title: Clustering of adverse drug events: analysis of risk factors for cerebellar toxicity with high-dose cytarabine.
abstract: BACKGROUND
  Cerebellar toxicity is a severe, therapy-limiting adverse reaction of cytarabine given in high doses. The Food and Drug Administration received a report of an increased frequency of cerebellar toxicity at the University of Wisconsin Hospital and Clinics after a switch from the product (Cytosar-U) manufactured by The Upjohn Co., Kalamazoo, Mich., to the generic form made by Quad Pharmaceuticals, Inc., Indianapolis, Ind.
  
  
  OBJECTIVE
  To compare the incidence of cerebellar toxicity in Quad-treated patients with Upjohn-treated patients, a record-based cohort study was conducted at the University of Wisconsin Hospital and Clinics between January 1986 and August 1989.
  
  
  METHODS
  The incidence 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 toxicity was adjusted for other known risk factors.
  
  
  RESULTS
  Patients in the manufacturer-defined treatment groups did not differ significantly with respect to age, sex, type of leukemia, disease stage, calculated creatinine clearance, presence of abnormal liver function tests, or total dose received. The crude relative risk of cerebellar toxicity comparing the Quad product with the Upjohn product was 5.0 (95% confidence interval = 1.8-13.7). Adjustment for potential confounders did not alter the association. Other risk factors for cerebellar toxicity, independent of manufacturer, were age greater than 50 years, type of leukemia, disease stage, total dose greater than or equal to 20 g/m2, abnormal pretreatment liver function, and reduced creatinine clearance.
  
  
  CONCLUSIONS
  This study found a significantly higher incidence of cerebellar toxicity with high-dose cytarabine manufactured by Quad Pharmaceuticals 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 findings suggest that a dose reduction in high-dose cytarabine therapy may be indicated for patients with reduced glomerular filtration rates.
authors.affiliation: Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Md 20857.
authors.forename: H M
authors.initials: HM
authors.lastname: Jolson
authors.forename: L
authors.initials: L
authors.lastname: Bosco
authors.forename: M G
authors.initials: MG
authors.lastname: Bufton
authors.forename: B B
authors.initials: BB
authors.lastname: Gerstman
authors.forename: S S
authors.initials: SS
authors.lastname: Rinsler
authors.forename: E
authors.initials: E
authors.lastname: Williams
authors.forename: B
authors.initials: B
authors.lastname: Flynn
authors.forename: W D
authors.initials: WD
authors.lastname: Simmons
authors.forename: B V
authors.initials: BV
authors.lastname: Stadel
authors.forename: G A
authors.initials: GA
authors.lastname: Faich
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002526:Cerebellar Diseases / Q000139:chemically induced* / Q000652:urine; D002531:Cerebellum / Q000187:drug effects*; D015331:Cohort Studies; D003404:Creatinine / Q000652:urine; D003561:Cytarabine / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000652:urine; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000652:urine; D012307:Risk Factors
chemical_list: D003561:Cytarabine; D003404:Creatinine