Urate-Lowering Therapy for Gout: Focus on Febuxostat

Bryan L. Love, Pharm.D.; Robert Barrons, Pharm.D.; Angie Veverka, Pharm.D.; K. Matthew Snider, Pharm.D.

Disclosures

Pharmacotherapy. 2010;30(6):594-608. 

In This Article

Febuxostat

Pharmacology

Febuxostat lowers sUA concentrations by interfering with purine catabolism, specifically the oxidation of hypoxanthine to xanthine and xanthine to uric acid at a molybdenum-pterin center. Although febuxostat is an inhibitor of xanthine oxidase, it is structurally quite different from allopurinol (Figure 2), has an alternate mechanism of enzyme inhibition, and is more potent.[38] Unlike allopurinol, which undergoes oxidation to the active metabolite oxypurinol and interacts chemically with the molybdenum center of xanthine oxidase, febuxostat remains unchanged and inhibits xanthine oxidase by binding in a narrow channel leading to the molybdenum center of the enzyme.[38] By this mechanism, febuxostat is able to inhibit both the reduced and oxidized form of xanthine oxidase to produce sustained reductions in sUA levels.[38] In terms of potency, febuxostat has an in vitro inhibition constant (Ki) of less than 1 nM, which is comparable to oxypurinol (Ki = 0.5 nM). However, the ability of febuxostat to inhibit both forms of the xanthine oxidase enzyme is an advantage since oxypurinol binds only weakly to the oxidized form and can be displaced during reoxidation of the molybdenum cofactor. This reaction can occur within hours and may only be overcome with multiple daily doses of allopurinol.[38,39] In addition, because febuxostat is structurally unrelated to purine or pyrimidines, it does not interfere with other enzymes in these metabolic pathways but is selective for xanthine oxidase.[39]

Figure 2.

Chemical structures of febuxostat and allopurinol.

Pharmacokinetics and Pharmacodynamics

When administered orally, febuxostat is absorbed rapidly, reaching maximum concentrations in plasma (Cmax) within 1 hour.[40,41] The absolute bioavailability of febuxostat is unknown, but absorption approximates 84%.[42,43] Febuxostat is highly protein bound, about 99% to albumin, has a moderate volume of distribution of 0.7 L/kg, and a half-life of 5–8 hours.[41,43–45] The primary method of clearance is hepatic. Approximately 22–44% of a dose undergoes conjugation by uridine diphosphate-glucuronyl transferase (UDPGT) enzymes to produce the acyl-glucuronide metabolite. Up to 8% of a given dose undergoes oxidation by cytochrome P450 (CYP) 1A2, 2C8, and 2C9 to produce the active metabolites 67M-1, 67M-2, and 67M-4. Only 1–6% of the drug is excreted unchanged in the urine.[40,41,43,46,47]

Febuxostat displays linear pharmacokinetics as evidenced by proportional increases in Cmax across a dose range of 10–120 mg, and area under the plasma concentration–time curve (AUC) for doses ranging from 10–240 mg. Dose-escalation studies in healthy volunteers demonstrated a 25–76% reduction in sUA levels with incremental dose increases of febuxostat up to 120 mg, at which point the pharmacodynamic effects plateaued.[40,41] In patients with gout and/or hyperuricemia, febuxostat 20 mg once/day produced a sustained hypouricemic effect, decreasing the mean AUC of sUA levels from 8.7 mg/100 ml to 5.8 mg/100 ml after 4 weeks of therapy, with maximum and minimum sUA levels in the 24 hours after final dose administration differing by less than 1 mg/100 ml.[45]

Special Populations The pharmacokinetic and pharmacodynamic effects of febuxostat have been evaluated across sexes, in elderly patients, and in patients with renal or hepatic dysfunction. One group of researchers evaluated the pharmacokinetic parameters and sUA level lowering of febuxostat 80 mg once/day for 7 days in men compared with women and in patients aged 18–40 years compared with those aged 65 years or older.48 Compared with males, females were identified as having higher Cmax and AUC of unbound drug (31.5 vs 23.6 ng/ml, p≤0.01, and 62.8 vs 53.9 ng•hr/ml, p≤0.05, respectively) as well as higher percent decreases in mean sUA concentrations (59% vs 52%, p≤0.01). This difference was not considered to be clinically significant however and was most likely related to weight differences between the sexes. Patients aged 65 years or older had comparable Cmax, AUC, and percent decreases of sUA levels compared with the younger patients. Based on these data, dosage adjustments are not required based on age or sex.

Two studies in patients with renal impairment confirmed that dosage adjustments of febuxostat are unnecessary with mild-to-moderate renal dysfunction.[46,47] The effects of a single dose of febuxostat 20 mg on renal function were assessed.[46] The mean AUC of unchanged febuxostat was similar in patients with normal (Clcr ≥ 80 ml/min) or mild (50 ≤ Clcr < 80 ml/min) renal impairment. Although patients with moderate renal impairment (30 ≤ Clcr < 50 ml/min) had a higher AUC of unchanged drug, the difference was less than 2-fold and was not considered clinically significant. Despite mean changes in plasma uric acid concentrations being higher in the renally impaired groups, these changes did not differ significantly from those with normal renal function.

Similar results were reported when febuxostat 80 mg/day administered for 7 days was evaluated in patients with normal renal function (Clcr > 80 ml/min), and mild (Clcr 50–80 ml/min), moderate (Clcr 30–49 ml/min) or severe (Clcr 10–29 ml/min) renal dysfunction.[47] On day 7, there was no statistically significant difference in Cmax among the four groups, but unbound AUC and half-life of febuxostat and its metabolites (67M-1, 67M-2, and 67M-4) were significantly increased in a linear relationship with Clcr. Again, this did not translate into significant increases in percent reductions of plasma or urinary uric acid concentrations among groups. Based on these pharmacokinetic data, the authors concluded that more conjugated drug underwent enterohepatic recycling and excretion through the biliary route in the patients with renal dysfunction. At this time, dosage adjustments of febuxostat in patients with renal impairment are not recommended; however, the two studies had only a combined total of 47 patients, and febuxostat has not been studied in patients with end-stage renal disease.

The effect of hepatic impairment on febuxostat was evaluated in one study.[44] Febuxostat 80 mg once/day was administered for 7 days to patients with normal hepatic function and those with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic dysfunction. Patients with mild or moderate hepatic impairment had a higher unbound Cmax, unbound AUC, and half-life than patients with normal hepatic function, but the differences were not statistically significant. Although percent decreases in sUA levels were significantly lower in patients with hepatic dysfunction (48.9% for mild and 47.8% for moderate dysfunction) compared with those with normal hepatic function (62.5%, p≤0.005 for both comparisons), this 14–15% difference was not considered to be clinically significant since the absolute reductions observed in patients with hepatic impairment were still comparable to reductions observed in previous studies of healthy subjects. Based on these data, febuxostat does not appear to need dosage adjustments in patients with mild-to-moderate hepatic impairment (Child-Pugh classes A and B). This is most likely due to compensatory changes in renal excretion of unchanged drug and glucuronide conjugates as oxidative metabolism and biliary excretion decreases. To our knowledge, febuxostat has not been studied in patients with severe hepatic impairment.

Clinical Efficacy

Short-term Studies In a multicenter, phase II, randomized, doubleblind, placebo-controlled, dose-response clinical trial, the safety and efficacy of febuxostat once/day were examined.[49] A total of 153 patients (aged 23–80 yrs) were randomized to febuxostat 40, 80, or 120 mg/day or placebo. Of these patients, 13 were excluded because baseline sUA levels were measured outside the desired time frame; thus, 140 patients were included in the intent-to-treat efficacy analysis. All of the original 153 randomized patients were included in the analyses of treatment safety and gout flares because all received at least one dose of the study drug. There were no significant differences in baseline characteristics; specifically, mean sUA levels were similar between groups and ranged from 9.24–9.92 mg/dl. During a 2-week washout period and throughout the first 2 weeks of the study, prophylaxis with colchicine 0.6 mg twice/day was provided. If the participants experienced acute gout flares after the initial 2 weeks, further treatment was determined by the investigators.

The primary outcome measure was the proportion of patients in each treatment group with sUA levels less than 6 mg/dl on day 28. Secondary measures included the proportion of patients with sUA levels less than 6 mg/dl on days 7, 14, and 21, the percent reduction in sUA level from baseline at each visit, and the percent reduction in daily urinary uric acid excretion from baseline to day 28.

Treatment with febuxostat resulted in prompt and persistent lowering of sUA levels. A significantly greater proportion of patients in the febuxostat groups achieved sUA levels less than 6 mg/dl at each visit compared with those in the placebo group (p<0.001 for each comparison). The majority of patients in each febuxostat group reached and maintained the targeted sUA concentration (< 6 mg/dl), some as early as day 7. The efficacy of febuxostat in lowering sUA was further demonstrated by a significantly greater proportion of febuxostat-treated patients achieving a sUA level of less than 4 mg/dl or less than 5.0 mg/dl compared with those receiving placebo on day 28 (p<0.05 for each comparison). It was later determined that participants with the highest baseline sUA levels were less likely to reach a sUA level of less than 6 mg/dl with febuxostat 40 mg/day compared with either 80 or 120 mg/day (p value not reported).

Febuxostat has been compared with allopurinol in two published and one unpublished phase III studies. The Febuxostat versus Allopurinol Controlled Trial (FACT )[50] and the Allopurinol- and Placebo-Controlled Efficacy Study of Febuxostat (APEX)[51] were conducted over 52 weeks and 28 weeks, respectively. In FACT, 760 patients from 112 centers in the United States and Canada were enrolled and received treatment,[50] whereas APEX enrolled 1072 patients in the United States only.[51] The Confirmation of Febuxostat in Reducing and Maintaining Serum Urate (CONFIRMS) trial, which is not yet published, enrolled 2268 patients and was conducted primarily to address cardiovascular safety concerns identified in FACT and APEX.[52] Eligible patients for all three studies met the criteria for acute gouty arthritis as determined by the American College of Rheumatology[14] and were adults with sUA levels of 8 mg/dl or higher. One major difference in the studies was the inclusion of patients with renal insufficiency. Patients in FACT were excluded for elevated serum creatinine concentrations of 1.5 mg/dl or greater, or estimated creatinine clearances less than 50 ml/minute; however, the other studies included patients with moderate renal impairment defined as a serum creatinine concentration of 1.5–2.0 mg/dl (APEX) and estimated Clcr 30–59 ml/min (CONFIRMS).[50–52]

After a 2-week washout period, patients in APEX or FACT were randomly assigned to receive febuxostat 80 or 120 mg/day or allopurinol 300 mg/day. The APEX also included placebo and febuxostat 240-mg/day groups, and patients with mild renal impairment received a reduced dose of allopurinol 100 mg/day. Prophylaxis against acute gout flares with naproxen 250 mg twice/day or colchicine 0.6 mg once/day was administered to all patients during the washout period and the first 2 months of study treatment. Gout flares during the study were treated at the discretion of individual investigators.

The primary efficacy outcome measure for both trials was the proportion of patients who achieved and maintained sUA levels less than 6 mg/dl during the last three monthly measurements. Secondary outcomes included the proportion of patients at each visit with sUA levels less than 6 mg/dl, and percent reduction from baseline in sUA concentrations. In addition, the reduction in tophi size and number, and the proportion of patients requiring treatment for acute gout flares during weeks 9 through study completion were assessed.

Baseline characteristics of the treatment groups were very similar with no significant differences reported between groups in FACT or APEX. For both trials, 92–97% of patients were male, 75–81% were Caucasian, and the mean age was 51–55 years. Patients had gout for an average of 10–12 years and had an average sUA level of 9.8 mg/dl.

In FACT, more patients receiving febuxostat achieved sUA levels less than 6 mg/dl than those receiving allopurinol (p<0.001).[50] The difference in the percentages of patients reaching the target SUA level persisted in favor of febuxostat regardless of the initial sUA level (p<0.001). Significantly more patients receiving febuxostat were more likely to have sUA levels less than 6 mg/dl by week 2 compared with the allopurinol group. In addition, these differences were maintained at all visits through week 52 (p<0.001). Considerably more patients with higher baseline sUA levels (≥ 9 mg/dl) receiving either dose of febuxostat achieved a sUA level less than 6 mg/dl at the last three visits when compared with patients receiving allopurinol (p<0.001). The mean percent reduction of sUA level from baseline was greater in both febuxostat groups than in the allopurinol group (p<0.001).

In APEX, participants receiving febuxostat 80, 120, or 240 mg/day achieved sUA levels less than 6 mg/dl at the last three visits significantly more often than those receiving allopurinol or placebo (48%, 65%, 69%, 22%, and 0% respectively, p<0.001 for all comparisons).[51] Patients with moderate renal impairment receiving febuxostat 80, 120, and 240 mg/day achieved the goal sUA level more often than patients receiving allopurinol 100 mg or placebo (44%, 46%, 60%, 0%, and 0%, respectively; p values not reported). These data are promising for patients with renal impairment. However, as the numbers of patients with renal impairment in APEX (35 patients) and in extension studies were small, febuxostat use in this population deserves further study.

Efficacy from the CONFIRMS trial was assessed similarly to APEX and FACT. The primary efficacy outcome measure was the percentage of patients with a sUA level less than 6 mg/dl at the final visit (6 mo).[52] Patients were randomized to receive allopurinol 300 mg/day or febuxostat 40 or 80 mg/day; patients with moderate renal insufficiency (not defined) who were randomized to receive allopurinol were dosed at 200 mg/day. Participants were equally matched with regard to baseline demographic and clinical characteristics such as sUA level, cardiovascular disease, and renal impairment. At the conclusion of the trial, 45% and 67% of patients receiving febuxostat 40 and 80 mg/day, and 42% of allopurinol-treated patients achieved sUA levels less than 6 mg/dl. Febuxostat 40 mg/day was determined to be noninferior to allopurinol; however, a statistically significantly benefit was apparent when comparing febuxostat 80 mg/day and allopurinol. Table 2 summarizes the results of these shortterm clinical trials (≤ 1-yr duration) that evaluated the efficacy of febuxostat for hyperuricemia in patients with gout.[49–52]

Long-term Studies Two long-term clinical studies have been conducted in an effort to determine the durability of urate lowering, safety, and tolerability of febuxostat. Both were open-label extension studies of previously published clinical trials. The Febuxostat Open-label Clinical Trial of Urate-Lowering Efficacy and Safety (FOCUS)[53] was a 5-year extension of the phase II trial[49] (discussed previously). A total of 116 patients continued treatment with febuxostat 80 mg/day. Dosage titrations to 40 mg/day, 80 mg/day, or 120 mg/day were allowed within the first 24 weeks, but a stable dosage was maintained from this point until study completion. Colchicine 0.6 mg twice/day was provided during the first 4 weeks of this study. Similar to previous studies, the primary outcome measure was the proportion of participants who achieved and maintained a sUA level less than 6 mg/dl. The secondary outcome was the overall percent reduction in sUA level from baseline. In addition, the proportion of patients with sUA levels less than 5 or less than 4 mg/dl, the proportion requiring treatment for a gout flare, and the proportion with resolution of palpable tophi were examined.[53]

The majority of patients were Caucasian (85%) and male (91%), with a mean age of 53.3 years. Baseline characteristics from the initial 28-day, phase II study were used for this study. Palpable tophi were present in 22% of participants. The majority of patients continued to take febuxostat 80 mg/day during the study. The numbers of patients who discontinued treatment were 38, 7, 5, 6, and 2 in years 1–5, respectively. The primary reasons for discontinuation were listed as personal reasons (22 patients), adverse events (13), gout flare (8), lost to follow-up (5), protocol violation (1), and other (9). A total of 58 patients completed the study, and of these patients, 54 (93%) met the goal sUA level. The proportion of patients achieving a sUA level less than 6 mg/dl at any febuxostat dose during years 1–4 were 78%, 76%, 84%, and 90%, respectively. The mean percent reduction in sUA levels in patients receiving febuxostat for 2 years or longer was nearly 50% from baseline.

The Febuxostat/Allopurinol Comparative Extension Long-term (EXCEL) study[54] included patients who had completed either FACT or APEX, both phase III comparator trials. Initially, all patients received febuxostat 80 mg/day (351 patients); however, the protocol was modified to randomize patients in a 2:2:1 ratio to open-label febuxostat 80 mg/day (299 [for a total of 650] patients), 120 mg/day (291 patients), or allopurinol (145 patients). As in APEX, most patients received allopurinol 300 mg/day, but the dose was adjusted to 100 mg/day in eight patients who had renal impairment. Treatment regimens could be modified at the investigators' discretion within the first 6 months of treatment. Patients with a sUA level greater than 6 mg/dl after 6 months of treatment were withdrawn from the study. The primary outcome measure was the proportion of patients with a sUA level less than 6 mg/dl evaluated at each visit. Other efficacy measures included the percent reduction in sUA levels from baseline, changes in the size and number of palpable tophi, and the frequency of gout flares requiring treatment. Although statistical analysis was included in the methods section by the study authors, neither p values or indicators of statistical significance were provided for any efficacy or safety measures.

The majority of patients in the EXCEL trial were Caucasian males with mean age older than 50 years. At least one palpable tophus was present in 20% of patients at baseline. There were no significant differences reported among treatment groups with regard to baseline characteristics, gout history, or comorbid conditions (statistics not provided). The majority of patients (98%) had normal renal function (serum creatinine concentration ≤ 1.5 mg/dl).

Patient withdrawal from EXCEL was significant, although anticipated in a trial of this duration. Of the 1086 patients enrolled, 422 (39%) withdrew before the end of the 3-year study. Primary reasons for withdrawal included lost to follow-up (8.3%), personal reasons (7.2%), adverse effects (7.2%), and treatment failures (6.4%). Patient compliance with assigned treatment was assessed at each visit by pill counts and was 95% in all treatment groups.

Whereas dosage titration was allowed during the study, most patients assigned to the febuxostat 80-mg group (606/650) were maintained at this dose. In the 120-mg group, however, there were 291 patients at enrollment; this number increased to 388 patients at 6 months. Of the 145 patients receiving allopurinol at baseline, only 92 patients were maintained on a stable dose of allopurinol at 6 months.

After the first month of therapy, 81% and 87% of patients receiving febuxostat 80 mg and 120 mg, respectively, met the goal sUA level compared with only 46% of allopurinol-treated patients. For the duration of the study, 80% or more of febuxostat-treated patients maintained sUA levels below 6 mg/dl. The percentage of allopurinoltreated patients reaching the sUA goal was reported as 82% at 12 months. However, this only accounted for patients initially treated with allopurinol and maintained on therapy and did not account for patients switched from febuxostat to allopurinol within the first 6 months. The mean percent reduction in sUA levels at the last visit from initial treatment was 47%, 53%, and 32% for febuxostat 80 mg, 120 mg, and allopurinol, respectively.

Overall, the size and number of palpable tophi decreased in patients regardless of treatment group; however, a greater percent decrease in size and number in the febuxostat-treated patients was noted. In addition, a greater percentage of patients receiving febuxostat versus allopurinol achieved complete resolution of tophi.

Table 3 summarizes the results of these longterm, open-label clinical trials that evaluated the efficacy of febuxostat for hyperuricemia in patients with gout.[53,54]

Safety and Tolerability

Febuxostat has been evaluated in more than 2700 patients in clinical studies ranging from 4 weeks[49] to more than 5 years.[53] Febuxostat was generally well tolerated in patients with gout and hyperuricemia; most treatment-related adverse events were mild to moderate in severity. Compared with patients who have normal renal function, no increased frequency of adverse events in patients with moderate renal impairment has been noted, although use in these patients has been limited.[49–51,53,54]

In a pooled analysis of three phase III controlled studies, the most commonly reported adverse events for febuxostat were liver function test abnormalities (5.4%), rash (1.2%), nausea (1.0%), and arthralgias (0.8%).[50–52] In the 5-year extension trial, FOCUS, 91% of participants (106/116) reported at least one adverse event.[53] Frequencies of adverse events with febuxostat 40, 80, and 120 mg/day were similar to those with allopurinol; however, in APEX, participants taking febuxostat 240 mg/day experienced a statistically significant increase in the frequency of diarrhea and dizziness.[51] No significant differences were found in the overall frequency of adverse events between febuxostat at FDA-approved doses (40 and 80 mg/day) and placebo.[49]

The primary reasons for discontinuation of febuxostat vary depending on the trial, but adverse events were generally mild to moderate in severity. The main causes for withdrawal were liver function test abnormalities, gout flares, diarrhea, and rash. In APEX, the reasons for patient withdrawal were similar in all treatment groups, except for gout flares, which were more frequent with febuxostat than with allopurinol.[51] The frequency of gout flares in the placebo-controlled study was 35–55% of febuxostat-treated patients and 37% of those receiving placebo.[49] In FACT, the percentage of patients requiring treatment for gout flares peaked within the first 3 months and gradually decreased thereafter.[50] Rebound gout flares after prophylaxis discontinuation were higher with febuxostat 120 mg/day compared with febuxostat 80 mg/day or allopurinol (p<0.001 for both comparisons). During weeks 9–52 the overall rates of gout flares were similar in the febuxostat 80-mg/day, febuxostat 120-mg/day, and allopurinol 300-mg/day groups: 64%, 70%, and 64%, respectively; the frequency of gout flares gradually decreased throughout the trial to 8%, 6%, and 11%, respectively, during weeks 49–52. In order to prevent gout flares when initiating febuxostat, prophylactic treatment with an NSAID or colchicine is recommended.[43]

Although not apparent in individual trials, cardiovascular thromboembolic events (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) have been observed at a higher rate with febuxostat (0.74/100 patient-yrs) than allopurinol (0.60/100 patient-yrs) when looking at pooled data. However, a direct causal relationship has not been established, and these differences were not statistically significant. Based on these data, the FDA required an additional study to evaluate the thromboembolic risk of febuxostat compared with allopurinol. Cardiovascular thromboembolic events in the CONFIRMS trial were few in number, both in total and in individual treatment groups. The rate of observed events was not higher with febuxostat than with allopurinol. Considering the available evidence, febuxostat possesses a reasonable risk-benefit balance, but additional long-term studies evaluating cardiovascular outcomes comparing febuxostat with allopurinol are necessary. Until the cardiovascular thromboembolic risk is fully elucidated, patients receiving febuxostat should be monitored for signs and symptoms of myocardial infarction and stroke.[43]

Transaminase level elevations greater than 3 times the upper limit of normal have been observed in clinical trials; no dose-effect relationship has been noted. The manufacturer recommends monitoring liver function at 2 and 4 months after starting febuxostat therapy, and periodically afterward.[43]

Drug Interactions

The role of febuxostat as a target and/or precipitant of pharmacologic and pharmacokinetic drug interactions was examined. Febuxostat may disrupt xanthine oxidase–dependent metabolism of theophylline, azathioprine, mercaptopurine, and didanosine. Case reports of toxicity when these drugs are administered concurrently with allopurinol have been reported. Although specific data regarding febuxostat are unavailable, similar interactions would be expected. Thus, concurrent use of febuxostat with theophylline, azathioprine, mercaptopurine, and didanosine should be avoided.[43,55–57]

The effect of food and antacids on febuxostat and sUA concentrations was investigated in a crossover study of 92 healthy subjects.[43,58] Food reduced the rate and extent of absorption of febuxostat; however, this was not associated with significant changes in sUA concentrations. Antacids reduced the rate, but not the extent, of febuxostat absorption. These findings suggest febuxostat can be administered with food or antacids without significant impact on response.

An in vitro trial assessed the drug-drug interaction potential of febuxostat with regard to binding characteristic to plasma albumin, and metabolism by CYP and UDPGT enzymes.[59] Febuxostat did not influence plasma albumin binding of ibuprofen or warfarin, nor did these drugs change plasma protein binding of febuxostat. Metabolism of febuxostat was widely distributed among UDPGT and CYP enzymes, which decreases the likelihood of interactions with drugs that may inhibit these enzyme systems. These findings suggest that febuxostat has a low overall drug-drug interaction potential.

Finally, interactions between febuxostat and drugs used in treatment of acute gouty arthritis were reviewed.[43,60] Febuxostat did not impact the pharmacokinetics of indomethacin, naproxen, or colchicine, nor did these drugs significantly affect the pharmacokinetics of febuxostat in healthy individuals. Febuxostat may be safely administered in patients receiving colchicine, indomethacin, or naproxen for prophylaxis of gouty flares associated with urate-lowering therapy.

Dosing and Administration

The FDA has approved febuxostat for the treatment of hyperuricemia in patients with gout. The recommended starting dosage is 40 mg once/day. If patients do not achieve a sUA level below 6 mg/dl after 2 weeks with febuxostat 40 mg/day, the dose should be increased to 80 mg/day.[43] Febuxostat may be taken without regard to meals or antacids, as any observed pharmacokinetic changes (AUC and Cmax) are not considered to be clinically significant.[58]

Unlike allopurinol, febuxostat does not require dosage adjustments in patients with mild-to-moderate renal impairment (Clcr 30–89 ml/min); the starting dosage is the same as for patients with normal renal function. Febuxostat should be used with caution in patients with severe renal impairment (Clcr < 30 ml/min). Febuxostat has not been studied in patients undergoing dialysis. Febuxostat requires no dosage adjustment in patients with mild or moderate hepatic impairment (Child-Pugh class A or B). No studies, to our knowledge, have been conducted in patients with severe hepatic impairment (Child-Pugh class C); thus caution should be exercised in these patients.[43]

Due to the inherent risk for precipitating an acute gouty flare when beginning febuxostat, prophylaxis is strongly recommended. The manufacturer recommends colchicine or an NSAID.[43] If a gout flare occurs during febuxostat treatment, febuxostat should not be discontinued, but the acute gout attack should be managed individually for each patient. Prophylactic therapy may be beneficial for up to 6 months.

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