Increase in antibody-mediated Pure Red Cell Aplasia (PRCA) cases with subcutaneous administration of Eprex® (epoetin alfa) in Singapore

Healthcare professionals to be vigilant to possible PRCA in users of erythropoiesis stimulating agents

HSA would like to update healthcare professionals on an unexpected increase in local cases of antibody-mediated Pure Red Cell Aplasia (PRCA) associated with subcutaneous administration of Eprex^®(epoetin alfa, Johnson & Johnson Pte Ltd). These cases were reported between the period 2012 and 2013.

Local PRCA cases reported from 2012 to 2013

The confirmed PRCA cases associated with Eprex® with date of onset between 2012 to June 2013 accounted for 90% of the total Eprex®-associated PRCA cases in the HSA Pharmacovigilance database since the reinstatement of the subcutaneous route for Eprex® in April 2009. While reporting rates cannot be used to estimate incidence rate, this is a disproportionately high number of PRCA cases reported compared to the baseline reporting trend.

During this period, nine PRCA cases were reported from two local healthcare institutions. One institution reported seven confirmed (antibody-positive) and one suspected (antibody status unknown) cases while another institution reported one confirmed case. All cases were reported with subcutaneous use of Eprex® in chronic kidney disease patients with duration of onset ranging from seven months to 19 months.

HSA is currently working with the company and healthcare institutions to monitor the situation closely and will take further regulatory actions when deemed necessary. A Dear Healthcare Professional Letter was issued on 13 June 2013 to inform Eprex® users about the increase in local PRCA cases.

Diagnosis and management of antibody-mediated PRCA

Antibody-mediated PRCA is a rare, serious disorder of erythropoiesis characterised by severe anaemia, low reticulocyte count, absence of erythroblasts, non-response to erythropoiesis stimulating agents (ESAs), and presence of neutralising antibodies against erythropoietin (EPO).^1-3 However, the mechanisms behind this immunological response remain only partially understood.^2,4 The patient generally presents with initial erythropoietic response to ESA treatment for six to 18 months and a stable haemoglobin level, followed by a sudden and rapid decline in haemoglobin level at a rate of approximately 1g/dL/week. The development of severe anaemia is refractory to dose increases of ESA, resulting in an increasing need for transfusions at approximately four units of packed red blood cells (RBCs) per month.⁵ The shortest time interval between the start of ESA therapy and loss of efficacy reported in literature was two months and the longest time interval was 90 months.¹

Haematological investigations in patients with PRCA revealed reticulocytopenia (<10,000 cells/mL) with generally normal white cell and platelet counts. Diagnosis of PRCA is confirmed through bone marrow examination and antibody assay showingnormal bone marrow cellularity with an almost complete eradication of erythroblasts (<5% erythroblasts) and presence of neutralising anti-EPO antibodies.⁵ Other known causes of PRCA include acquired PRCA in relation to tumours, autoimmune diseases, T-cell disorders and viral infections.⁶ Anti-EPO antibodies produced in response to ESAs cross-react with exogenous ESAs and endogenous EPO.^1-3 Upon diagnosis of ESA-induced PRCA, cessation of ESA therapy is universally accepted as first-line therapy with supportive RBC transfusions when necessary to avoid severe and life-threatening anaemia.

History of PRCA associated with Eprex®

From 1998 to 2004, a rise in PRCA cases associated with the use of Eprex® was observed globally.⁷ This unexpected increase in PRCA cases was attributed to several possible reasons, including substitution of human serum albumin with polysorbate 80 (a synthetic stabiliser), leaching from uncoated rubber stoppers, and breaks in the cold chain process which could lead to increased immunogenicity.^4,5 The association of PRCA with subcutaneous administration of Eprex® with polysorbate 80 and uncoated rubber stoppers was later corroborated by investigators from the Research on Adverse Drug Events and Reports (RADAR) project, who found that 95% of 191 haemodialysis patients with anti-EPO antibody-mediated PRCA were reported to have received Eprex® subcutaneously.³

In 2002, the European Union regulatory agencies contraindicated subcutaneous administration of Eprex® and mandated intravenous administration of Eprex® to haemodialysis patients. This resulted in a 90% decrease in the annual number of Eprex®-associated PRCA cases, as well as a decline in the exposure-adjusted incidence rates in these countries. With the introduction of Teflon-coated rubber stoppers in 2004, further reduction in reporting rates occurred. The subcutaneous route for Eprex® was eventually reinstated in most countries.

HSA's advisory

While HSA is investigating the unexpected increase in PRCA cases associated with subcutaneous Eprex® in chronic kidney disease patients in Singapore, healthcare professionals are advised to be vigilant to the possibility of PRCA occurring in ESA users.

Although the increase in local ADR reports of PRCA are currently associated with Eprex®, PRCA related to other ESAs has also been reported previously.⁷ Healthcare professionals are encouraged to report any suspected reactions with the use of ESAs to the Vigilance Branch of HSA.

HSA will update healthcare professionals on any new findings and regulatory actions taken arising from its investigations.

References

1. J Am Soc Nephrol 2005; 16: S67-9

2. Nephrol Dial Transplant 2008; 23: 3053-5

3. Transfusion 2008; 48: 1754-62

4. Kidney Int 2012; 81: 727-32

5. Nephrol Dial Transplant 2005; 20: viii 18-21

6. Br J Haematol 2000; 111: 1010-22

7. N Engl J Med 2004; 351: 1403-8

The editorial team would like to thank Dr Tan Chuen Wen (Registrar, Department of Haematology, SGH) for his clinical input in the above article.