Contraindication of subcutaneous administration of Eprex® (epoetin alfa) in Singapore in chronic kidney disease patients

HSA would like to update healthcare professionals that subcutaneous (SC) administration of Eprex®(epoetin alfa, Johnson & Johnson Pte Ltd) is contraindicated in Singapore in chronic kidney disease (CKD) patients, including end stage renal disease (ESRD) patients. This is due to the strong association of antibody-mediated pure red cell aplasia (Ab-mediated PRCA) with SC administration of Eprex® observed locally. This decision arose from HSA's benefit-risk assessment and its consultation with a local expert panel, comprising renal physicians and haematologists, who assessed that the benefit-risk profile of Eprex® when administered subcutaneously was no longer favourable for CKD patients in the Singapore context.¹

Based on information available to-date, this contraindication is specific to Eprex® administered subcutaneously for CKD patients. The contraindication does not affect Eprex® administered subcutaneously in other approved indications (e.g., anaemia in patients receiving chemotherapy, anaemia in HIV-infected patients treated with zidovudine, facilitation of autologous blood collection within a predeposit programme, and augmentation of erythropoiesis in the perisurgical period of major elective orthopaedic surgery) as well as other erythropoiesis stimulating agents (ESA) approved for SC administration in CKD patients.

Summary of current local situation

Nine Ab-mediated PRCA cases were reported to HSA between 2012 and June 2013 from two local healthcare institutions. The initial signal of six local cases from one healthcare institution was first shared with healthcare professionals through a Dear Healthcare Professional Letter (DHCPL) issued on 13 June 2013.² Subsequently, additional cases were reported from the same healthcare institution as well as one report from another healthcare institution. While investigations were ongoing, healthcare professionals were kept updated about these cases via the August 2013 issue of the HSA Adverse Drug Reaction News bulletin.³ All cases were reported in CKD patients with Eprex® as the only suspected ESA. In addition, all cases involved SC administration of Eprex®, except for two cases where Eprex® was administered by both the SC and intravenous (IV) routes. Since the last update in August 2013, all reported cases have been confirmed as Ab-mediated PRCA cases through bone marrow examinations and antibody testing.

HSA's assessment and regulatory decision

A comprehensive review was conducted to investigate possible causes of the unexpected increase in local Eprex®-associated Ab-mediated PRCA cases reported recently in 2012 and 2013. This included a review of past history of local cases of Eprex®-associated Ab-mediated PRCA. Locally, between 2000 to 2002 when both SC and IV routes were approved for use for Eprex®, eight cases of Ab-mediated PRCA in CKD patients were reported with Eprex® as the only suspected ESA. After the recommendation by HSA to use only IV administration of Eprex® from 2003 to March 2009 in CKD patients, Eprex®-associated Ab-mediated PRCA cases were reduced substantially, with only one case reported each in 2003 and 2006 based on loss of efficacy onset date. However, following the local reinstatement of the SC administration route of Eprex® for CKD patients in 2009, resulting in both SC and IV routes being approved for administration, there was an unexpected increase in local Eprex®-associated Ab-mediated PRCA cases reported in CKD patients in 2012 and 2013.

HSA has concluded that while root causes behind the Eprex®-associated Ab-mediated PRCA cases (such as storage/handling issues and quality/manufacturing issues) have been assessed to be inconclusive, the totality of the information available to-date indicated a strong association of Ab-mediated PRCA with SC administration of Eprex® in CKD patients. Given the increased frequency of Eprex®-associated Ab-mediated PRCA locally, which is a serious and potentially life-threatening adverse event, a contraindication of SC administration of Eprex® in Singapore in CKD patients is warranted to minimise the risk of Ab-mediated PRCA occurring in these patients and to safeguard public health.

HSA's advisory

HSA is working with the company to strengthen the local package inserts to reflect the contraindication of the SC administration route of Eprex® in CKD patients. This contraindication does not apply to Eprex® administered intravenously, Eprex® administered subcutaneously for other approved indications, or other ESAs approved for SC administration in CKD patients.

A DHCPL was issued on 2 October 2013 to inform of the following¹:

• SC administration of Eprex® is contraindicated in Singapore in patients with CKD including patients with end stage renal disease. CKD patients who are currently receiving Eprex® subcutaneously should be reviewed as soon as it is possible so that they can be switched to IV Eprex® or alternative therapeutic options be considered.

• ESA therapy should be discontinued immediately if Ab-mediated PRCA is suspected.

• Healthcare professionals are reminded to ensure that Eprex® and other ESAs are stored between2ºC and 8ºC (as stated in their package inserts) and to advise their patients on the appropriate storage/handling of these ESAs.

Healthcare professionals are also encouraged to report any suspected reactions with the use of ESAs to the Vigilance Branch of HSA.

References

1. HSA Dear Healthcare Professional Letter: Contraindication of the subcutaneous administration of Eprex® in chronic kidney disease patients. 2 Oct 2013, No. 50

2. Dear Healthcare Professional Letter issued by Janssen, 13 Jun 2013.

3. HSA ADR News Bulletin 2013 Aug; 15: 7