Background/Purpose: Documentation of the safety profile of allopurinol at doses ≥300 mg/day is important for its ongoing use as first-line monotherapy or in combination with newer agents. Current data are limited. This study examined the safety profile of allopurinol titrated as described below (ClinicalTrials.gov Identifier: NCT01391325). 

Methods: Patients meeting ARA criteria for the Classification of Acute Arthritis of Primary Gout and at least 2 gout flares in the preceding year were enrolled; caregivers were encouraged but not required to titrate allopurinol doses to achieve serum urate levels (sUA) of <6.0 mg/dL. Patients receiving pretrial urate-lowering therapy other than allopurinol underwent a 7-day washout period before initiating (or re-initiating) allopurinol therapy. Regular safety assessments were made; AEs were monitored throughout the study.

Results: Of 1735 patients enrolled, 1732 received at least 1 dose of allopurinol and constituted the safety population (93% male; 75% white; mean age, 51 years; mean BMI, 34.4 kg/m²). Baseline characteristics and comorbidity rates were similar across dosage ranges, but a higher percentage (29.2%) of those receiving <300 mg as maximal dose had moderately impaired renal function (CrCL <60 mL/min) than those who received 300 mg (13.8%) or >300 mg (9.7%). Patients who received >300-mg maximal daily dose had more severe disease at baseline (longer gout duration, tophi, more gout flares in prior year). Maximum daily dose was <300 mg in 250 patients (14.4%), 300 mg in 1132 patients (65.4%), and >300 mg in 350 patients (20.2%). In the safety population, only 744 patients (43%) achieved sUA levels <6.0 mg/dL at their last dose.

Table. Summary of Treatment-Emergent AEs (TEAEs, Safety Population)

No clinically meaningful changes in laboratory values, including liver function tests, occurred. Rash incidence was low overall (1.5%), and allopurinol hypersensitivity syndrome was not encountered. The discontinuation rate in patients with a maximal dose of <300 mg was 49.6% vs 19.4% in those who received >300 mg.

Conclusion: This study revealed no new safety signals with medically appropriate allopurinol doses (approximately 300 mg/day). Data inspection showed few differences in TEAEs possibly related to allopurinol. Fewer than 50% of patients achieved the target sUA of <6 mg/dL at 6 months.