Q&A 60.6
How should haemarginate (human hemin) be administered in the management of acute porphyria?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
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Date prepared: 18 May 2016
Background
The acute porphyrias are a group of rare, inherited disorders of haem biosynthesis, in which defects in specific enzymes lead to the accumulation of haem precursors including aminolevulinic acid (ALA), porphobilinogen (PBG) and porphyrins. They are classified as acute and non-acute reflecting their clinical presentation (1). The acute porphyrias include acute intermittent porphyria (AIP), variegate porphyria and hereditary coproporphyria andpatients may be subject to acute, potentially life threatening neurovisceral attacks (2,3). Acute attacks are very rare before puberty (2). For more information on the acute porphyrias visit the European Porphyria Initiative website ( (4).
Haemarginate / human hemin (Normosang®) is thetreatment of choice for severe or recurrent acute porphyria attacks, which is aimed at aborting the attack (2,4). Haemarginatewill not reverse an established neuropathy (2,5), although it may prevent its onset and may halt further progression of neuropathy if given sufficiently early (4). By replenishinghepatic haem stores the initial rate-limiting enzyme ALA synthase is inhibited by a process of negative feedback. The formation of porphyrins and their precursors, ALA and PBG, is almost immediately reduced to low levels and symptoms improve(5). Haemarginate 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 (3,6). Haemarginateis believed to be more efficacious if started as soon as possible (within 12-24 hours (7)) after the diagnosis of an acute attack has been established, unless it is clinically mild and obviously resolving (4).
Answer
Dose:
For the treatment of an acute porphyria attack the recommended dose of haemarginate is 3mg/kg (to a maximum of 250mg) once daily for four consecutive days (6). Some references suggest that, for convenience, 250mg (1 x 10ml ampoule) for adults may be given irrespective of their weight (4,8). 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 (4,6). For monitoring details, please refer to the British and Irish Porphyria Network (BIPNET) guidelines (9).
Administration:
Haemarginate is a dark solution, which makes it difficult to check for absence of particles. Therefore, it is recommended that it is administered using an in-line filter (6). This can be done by using anormal intravenous giving set with an integrated, appropriate sized filter. (N.B. Most intravenous giving sets contain a 15 micron filter, but please check packaging (10)). Haemarginate is irritant to the veins and may cause thrombophlebitis, so should be administered through a large bore peripheral cannula or preferably via a central line, over at least 30 minutes in 100mL of sodium chloride 0.9% (6). Some references suggest a slightly shorter infusion duration of 15-20 minutes (4,5,8,11). The product should be protected from light during the infusion (12). 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 (6). If the intravenous cannula is in place for too long due to mechanical irritation and also due to irritation by the injection fluid, vascular damage may occur which may lead to extravasation. The cannula should be checked prior to infusing haemarginate and be checked regularly during the infusion (6). The infusion is hypertonicand contains polyethylene glycol (6) so should be stopped immediately if drug extravasation is suspected. Extravasation may cause skin discolouration (6).
The manufacturer also recommends that haemarginate 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 (6). 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 (12).
Repetitive peripheral use of haemarginatemay 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, some anecdotal experience suggests that administration of haemarginate in 100mL of human albumin may help reduce these problems (4), and this is used in several countries (e.g. South Africa and France). There currently appears to be no formal consensus on what strength of human albumin to use and 4-20% has been used (4). 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 (13). Using 20% albumin, as in South Africa (14), 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 (15). Therefore, the rate of haemarginate 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 (15).
Haemarginate (Human hemin) availability:
The National Acute Porphyria Service (NAPS) was established in 2012. This service provides clinical advice,authorisationfor use and supply ofhaemarginate treatment 24 hours a day, seven days per week. Authorised use of haemarginatewithin England and Scotland will be reimbursed by the service as this is funded centrally by NAPS. The service is provided in rotation from one of twocentres:
King’s 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:
- Telephone University Hospital of Wales Switchboard 029 20747747 and ask for the National Acute Porphyria Service.
- The switchboard will advise the user which centre is providing the emergency cover that week according to an agreed rota.
- 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 haemarginate 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 preferably via a central line.
Anin-line filter should be used to filter out any unseen particles from the dark solution (most giving sets contain a 15 micron filter, but check packaging first).
Haemarginate infusion should be protected from light.
It is recommended that haemarginate 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 containersand the infusion should be administered immediately.
Haemarginate is irritant to the veins and may cause thrombophlebitis.Extravasation is a risk factor with treatment.
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. Haemarginate 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 or UK Porphyria Medicines Information Service (UKPMIS).
References
(1)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: 23/3/16).
(2)Puy H, Gouya L, Deybach JC. Porphyrias. Lancet 2010; 375: 924-37
(3)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
(4)European Porphyria Initiative. Treatment of the acute attack. Accessed via: 23/3/16.
(5)Porphyria South Africa. Haemarginate for the acute attack of porphyria. Accessedvia: 23/3/16.
(6)Summary of Product Characteristics - Normosang® (Haemarginate)Orphan Europe. Accessed via: on 23/3/16.Date of revision of text4/11/15.
(7)Personal communication. Dr Mike Badminton, Honorary Consultant and Clinical Lead, NAPS (Cardiff)May 2016.
(8)Elder GH. Hift RJ. Treatment of acute porphyria. Hosp Med 2001; 62(7): 422-5.
(9)Stein P, Badminton M, Barth J et al. BestPractice Guidelines on Clinical Management of Acute Attacks of Porphyria and Their Complications. Annals of Clinical Biochemistry. 2013; 50: pp. 217 - 223. Accessed via (cited 23/3/16)
(10)Personal communication. Ms Louise Williams, Nurse Advisor, Medicines Management, University Hospital of Wales, Cardiff July 2016.
(11)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.
(12)Normosang(Haemarginate). Intravenous. In: Injectable Medicines Guide [date of revision of text6/7/15] [cited 25/5/16]. Available from:
(13)Anderson KE, Bonkovsky HL, Bloomer JR, et al. Reconstitution of Hematin for intravenous infusion. Ann Intern Med 2006; 144 (7): 537-8.
(14)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.
Quality Assurance
Author
Cerys Lockett, UKPMIS, Welsh Medicines Information Centre, University Hospital of Wales (based on earlier work by Gail Woodland, Alana Adams and Susan George)
Date this version written
18 May 2016
Checked by
Gail Woodland, UKPMIS,Welsh Medicines Information Centre, University Hospital of Wales
Date of check
1 July 2016
Search strategy
- Medline (exp.Heme/ad OR exp.Hemin/ad OR heme arginate.mp; Limit to yr: 2009 -current)
- Embase(hemearginate AND intravenous drug administration; Limit to yr: 2009 -current) (heme/ad,do,iv OR hematin/do,ad, iv OR hemearginate/do,ad,iv OR hemin/do,ad,iv; Limit to yr: 2009 - current)
- Micromedex (haemarginate OR hemin)
- In-house database/ resources (MiDatabank, Porphyria Bulletin 2008)
- NELM(haemarginate) (hemearginate)
- NICE evidence(haemarginate) (hemearginate)
- IDIS (heme 20040410; years: 2009-2012)
- Summary of Product Characteristics – Normosang®.
- European Porphyria Initiative website (
- Porphyria South Africa website (
- British Porphyria Association (
- British National Formulary
- Dr M Badminton, Honorary Consultant and Clinical Lead, NAPS, Cardiff Porphyria Service.
- Dr P Stein, Associate Porphyria Specialist, NAPS, Kings College Hospital, London.
- Ms Tricia Gardiner, Clinical Nurse Specialist, NAPS, Cardiff Porphyria Service.
- Martindale: The Complete Drug Reference.
- Medusa – electronic IV guide, accessed via
- British and Irish Porphyria Network (BIPNET) website (
- American Porphyria Foundation website (