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Q&A 212.5

Can epoetin be used in Jehovah’s Witness patients in accordance with their beliefs?

Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals

Before using this Q&A, read the disclaimer at ukmi.nhs.uk/activities/medicinesQAs/default.asp

Date prepared: 1st February 2016

Background

Jehovah’s Witnesses’ beliefs

On the basis of biblical statements, Jehovah’s Witnesses decline the transfusion of whole blood, red cells, white cells, plasma and platelets (1,2). Depending on personal viewpoints, certain blood derivatives (‘fractions’) might be accepted (e.g. clotting factors, albumin, immunoglobulins) (1). Their position is based on biblical passages forbidding the eating of blood, which Jehovah’s Witnesses interpret to preclude transfusion of blood (3). Jehovah’s Witnesses believe that the intake of blood is not allowed because blood ‘symbolises life’, so conscientiously refusing transfusions is considered a way of ‘showing respect for life’ (4).

Transfusion without consent is considered to be a gross physical violation by Jehovah’s Witness patients (1,2). However, treating these patients without blood transfusion can pose medical, ethical and medicolegal challenges to their management (3).

Jehovah’s Witness patients are keen to co-operate with healthcare professionals in obtaining the best medical care and alternatives to blood. Their organisation has a number of Hospital Liaison Committees, which aim to help Jehovah’s Witness patients to work with medical staff and to facilitate communication between the two parties (4,5).

The General Medical Council advises that doctors “must treat patients fairly and with respect whatever their life choices and beliefs” (6). Trust and good communication are essential components of the relationship between the patient and healthcare professional (7). Discussing personal beliefs sensitively may help with working in partnership with patients to address their particular treatment needs. It is essential to respect patients’ rights to hold religious or other beliefs and take these into account where relevant to treatment options. Assumptions should not be made about the decisions that a Jehovah’s Witness patient might make about treatment with blood or blood products, as individuals vary in their choices (5). Their views should be sought and respected and their questions answered honestly. It is also important to respect the patient’s right to confidentiality (7).

Blood transfusions

Blood transfusion is the replacement of lost blood by blood or blood products usually donated by another person (8).

Jehovah’s Witness patients decline both allogeneic (previously known as homologous) and autologous blood transfusions (9,10):

□ ‘Allogeneic’ blood transfusions, the standard type, are where blood is donated i.e. from one person to another (11).

□ ‘Autologous’ blood transfusions allow the patient to be transfused with their own blood (11):

• Pre-deposit: Erythropoetin may be used before elective surgery to increase the yield of blood collected for autologous blood transfusion (12). This blood is then stored for later re-infusion (1). Autologous blood transfusions (pre-deposit donations) are generally regarded as unacceptable to Jehovah’s Witnesses, because they believe that any blood removed from their body, even their own, should not be given back (1,13).

• Intra-operative and/or post-operative: The use of other autologous procedures such as blood salvage (intra- and post-operative) and haemodilution is a matter of patient choice for individual Jehovah’s Witnesses (1).

It is therefore important to discuss with each Jehovah’s Witness patient which procedure is acceptable (1,5).

Erythropoietin

Endogenous human erythropoietin is a hormone normally produced by the kidney that regulates erythropoiesis (production of erythrocytes i.e. red blood cells) (8,14,15). Erythropoietin is available as recombinant human erythropoietin (rHuEPO), either as epoetin alfa, epoetin beta or epoetin zeta. The name ‘epoetin’ is often applied to the recombinant form (12).

In the UK, epoetin alfa is marketed as Eprex® (16), epoetin beta as NeoRecormon® (17) and epoetin zeta as Retacrit® (18). These are all produced by recombinant DNA technology in Chinese Hamster Ovary (CHO) cell lines (16-18).

Binocrit® (epoetin alfa) is no longer marketed in the UK, although the Summary of Product Characteristics (SPC) for this product remains listed on the electronic Medicines Compendium website (19,20).

Answer

Epoetin alfa (Eprex), epoetin beta (NeoRecormon) and epoetin zeta (Retacrit) are all licensed for increasing the yield of autologous blood from patients in a pre-donation programme (16-18). Use must be balanced against the reported risks, including thrombotic vascular events, and pure red cell aplasia. Treatment should only be given to patients with moderate anaemia, if blood-saving procedures are not available or are insufficient when the scheduled major elective surgery requires a large volume of blood.

Epoetin alfa (Eprex) and epoetin zeta (Retacrit) are also licensed to reduce exposure to allogeneic blood transfusions in adult non-iron deficient patients with moderate anaemia prior to major elective orthopaedic surgery. This is where there is a high perceived risk for transfusion complications, and where an autologous pre-donation programme is not available and a moderate blood loss is expected (16,18).

Neither epoetin alfa (Eprex), epoetin beta (NeoRecormon) nor epoetin zeta (Retacrit) have a licence for other surgical indications (16-18).

The NICE (National Institute for Health and Care Excellence) Guidelines on Blood Transfusion (2015) do not recommend use of erythropoetin as an alternative to blood transfusion for patients having surgery (21). However the guidelines make an exception if the patient “has anaemia and meets the criteria for blood transfusion, but declines it because of religious beliefs or other reasons”.

Jehovah’s Witnesses usually want to use epoetin to increase their blood cell count without actually taking the blood outside of their body, which differs from autologous blood donation (22). In this situation, use of NeoRecormon (eopetin beta) would be ‘off-licence’ as the product is not authorised for use in any blood-sparing situation apart from the pre-donation programme (17,22).

However Eprex (epoetin alfa) and Retacrit (epoetin zeta) may be considered licensed as a blood-sparing strategy, but only for use as described above, i.e. “prior to major elective orthopaedic surgery” (16,18). They are not licensed for reducing exposure to allogeneic blood transfusions in any other situation.

Accordance with Jehovah’s Witnesses beliefs

Personal choice is exercised as to what blood products Jehovah’s Witnesses will accept, so it is important to discuss with each individual patient the extent of their beliefs and generally ascertain exactly what procedures and substances are acceptable to the individual (1,23,24). Most Jehovah’s Witnesses carry legally binding advance decision documents and these should be reviewed in all cases (4).

The Jehovah’s Witness population usually accept rHuEPO because it is a recombinant product (13,15). Previous formulations of rHuEPO contained trace amounts of human serum albumin, which many Jehovah’s Witnesses would not accept due to it being a blood product. However, the recombinant epoetin products currently on the market, epoetin alfa (Eprex), epoetin beta (NeoRecormon) and epoetin zeta (Retacrit) contain no human serum albumin so are usually acceptable to Jehovah’s Witness patients (16-18,22,25).

The following statement was provided by Janssen-Cilag Ltd regarding Eprex: (25):

“Eprex® (Epoetin alfa, a recombinant human erythropoietin, r-HuEPO) in prefilled syringes has

been prepared using the carrier protein, polysorbate 80, since October 1998 and, as such, no

longer contains Human Serum Albumin. Consequently, there should be no objections from

Jehovah’s Witnesses to using the product”.

Roche provided the following statement for NeoRecormon (epoetin beta) (22).

“...as a result of the manufacturing process for NeoRecormon, there will not be residues of cell line in the syringes. Also, no human serum albumin is used at the drug product level.”

And Hospira provided the following statement for Retacrit (epoetin zeta) (26)

“...in principle, any drug containing a recombinant eopoetin would be expected to contain some residues of the respective host cell”.

“....host cell residues measured in the Retacrit drug substance are routinely undetectable. Where detectable these levels are within specification limits accepted by authorities for the current state of the art for mammalian cell culture derived protein products. No additional host cell proteins are introduced during the manufacture of the drug substance to the drug product.”

Summary

□ Personal choice is exercised by Jehovah’s Witnesses as to what blood products and procedures they will accept, so it is important to discuss with each individual patient the extent of their beliefs

□ NICE Guidelines on blood transfusion advise that erythropoietin should not be used to reduce the need for blood transfusion in patients having surgery, but that patients with anaemia who meet the criteria for blood transfusion but decline it because of religious beliefs or other reasons, may be an exception.

□ Epoetin alfa (Eprex), epoetin beta (NeoRecormon) and epoetin zeta (Retacrit) should all be suitable for Jehovah’s Witnesses on the basis of their beliefs because these products:

• are recombinant human erythropoietin (rHuEPO).

• routinely have no residues of the host cell line detectable at concentrations of the active ingredient used in humans.

• have no human serum albumin (HSA) content.

□ The only products licensed for reducing exposure to allogeneic blood transfusions as a blood-sparing strategy, are Eprex (epoetin alfa) and Retacrit (epoetin zeta). However they are only licensed for use specifically prior to elective major orthopaedic surgery, and not in any other situation. Epoetin beta (NeoRecormon) is unlicensed for use in any blood-sparing situation apart from the pre-donation programme.

Limitations

□ The clinical efficacy and safety of rHuEPO therapy in the management of Jehovah’s Witness patients is beyond the scope of this Medicines Q&A.

□ For further guidance on dosing and route of administration, haematological expertise should be sought for individual patients.

□ Concomitant therapy e.g. iron replacement is also beyond the scope of this article, but should be considered for rHuEPO therapy to be effective

□ Published reports of rHuEPO therapy in Jehovah’s Witnesses are limited to case reports and case series, and small open trials.

□ This Medicines Q&A applies only to those brands of epoetin stated at the time of writing.

□ This Medicines Q&A does not cover chemotherapy induced anaemia in cancer patients.

Acknowledgement

This Medicines Q&A has been prepared in consultation with the Co-ordinator at the Hospital Information Services for Jehovah’s Witnesses.

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References

1) Management of anaesthesia for Jehovah’s Witnesses. 2nd Edition. The Association of Anaesthetists of Great Britain and Ireland. London. November 2005. Accessed via 's%20Witnesses_0.pdf on 16th December 2015.

2) Rahman IA, Hoth T, Doughty H et al. Thoraco-abdominal aneurysm repair in a Jehovah’s Witness: maximising blood conservation. Perfusion 2007;22:363-364.

3) Mann MC, Votto J, Kambe J et al. Management of the severely anemic patient who refuses transfusion: lessons learned during the care of a Jehovah’s Witness. Ann Intern Med 1992;117:1042-1048.

4) Yang L, Jankovic Z. Orthotopic liver transplantation in Jehovah’s Witnesses. Current Anaesthesia and Critical Care 2008;19:34-41.

5) Joint United Kingdom Blood Transfusion & Tissue Transplantation Services Professional Advisory Committee. Norfolk D, ed. Handbook of Transfusion Medicine, 5th edition. Crown Copyright 2013 Chapter 12. Accessed via on 16th December 2015

6) General Medical Council. Personal Beliefs and Medical Practice; March 2013. Accessed via on 16th December 2015

7) General Medical Council. Confidentiality; October 2009. Accessed via on 16th December 2015

8) Cuschieri A, Grace PA, Darzi A et al. Clinical Surgery. 2nd Edition. Blackwell Publishing 2003. pp.80,81,87.

9) Wolff M, Fandrey J, Hirner A et al. Perioperative use of recombinant human erythropoietin in patients refusing blood transfusions. Pathophysiological considerations based on 5 cases. Eur J Haematol 1997;58:154-159.

10) Chikada M, Furuse A, Kotsuka Y et al. Open-heart surgery in Jehovah’s Witness patients. Cardiovasc Surg 1996;4:311-314.

11) Joint United Kingdom Blood Transfusion & Tissue Transplantation Services Professional Advisory Committee. Dictionary of Transfusion and Transplantation Medicine Terminology. Accessed via on 16th December 2015

12) Brayfield A, editor. Martindale: The Complete Drug Reference. Electronic edition. London: Pharmaceutical Press: Epoetins monograph. Accessed via on 16th December 2015

13) Remmers PA, Speer AJ. Clinical strategies in the medical care of Jehovah’s Witnesses. Am J Med 2006;119:1013-1018.

14) Charles A, Purtill M, Napolitano LM. Recombinant human erythropoietin in severe anaemia: issues of dosing and duration. Anaesth Intensive Care 2006;34:793-796.

15) Koenig HM, Levine EA, Resnick DJ et al. Use of recombinant human erythropoietin in a Jehovah’s Witness. J Clin Anesth 1993;5:244-247.

16) Summaries of Product Characteristics. Eprex (epoetin alfa) 2000, 4000, 10,000 and 40,000 IU/ml solution for injection in pre-filled syringe. Janssen-Cilag Ltd. Accessed 16th December 2015 via

17) Summary of Product Characteristics. Neorecormon (epoetin beta) solution for injection in pre-filled syringe. Roche Products Ltd. Accessed 16th December 2015 via

18) Summary of Product Characteristics. Retacrit (epoetin zeta) solution for injection in pre-filled syringe. Hospira UK Ltd. Accessed 16th December 2015 via

19) Summary of Product Characteristics. Binocrit (epoetin alfa) solution for injection in a pre-filled syringe. Sandoz Limited. Accessed 16th December 2015 via

20) Personal communication with Medical Information. ProPharma Group on behalf of Sandoz Limited. 16th December 2015.

21) National Institute for Health and Care Excellence (NICE). NG24: Blood Transfusion; November 2015. Accessed 15th December 2015 via

22) Personal communication with Medical Information. Roche Products Ltd. 15th January 2016

23) NHS Department of Health. Religion or Belief: a Practical Guide for the NHS; January 2009. Accessed 16th December 2015 via

24) Royal College of Surgeons. The Code of Practice for the Surgical Management of Jehovah’s Witnesses; 2002. (this document is under review and may not represent current surgical practice or policy). Accessed via on 15th December 2015

25) Personal communication with Medical Information. Janssen-Cilag Ltd. December 2015

26) Personal communication with Medical Information. Hospira UK Ltd. January 2016.

Quality Assurance

Prepared by

Samantha Owen (based on earlier work by Kate Pickett and Sandra Hicks), Principal Pharmacist Critical Evaluation, Southampton Medicines Advice Service, University Hospital Southampton NHS Foundation Trust.

Date Prepared

1st February 2016

Checked by

Simon Wills, Head of Southampton Medicines Advice Service, Southampton Medicines Advice Service, University Hospital Southampton NHS Foundation Trust.

Date of check

19th February 2016

Search strategy

• Embase via NHS Evidence: [exp ERYTHROPOIETIN/ OR exp RECOMBINANT ERYTHROPOETIN/] AND exp JEHOVAH’S WITNESS/ [Limit to Human and English Language]

• Medline via NHS Evidence: exp ERYTHROPOIETIN/ AND exp JEHOVAH’S WITNESSES/

• Electronic medicines compendium via

• Jehovah’s Witnesses official website

• British Society for Haematology website. Accessed via

• Joint United Kingdom (UK) Blood Transfusion and Tissue Transplantation Services Professional Advisory Committee website. Accessed via

• The Association of Anaesthetists of Great Britain and Ireland website. Accessed via

• Royal College of Surgeons website. Accessed via

• NICE Evidence website. Accessed via evidence.nhs.uk

• NICE website. Accessed via .uk

• Personal communication with Janssen-Cilag Ltd, Roche Products Ltd, Sandoz Ltd and Hospira UK Ltd via email on 15th December 2015

• In-house database and textbook resources

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