CLUSTERING OF ADVERSE DRUG EVENTS - ANALYSIS OF RISK-FACTORS FOR CEREBELLAR TOXICITY WITH HIGH-DOSE CYTARABINE

Background: Cerebellar toxicity is a severe, therapy-limiting adverse reaction of cytarabine given in high doses. The Food and Drug Administ ration received a report of an increased frequency of cerebellar toxic ity at the University of Wisconsin Hospital and Clinics after a switch from the product (Cytosar-U) manufactured by The Upjohn Co., Kalamazo o, Mich., to the generic form made by Quad Pharmaceuticals, Inc., Indi anapolis, Ind. Purpose: To compare the incidence of cerebellar toxicit y in Quad-treated patients with Upjohn-treated patients, a record-base d cohort study was conducted at the University of Wisconsin Hospital a nd Clinics between January 1986 and August 1989. Methods: The incidenc e of cerebellar toxicity was studied in 63 leukemia patients according to the manufacturer of the product received (34 Upjohn only, 25 Quad only, and four both manufacturers). The relative risk of cerebellar to xicity was adjusted for other known risk factors. Results: Patients in the manufacturer-defined treatment groups did not differ significantl y with respect to age, sex, type of leukemia, disease stage, calculate d creatinine clearance, presence of abnormal liver function tests, or total dose received. The crude relative risk of cerebellar toxicity co mparing the Quad product with the Upjohn product was 5.0 (95% confiden ce interval = 1.8-13.7). Adjustment for potential confounders did not alter the association. Other risk factors for cerebellar toxicity, ind ependent of manufacturer, were age greater than 50 years, type of leuk emia, disease stage, total dose greater than or equal to 20 g/m2, abno rmal pretreatment liver function, and reduced creatinine clearance. Co nclusion: This study found a significantly higher incidence of cerebel lar toxicity with high-dose cytarabine manufactured by Quad Pharmaceut icals when compared with the incidence of cerebellar toxicity with the Upjohn product. Further research at independent institutions would be necessary to allow generalization of this finding. In addition, our f indings suggest that a dose reduction in high-dose cytarabine therapy may be indicated for patients with reduced glomerular filtration rates .