For gout, how safely can allopurinol dosing be escalated?

Last Updated: 2017-09-12

By Reuters Staff

NEW YORK (Reuters Health) - Most people with gout, and perhaps even those with kidney impairment, can tolerate higher than creatinine clearance-based doses of allopurinol to achieve and maintain a target level of serum urate (SU), researchers say.

Dr. Lisa Stamp of University of Otago in Christchurch, New Zealand, and colleagues analyzed data from an open-label extension phase of a one-year randomized controlled trial designed to test the efficacy and safety of allopurinol dose escalation (DE) to achieve target SU in people with gout, including those with chronic kidney disease.

The original trial report, published earlier this year in Annals of the Rheumatic Diseases (http://bit.ly/2wNx07h), noted that an 800-mg daily dose of allopurinol is approved in the U.S., but doses >300 mg daily are uncommon due to concerns about adverse events. One such event - a rare hypersensitivity syndrome - is more likely in patients with chronic kidney disease, leading to recommendations in Europe that maximum allopurinol dose be based on creatinine clearance (CrCl).

At enrollment, mean SU was 7.15 mg/dL and mean allopurinol dose was 269 mg/day. CrCl was <60 mL/min in 52% of participants.

In patients randomized to DE, the dose was increased monthly by 50 mg/d for those with CrCL <60 mL/min and 100 mg/d in those with higher CrCL, until SU was <6 mg/dL.

At 12 months, mean changes in SU were 0.34 mg/dL in the control group and 1.5 mg/dL in the DE group (P<0.001). SU <6 mg/dL was achieved by 32% of controls and 69% in the dose escalation group. The mean daily allopurinol dose was 288 mg in the control group and 413 mg in the DE group.

In the extension phase, reported in Annals of the Rheumatic Diseases online August 22, participants in the immediate DE group who had achieved their target SU continued on their current dose (DE/DE group). Participants in the control group began DE if their SU was at or above 6 mg/dL (control/DE group).

Of the 93 control/DE and 90 DE/DE participants who entered the trial, about 79% in each group completed month 12 and about 73% of the control/DE and 77% of the DE/DE participants completed the extension phase.

From month 12 to 24, there was a mean 1.1-mg/dL drop in SU in the control/DE group and a mean 0.1-mg/dL rise in the DE/DE group, a statistically significant difference. The mean allopurinol dose at month 24 was 391 mg/day in the control/DE group and 410 mg/day in the DE/DE group.

Eighteen people in the control group did not have their dose raised in the DE phase because their SU was <6 mg/dL.

By month 24, allopurinol had been stopped in five DE/DE participants, including three who stopped it between months 12 and 24, and two control/DE patients.

In both groups, compared to baseline, the percentage of participants having gout flares in the month before months 12 and 24 was significantly lower, as was the mean change in tophus size over 24 months - but with no difference between the groups. The two groups also did not differ significantly in numbers of adverse events or serious adverse events.

Dr. Stamp told Reuters Health, "For patients established on allopurinol, slow allopurinol dose escalation above doses based on kidney function is very effective at lowering blood urate levels and is well tolerated, even in people with kidney impairment."

"It is important to monitor liver and kidney function and be aware of the potential for rashes," she said by email. "We also note that the study was not designed to detect very rare hypersensitivity reactions."

Dr. Francis Luk, assistant professor of rheumatology and immunology at Wake Forest Baptist Medical Center in Winston-Salem, North Carolina, told Reuters Health that the findings "are consistent with other studies and with the with 2012 American College of Rheumatology guidelines."

"In my practice I have safely and successfully used allopurinol at doses higher than the creatinine clearance-based doses and achieved good outcomes," he said by email.

"Some caveats I would highlight are that adverse effects of allopurinol can occur regardless of severity of chronic kidney disease or even in patients who have no CKD," he noted. "So we have to warn patients about the possibility of allergic reaction, hepatotoxicity, GI upset (including diarrhea, nausea), gout flare, rash, and risk of Stevens-Johnson syndrome (a severe allergic reaction involving sloughing of skin and mucous membranes)."

Moreover, clinicians should be aware that "starting allopurinol does increase risk of gout flare in the first six months," he said, "so another agent such as prednisone, colchicine, or a nonsteroidal anti-inflammatory drug should be started along with allopurinol to prevent gout flares."

SOURCE: http://bit.ly/2wN8we1

Ann Rheum Dis 2017.