Safety update — allopurinol
Published in Health News and Evidence
Date published: About this date
Allopurinol lowers plasma urate level and is commonly used as first-line therapy in long-term gout prophylaxis.1 Some patients may develop allopurinol hypersensitivity (AH), commonly characterised by rash but sometimes causing systemic symptoms.2 AH can occur as severe cutaneous adverse reactions (SCAR), which includes Stevens–Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN).3,4 These reactions have a low incidence but have a mortality rate of 1–5% for SJS, and 25–30% for TEN.3
Genetic susceptibility factors, in particular, human leukocyte antigen (HLA) alleles, have been identified as risk factors for hypersensitivity reactions. Susceptibility to AH has been linked specifically to the HLA-B*5801 gene allele.4–10 This allele occurs in high frequency in people from certain ethnic groups, particularly those with Han-Chinese ancestry.6 While the allele confers risk, being a carrier does not necessarily cause the development of AH6 and routine testing for HLA-B*5801 is not recommended.
Use caution when selecting allopurinol for gout prophylaxis in populations with a strong association with, or if the patient is a known carrier of, HLA-B*5801.3 In all patients taking allopurinol it is important to monitor for signs and symptoms of SCAR.11 Do not use in people with a known hypersensitivity.12
Allopurinol lowers plasma urate level by inhibiting its production; it is commonly used and recommended as first-line therapy in long-term prophylaxis for gout.1
Australian guidelines recommend:
- introducing allopurinol in people who experience recurrent gout attacks despite minimising potential contributing factors to hyperuricaemia, such as diuretics and alcohol.1 Start treatment in the interval between attacks, as initiating allopurinol or changing the dose during an acute attack may lead to exacerbation.1
- starting at a low dose in patients with chronic gout and resolving the inflammation if possible with concurrent NSAID and/or colchicine.1 With chronic gout there is no asymptomatic period in which to start urate-lowering therapy.1
- measuring plasma urate concentration monthly during the titration phase, adjusting the dose with the aim to bring the plasma urate concentration down to ≤ 0.3 mmol/L.1
General agreement among clinicians and researchers is that AH is immune mediated.13,14 However, the pathophysiological mechanisms of AH are not well understood. The term hypersensitivity is used when an agent results in an increased or exaggerated immune response.15
AH can occur as severe cutaneous adverse reactions — Stevens–Johnson syndrome or toxic epidermal necrolysis — which have high mortality rates3,4
SJS and TEN have a low annual incidence, with about one person in 56,000 developing allopurinol-induced SCAR.16 AH also includes less serious skin and systemic hypersensitivity reactions — drug-induced hypersensitivity syndrome (DIHS) and drug reaction with rash, eosinophilia and systemic symptoms (DRESS).17 Less is known about the mechanism behind these reactions.17
Genetic factors have been identified as predisposing to AH4–10
Because of the serious morbidity and mortality related to SCAR2 there has been a sustained effort to find markers that can predict individual susceptibility to these conditions.9 AH has been linked to the HLA-B*5801 allele of the HLA gene locus, a key immune modulation protein.3–9 The prevalence of HLA-B*5801 varies among ethnic populations.2
Abacavir and carbamazepine hypersensitivity have also been linked to polymorphisms in the HLA locus.6 Studies confirming the sensitivity of certain DNA markers as predictive of phenotype offer an opportunity to examine the association of certain alleles with rare skin reactions.4
Strong association between HLA-B*5801 and AH in the Han-Chinese population
Han-Chinese constitute about 91.5% of the population of the People's Republic of China (mainland China).18 A recent study found the HLA-B*5801 allele to be strongly associated with AH in the Han-Chinese population, but 20 (15%) of 135 allopurinol-tolerant patients had the HLA-B*5801 allele, which indicates that factors other than presence of this allele must be involved in AH.5 The association of HLA-B*5801 with the diagnosis of less severe DIHS/DRESS has only been reported in the Han-Chinese population.6,17
More research is required to clarify the role of this allele in AH. A major limitation of the current evidence stems from the low incidence of SCAR, which generates observational studies with relatively small sample sizes and insufficient power, making it difficult to establish the strength of association of HLA-B*5801.11
AH may present differently among patients2, making it difficult to diagnose and identify a causative mechanism. Other risk factors include:
- chemical exposures, mycoplasma pneumonia, viral infections, and immunisations19
- chronic renal impairment6,11
- recent starting of treatment and high doses (≥ 200 mg/day) when starting treatment, as seen in a multinational case–control surveillance of HLA-B in SCAR (the EuroSCAR study).20
- HLA molecules — they may be functionally involved in the pathogenesis of the disease, as there is a strong association between them and severe adverse drug reactions.3,5,21
Further research on environmental contributors to AH is required. Patients with chronic renal impairment have a higher risk association.6,11 However, data from 120 patients with gout receiving allopurinol shows dose adjustment according to creatinine clearance rate has no significant effect on reducing AH.2212
If AH does not develop within 2 months of starting of allopurinol treatment, it is unlikely to occur.17
Only consider allopurinol if the benefits exceed the risks in a person who is a known carrier of HLA-B*5801.22
Extra vigilance for signs of hypersensitivity syndrome or SJS/TEN is required. Inform the patient of the need to stop treatment immediately at the first appearance of symptoms.22Monitor for signs and symptoms of SCAR.11
Discontinue allopurinol at the first appearance of skin rash or other signs that may indicate an allergic reaction.12
SJS/TEN reactions normally occur 5 days to 3 weeks after starting allopurinol.23
When clinically evaluating a suspected reaction, check for the sentinel signs or symptoms that warn of a potentially severe eruption or serious systemic drug reaction. Two or more sentinel signs or symptoms are early indicators of multi-organ reactions and/or precede skin blistering in many individuals who develop SJS or TEN. These symptoms may precede, coincide with or follow skin eruption onset by several days:23
- high fever
- sore throat/pharyngitis
- gritty eyes, photophobia
- mouth or genital ulcers
- swollen tender lymph glands, and/or head and neck swelling or puffy eyes
- malaise, myalgia, arthralgia and/or arthritis
- headache, neck stiffness
- dyspnoea, cough, rhinorrhoea and/or ear pain
- skin tenderness.
Alternative hypouricaemic drugs are available.17
Reduce unnecessary use of allopurinol.
The incidence of AH can be reduced by carefully evaluating whether allopurinol is indicated. For example, asymptomatic hyperuricemia is not an indication for allopurinol treatment.1,3
Administer with caution in patients with renal impairment and monitor carefully.12
Reduce the dose in these patients to avoid toxicity from accumulation of allopurinol, oxypurinol and other metabolites.6,12 Testing these patients for the HLA-B*5801 allele may be more effective than dose adjustment to avoid allopurinol-induced SCAR.6
After recovery from mild reactions, reintroduce allopurinol at low dose (e.g. 50 mg/day) and gradually increase.12
If the rash recurs, allopurinol should be permanently withdrawn, as more severe hypersensitivity reactions may occur.12
HLA-B*5801 testing alone is not an effective population screening test due to the low overall incidence of AH and the weak association between presence of the allele and AH in some populations.6,24 Screening at a population level may unnecessarily exclude some people from allopurinol treatment. Testing does not eliminate all risk of developing SCAR, and monitoring patients for signs and symptoms is still a priority.4
In contrast, between 5% and 9% of patients taking abacavir develop abacavir hypersensitivity, and the presence of HLA-B*5701 is highly predictive of this reaction.25 The Prospective Randomized Evaluation of DNA Screening in a Clinical Trial (PREDICT-1) study evaluated use of HLA screening for abacavir hypersensitivity prevention; results were in favour of its use.26 In Australia, genetic screening is routinely administered before starting abacavir and is subsidised through Medicare.25 For more information on genetic-based tests with clinical utility for personalised medicine see the NPS Direct article Genetic testing in the genomics era — the new frontier of personalised medicine for information on other genetic based tests.
- Therapeutic Guidelines: Rheumatology. eTG complete, CD-ROM. Version 2, updated 2010 edn. Melbourne: Therapeutic Guidelines Ltd, 2011.
- Singer JZ, Wallace SL. The allopurinol hypersensitivity syndrome. Unnecessary morbidity and mortality. Arthritis Rheum 1986;29:82–7. [PubMed]
- Lee MT, Hung SI, Wei CY, et al. Pharmacogenetics of toxic epidermal necrolysis. Expert Opin Pharmacother 2010;11:2153–62. [PubMed]
- Tassaneeyakul W, Jantararoungtong T, Chen P, et al. Strong association between HLA-B*5801 and allopurinol-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in a Thai population. Pharmacogenet Genomics 2009;19:704–9. [PubMed]
- Chung WH, Hung SI, Chen YT. Human leukocyte antigens and drug hypersensitivity. Curr Opin Allergy Clin Immunol 2007;7:317–23. [PubMed]
- Hung SI, Chung WH, Liou LB, et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci USA 2005;102:4134–9. [PubMed]
- Kaniwa N, Saito Y, Aihara M, et al. HLA-B locus in Japanese patients with anti-epileptics and allopurinol-related Stevens-Johnson syndrome and toxic epidermal necrolysis. Pharmacogenomics 2008;9:1617–22. [PubMed]
- Lonjou C, Borot N, Sekula P, et al. A European study of HLA-B in Stevens-Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs. Pharmacogenet Genomics 2008;18:99–107. [PubMed]
- Kang HR, Jee YK, Kim YS, et al. Positive and negative associations of HLA class I alleles with allopurinol-induced SCARs in Koreans. Pharmacogenet Genomics 2011;21:303–7. [PubMed]
- Jung JW, Song WJ, Kim YS, et al. HLA-B58 can help the clinical decision on starting allopurinol in patients with chronic renal insufficiency. Nephrol Dial Transplant 2011;26:3567–72. [PubMed]
- Somkrua R, Eickman EE, Saokaew S, et al. Association of HLA-B*5801 allele and allopurinol-induced Stevens Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis. BMC Med Genet 2011;12:118. [PubMed]
- Aspen Pharma Pty Ltd. Product information. Zyloprim. 2008. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-01555-3 (accessed 21 January 2013).
- Shapiro LE, Shear NH. Mechanisms of drug reactions: the metabolic track. Semin Cutan Med Surg 1996;15:217–27. [PubMed]
- Pichler WJ. Delayed drug hypersensitivity reactions. Ann Intern Med 2003;139:683–93. [PubMed]
- Lee A, Thomson J. Adverse Drug Reactions, 2nd edn. Pharmaceutical Press, 2006. http://www.pharmpress.com/files/docs/ADRe2Ch05.pdf (accessed 21 January 2013.
- Lee MH, Graham GG, Williams KM, et al. A benefit-risk assessment of benzbromarone in the treatment of gout. Was its withdrawal from the market in the best interest of patients? Drug Saf 2008;31:643–65. [PubMed]
- Lee MH, Stocker SL, Anderson J, et al. Initiating allopurinol therapy: do we need to know the patient's human leucocyte antigen status? Intern Med J 2012;42:411–6. [PubMed]
- Central Intelligence Agency. The World Factbook. East and Southeast Asia. 2013. https://www.cia.gov/library/publications/the-world-factbook/geos/ch.html#People (accessed 21 January 2013.
- Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med 1994;331:1272–85. [PubMed]
- Halevy S, Ghislain PD, Mockenhaupt M, et al. Allopurinol is the most common cause of Stevens-Johnson syndrome and toxic epidermal necrolysis in Europe and Israel. J Am Acad Dermatol 2008;58:25–32. [PubMed]
- Klein J, Sato A. The HLA system. First of two parts. N Engl J Med 2000;343:702–9. [PubMed]
- European Medicines Agency. PhVWP monthly report on safety concerns, guidelines and general matters. July 2012 – Issue number: 1207. http://www.ema.europa.eu/docs/en_GB/document_library/Report/2012/07/WC500130391.pdf (accessed 24 January 2013).
- Therapeutic Guidelines: Dermatology. eTG complete, CD-ROM. Version 3, updated 2009 edn. Melbourne: Therapeutic Guidelines Ltd, 2009.
- Chung WH, Hung SI, Hong HS, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature 2004;428:486. [PubMed]
- Therapeutic Guidelines: Antibiotic. eTG complete, CD-ROM. Version 14, updated 2010 edn. Melbourne: Therapeutic Guidelines Ltd, 2010.
- Mallal S, Phillips E, Carosi G, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 2008;358:568–79. [PubMed]