Unexpected serious adverse drug reactions (sADRs) affecting patients with chronic kidney disease (CKD) who received erythropoiesis-stimulating agents were identified by study co-authors. These included pure red cell aplasia (PRCA) after administration of the Eprex formulation of epoetin or the epoetin biosimilar HX575 and fatal anaphylaxis associated with peginesatide, an erythropoietin receptor agonist. We developed and applied a structured framework to describe these sADRs, including root cause analyses and eradication efforts.
A 10-step framework termed “ANTICIPATE,” focusing on signal identification, incidence, causality, and eradication guided our evaluations.
Initial cases were identified by a hematologist (Eprex), clinical study monitors (HX575), and 4 nurses (peginesatide). The number of persons with individual ADRs was 13 PRCA cases for epoetin, 2 antibody-mediated PRCA cases for HX575, and 5 fatal anaphylaxis cases for peginesatide. Initial incidence estimates per 1000 treated persons were 0.27 for Eprex-associated PRCA, 11 for HX575-associated PRCA, and 0.38 for peginesatide fatalities. Likely causes were subcutaneous administration of epoetin formulated with polysorbate 80 (Eprex), tungsten leaching from pins included in product syringes (HX575), and inclusion of a phenol stabilizer (peginesatide). Eradication strategies included restricting Eprex administration to the intravenous route, excluding tungsten from HX575 syringes, and for peginesatide, proposed eradication was to return to single-dose vials without preservatives.
Although the number of cases of each sADR was small, eradication was successful for 2 sADRs, and a proposed eradication was developed for a third sADR. The structured framework used to describe the above 3 sADRs in patients with CKD can also be used in other clinical settings.
1The Southern Network on Adverse Reactions (SONAR) Program, University of South Carolina College of Pharmacy, Columbia, SC;
2Department of Medicine, William Jennings Bryan Dorn Veterans Administration Medical Center, Columbia, SC;
3Kings College Hospital, London, United Kingdom;
4The Arnold School of Public Health, University of South Carolina, Columbia, SC;
5The Medical University of South Carolina Hollings Cancer Center, Charleston, SC; and
6College of Health and Human Services, George Mason University, Fairfax, VA.
Address for correspondence: Department of Medicine, Division of Cardiology, WJB Dorn VA Medical Center, 6439 Garners Ferry Road, Columbia, SC 29209. E-mail: firstname.lastname@example.org.
Supported by grants from the National Cancer Institute (1R01CA165609-01A1), the South Carolina Center of Economic Excellence Center for Medication Safety Initiative (C. L. Bennett), and philanthropic support from Doris Levkoff Meddin and Frank P and Josie M Fletcher to the South Carolina SmartState Center for Medication Safety and Efficacy. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
The authors have no conflicts of interest to declare.