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Lower starting dose may limit allopurinol hypersensitivity

NEW YORK (Reuters Health) – Starting allopurinol at lower doses and then raising them as necessary may help cut the risk of allopurinol hypersensitivity syndrome (AHS), researchers from New Zealand say.

“A starting dose based on eGFR of 1.5 mg/mL/min was chosen as reasonable trade-off between a clinically practicable dose and the absolute risk of AHS,” Dr. Lisa K. Stamp of the University of Otago, Christchurch and colleagues wrote in a March 27th online paper in Arthritis & Rheumatism.

Dr. Stamp warned Reuters Health by email that while starting at much lower doses than previously used “may seem overly cautious given the rarity of AHS, this syndrome is potentially fatal.”

Guidelines suggest that doses beyond 300 mg per day, particularly in patients with renal impairment, may be associated with AHS. That’s not very specific, however. Furthermore, the investigators say, “current allopurinol dose guidelines do not differentiate between starting dose and maintenance dose.”

They note that allopurinol is the most commonly used urate lowering therapy in gout.

For their new analysis they identified 54 patients who developed AHS between 1998 and 2010 and matched them with 157 gout patients who did not develop AHS.

Renal function was similar in both groups with 66.6% of cases and 68.9% of controls having an eGFR less than 60 mL/min.

Patients who developed AHS started allopurinol at a significantly higher dose compared to controls (183.5 vs 112.2 mg/day). As the starting dose of allopurinol corrected for eGFR increased, there was an increase in risk of AHS. At the highest quintile of starting dose/eGFR the odds ratio for AHS was 23.2.

In total, 91% of AHS cases and 36% of controls started on a dose of allopurinol at or beyond 1.5 mg allopurinol per unit eGFR (mg/mL/min). In comparison, 79% of AHS cases and 53% of controls started on a dose of 2.0 mg or more of allopurinol per unit eGFR.

The authors say that in part because the risk is highest in the first 30 days, they “advocate increasing the allopurinol dose at monthly intervals until the target serum urate is achieved.”

They add that they “did not identify an upper limit of allopurinol dose where an increased risk of AHS occurred.”

Overall, concluded Dr. Stamp, “There is no rush to lower serum urate concentrations, so a start low and slowly increasing allopurinol regimen is appropriate and may reduce the number of gout flares patients experience when starting allopurinol thereby increasing compliance.”


Arthritis Rheum 2012.