Multiple Cause of Loss of Recombinant Erythropoietin Efficacy: Physicians Beware.
Authors: Carson Kenneth R. , Raisch Dennis W. , Bennett Charles L. 
Published: April 2020

Abstract
Introduction: Loss of response to recombinant erythropoietin is a rare event typically seen only in the setting of iron deficiency or serious blood dyscrasia. In 2004, the Research on Adverse Drug Events and Reports group reported on 191 cases of antibody-mediated pure red cell aplasia (PRCA) primarily associated with the human albumin free formulation of Eprex. There were no reports of loss of response to darbepoetin alfa at that time. Since 2004, additional causes of loss of efficacy of epoetin therapy have been identified or described in detail.
Methods: Data were obtained from the FDA’s adverse event reporting system (AERS), and published literature, both medical and non-medical.
Results: In the AERS system, we found nine reports of patients who developed anti-erythropoietin antibodies after exposure to darbepoetin alfa, seven of which occurred after recent exposure to Eprex. All of these patients received darbepoetin alfa for the anemia of chronic kidney disease (CKD). We also identified eight cases of loss of efficacy due to counterfeit epoetin in the literature and AERS reports. All of these patients received epoetin alfa for an indication other than anemia of CKD. Of the seven counterfeit cases found in AERS, five were reported by pharmacists, one by a consumer, and one by a nurse. In contrast, more than 90% of the 191 initial cases of antibody-mediated PRCA and all 9 cases associated with darbepoietin alfa were reported by physicians. Three cases of exposure to counterfeit epoetin in our series were linked to a single counterfeit supplier. Only two of these three cases were found in AERS out of an estimated 25,000–75,000 patients exposed to epoetin vials from that counterfeit supplier, for a reporting rate of less than 1/12,000 (.01%). This is lower than the estimated reporting rate for all adverse events of 1% to 10%, and markedly lower than the 90% or greater estimated reporting rate for antibody associated PRCA.
Conclusion: Physicians should be aware of multiple the multiple possible etiologies for decreased recombinant erythropoietin efficacy, including the possible link between darbepoetin alfa and antibody mediated PRCA in patients with CKD. In addition, loss of efficacy related to counterfeit recombinant erythropoietin should be considered, especially in patients with anemia from conditions other than CKD. Underreporting of counterfeit epoetin exposure occurred despite the fact that “dear doctor” warning letters were sent to physicians at the time of two major counterfeit events. Unlike the warning letters for antibody-mediated PRCA, these letters did not contain information about clinical signs and symptoms that could be observed or elicited from patient history. In the future, warning letters for counterfeit pharmaceutical products should describe the potential clinical effects of the counterfeit medications in an effort to improve reporting and tracking of counterfeit medications through AERS.
Table of Findings darbepoetin alfa epoetin alfa/beta counterfeit epoetin alfa Number of cases 9 191 8 Causality established No Yes Yes Reported by MD 100% &gt;90% 0% Reported in AERS 100% 95% 88% Clinical findings Loss of Efficacy, rapid onset anemia, transfusion requirement Loss of efficacy, rapid onset anemia, transfusion requirement Loss of efficacy, slow onset anemia, may need transfusion Clinical findings described in warning letter Yes Yes No