International position paper on febuxostat

Appendix

Attachment 1: pivotal clinical efficacy studies of febuxostat and side effects

Becker et al. randomly assigned 762 patients with gout and with serum urate concentrations of at least 8.0 mg/dl (480 µmol/l) to receive either febuxostat (80 or 120 mg) or allopurinol (300 mg) once daily for 52 weeks; 760 patients received the study drug [10]. Prophylaxis against gout flares with naproxen or colchicine was provided during weeks 1 through 8. The primary endpoint was a target SUA <6.0 mg/dl (360 µmol/l) at the last three monthly measurements. The secondary endpoints included reduction in the incidence of gout flares and in tophus area. The primary endpoint was reached in 47–59% of patients receiving 80 mg of febuxostat, 44–74% of those receiving 120 mg of febuxostat and 8–40% of those receiving 300 mg allopurinol (P < 0.001 for comparison of each febuxostat group with the allopurinol group). Febuxostat was concluded, at a daily dose of 80 or 120 mg, to be more effective than 300 mg allopurinol in lowering SUA. Similar reductions in gout flares and tophus area occurred in all treatment groups (Table 1).

Schumacher et al. randomly assigned 1,072 patients with gout, including persons with impaired renal function, and with SUA concentrations of at least 8.0 mg/dl (480 µmol/l) to receive either febuxostat (80, 120 or 240 mg) versus allopurinol (300 or 100 mg) once daily for 28 weeks versus placebo [11]; significantly higher percentages of subjects treated with febuxostat 80 mg (48%), 120 mg (65%) and 240 mg (69%) attained the primary endpoint of at least three monthly SUA levels <6.0 mg/dl (360 µmol/l) compared with allopurinol (22%) and placebo (0%). A significantly higher percentage of patients with impaired renal function treated with febuxostat 80 mg (4 out of 9 = 44%), 120 mg (5 out of 11 = 45%) and 240 mg (3 out of 5 = 60%) achieved the primary endpoint compared with those treated with 100 mg allopurinol (0 out of 10 = 0%).

Serious adverse events occurred similarly in all groups, although diarrhea and dizziness were more frequent in the 240-mg febuxostat group. Primary reasons for withdrawal were similar across groups except for gout flares, which occurred more frequent with febuxostat than with allopurinol. Schumacher et al. concluded that, at all doses studied, febuxostat more effectively lowered and maintained serum urate levels below 6.0 mg/dl (360 µmol/l) than allopurinol or placebo did in subjects with hyperuricaemia and gout, including in those with mild-to-moderate impaired renal function [11]. Becker et al. randomly assigned 153 patients in a phase II RCT, including patients aged 23 up to 80 years, to receive either febuxostat 40 versus 80 versus 120 mg or placebo once daily for 28 days with colchicine prophylaxis [12]. SUA concentrations reached levels below 360 µmol/l in 56% versus 76% versus 94% versus 0% in respective febuxostat dosages. SUA below 300 µmol/l was reached in, respectively, 21%, 49%, 88% and 0%. The authors thus concluded that febuxostat is effective, well tolerated and safe for the short-term treatment. For the last two conclusions, we now have a 5-year open-label extension study, including 116 patients after the 28-day double-blind study (with only 58 completers) [13]. Febuxostat resulted in a durable maintenance of SUA below 360 µmol/l for most subjects. This was associated with nearly complete abolition of gout flares and resolving tophi in the majority of patients at the cost of some side effects [13], see Table 2. In the long-term study, 13 out of 116 (11%) reported an adverse event as primary reason for premature discontinuation. The most common adverse events leading to withdrawal were abnormal liver function tests (n = 3), cancer (n = 3) and increase serum creatinine (n = 2). These abnormalities resolved within 10–106 days, and the three abnormal liver function tests and one of the renal dysfunction were considered to be related with study drug treatment, though alcohol abuse was not fully excluded in two out of three liver function abnormalities. The long-term study, however, had a flaw in design as it started with a selection bias, including preferentially responsive and compliant and febuxostat was well tolerated by all patients.

Attachment 2

It is strongly advised to report serious adverse events to local authorities. Adverse events in the 5-year follow-up study [13]:

Most frequently reported adverse events	In 116 subjects	Percentage
Upper respiratory tract infection	51	53
Locomotor complaints	42	36
Joint-related signs/symptoms	33	28
Diarrhea	24	21
Influenza	20	17
Headache	18	16
Par/dysaesthesia	16	14
Lower respiratory tract infections	15	13
Liver function analyses	15	13
Vascular hypertensive disorders	15	13
Gastrointestinal/abdominal complaints	14	12
Rash/eruption/exanthema	14	12
Oedema	12	10
Pain and discomfort	12	10
Tendon disorders	12	10
Serious adverse events
Subjects with at least one serious event	21	18
AV block or atrial fibrillation	6	5
Small intestinal obstruction/diverticular or appendicular perforation	3	3
Non-cardiac chest pain	1	<1
Cholecystitis	2	2
Infections/infestations	4	3
Concussion/traumatic fracture/excoriation	3	3
Intervertebral disc degeneration/rotator cuff syndrome/osteoporosis fracture	5	4
Neoplasm	4	3
Alzheimer/cerebrovascular accident	2	2
Depression	1	<1
Urinary retention	1	<1