Re-importation of pharmaceuticals may be unsafe: Lessons learned from the RADAR assessment of erythropoietin (EPO)-associated pure red cell aplasia (PRCA)

Abstract

2512 Background: Recombinant human erythropoietin (EPO) has been a breakthrough in cancer- and renal insufficiency-associated anemia since 1988. Antibody-mediated PRCA is a rare, serious toxicity characterized by severe anemia and neutralizing antibodies to EPO. Methods: The Research on Adverse Drug events And Reports (RADAR) project reviewed all suspected (n=448) and antibody-confirmed cases of PRCA reported worldwide from 1988 to Oct 2003. Results: Among 208 confirmed cases, median age was 66 (range, 14–86), male to female ratio was 2.4:1, median time from EPO initiation to PRCA suspicion was 9.4 months, and reports varied according to geography [Europe (58%), Asia (19%), Canada (13%), Australia (7%), and USA (3%)]; type of EPO used (EPO alpha alone, 81% and EPO alpha plus EPO beta, 16%); administration route (subcutaneous 97%); and year {incidence: pre-1998, 3 cases per million patient-years (MPY) and post-1998 [Australia (64 MPY), France (48 MPY), England (57 MPY), Canada (46 MPY), Spain (37 MPY), Italy (8 MPY), and Germany (7 MPY)]. 97% of cases were associated with Eprex brands. Reporting according to 4 milestones was evaluated: FDA approval in 1988 to Human Serum Albumin (HSA) removal from Eprex in Europe and Canada (1998; T1); from HSA removal to the first warning about PRCA from its manufacturer in 2001 (T2); to the second sponsor warning recommending a change from SC to IV administration in 2002 (T3), to the packet insert for Eprex brands of EPO contraindicating SC use for renal patients (T4), to Oct 2003 (T5), with variations according to country. In the more recent time periods, Canada had the highest incidence. Conclusions: EPO-associated PRCA remains an international concern, especially in Canada. Re-importation of Eprex products from Canada may allow for this severe complication to occur in the U.S. No significant financial relationships to disclose.