Serious skin reactions associated with allopurinol

HSA would like to alert healthcare professionals on a series of local suspected adverse drug reaction (ADR) reports of death associated with the use of allopurinol locally. Allopurinol, a widely prescribed xanthine oxidase inhibitor used in the treatment of hyperuricaemia, is known to cause serious skin reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) that leads to significant morbidity and mortality.

Recent death reports associated with allopurinol

Four fatal cases linked to allopurinol use were reported to HSA over the first five months of 2009. Of these reports, three of the patients developed TEN while the fourth patient developed hypersensitivity syndrome to allopurinol. All of them were elderly patients (68-80 years old), with co-morbidities such as ischaemic heart disease, chronic renal failure, diabetes and hypertension. Three of the patients were on concurrent medications, such asvancomycin, frusemide and irbesartan which were also suspected to have contributed to the serious skin conditions.

In addition to the four death cases mentioned above, there were another 19 reports of fatality received over the period 1997 to 2008, of which 16 cases were associated with SJS, TEN or Allopurinol Hypersensitivity Syndrome (AHS).

Serious skin reactions associated with allopurinol

a) Local reports
The Pharmacovigilance Branch of HSA has received 183 local suspected ADR reports associated with allopurinol from 1993 to May 2009. Majority of these reports (80%) comprised skin reactions of which almost half of them included reactions such as SJS, TEN, AHS and erythema multiforme.

Allopurinol hypersensitivity syndrome (AHS) is a life threatening hypersensitivity reaction to allopurinol and is accompanied by symptoms such as fever, rash, leukocytosis, eosinophilia, hepatitis and acute renal failure.¹

b) Overseas reports
From 2004 to 2008, a total of 2,541 overseas adverse drug reaction reports associated with allopurinol were reported in the WHO Vigibase*. Of these reports, more than 15% describe serious skin reactions namely, hypersensitivity reactions (67 reports), SJS (233 reports) and TEN (107 reports).

*WHO Vigibase is a global database of reported adverse reactions to medicinal products, maintained and developed by the Uppsala Monitoring Centre (UMC), the WHO Collaborating Centre for International Drug Monitoring. It receives spontaneous ADR reports provided by national pharmacovigilance centres in more than 80 countries, including Singapore.

HLA-B*5801 associated allopurinol-induced severe cutaneous adverse reactions (SCAR)

HLA-B*5801 allele has been identified as a genetic marker for severe cutaneous adverse reactions (SCAR) caused by allopurinol. In a pharmacogenetic study on allopurinol-induced SCAR², a strong association of the allele HLA-B*5801 with the susceptibility of allopurinol-induced AHS, SJS and TEN in Han Chinese was identified. Although other ethnic patients with allopurinol-induced SCAR were not included in the study, it was suggested that this association may also exist in other ethnic groups as HLA-B*5801 is also present in other populations (7% in African, ~ 2-7% in Caucasian, and 8% in Asian Indian).

HSA's earlier advisory on the use of allopurinol

In 2001, the Pharmacovigilance Branch conducted a safety assessment of all local spontaneous ADRs associated with the use of allopurinol and found that 50% of the ADRs reported with allopurinol were serious skin reactions such as SJS, TEN and AHS. In addition, two local studies^3,4 revealed 18 cases of serious local reports of ADRs to allopurinol which comprised mainly of AHS. In view that these adverse reactions are associated with significant morbidity and mortality, a Dear Healthcare Professional Letter⁵ was issued to advise doctors on the appropriate use of this drug.

In the advisory, doctors were advised to prescribe allopurinol with care for the treatment of:

1. Recurrent episodes of acute gout unresponsive to prophylactic colchicines and when uricosuric agents cannot be used due to intolerance, lack of efficacy, renal insufficiency or poor patient compliance

2. Chronic tophaceous gout

3. Recurrent uric acid calculi

4. Recurrent calcium oxalate renal calculi when associated with hyperuricosuria

5. Prevention of acute urate nephropathy in patients receiving cytotoxic therapy for malignancies

In particular, doctors were also advised that the dose of allopurinol should be reduced in patients with impaired renal function.

HSA's Advisory

Healthcare professionals should be mindful of the local cases of serious skin reactions associated with allopurinol and exercise caution with the use of this drug during treatment of hyperuricaemia and its complications, including its prophylactic use in the prevention of hyperuricaemia associated with cancer treatment.

As early signs of rash and skin reactions may be indicative of a more serious reaction such as SJS or AHS, healthcare professionals are advised to educate their patients on early recognition of allergic reactions, on the importance of prompt withdrawal of the drug at the first sign of rash and to seek medical advice.

Healthcare professionals are encouraged to continue reporting suspected ADRs associated with allopurinol to the Pharmacovigilance Branch of HSA.

References

1. Singapore Med J 2008; 49 (5): 384 – 7.

2. Proc. Natl. Acad. Sci. USA; Apr 05, Vol 102, No 11, 4134-9.http://www.pnas.org/cgi/doi/10.1073/pnas.0409500102.

3. Singapore Med J 2000; 41: 156 –60.

4. Thong B YH, Leong KP, Chng HH. Allopurinol hypersensitivity syndrome in a general hospital (abstract). 34^th Singapore-Malaysia Congress of Medicine/Combined Hospitals Medical and Dental Scientific Meeting, 3-6 Aug 2000, Singapore.

5. HSA Drug Safety Information. Risk Assessment of Allopurinol. 22 Oct 2001