But febuxostat should not be considered completely free from renal concerns, said Dr. Ted R. Mikuls, a rheumatologist at the University of Nebraska in Omaha. “Studies of febuxostat have not included patients with a serum creatinine level of more than 2.0 mg/dL that I'm aware of,” he said in an interview. “The medical community must demand a lot more data before using [febuxostat] widely in patients with renal failure.” In addition, “I'm not aware of data that allopurinol damages kidneys. What most rheumatologists do is dose it very judiciously in patients with renal dysfunction, gradually increasing it to get the uric acid level where it needs to be.” Dr. Mikuls said he had no disclosures relevant to febuxostat and allopurinol.
“I am not convinced that careful allopurinol dose titration cannot achieve successful management of patients with impaired renal function,” said Dr. Michael A. Becker, a rheumatologist at the University of Chicago. But febuxostatimay already be the “standard of care” for renal dysfunction patients, he said in an interview. Dr. Becker said he has been a consultant to Takeda, and he was a coinvestigator on several of the febuxostat pivotal trials.
Allopurinol Intolerance
A small percentage of gout patients (perhaps fewer than 10%) are intolerant of allopurinol. Intolerance can range from a serious hypersensitivity reaction to a milder allergic reaction or another form of adverse reaction, such as gastrointestinal distress. A patient with hypersensitivity to allopurinol is someone for whom “febuxostat could be really helpful,” but this is “pretty rare, far less than a few percent,” Dr. Mikuls said. “More common are other problems [with allopurinol], such as stomach upset. These reactions may occur in 5%–10% of patients, and this is another group of patients for whom “febuxostat can be really important.” Dr. Simkin differed slightly, estimating the total percentage of allopurinol-intolerant patients to be fewer than 5%.
Lack of Allopurinol Efficacy
In treating symptomatic gout, the guiding number rheumatologists look at is the serum level of uric acid. When the level drops below 6.0 mg/dL, existing uric acid crystals disappear by dissolving into the blood, thereby alleviating symptoms.
Although many patients respond to an allopurinol dosage of less than or up to 300 mg/day (especially if they have renal dysfunction such that their blood level of oxypurinol is unusually high relative to their allopurinol dose), the majority of patients needs more than 300 mg/day, Dr. Simkin said. “It's appropriate to use up to 800 mg/day,” and dosages of 300–800 mg/day are usually effective, he added. But doses this high are also not often prescribed by physicians. “The main reason [why patients have uncontrolled gout] is misuse of allopurinol. Patients don't get treated with adequate doses.”
Patients who don't respond to high allopurinol doses are “very rare,” Dr. Simkin noted. He currently has “two such patients, and they're doing better on febuxostat. There is no reason to think that febuxostat won't be effective in patients who had issues with allopurinol, he said.
“It is clear that a majority of the current gout patient population does not achieve a goal serum urate range of less than 6.0 mg/dL on 300 mg allopurinol,” said Dr. Becker. “Many physicians do not like to go to a higher allopurinol dose.” One reason is that “there is little evidence for allopurinol safety and efficacy [in dosages] greater than 300 mg/day,” he said. Despite the lack of data, “I suspect that very few patients fail treatment with an allopurinol dosage of 600 mg or 800 mg/day,” Dr. Becker said. Patients who do fail at these higher dosages are “probably not likely” to do any better on febuxostat, he added.
When patients don't respond adequately to 300 mg/day of allopurinol, Dr. Mikuls pushes the dosage as high as 800 mg/day, although he's not comfortable treating patients at this level. Patients who are still not at the serum uric acid goal at 800 mg/day should be switched to febuxostat, although it remains unclear how these patients respond following the switch. “I think we'd all like to see a data-driven answer to that question,” he said. But some experts are cautious about any allopurinol dosage above 300 mg/day. No safety data exist for dosages over 300 mg/day of allopurinol, said Dr. Schlesinger. “Now that we have an option, these patients should probably be on febuxostat.”
“In the rheumatology community, most of us routinely use [dosages of] allopurinol greater than 300 mg/day, but data collected by Takeda demonstrate that in the general medical community, 300 mg/day or less” is the dosage typically prescribed, said Dr. Dore. “Personally, I will increase the dose up to 400–500 mg of allopurinol per day before switching to febuxostat.”