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Associate Professor of Pharmacy Practice College of Pharmacy and Health Sciences Drake University 2507 University Avenue Des Moines, Iowa 50311-4505 fax 515/241-5085 geoff.wall{at}drake.edu Internal Medicine Clinical Pharmacist Iowa Methodist Medical Center Des Moines
Associate Professor of Pharmacy Practice College of Pharmacy and Health Sciences Drake University
Published Online, July 11, 2006. www.theannals.com, DOI 10.1345/aph.1G589a
The most feared toxicity from allopurinol is the so-called allopurinol hypersensitivity syndrome (AHS). This rare syndrome, with symptoms including exfoliative dermatitis, liver or renal dysfunction, and eosinophilia, is fatal in up to 20% of cases.2 The mechanism of AHS is unknown but is thought to be immunologic in origin. Many immunologic toxicities are considered idiopathic rather than dose-related, yet the possible association with increasing concentrations of allopurinol's primary metabolite oxypurinol led Hande et al.,3 to recommend reducing the allopurinol dose in patients with renal failure. In this retrospective review of 78 patients (6 of their own patients, 72 cases reported in the literature) with AHS, 81% had significant renal insufficiency and were started on standard doses of allopurinol. Symptoms of AHS occurred within 3 weeks in nearly all patients. Hande et al.'s report suggested an association (not causation) of higher doses of allopurinol and the development of AHS.
This report was challenged by another retrospective study of 120 patients with gout, 44% of whom had an estimated creatinine clearance of less than 50 mL/min.4 These investigators compared patients who received a reduced dosage concordant with this degree of renal insufficiency with patients whose dosage was not reduced and found no significant increase in any adverse effects in the latter group. Indeed, the only patient in the study who developed AHS had normal renal function and had received a standard dosage of allopurinol.
The matter of dose is important, because the ability of allopurinol to lower serum uric acid level is dose-related. Some have suggested that a major reason for clinical failure of allopurinol is underdosing. A lack of familiarity with previous studies regarding allopurinol dosing issues may be a reason for this underdosing. We are certainly not suggesting that monitoring serum creatinine is unimportant in patients with gout who are taking allopurinol. The possibility of uric acid nephropathy is reason enough to warrant such monitoring. However, we agree with the quality of care guidelines that the initial dose of allopurinol should be adjusted according to the patient's baseline renal function.5 If dose increases are required to achieve a target serum uric acid level, this should be done and the patient should be monitored closely over at least 30 days.
References
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