A critical reappraisal of allopurinol dosing, safety, and efficacy for hyperuricemia in gout

Abstract

Allopurinol, the first-line drug for serum urate-lowering therapy in gout, is approved by the US Food and Drug Administration for a dose up to 800 mg/d and is available as a low-cost generic drug. However, the vast majority of allopurinol prescriptions are for doses < or = 300 mg/d, which often fails to adequately treat hyperuricemia in gout. This situation has been promoted by longstanding, non-evidence-based guidelines for allopurinol use calibrated to renal function (and oxypurinol levels) and designed, without proof of efficacy, to avoid allopurinol hypersensitivity syndrome. Severe allopurinol hypersensitivity reactions are not necessarily dose-dependent and do not always correlate with serum oxypurinol levels. Limiting allopurinol dosing to < or = 300 mg/d suboptimally controls hyperuricemia and fails to adequately prevent hypersensitivity reactions. However, the long-term safety of elevating allopurinol dosages in chronic kidney disease requires further study. The emergence of novel urate-lowering therapeutic options, such as febuxostat and uricase, makes timely this review of current allopurinol dosing guidelines, safety, and efficacy in gout hyperuricemia therapy, including patients with chronic kidney disease.

Allopurinol for the treatment of chronic kidney disease: asystematic review

“…28 However, such doses may not be effective for the treatment of gout. 29 While it is generally recommended that doses be increased from a low dose, 23,24 it has been reported that, in practice, this rarely happens. 27 According to the British Society for Rheumatology, dosing should be based on achieving a target level of serum uric acid of <300µmol/l.…”

Hypertension in pediatric patients with chronic kidney disease: management challenges

“…79,86 However, allopurinol can also lead to hypersensitivity reactions in children, and should be prescribed with cautious regard for dose. 87 …”

Italian Society of Rheumatology recommendations for the management of gout

“…These results support the need of slow titration of the allopurinol dose till the attainment of target levels. A 'dose-escalation' study has shown that a daily dose increment of 300 to 600 mg is associated with serum uric acid levels of <5.5 mg/dL in 78% of patients (68,69). Allopurinol can cause potentially serious adverse reactions such as the hypersensitivity syndrome characterised by cutaneous desquamation, fever, hepatitis, eosinophilia, renail failure and a mortality rate of up to 20% (68,70).…”

“…A 'dose-escalation' study has shown that a daily dose increment of 300 to 600 mg is associated with serum uric acid levels of <5.5 mg/dL in 78% of patients (68,69). Allopurinol can cause potentially serious adverse reactions such as the hypersensitivity syndrome characterised by cutaneous desquamation, fever, hepatitis, eosinophilia, renail failure and a mortality rate of up to 20% (68,70). Despite its potential benefit in mild hypersensitivity reactions, desensitisation is not recommended since it is deemed as an obsolete and potentially harmful procedure.…”