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Health Sciences Authority
Safety Alerts

Risk of severe cutaneous adverse reactions with recombinant human erythropoietins

11 May 2018

Audiences

Healthcare professional

Industry member

Product-type

Therapeutic Products

This article has been migrated from an earlier version of the site and may display formatting inconsistencies.

Severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported overseas in patients treated with recombinant human erythropoietins (r-HuEPOs). Some of these cases were life-threatening or fatal.

Background

r-HuEPOs are a class of biologics generally used for the treatment of anaemia associated with chronic renal failure. Some r-HuEPOs are also indicated for the treatment of anaemia in patients with non-myeloid malignancies receiving chemotherapy, facilitation of autologous blood collection and augmentation of erythropoiesis in the perisurgical period. SCAR occur rarely with r-HuEPOs and more severe reactions have been observed with long-acting r-HuEPOs (darbepoetin alfa and methoxy polyethylene glycol-epoetin beta). Signs and symptoms of SCAR include reddish target-like macules or circular patches often with central blisters on the trunk, skin peeling, ulcers of mouth, throat, nose, genitals and eyes, and can be preceded by fever and flu-like symptoms.

There are four r-HuEPOs registered in Singapore since 1995, namely epoetin alfa (Eprex®, Johnson & Johnson Pte Ltd), darbepoetin alfa (Nesp®, Kyowa Hakko Kirin (Singapore) Pte Ltd), epoetin beta (Recormon®, Roche Singapore Pte Ltd) and methoxy polyethylene glycol-epoetin beta (Mircera®, Roche Singapore Pte Ltd).

International Regulatory Actions

a)     European Medicines Agency (EMA)1,2

In July 2017, the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) completed its review on SCAR associated with r-HuEPOs. The review was triggered by a new emerging signal of SCAR (in particular SJS and TEN) arising from post-marketing reports. The review assessed all cases worldwide received up to February 2017, and identified a total of 23 reports of SJS and 14 reports of TEN with r-HuEPOs. Of these, a causal association was found for eight reports of SJS and one case of TEN. The more severe reactions were reported with long-acting r-HuEPOs (darbepoetin alfa and methoxy polyethylene glycol-epoetin beta) and included cases with positive dechallenge and positive rechallenge. EMA’s analysis of all SCAR cases from their adverse drug reaction (ADR) database (Eudravigilance) and data from companies concluded that SCAR can be considered a very rare class effect of all r-HuEPOs.

Based on its review outcomes, the PRAC recommended that the package inserts (PIs) and patient information leaflets of these products should be strengthened to warn about SCAR and a Dear Healthcare Professional Letter (DHCPL) be issued to communicate this safety issue.

b)     Health Canada (HC)3

HC also highlighted this safety concern earlier in May 2017, but its review focused mainly on SCAR associated with Aranesp® (darbepoetin alfa). As of 5 April 2017, HC identified 11 cases of SJS and four cases of TEN from international reports of patients treated with darbepoetin alfa across a cumulative exposure of over six million patient-years in the post-marketing setting. The Canadian PI for Aranesp® was updated to include safety information on SCAR.

Local situation and HSA’s advisory

To date, HSA has not received any local ADR report of SCAR, SJS or TEN associated with the use of epoetin alfa, darbepoetin alfa, epoetin beta and methoxy polyethylene glycol-epoetin beta. The Singapore PIs for these r-HuEPOs are in the process of being updated to include the risk of SCAR, including SJS and TEN.

Healthcare professionals are advised to educate their patients on the early recognition of signs and symptoms of allergic reactions, the importance of prompt withdrawal of r-HuEPOs if signs and symptoms suggestive of SCAR appear and the need to seek medical advice. They are also encouraged to report suspected ADRs associated with r-HuEPOs including information on the brand name and batch number, to the Vigilance and Compliance Branch of HSA.

References

  1. http://www.ema.europa.eu/docs/en_GB/document_library/ (opens in new tab)
    PRAC_recommendation_on_signal/2017/07/WC500232408.pdf (opens in new tab)

  2. https://www.gov.uk/drug-safety-update/recombinant-human-erythropoietins-very-rare-risk-of-severe-cutaneous-adverse-reactions-scars (opens in new tab)

  3. http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2017/63198a-eng.php?_ga=2.202917266.2066779798.1513240696-1105635081.1500348561 (opens in new tab)