Allopurinol, Benzbromarone Both Effective in High Doses

Gout patients have equal rates of success in attaining a serum urate concentration of 0.30 mmol/L or less—a value thought to predict good control of flares and a reduction of tophi—with either allopurinol or benzbromarone, as long as the doses are slightly higher than normal and based on serum urate values, according to the results of a randomized, open-label trial.

The data were presented at the annual meeting of the European League Against Rheumatism in Paris.

“In this small study, tolerability is not affected by doubling the dosage in patients not reaching target levels,” study investigator Mattheus Reinders, a hospital pharmacist at the Atrium Medisch Centrum, Heerlen (the Netherlands), said in an interview.

The results of the study make it clear that there is no difference in efficacy between allopurinol and benzbromarone when given in adequate doses, despite their different mechanisms of action. It also shows “allopurinol must be dosed higher than usually done in trials and in clinical practice [300 mg/day] to reach target serum levels,” Mr. Reinders said.

Gout flares and tophi mostly occur in those body parts with the lowest temperature: the extremities. It is often said that serum urate (uric acid) concentration—a well-accepted biomarker for evaluation of gout treatment—must be lower than the solubility at 37 °C (0.42 mmol/L) for good treatment.

But solubility drops dramatically with lower temperature, and so lower serum urate values are needed.

A serum urate concentration of 0.30 mmol/L or lower has been shown to be adequate in previous research, Mr. Reinders said in the interview.

EULAR's evidence-based recommendations for gout advise titrating the allopurinol dosage according to the level of serum urate that is attained. There is a lack of information about this approach and the effects of the higher dosages of serum urate-lowering drugs that will be required to decrease serum urate in patients who are not reaching target levels. Many clinicians also are prescribing only a fixed dosage of allopurinol 300 mg/day, he said.

Therefore, Mr. Reinders and his coinvestigators randomized 55 patients with newly diagnosed gout in an open-label trial comparing the efficacy and tolerability of allopurinol and benzbromarone. Allopurinol began at a dosage of 300 mg/day and was increased to 600 mg/day if necessary, while benzbromarone started at 100 mg/day and could be increased to 200 mg/day.

The gout diagnosis was confirmed by microscopic evidence of urate crystals in punctate from synovial fluid or periarticular structures or presence of tophi. The patients were indicated for serum urate-lowering treatment if they had tophi or more than two gout attacks per year. None of the patients had relevant liver or renal disease, and none had previously received either medication. Mr. Reinders conducted the research when he was in training at the Medisch Centrum Leeuwarden, also in the Netherlands, which funded the study.

After 2 months of treatment, a significantly greater percentage of patients who took benzbromarone 100 mg/day reached the target serum urate concentration of 0.30 mmol/L (13 of 25 patients, or 52%) than did patients who took allopurinol 300 mg/day (8 of 30 patients, or 27%).

After the investigators doubled the daily dosage of each drug in patients who had not met the treatment target, there was no significant difference in the total percentage of patients who had successful treatment with allopurinol (21 of 27, or 78%), compared with benzbromarone (18 of 23, or 78%).

Even before the dose increase, two patients stopped taking allopurinol and three stopped taking benzbromarone because of adverse drug reactions.

No more adverse reactions occurred after the dosages were increased in the nonresponders.

'Allopurinol must be dosed higher than usually done in trials and in clinical practice to reach target serum levels.' MR. REINDERS

Gout patients have equal rates of success in attaining a serum urate concentration of 0.30 mmol/L or less—a value thought to predict good control of flares and a reduction of tophi—with either allopurinol or benzbromarone, as long as the doses are slightly higher than normal and based on serum urate values, according to the results of a randomized, open-label trial.

The data were presented at the annual meeting of the European League Against Rheumatism in Paris.

“In this small study, tolerability is not affected by doubling the dosage in patients not reaching target levels,” study investigator Mattheus Reinders, a hospital pharmacist at the Atrium Medisch Centrum, Heerlen (the Netherlands), said in an interview.

The results of the study make it clear that there is no difference in efficacy between allopurinol and benzbromarone when given in adequate doses, despite their different mechanisms of action. It also shows “allopurinol must be dosed higher than usually done in trials and in clinical practice [300 mg/day] to reach target serum levels,” Mr. Reinders said.

Gout flares and tophi mostly occur in those body parts with the lowest temperature: the extremities. It is often said that serum urate (uric acid) concentration—a well-accepted biomarker for evaluation of gout treatment—must be lower than the solubility at 37 °C (0.42 mmol/L) for good treatment.

But solubility drops dramatically with lower temperature, and so lower serum urate values are needed.

A serum urate concentration of 0.30 mmol/L or lower has been shown to be adequate in previous research, Mr. Reinders said in the interview.

EULAR's evidence-based recommendations for gout advise titrating the allopurinol dosage according to the level of serum urate that is attained. There is a lack of information about this approach and the effects of the higher dosages of serum urate-lowering drugs that will be required to decrease serum urate in patients who are not reaching target levels. Many clinicians also are prescribing only a fixed dosage of allopurinol 300 mg/day, he said.

Therefore, Mr. Reinders and his coinvestigators randomized 55 patients with newly diagnosed gout in an open-label trial comparing the efficacy and tolerability of allopurinol and benzbromarone. Allopurinol began at a dosage of 300 mg/day and was increased to 600 mg/day if necessary, while benzbromarone started at 100 mg/day and could be increased to 200 mg/day.

The gout diagnosis was confirmed by microscopic evidence of urate crystals in punctate from synovial fluid or periarticular structures or presence of tophi. The patients were indicated for serum urate-lowering treatment if they had tophi or more than two gout attacks per year. None of the patients had relevant liver or renal disease, and none had previously received either medication. Mr. Reinders conducted the research when he was in training at the Medisch Centrum Leeuwarden, also in the Netherlands, which funded the study.

After 2 months of treatment, a significantly greater percentage of patients who took benzbromarone 100 mg/day reached the target serum urate concentration of 0.30 mmol/L (13 of 25 patients, or 52%) than did patients who took allopurinol 300 mg/day (8 of 30 patients, or 27%).

After the investigators doubled the daily dosage of each drug in patients who had not met the treatment target, there was no significant difference in the total percentage of patients who had successful treatment with allopurinol (21 of 27, or 78%), compared with benzbromarone (18 of 23, or 78%).

Even before the dose increase, two patients stopped taking allopurinol and three stopped taking benzbromarone because of adverse drug reactions.

No more adverse reactions occurred after the dosages were increased in the nonresponders.

'Allopurinol must be dosed higher than usually done in trials and in clinical practice to reach target serum levels.' MR. REINDERS

Gout patients have equal rates of success in attaining a serum urate concentration of 0.30 mmol/L or less—a value thought to predict good control of flares and a reduction of tophi—with either allopurinol or benzbromarone, as long as the doses are slightly higher than normal and based on serum urate values, according to the results of a randomized, open-label trial.

The data were presented at the annual meeting of the European League Against Rheumatism in Paris.

“In this small study, tolerability is not affected by doubling the dosage in patients not reaching target levels,” study investigator Mattheus Reinders, a hospital pharmacist at the Atrium Medisch Centrum, Heerlen (the Netherlands), said in an interview.

The results of the study make it clear that there is no difference in efficacy between allopurinol and benzbromarone when given in adequate doses, despite their different mechanisms of action. It also shows “allopurinol must be dosed higher than usually done in trials and in clinical practice [300 mg/day] to reach target serum levels,” Mr. Reinders said.

Gout flares and tophi mostly occur in those body parts with the lowest temperature: the extremities. It is often said that serum urate (uric acid) concentration—a well-accepted biomarker for evaluation of gout treatment—must be lower than the solubility at 37 °C (0.42 mmol/L) for good treatment.

But solubility drops dramatically with lower temperature, and so lower serum urate values are needed.

A serum urate concentration of 0.30 mmol/L or lower has been shown to be adequate in previous research, Mr. Reinders said in the interview.

EULAR's evidence-based recommendations for gout advise titrating the allopurinol dosage according to the level of serum urate that is attained. There is a lack of information about this approach and the effects of the higher dosages of serum urate-lowering drugs that will be required to decrease serum urate in patients who are not reaching target levels. Many clinicians also are prescribing only a fixed dosage of allopurinol 300 mg/day, he said.

Therefore, Mr. Reinders and his coinvestigators randomized 55 patients with newly diagnosed gout in an open-label trial comparing the efficacy and tolerability of allopurinol and benzbromarone. Allopurinol began at a dosage of 300 mg/day and was increased to 600 mg/day if necessary, while benzbromarone started at 100 mg/day and could be increased to 200 mg/day.

The gout diagnosis was confirmed by microscopic evidence of urate crystals in punctate from synovial fluid or periarticular structures or presence of tophi. The patients were indicated for serum urate-lowering treatment if they had tophi or more than two gout attacks per year. None of the patients had relevant liver or renal disease, and none had previously received either medication. Mr. Reinders conducted the research when he was in training at the Medisch Centrum Leeuwarden, also in the Netherlands, which funded the study.

After 2 months of treatment, a significantly greater percentage of patients who took benzbromarone 100 mg/day reached the target serum urate concentration of 0.30 mmol/L (13 of 25 patients, or 52%) than did patients who took allopurinol 300 mg/day (8 of 30 patients, or 27%).

After the investigators doubled the daily dosage of each drug in patients who had not met the treatment target, there was no significant difference in the total percentage of patients who had successful treatment with allopurinol (21 of 27, or 78%), compared with benzbromarone (18 of 23, or 78%).

Even before the dose increase, two patients stopped taking allopurinol and three stopped taking benzbromarone because of adverse drug reactions.

No more adverse reactions occurred after the dosages were increased in the nonresponders.

'Allopurinol must be dosed higher than usually done in trials and in clinical practice to reach target serum levels.' MR. REINDERS