Allopurinol is a drug that is widely used for the treatment of hyperuricemia, which is defined by values of uric acid >6.8-7 mg/dl.1
At the end of 2012 in Italy the consumption figures for allopurinol, expressed as defined daily dose (DDD), was around 185 million.2
Allopurinol is often prescribed for asymptomatic hyperuricemia, although in fact, only three situations justify the treatment in these patients:
- persistent hyperuricemia in patients with uric acid levels >13 mg /dl in men, or >10 mg/dl in women, because they may increase the risk of nephrotoxicity;
- urinary excretion of uric acid >1,100 mg/day, associated with a 50% risk of developing uric acid calculi. The aim is to bring the excretion of uric acid to <800 mg/day. First line therapy remains dietetics;
- in patients undergoing radiation or chemotherapy, to prevent uric acid nephropathy and other manifestations of tumour lysis syndrome.2
Although hyperuricemia plays a role in some renal, cardiovascular and metabolic diseases, often associated with gout,1,3,4,5 no evidence is available to justify the treatment of asymptomatic hyperuricemia, except in the three cases described above.
About 5% of patients starting to take allopurinol have to discontinue them because of adverse events.6 The most frequent adverse drug reactions related to allopurinol are skin reactions, gastrointestinal and haematological disorders.
This drug is one of the most common causes of potentially fatal severe skin reactions, including Stevens-Johnson syndrome and Lyell syndrome (toxic epidermal necrolysis) with an incidence <1%; more rarely, allopurinol may induce DRESS syndrome, also known as AHS (Allopurinol Hypersensitivity Syndrome), which is characterized by a skin rash, eosinophilia, leucocytosis, fever, and impaired kidney and liver function.7,8,9 Mortality associated with AHS is above 27%.6
In December 2014, the Italian National Pharmacovigilance Network had 1,433 reports of suspected adverse reactions, in which allopurinol has been reported as a suspected drug, of which 1,075 involved the population aged >65 years. 53% of these reactions were classified as severe. Among the reactions reported, about 60% involved the skin and subcutaneous tissue, 36 cards reported DRESS syndrome, 118 reported Lyell's syndrome and 88 reported Stevens-Johnson syndrome as an adverse reaction.
Risk factors for the onset of adverse reactions to allopurinol are varied: advanced age, impaired renal function, the presence of allele HLA-B*5801, use of diuretics, alcoholism, high doses of allopurinol and severe hepatic dysfunction.6,9
An observational study conducted from 2001 to 2010 by the University of Cagliari assessed severe adverse skin reactions to the drug occurring in patients (mean age 74 years) followed up in that period by the Department of Dermatology of a Sardinian hospital, which showed that 10.7% of these had been caused by allopurinol. In 96% of cases, hospitalization was required because of the severity of the clinical manifestation. In 95.5% of cases, the indication for treatment with allopurinol was asymptomatic hyperuricemia, and 12% had already presented a reaction to allopurinol after a previous administration. A careful assessment of the risk of adverse reactions must be conducted for every patient, taking into account advanced age and the number of drugs taken (>3), including thiazide diuretics, which are implicated in reducing the elimination of allopurinol. Only 14.3% of patients received a dose of medication appropriate to their creatinine clearance.10
Finally allopurinol, having numerous interactions with other drugs such as chlorpropamide, 6-mercaptopurine, azathioprine, warfarin, cyclosporin and thiazide diuretics11 requires a dose reduction in some patients.
Clinicians should pay particular attention to assessing the risks and benefits before prescribing allopurinol, especially in elderly patients where there is more comorbidity and polypharmacy, which are significant risk factors for the more serious adverse reactions.
1 Geriatrics A, Azienda Ospedaliera Universitaria Integrata, Verona
2 USO Pharmacology, Azienda Ospedaliera Universitaria Integrata, Verona
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