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Health Sciences Authority
Safety Alerts

Erythropoietin stimulating agents (ESAs): A safety update

Audiences

Healthcare professional

Industry member

Product type

Therapeutic Products

19 April 2010

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

HSA would like to remind healthcare professionals of key safety issues associated with the use of erythropoietin stimulating agents (ESAs). There are four ESAs currently registered in Singapore - epoetin alfa (Eprex®, Johnson & Johnson), epoetin beta (Recormon®, Roche), darbepoetin (Aranesp®, Kyowa Hakko Kirin) and methoxy polyethylene glycol-epoetin beta (Mircera®, Roche). All these ESAs, except Mircera®, are indicated for the treatment of anaemia in patients associated with renal failure and for treatment of anaemia as a result of chemotherapy in cancer patients. Mircera® is licensed locally only for the treatment of anaemia associated with chronic kidney disease.

Safety issues associated with the use of ESAs

Shorter time to tumour progression

Several studies conducted in cancer patients showed higher mortality or shorter time to tumour progression in patients randomized to receive an ESA as compared to placebo . The types of cancers investigated include breast, head and neck, non-small cell lung cancers. In some of these trials, patients were treated with ESA to achieve haemoglobin levels > 12 g/dL. This level is higher than the recommended haemoglobin target level for ESA therapy, which is ≤ 12 g/dL. Other trials included anaemic patients who were not on chemotherapy or radiotherapy.2

Cardiovascular-related adverse events

In 2006, the New England Journal of Medicine (NEJM) published an editorial and two clinical studies (CHOIR and CREATE) in patients with chronic renal failure not on dialysis. The Correction of Haemogloblinand Outcomes in Renal Insufficiency (CHOIR) and Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) trials addressed safety concerns with the use of ESAs in the treatment of anaemia of chronic renal failure (CRF). In these studies, patients who were randomised to receive an ESA to achieve higher haemoglobin levels (13.5g/dL in CHOIR and 13.0 to 15.0g/dL in CREATE) experienced more serious adverse cardiovascular outcomes such as congestive heart failure hospitalisation, non-fatal myocardial infarction, non-fatal stroke as compared to those who received an ESA to achieve lower haemoglobin levels (11.3g/dL in CHOIR and 10.5 to 11.5g/dL in CREATE).

Thrombovascular adverse events

In 2009, the results of a prospective, open-labelled, randomized, parallel-group study at 80 centres were published.3 The study documented a higher incidence of deep vein thrombosis and similar rates of other clinically relevant thrombovascular events with epoetin alfa versus standard of care for blood conservation in subjects who did not receive prophylactic anticoagulation before spinal surgery. The authors recommended that antithrombotic prophylaxis be considered when erythropoietin is used in the surgical setting. As ESAs collectively have the same mechanism of action, the above safety concerns are applicable to all ESAs.

Actions taken by other regulatory agencies

In the United States and European countries, the product information of ESAs have been updated to reflect the above safety information.4,5 In addition, the US Food and Drug Administration (FDA) also requires all healthcare professionals to discuss the risks associated with the use of ESAs with their patients prior to prescribing ESAs.

Conclusion

To date, there are no local reports of ADR associated with tumour progression or cardiovascular/thrombotic events in cancer patients using ESAs.

The local package inserts of the ESAs carry the above-mentioned safety information associated with the use of ESAs. Healthcare professionals are advised that the target haemoglobin concentration for all indications of ESAs should not exceed 12 g/dL.

References

  1. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm126481.htm (opens in new tab)

  2. Spine 2009, Nov 1;34(23):2479-85

  3. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm200297.htm (opens in new tab)

  4. http://www.ema.europa.eu/pdfs/human/press/pr/33396308en.pdf (opens in new tab)