Medicines Q&As

Q&A 60.5

How should haem arginate (human hemin) be administered in

the management of acute porphyria?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at
www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Date prepared: 25 July 2013 (date of partial revision 26 June 2014)

Background
The acute porphyrias are a group of rare, inherited disorders of haem biosynthesis. They
include acute intermittent porphyria (AIP), variegate porphyria and hereditary coproporphyria.
Patients with acute porphyria may be subject to acute, potentially life threatening
neurovisceral attacks (1,2). Acute attacks are very rare before puberty (1). For more
information on the acute porphyrias visit the European Porphyria Initiative website
(www.porphyria-europe.org) (3).
Haem arginate / human hemin (Normosang ) is the treatment of choice for acute porphyria
attacks, which is aimed at aborting the attack (1,3). Haem arginate will not reverse an
established neuropathy (1,4), although it may prevent its onset and may halt further
progression of neuropathy if given sufficiently early (3). By replenishing hepatic haem stores
the rate-limiting enzyme ALA synthase is inhibited by a process of negative feedback. This
reduces the formation of porphyrins and their precursors (4). Haem arginate is a
concentrated haem solution providing 250mg per 10mL ampoule. The haem is stabilised as a
complex with arginine and suspended in a mixture of ethanol and propylene glycol (3,5). It
must be diluted prior to infusion (2,5). Haem arginate is believed to be more efficacious if
started as soon as possible (within 12-24 hours (6)) after the diagnosis of an acute attack has
been established, unless it is clinically mild and obviously resolving (3).

Answer
Dose:
For the treatment of an acute porphyria attack the recommended dose of haem arginate is
3mg/kg (to a maximum of 250mg) once daily for four consecutive days (5). Some references
suggest that, for convenience, 250mg (1 x 10ml ampoule) for adults may be given irrespective
of their weight (3,7). This would be suitable for patients weighing 70kg. For patients
weighing less than this rounding the dose to the nearest 25mg (1mL) would seem
appropriate. In exceptional cases, where response to treatment is inadequate, the course
may be repeated after a day or two, with close biochemical monitoring, however the
effectiveness of long-term treatment has not been evaluated (3,5). For monitoring details,
please refer to the British and Irish Porphyria Network (BIPNET) guidelines (8).
Administration:
Haem arginate is irritant to the veins, so should be administered through a large vein or via a
central line, over at least 30 minutes in 100mL of sodium chloride 0.9% (5). Some references
suggest a slightly shorter infusion duration of 15-20 minutes (3,4,7,9). The product should be
protected from light during the infusion (10). After infusion, the vein should be flushed well
with 100mL of sodium chloride 0.9%, initially as three or four 10mL boluses and then the
remaining volume may be infused over 10-15 minutes (5). The infusion is hypertonic (5) and
contains polyethylene glycol (10) so should be stopped immediately if drug extravasation is
suspected. Haem arginate is a dark solution, which makes it difficult to check for absence of
particles. Therefore, it is recommended that it is administered using a 15-20 micron in-line

Available through NICE Evidence Search at www.evidence.nhs.uk

filter (5). This can be done by using a normal intravenous giving set with an integrated,
appropriate sized filter.
The manufacturer also recommends that haem arginate should be diluted with sodium
chloride 0.9% in a glass bottle and used within one hour of preparation. This is because once
diluted, the haem becomes unstable and the manufacturer has in-house studies that suggest
slightly faster degradation of hemin in PVC plastic containers (5). However, there may be
difficulties obtaining supplies of sodium chloride 0.9% in glass bottles. Therefore, a pragmatic
approach, to avoid delaying emergency treatment, would be to use plastic containers
(unlicensed method of administration) and the infusion should be administered immediately
(10).
Haem arginate is irritant to the veins and may cause thrombophlebitis. Repetitive peripheral
use may lead to the loss of the superficial venous system and the consequent need for a
central line. Central lines may also, in time, become obstructed with haem deposits.
Although unlicensed and lacking robust evidence, experience suggests that administration of
haem arginate in 100mL of human albumin helps reduce these problems (3), and this has
become accepted practice in several countries (e.g. South Africa, France, UK). There
currently appears to be no formal consensus on what strength of human albumin to use and
4-20% has been used (3). However, as each molecule of albumin has a single high-affinity
haem binding site, theoretically a 1:1 molar ratio of albumin to haem is suggested to ensure
binding of all haem molecules (11). Using 20% albumin, as in South Africa (12), would
appear logical as this will provide the closest to a 1:1 ratio. The maximum recommended rate
of infusion of human albumin 20% solution is 2mL per minute (13). Therefore, the rate of
haem arginate administration may need to be altered to take this into account. As a
pragmatic approach, administering the dose in 100mL of human albumin 20% over 60
minutes would appear reasonable. Human albumin 20% is hyperosmotic so adequate
hydration should be maintained and electrolytes monitored (13).
Haem arginate (Human hemin) availability:
The National Acute Porphyria Service (NAPS) was established in 2012. This service provides
clinical advice, authorisation for use and supply of haem arginate treatment 24 hours a day,
seven days per week. Authorised use of haem arginate will be reimbursed by the service as
this is funded centrally by NAPS. The service is provided in rotation for one week at a time
from one of two centres:
Kings College Hospital, London
University Hospital of Wales, Cardiff
In order to contact the service during or out of normal working hours users are asked to follow
the following procedure:
1. Telephone University Hospital of Wales Switchboard 029 20747747 and ask for the
National Acute Porphyria Service.
2. The switchboard will advise the user which centre is providing the emergency cover
that week according to an agreed rota.
3. The switchboard will provide the user with a telephone contact number or long range
pager number as arranged by each centre.

Summary

The recommended dose for haem arginate is 3mg/kg (to a maximum of 250mg) once
daily for 4 consecutive days.
It should be administered as an intravenous infusion in 100mL of sodium chloride 0.9%
over 30 minutes into a large vein or via a central line.
Available through NICE Evidence Search at www.evidence.nhs.uk

A 15-20 micron in-line filter should be used to filter out any unseen particles from the dark
solution.
Haem arginate infusion should be protected from light.
It is recommended that haem arginate is diluted in sodium chloride 0.9% in a glass bottle.
However, as there may be difficulties obtaining these a pragmatic approach, to avoid
delaying emergency treatment, would be to use plastic containers and the infusion should
be administered immediately.
Haem arginate is irritant to the veins and may cause thrombophlebitis. Repetitive
peripheral use may lead to the loss of the superficial venous system and the consequent
need for a central line. Central lines may also, in time, become obstructed with haem
deposits. Haem arginate may be administered in 100mL of human albumin (20%) to help
reduce these problems (unlicensed use) and infused over 60 minutes.

Limitations
This Q&A does not consider other management issues in treating acute porphyria attacks.
More detailed clinical advice can be obtained by contacting NAPS.
References
(1) Puy H, Gouya L, Deybach JC. Porphyrias. Lancet 2010; 375: 924-37
(2) Stein PE, Badminton MN, Barth JH, et al. Lessons of the month (1): Acute Intermittent
Porphyria: fatal complications of treatment. Clinical Medicine 2012; 12 (3): 293-4
(3) European Porphyria Initiative. Treatment of the acute attack. Accessed via:
www.porphyria-europe.org on 04/12/13.
(4) Porphyria South Africa. Haem arginate for the acute attack of porphyria. Accessed via:
http://web.uct.ac.za/depts/porphyria/professional/prof-haem-therapy.htm on 04/12/13.
(5) Summary of Product Characteristics - Normosang (Haem arginate) Orphan Europe.
Accessed via: www.emc.medicines.org.uk on 04/12/13. Date of revision of text 24/10/12.
(6) Personal communication. Dr Mike Badminton, Honorary Consultant and Clinical Lead,
NAPS (Cardiff) July 2013.
(7) Elder GH. Hift RJ. Treatment of acute porphyria. Hosp Med 2001; 62(7): 422-5.
(8) Stein P, Badminton M, Barth J et al. Best Practice Guidelines on Clinical Management of
Acute Attacks of Porphyria and Their Complications. Annals of Clinical Biochemistry.
2013; 50: pp. 217 - 223. Accessed via http://www.bipnet.org.uk/index.php/bipnet-clinicalguidelines/management-of-acute-porphyria.html (cited 07/11/13)
(9) Ventura P, Cappellini MD, Rocchi E. The acute porphyrias: a diagnostic and therapeutic
challenge in internal and emergency medicine. Intern Emerg Med 2009; 4: 297-308.
(10)Normosang (Haem arginate). Intravenous. In: Injectable Medicines Guide [date of
revision of text 19/8/10] [cited 04/12/13]. Available from: http://medusa.wales.nhs.uk/
(11)Anderson KE, Bonkovsky HL, Bloomer JR, et al. Reconstitution of Hematin for
intravenous infusion. Ann Intern Med 2006; 144 (7): 537-8.
(12)Hift RJ, Meissener PN. An analysis of 112 acute porphyric attacks in Cape Town, South
Africa: Evidence that acute intermittent porphyria and variegate porphyria differ in
susceptibility and severity. Medicine 2005; 84: 48-60.
(13)Haem derivatives. In: Sweetman S (Ed), Martindale: The Complete Drug Reference.
London: Pharmaceutical Press. Electronic version. Truven Health Analytics, Greenwood
Village, Colorado, USA. Available at: http://www.micromedexsolutions.com/ (cited
04/12/13).

Quality Assurance
Author
Cerys Lockett, Welsh Medicines Information Service, University Hospital of Wales (based on
earlier work by Gail Woodland, Alana Adams and Susan George) (partial revision by Cerys
Lockett)
Date this version written
25th July 2013 (date of partial revision 26th June 2014)
Available through NICE Evidence Search at www.evidence.nhs.uk

Checked by
Alana Adams, Welsh Medicines Information Service, University Hospital of Wales (partial
revision checked by Gail Woodland)
Date of check
6th December 2013 (partial revision checked 26th June 2014)
Search strategy
Medline (exp.Heme/ad OR exp.Hemin/ad OR heme arginate.mp; Limit to yr: 2009
-current)
Embase (heme arginate AND intravenous drug administration; Limit to yr: 2009
-current) (heme/ad, do, iv OR hematin/do, ad, iv OR heme arginate/do,ad,iv OR
hemin/do, ad, iv; Limit to yr: 2009 - current)
Micromedex (haem arginate OR hemin)
In-house database/ resources (MiDatabank, Porphyria Bulletin 2008)
NELM (haem arginate) (heme arginate)
IDIS (heme 20040410; years: 2009-2012)
Summary of Product Characteristics Normosang.
European Porphyria Initiative website (www.porphyria-europe.com)
Porphyria South Africa website (http://web.uct.ac.za/depts/porphyria/)
British Porphyria Association (www.porphyria.org.uk/)
British National Formulary, accessed online at:
http://www.medicinescomplete.com/mc/bnf/current/PHP6364-haem-arginate.htm.
Dr M Badminton, Honorary Consultant and Clinical Lead, NAPS, Cardiff Porphyria
Service.
Dr P Stein, Associate Porphyria Specialist, NAPS, Addenbrookes Hospital,
Cambridge.
Ms Tricia Gardiner, Clinical Nurse Specialist, NAPS, Cardiff Porphyria Service.
Martindale: The Complete Drug Reference.
Medusa electronic IV guide, accessed via http://medusa.wales.nhs.uk/
British and Irish Porphyria Network (BIPNET) website (www.bipnet.org.uk)

Available through NICE Evidence Search at www.evidence.nhs.uk