title: The increased incidence of pure red cell aplasia with an Eprex formulation in uncoated rubber stopper syringes.
abstract: BACKGROUND
  The incidence of pure red cell aplasia (PRCA) in chronic kidney disease patients treated with epoetins increased substantially in 1998, was shown to be antibody mediated, and was associated predominantly with subcutaneous administration of Eprex. A technical investigation identified organic compounds leached from uncoated rubber stoppers in prefilled syringes containing polysorbate 80 as the most probable cause of the increased immunogenicity.
  
  
  METHODS
  This study investigated whether the incidence of PRCA was higher for exposure to the product form containing leachates than for leachate-free product forms. Antibody-mediated PRCA cases were classified according to indication, product form, and route of administration. Exposure estimates were obtained by country, indication, route of administration, and product form.
  
  
  RESULTS
  For 2001 to 2003, the PRCA incidence rate for patients with subcutaneous exposure to Eprex in prefilled syringes with polysorbate 80 and uncoated rubber stoppers (leachates present) was 4.61/10,000 patient years (95% CI 3.88-5.43) versus 0.26/10,000 patient years (95% CI 0.007-1.44) for syringes with coated stoppers (leachates absent). The rate difference was 4.35/10,000 patient years (95% CI 3.44-5.26; P < 0.0001); the rate ratio was 17 (95% CI 3.14-707). A substantial rate difference remained in sensitivity analyses that adjusted for exposure to multiple product forms.
  
  
  CONCLUSIONS
  The epidemiologic data, together with the chemical and immunologic data, support the hypothesis that leachates from uncoated rubber syringe stoppers caused the increased incidence of PRCA associated with Eprex. Currently, all Eprex prefilled syringes contain fluoro-resin coated stoppers, which has contributed to decreased incidence of PRCA with continued surveillance.
authors.affiliation: Johnson and Johnson, Pharmaceutical Research and Development, L.L.C, Raritan, New Jersey, USA.
authors.forename: Katia
authors.initials: K
authors.lastname: Boven
authors.forename: Scott
authors.initials: S
authors.lastname: Stryker
authors.forename: John
authors.initials: J
authors.lastname: Knight
authors.forename: Adrian
authors.initials: A
authors.lastname: Thomas
authors.forename: Marc
authors.initials: M
authors.lastname: van Regenmortel
authors.forename: David M
authors.initials: DM
authors.lastname: Kemeny
authors.forename: David
authors.initials: D
authors.lastname: Power
authors.forename: Jerome
authors.initials: J
authors.lastname: Rossert
authors.forename: Nicole
authors.initials: N
authors.lastname: Casadevall
mesh_terms: D002626:Chemistry, Pharmaceutical; D004921:Erythropoietin / Q000008:administration & dosage* / Q000009:adverse effects*; D006801:Humans; D015994:Incidence; D011136:Polysorbates / Q000008:administration & dosage; D011994:Recombinant Proteins; D012010:Red-Cell Aplasia, Pure / Q000139:chemically induced* / Q000453:epidemiology; D013594:Syringes
chemical_list: D011136:Polysorbates; D011994:Recombinant Proteins; D004921:Erythropoietin