For gout patients who require urate lowering, only three options are currently available in the US: allopurinol, probenecid, and now febuxostat. In contrast to allopurinol and febuxostat, probenecid works to stimulate renal uric acid excretion by blocking renal tubular resorption of urate via inhibition of the URAT1 organic ion transporter. Probenecid is most effective in patients with normal glomerular filtration rates (GFR) who, as a result of intrinsic renal tubular defects, under-excrete uric acid. Probenecid has limited or no effect in patients with reduced GFR, whether due to chronic or acute kidney disease. Moreover, since probenecid increases uric acid delivery to the collecting system, it may raise the risk of calcium acid renal stones as described above. Consequently, even patients who do not have a history of renal stones require consumption of copious amounts of water or beverages daily to reduce stone risk. Given a history of uric acid stones, potassium or sodium citrate should be prescribed to alkalinize the urine. The relatively short half-life of probenecid requires that it be administered thrice daily. Therefore, although probenecid is a generally safe and effective drug, even the subset of patients for whom probenecid is a good choice tend to prefer an easier alternative.
For more than five decades, allopurinol has been that alternative. Most patients take allopurinol on a once-daily dosing schedule, and beyond anti-inflammatory prophylaxis, no ancillary medications are needed. In the majority of patients, allopurinol has little or no toxicity. However, a small number of patients develop the allopurinol hypersensitivity syndrome, which can involve liver, renal and marrow toxicity. For those patients – or for patients who develop a rash on allopurinol, since a rash may be a harbinger of the hypersensitivity syndrome – there are few if any good alternatives. Another drawback of allopurinol is the fact that many patients taking allopurinol fail to achieve targeted serum urate levels. In a spot study that we recently conducted, the mean serum uric acid level in patients receiving allopurinol from the primary care clinics of a large veterans hospital was 6.9 mg/dL, nearly a point above the recommended maximum target serum urate level.38
The reasons for this failure of allopurinol are not fully elucidated, but most likely relate to the relatively limited efficacy of the 300 mg dose; the failure of many physicians to appreciate that allopurinol should be titrated not to a specific dose, but to a serum urate target level; and the fact that in “real world medicine,” the time required to titrate a patient to the necessary dose can sometimes be quite extended and provide ample opportunity for compliance failure. The superiority of febuxostat to allopurinol 300 mg should not be construed as superiority to allopurinol overall, since allopurinol is US Food and Drug Administration (FDA)-approved at doses up to 800 mg/day. On the other hand, patients who need such high levels of allopurinol will frequently take a long time to achieve the target dose, and will typically need to advance to twice-daily dosing.
For patients with CKD, controversy exists as to the safety of allopurinol, with some studies suggesting an increase in toxicity and others suggesting none, particularly when allopurinol dosing is started low and adjusted specifically to target urate (ie, to avoid prescribing more than is actually necessary). In general, the community consensus would appear to be moving to the latter point of view.39
It is likely, therefore, that adequate results can be achieved with allopurinol in renal patients, even those needing a higher dose; however, the safety profiles of such doses has not been well established. Moreover, the use of allopurinol in patients with renal insufficiency may require a slower titration period and more monitoring, with its attendant inconvenience to the patient. The fact that febuxostat is approved for individuals with mild to moderate renal insufficiency, defined as CrCl > 30 mL/min, and does not need dosing adjustment in these individuals, makes for a simpler management algorithm for patients and physicians alike. It is important to note that all long term follow up studies excluded patients with creatinine higher than 2 mg/dL. In addition, although elevation of creatinine has been reported as a very rare AE, monitoring of kidney function is prudent.
From the patient’s point of view, therefore, febuxostat may offer several advantages. It can be given as an alternative to allopurinol for those patients who have allopurinol hypersensitivity; it will typically provide a more rapid time-to-target serum urate than allopurinol; its dosing is always once a day, and simplified by the fact that only two dose levels (40 mg and 80 mg) are available (and generally needed). When compared with the 300 mg dose of allopurinol at least, febuxostat works better and faster to lower urate, and appears to be a better agent for reducing tophi. Patients who are less motivated to work with their physicians, have mild to moderate CKD, or who need relief more quickly, may therefore benefit from the simplicity of febuxostat. On the other hand, it must be recognized that patients starting on febuxostat are more likely to experience a temporary increase in gouty flares than those starting allopurinol; the importance of rigorous anti-inflammatory prophylaxis therefore deserves emphasis. Given a possible slight increase in cardiac events, patients with cardiovascular disease should probably discuss this issue with their physicians. Moreover, to the extent that patients are also consumers, the relative costs of febuxostat vs generic allopurinol (US$161.40 vs US$14.70 for 30 days) will also warrant consideration.42