 92 per cent of cases involved the use of subcutaneous administration of Eprex to persons receiving renal dialysis. Although epoetin is widely used by cancer patients, none of the cases of pure red-cell aplasia occurred in this setting. The number of cases of epoetin-associated pure red-cell aplasia began to increase dramatically in patients with chronic kidney disease in France, England, Spain and Canada in 1998 and peaked in 2001 in the three European countries and in Canada in 2002.
In 1998, the formulation of Eprex was changed in response to concern that the human serum albumin used in the manufacture of the drug could transmit a variant of Creutzfeldt-Jakob disease. Also, countries with large numbers of cases had been administering the new formulation of Eprex subcutaneously to dialysis patients, while countries with few cases administered the product predominantly via the intravenous route. Beginning in 2002 in Europe and one year later in Canada, after improvements were made in the storage and handling of all Eprex formulations and limiting Eprex administration to the intravenous route in patients with chronic kidney disease, the incidence of Eprex-associated pure red-cell aplasia decreased by 83 per cent, dropping nearly to pre-1998 levels.
The two groups of investigators have joined forces and will closely monitor this serious complication internationally, elucidate its apparent multifactorial causes, and formulate recommendations that may improve the global efficacy of post-marketing safety assessments for all pharmaceutical products.