Febuxostat: drug review and update.

Drug Evaluation

Febuxostat: drug review and update

Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Uppsala Universitetsbibliotek on 10/04/14 For personal use only.

Harmanjot K Grewal†, Joseph R Martinez & Luis R Espinoza 1.

Introduction

Louisiana State University - School of Medicine, New Orleans, LA, USA

2.

Overview of the market

3.

Febuxostat

4.

Clinical trials evaluating

Introduction: Gouty arthritis and hyperuricemia have ailed humans for centuries. Recent advances in understanding of the mechanism(s) of their development have changed our perception of the disease process. Despite these gains, the treatment options available are limited. The FDA approval of febuxostat for the treatment of hyperuricemia in gout has been a significant step forward. Since its approval in 2009, febuxostat has proven to be safe and efficacious although concerns remain regarding its long-term effects and superiority to other uricosuric agents, such as allopurinol. Areas covered: A comprehensive literature review of PubMed and Ovid examining clinical trials and post-marketing studies yielded congruent findings on efficacy and safety in elderly populations and those with mildto-moderate renal/hepatic impairment. A lack of literature and clinical studies was found with regard to comparison of febuxostat to FDA-approved highdose allopurinol (> 300 mg), the safety of febuxostat in the treatment of severe renal/hepatic impairment and the benefit in the treatment of secondary cases of hyperuricemia. Expert opinion: Febuxostat is effective in the treatment of mild-to-moderate renal/hepatic impairment with dramatic effects on the serum urate level. It can be used safely in patients with hypersensitivity reactions to allopurinol. Further research is needed to determine the long-term benefits and risks.

febuxostat 5.

Conclusion

6.

Expert opinion

Keywords: arthritis, febuxostat, gout, hyperuricemia, uloric, uric acid, xanthine oxidase Expert Opin. Drug Metab. Toxicol. (2014) 10(5):747-758

1.

Introduction

Gouty arthritis is an inflammatory arthritis characterized by the presence of monosodium urate crystal deposition that can occur within a joint or the surrounding tissue [1-4]. Dating as far back as ancient Egypt, references and physical findings of gout have been documented throughout history (Figure 1) [5-7]. Gouty arthritis has been referred to as the ‘unwalkable disease’ and later coined the ‘disease of the wealthy’ and ‘disease of the kings’ due to its frequency in affluent populations [5-7]. It was not until 1859 that the relationship between gouty arthritis and monosodium urate crystals was suggested by Garrod and then confirmed in 1961 with the use of polarizing microscopy to identify the crystals [5]. This critical advancement in science allowed for the accurate diagnosis of gouty arthritis differentiating it from diseases with similar presentation and setting the stage for research and development of therapeutic modalities [7-9]. The fine balance of serum urate (sUA) present in the body is determined by the combination of de novo production, dietary intake and excretion [2,10-13]. It is well known that monosodium urate deposition for prolonged periods leads to destructive arthropathy [2,7]. Damage from deposition of these crystals is not only limited to the joints but also the surrounding tissues; crystals that deposit in the kidneys cause nephrolithiasis [7,14]. Hyperuricemia is also often associated with cardiovascular disease, chronic kidney disease, metabolic syndrome and insulin resistance [11,15-20]. In addition, monosodium urate crystals have been shown to 10.1517/17425255.2014.904285 © 2014 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 All rights reserved: reproduction in whole or in part not permitted

747

H. K. Grewal et al.

Box 1. Drug Summary. Drug name Phase Indication Pharmacology description/mechanism of action


Oxidation enzymes Conjugation enzymes Metabolites in vivo Route of administration Chemical structure

Febuxostat FDA approved for gout prophylaxis treatment Chronic management of hyperuricemia in patients with gout Non-purine selective inhibitor of oxidized and reduced form of xanthine oxidase by noncompetitively blocking molybdenum pterin CYP enzymes CYP1A2/2C8/2C9 Uridine diphosphate glucuronosyl transferase (UGT) enzyme UGT1A1/1A3/1A9/2B7 67M-1, 67M-2, 67M-4 Oral H 3C

CH3

O N

S

N

CH3

O OH

Pivotal trial(s)

FACT [36] APEX [75] CONFIRMS [74] FOCUS [76] EXCEL [77]

Pharma projects -- copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline.citeline.com) and Citeline (http://informa.citeline.com).

act as ‘danger signals’ that activate inflammasome, leading to the release of potent inflammatory cytokines, IL1b and IL18, throughout the body [21-23]. Progression of gout includes the asymptomatic stage of hyperuricemia, symptomatic hyperuricemia and chronic gouty arthritis -- a transition period that can span years. Gouty arthritis typically affects middle-aged to elderly adults, especially men; there is an increase in prevalence among postmenopausal women secondary to decreased circulating estrogen that behaves as a uricosuric agent [7,9,23,24]. From a population standpoint, gouty arthritis appears to be a steadily rising clinical entity [25,26]. According to the national health interview survey (NHIS), the prevalence of gouty arthritis in a 1-year period was 940 per 100,000 adults aged ‡ 18 years, with prevalence increasing with age [27]. The peak age of patients who are affected with gouty arthritis is ranging from 70 to 79 years, with an estimated prevalence of 8000 per 100,000 [27]. In total, it is estimated that 6.1 million adults aged ‡ 20 years have been told that they have gout [28]. Looking back, we have come a long way in our knowledge of the pathogenesis and management of gouty arthritis; we have learned that there are potential genetic predispositions 748

to develop gout in addition to the role of NALP3 inflammasome [16,29-32]. Despite this increase in knowledge, the advancement in treatment has not been as robust. There are still many obstacles in the treatment of gout, particularly in those patients with abnormal renal and hepatic function. 2.

Overview of the market

Urate-lowering strategies include inhibition of xanthine oxidase and enhancement of urinary excretion (Table 1). Medications currently available for the treatment of gout include those that aim to: i) inhibit xanthine oxidase to reduce uric acid production; ii) enhance urinary uric acid excretion; and iii) break down uric acid with enzyme replacement [33]. The most commonly used agent to achieve a target sUA (£ 6 mg/dl) is allopurinol. Allopurinol, first approved for use in 1964, is clinically effective in lowering sUA and reducing the number of gout flares; it is the mainstay of uratelowering therapy [1,2]. Allopurinol is approved for primary and secondary hyperuricemia at dosages up to 800 mg daily, requiring adjustment in dosage with renal insufficiency. Its mechanism of action involves disruption of purine biosynthesis via competitive inhibition of activity of the oxidized form

Expert Opin. Drug Metab. Toxicol. (2014) 10(5)

Febuxostat

Hippocrates described ‘unwalkable disease’ |


2640 B.C A.D | Identify podagra

5th Century B.C

Crystals from tophus described | 6th Century A.D

1679 A.D

| 1st use of colchicine for gout

FDA approval: probenecid | Aug 1966 | FDA approval: allopurinol

Mar 1980

1776 Egyptians

Uric acid

FDA approval: colcrys/colchicine | Feb 13, 2009 | FDA approval: febuxostat

Oct 2009

Sept 2010 | FDA approval: pegloticase

Figure 1. Timeline of historical events involving gouty arthritis.

Table 1. Mechanism of action for therapies utilized for the treatment of gout. Drug Allopurinol Benzbromarone Colchicine

Febuxostat Pegloticase Probenecid Sulfinpyrazone

Mechanism of action Inhibitor of xanthine oxidase Non-competitive inhibitor of xanthine oxidase Inhibits tyrosine phosphorylation in neutrophils; interferes with microtubule function; inhibits activity of adhesion molecules Non-purine selective inhibitor of xanthine oxidase that noncompetitively blocks molybdenum pterin Catalyzes the oxidation of uric acid to allantoin Competitively inhibits active reabsorption of urate at the proximal tubule of the kidney Competitively inhibits uric acid reabsorption in the proximal tubule of the kidney

of xanthine oxidase, an enzyme needed to oxidize both hypoxanthine and xanthine to uric acid [7,34]. There are, however, several issues with the use of this drug; however, it has limitations. In clinical use, allopurinol is frequently under-titrated by prescribing physicians and is often ineffective in maintaining and achieving target sUA at these lower doses [1,35-39]. Although we now know that allopurinol is relatively safe to use in patients with renal insufficiency, the dose should be escalated slowly with frequent laboratory monitoring as the active metabolite of allopurinol, oxypurinol, is excreted primarily via the kidneys [1,40]. There are also severe adverse reactions that can occur with the use of allopurinol such as hypersensitivity syndrome, Steven--Johnson syndrome and toxic epidermal necrolysis, all of which are potentially life threatening; there is also an increased risk of hypersensitivity syndrome with allopurinol use in patients of Asian descent who carry HLA-B*5801 gene [1,2,35,40-44]. Although such adverse events occur in ~ 2% of cases, the mortality associated with these complications is up to 20% [2,41-43]. Few options are available for those patients who have failed to reach target sUA levels or are intolerant of allopurinol.

Alternative uricosuric pharmacologic therapies that do not involve xanthine oxidase inhibition include benzbromarone (withdrawn from US market), probenecid, sulfinpyrazone and pegloticase (Table 2). These agents, aside from pegloticase, increase renal elimination of uric acid [37,45,46]. Pegloticase, a pegylated uric acid-specific enzyme, reduces uric acid by increasing its conversion to allantoin, which is readily cleared by renal excretion. While underexcretion is the predominant issue in most patients with gout, xanthine oxidase inhibitors remain the most frequently used agents [33,46]. New therapies for hyperuricemia and gout that are in early stages of development and/or clinical trials are shown in Table 3. For many years, a safe and efficacious alternative to allopurinol for treatment of hyperuricemia and gout has been absent. Although there has been the introduction of pegloticase or off-label use of IL-1 inhibitors for treatment of refractory gout, there remained a void for treatment options in patients unable to receive either medication [24,33,47-53]. The novel medication febuxostat has proven to be a valid treatment modality for these patients (Box 1).


749

H. K. Grewal et al.


Table 2. Pharmacologic therapies for the prevention and treatment of gout. Drug

Flare prophylaxis

Colchicine NSAID Allopurinol Benzbromarone Febuxostat Pegloticase Probenecid Sulfinpyrazone

ü ü

Urate lowering

ü ü ü ü ü ü

NSAID: Non-steroidal anti-inflammatory drug.

Table 3. Future therapies for gouty arthritis. Interleukin 1 inhibition Rilonacept Anakinra Canakinumab URAT1 inhibition RDEA594 Lesinurad Purine nucleotide phosphorylase inhibition BCX 4208

This review will examine the literature available on febuxostat, its use, pharmacology, pharmacokinetics, efficacy and safety. 3.

Febuxostat

Introduction Febuxostat functions as a urate-lowering drug approved for use in Europe on April 21, 2008 for gouty arthritis shortly followed by US FDA approval on February 13, 2009 [2]. The US FDA-approved doses include both 40 and 80 mg daily dosages (clinical trials have shown safety with doses up to 240 mg) [54-57]. Dosing recommendations are to start with 40 mg daily and sUA level has to be checked at 2 weeks; if sUA remains > 6 mg/dl, an increase in dose to 80 mg daily is recommended. Although in Europe higher doses of febuxostat are approved for clinical use, US FDA elected not to approve 120 or 240 mg due to the side effects and trial data demonstrating efficacy of febuxostat only at lower prescribing doses of 40 and 80 mg daily. 3.1

Chemistry Febuxostat (TEI-6720, TMX-67), 2-(3-cyano-4-[2-methylpropoxyl]phenyl)-4-methylthiazole-5-carboxylic acid, is a thiazolecarboxylic acid derivative with the empirical formula C16H16N2O3S [2,58]. This compound has a molecular mass of 316.38 g/mol and is largely bound to albumin with a volume of distribution at steady state of 0.7 mg/kg [59-61]. It is a non-purine selective inhibitor of xanthine oxidase that 3.2

750

noncompetitively blocks molybdenum pterin (active site on xanthine oxidase) [1,2,55,56]. As febuxostat inhibits both the oxidized and reduced form of xanthine oxidase, it is not easily displaced from the molybdenum pterin site [1]. In addition, febuxostat does not have significant effect on other enzymes involved in purine and pyrimidine metabolism [1]. Structurally, febuxostat differs from allopurinol by the absence of purine ring [1].

Pharmacokinetics/metabolism In healthy human subjects, febuxostat is absorbed at a rate of 49%, of which 99.2% of the compound is bound to albumin [57]. It is excreted both in the urine and in the feces in urine, 49% is excreted as metabolite and 3% as unchanged compound, whereas in feces, 45% is excreted as metabolite and 12% excreted as unchanged compound [59,61-63]. The half-life of febuxostat is 5 -- 8 h [1,2,59,64]. Febuxostat is metabolized via both conjugation by uridine diphosphate glucuronosyltransferase (UGT) enzymes (UGT1A1, UGT1A3, UGT1A9 and UGT2B7) and oxidation by CYP enzymes (CYP1A2, CYP2C8 and CYP2C9); oxidation of the isobutyl side chain leads to the formation of active metabolites. The metabolites include both acyl glucuronide metabolites and oxidative metabolites (67M-1, 67M-2, 67M-4 and a secondary metabolite from 67M-1) [58,65]. The metabolite 67M-3 is also produced via CYP 1A1 but in low amounts [65]. Mukoyshi et al. also found that although oxidation via CYP 3A4 forms the metabolite 67M-2, its role is limited; this is a key finding since CYP 3A4 is a predominate enzyme in the liver involved with the metabolism of many medications [65]. Studies have shown a rapid onset of action of febuxostat with a time to peak plasma level of 1 -- 1.5 h; for this reason, sUA should be rechecked within 2 weeks of medication initiation [60,62]. Febuxostat efficacy and absorption is not affected by food or achlorhydria, but high fat foods may delay its absorption without any significant effect on its efficacy [57]. Evaluation of febuxostat across patients with varying degrees of renal impairment shows unchanged peak plasma concentration, as well as time to reach peak plasma concentration, when compared to healthy controls [58]. It was noted that there was a rise in serum febuxostat oxidative metabolites with decreasing renal function; however, there did not appear to be any effect on safety or tolerability [58,66]. With mild-tomoderate renal impairment (CrCl 30 -- 89 ml/min), no dose adjustment is required [58]. In patients with severe renal dysfunction (CrCl < 30 ml/min), there is an increase in concentration of febuxostat and safety of febuxostat in this population has not been determined. Mild-to-moderate hepatic impairment (Child--Pugh Class A and B) does not affect the pharmacokinetics of febuxostat; thus it does not require dose adjustment [67]. The reduction in sUA in both mild and moderate hepatic impairment is comparable to that of healthy controls [67]. Studies examining the use of febuxostat with severe hepatic impairment 3.3



Febuxostat

(Child--Pugh Class C) have not been conducted and caution is advised. Febuxostat has similar pharmacokinetics in geriatric populations (> 65 years) and does not require dose adjustment. In addition, no differences were noted with gender [57]. Specific studies looking at race were not conducted. Febuxostat has not been studied in patients under the age of 18 years and is classified as category C for use during pregnancy. Drug interactions have been found with azathioprine and 6-mercaptopurine with a respective increase in drug plasma levels and associated toxicity; concomitant administration with drugs that are metabolized by xanthine oxidase, such as azathioprine or 6-mercaptopurine, is not recommended [1,2,60]. Febuxostat has also been shown to interact with the pharmacokinetics of 1-methylxanthine and 1-methyl uric acid, but there have been no pharmacologic effects demonstrated [60]. Febuxostat has been shown to be safely tolerated with hydrochlorothiazide, colchicine, select NSAIDs (naproxen and indomethacin) and warfarin [1,57,60,62,68-72]. Of note, febuxostat neither inhibit P450 enzymes CYP1A2, 2C9, 2C19, 2D6 or 3A4 nor induce CYP1A2, 2B6, 2C9, 2C19 or 3A4 [65]. For this reason, febuxostat interactions involving medications that are metabolized via these enzymes are doubtful [65]. Pharmacodynamics Studies have confirmed an enhanced potency of febuxostat compared to allopurinol. Initial in vitro studies using mice showed the serum level of febuxostat required to lower sUA levels by 50% in bovine milk, mouse liver and rat liver (1.4, 1.8 and 2.2 nM) compared to allopurinol (1700, 380 and 1100 nM) were lower [56,64]. A later study involving chimpanzees similarly showed lower serum febuxostat levels required to reduce sUA levels as compared to allopurinol [64,72,67]. Studies show that there is a dose-dependent decrease in 24 h mean sUA and total daily urinary xanthine excretion with corresponding increase in serum xanthine concentration with the use of febuxostat [73]. 3.4

4.

Clinical trials evaluating febuxostat

Several Phase I studies were conducted in the initial stages of clinical evaluation of febuxostat. One of the initial studies conducted was a 2-week multiple-dose, placebo-controlled dose-escalation study including 154 healthy adult volunteers, subdivided into 12 dosing groups over a 2-week study period [73]. Results showed that daily febuxostat dosing (10 -- 120 mg) was safe to use in humans nearly in a doselinear manner up to dosing of 120 mg daily. Additionally, it did not appear that total purine synthesis was reduced, reflecting xanthine oxidase inhibition as the primary mechanism of action. This initial study also concluded that hepatic metabolism (via conjugation and oxidation) is the primary elimination pathway of febuxostat with minimal renal elimination. Subsequent studies have shown that doses of up to 240 mg daily are safe to use in human subjects [74].

Data obtained from the Phase I trials allowed for further examination of febuxostat in the larger Phase II trials. Becker et al. in a double-blind, placebo-controlled trial examined the safety and efficacy of febuxostat. Primary end point of the study included sUA levels < 6.0 mg/dl on day 28 in gout patients with hyperuricemia (sUA ‡ 8.0 mg/dl) [73]. A total of 153 patients were assigned febuxostat (40, 80 or 120 mg) or placebo once daily for duration of 28 days. Each patient received colchicine for 14 days prior to and after randomization. Results showed clinically significant reduction in sUA to < 6 mg/dl in those patients treated with febuxostat on day 28 (56% taking 40 mg, 76% taking 80 mg and 94% taking 120 mg of febuxostat) when compared to placebo (0%) (p < 0.001 for each comparison). Gout flares were similar in frequency for the placebo (37%) and 40 mg febuxostat (35%) groups with increased frequency in the higher dosages of febuxostat (43% taking 80 mg; 55% taking 120 mg). During the period of colchicine prophylaxis, gout flares occurred less frequently (8 -- 13%). Incidence of treatment-related adverse events was similar in the febuxostat and placebo groups. Conclusions from this study indicate that febuxostat at 40, 80 and 120 mg at once daily dosing is both safe and efficacious for successfully lowering sUA levels. Similar results were found in the late Phase II study by Naoyuki et al. [75]. Ensuing long-term open-label extension studies further examined the safety and efficacy of febuxostat. Phase III trials focused on comparison of febuxostat and allopurinol for the treatment of gout and included the following studies: 1) Febuxostat versus Allopurinol Controlled Trial (FACT), 2) Allopurinol Placebo-Controlled Efficacy Study of Febuxostat (APEX) and 3) CONFIRMS trial followed by two long-term extension studies: i) FOCUS and ii) Febuxostat Comparative Extension Long-Term Study (EXCEL). A summary of the trials is provided in Table 4 and Figure 2. The FACT trial, a 52-week randomized trial, included 762 patients with sUA ‡ 8.0 mg/dl treated with either febuxostat (80 or 120 mg) or allopurinol (300 mg) once daily (Table 5) [36]. In addition, study patients were given naproxen or colchicine for the first 8 weeks of the study as prophylaxis against gout flares. The primary end point was an sUA concentration < 6 mg/dl at the last 3 monthly measurements. Secondary end points were reduction in the incidence of gout flares and tophus area. sUA < 6 mg/dl was achieved in 53% receiving febuxostat 80 mg, 62% receiving febuxostat 120 mg and 21% receiving allopurinol (p < 0.001 for each comparison group with allopurinol) showing that febuxostat at either 80 or 120 mg as a once daily dose was found to be more effective than allopurinol 300 mg in lowering sUA levels. The incidence of gout flares was similar in all groups (febuxostat 80 mg/febuxostat 120 mg/allopurinol -64/70/64%, respectively) with no statistical significance. There was no statistically significant difference in the reduction of tophus area among all groups. This study had a higher dropout rate in those treated with febuxostat 120 mg, and


751

H. K. Grewal et al.


Table 4. Significant Phase III and long-term extension trials evaluating febuxostat. Trial (year)

Duration of study

Flare prophylaxis

FACT 2005

52 weeks

Yes*

APEX 2008

28 weeks

Yes*

EXCEL 2009

160 weeks

Yes*

FOCUS 2009

5 years

Yesz

CONFIRMS 2010

24 weeks

Yes§

Primary end point(s)

sUA < 6 mg/dl at last 3 monthly measurements sUA < 6.0 mg/dl at last 3 monthly measurements

Proportion of patients with sUA < 6 mg/dl at each visit Achieve and maintain target sUA < 6.0 mg/dl sUA < 6.0 mg/dl at final visit

Secondary end point(s)

Reduction in i) incidence of gout flares; and ii) tophus area sUA < 6.0 mg/dl at each visit; % reduction in sUA from baseline at each visit; proportion of patients requiring treatment for gout flare between week 8 and 28; % reduction in tophi size and number % reduction from baseline sUA; proportion of patients with sUA decreasing to < 6.0 mg/dl; reduction in incidence of gout flares; % reduction in number and size of tophi % reduction from baseline sUA; proportion of patients with sUA < 5.0 and < 4.0 mg/dl; proportion of patients requiring treatment for gout flare Proportion of patients with mild-to-moderate renal impairment and final sUA < 6.0 mg/dl; proportion of patients with sUA < 6.0, < 6.0 and < 4.0 mg/dl at each visit

*Colchicine 0.6 mg per day or naproxen 250 mg BID during washout period if patients received prior urate-lowering therapy and for first 8 weeks of study for prophylaxis. z Colchicine 0.6 mg BID during initial 4 weeks. § Colchicine 0.6 mg/d or naproxen 250 mg BID during washout period and for duration of study; patients who received naproxen were also administered lansoprazole 15 mg/d. sUA: Serum urate.

10.00% 9.00% 8.00% 7.00% 6.00%

FACT

5.00%

APEX

4.00%

EXCEL

3.00%

CONFIRMS

2.00% 1.00% 0.00% Febuxostat Febuxostat Febuxostat Febuxostat Allopurinol 40 mg 80 mg 120 mg 240 mg

Placebo

Figure 2. Comparison of dropouts from clinical trials due to adverse drug reactions. Note: Focus trial results included dropouts (13 patients/11.2%) due to adverse events; however, they were not seperated by dosage of febuxostat.

there were four deaths in the febuxostat treatment groups due to other comorbidities unrelated to the use of febuxostat. The purpose of the 28-week multicenter APEX trial was to compare the safety and efficacy of febuxostat with allopurinol in both healthy patients and those with impaired renal 752

function. The study included 1072 patients with sUA > 8.0 mg/dl and patients with renal impairment [74]. The primary end point was the proportion of subjects with the last 3 monthly sUA at < 6 mg/dl. Patients were randomized to receive either febuxostat (80 or 120 or 240 mg)


Febuxostat

Table 5. Summary of findings of the Phase III FACT trial. Drug


Febuxostat Febuxostat Allopurinol

Dose

80 mg po q day 120 mg po q day 300 mg po q day

Percentage of patients meeting primary end point

Decrease in incidence of gout flares week 9 -- 52

Reduction in tophus area

53%* 62%* 21%*

64%z 70%z 64%z

83%§ 66%§ 50%§

*p < 0.001 for comparison of each febuxostat group with allopurinol group. z p = 0.99 for 80 mg of febuxostat versus allopurinol; p = 0.23 for 120 mg of febuxostat versus allopurinol. § p = 0.08 for 80 mg of febuxostat versus allopurinol; p = 0.16 for 120 mg of febuxostat versus allopurinol.

without adjustment for renal function, allopurinol with dosage adjustment for renal function, 300 mg with normal renal function (serum creatinine £ 1.5 mg/dl) and 100 mg with impaired renal function (serum creatinine > 1.5 to £ 2.0 mg/dl) or placebo daily. The analysis of patients treated with febuxostat showed that the primary end point was achieved in a higher percentage of patients compared to the other two arms of the study. For patients treated with febuxostat 80 or 120 or 240 mg, the percentage that achieved sUA < 6 mg/dl in the last 3 months (p £ 0.05) was 48, 65 and 69%, respectively, compared with allopurinol (22%) and placebo (0%). In those patients with impaired renal function, a significantly higher percentage of patients treated with febuxostat achieved the primary end point (80 mg 44%, 120 mg 45% and 240 mg 60%), whereas 0% of the allopurinol- and placebo-treated patients achieved this treatment goal. Distribution of adverse events was similar in all groups with the exception of dizziness and diarrhea, which were more common in the febuxostat 240 mg treatment group. In addition, a higher number of withdrawals occurred in the febuxostat group due to higher frequency of gout flares. In the CONFIRMS trial, a double-blinded randomized control study, 2269 patients were randomized to febuxostat (40 or 80 mg) or allopurinol (300 or 200 mg with renal impairment) once daily dosing [76]. The primary goal of the study was to compare the efficacy (achieving sUA < 6.0 mg/dl) and safety of both febuxostat and allopurinol in patients with sUA ‡ 8 mg/dl over a 6-month period with concomitant renal impairment (mild to moderate). In addition, the study examined the safety profile with special focus on cardiovascular events. Findings showed that with febuxostat 40 mg/febuxostat 80 mg/allopurinol, the percentage of patients who achieved primary end point was 45/67/42%, respectively. Febuxostat 80 mg was found to be superior to both allopurinol and febuxostat 40 mg (p < 0.001), whereas febuxostat 40 mg was found to be non-inferior to allopurinol. In addition, there was no statistical difference in regard to adverse events among all treatment groups. The achieved target sUA of < 6 mg/dl in patients with renal impairment was statistically significant with febuxostat 80 mg (72%; p < 0.001; febuxostat 40 mg 50%, allopurinol 42%). In addition, febuxostat 40 mg was found to have better efficacy than allopurinol (p = 0.021).

Overall the rate of adverse events did not vary greatly among the treatment groups. The trial utilized the AntiPlatelet Trialists’ Collaboration (APTC) end points to examine the safety profile. Cardiovascular event rates for febuxostat 40 mg/febuxostat 80 mg/allopurinol were 0.0/0.4/0.4%, respectively, with one death in each febuxostat group and three in the allopurinol group [76]. The open-labeled FOCUS trial, a 5-year extension study, examined the long-term safety of febuxostat and the efficacy [77]. The primary end point of the study was to achieve and maintain a target sUA < 6.0 mg/dl. In this extension study, 116 patients were enrolled and received an initial dose of febuxostat 80 mg daily, which at week 4 and 24 could be adjusted to febuxostat 40 or 120 mg. Of the enrolled patients, 44 (38%) required an adjustment of febuxostat dosing. Findings showed that at 5 years 93% of the enrolled patients reached sUA < 6.0 mg/dl. The study also included 26 patients with tophi of which 69% had resolution at the end of the study. It is important to note that 50% of the initial enrolled subjects discontinued the study prematurely of which 13 withdrew due to adverse events. The objective of the EXCEL trial was to determine the long-term urate-lowering effects of febuxostat and its safety compared against allopurinol [78]. This open-labeled extension study included 1086 patients over a 40-month period who were placed on febuxostat (80 or 120 mg) or allopurinol (300 mg) with dosage adjustments allowed during months 1 and 6. Goal uric acid was between 3 mg/dl and < 6 mg/dl. Results concluded that > 80% of patients receiving febuxostat and 46% of those receiving allopurinol achieved sUA < 6 mg/dl after 1 month. Maintaining sUA < 6.0 mg/dl resulted in resolution of baseline tophus in 46/36/29% of patients in the febuxostat 80 mg/febuxostat 120 mg/allopurinol 300 mg, respectively. Overall, the number of gout flares was also reduced and adverse events were not different in either treatment groups.

Post-marketing surveillance, safety and tolerability

4.1

The most common side effects reported with febuxostat use include nausea, diarrhea, arthralgia, headache, elevated liver function tests and rash. There were several deaths in the


753


H. K. Grewal et al.

clinical trials as outlined earlier; however, they were not attributed to the use of febuxostat. There have been post-marketing cases of hepatic failure associated with febuxostat including significant hepatic transaminitis (> 3x ULN) and increased serum total bilirubin (2x ULN) [38,79,80]. Recommendations are that liver function tests should be evaluated at baseline and at 2 and 4 months after initiation of therapy and periodically thereafter [81]. With mild-to-moderate hepatic impairment (Child--Pugh Class A or B), there is no dose adjustment needed [67,82]. There are no sufficient data available for severe hepatic impairment (Child--Pugh Class C); therefore, caution is recommended [67,78]. Notably Canadian labeling does not recommend the use of febuxostat in those with severe hepatic impairment [67,82]. Febuxostat is shown to be safe for use in patients with mild-to-moderate renal impairment (CrCl 30 -- 89 ml/min) without the need for dose adjustment. There are no sufficient data available for severe renal impairment (CrCl < 30 ml/min) or hemodialysis, and caution is advised when prescribing febuxostat. Canadian labeling recommends not using febuxostat in those patients with severe renal impairment [82,80]. It was shown in the study by Whelton et al. that with the use of febuxostat there is maintenance or even improvement in the glomerular filtration rate (GFR) with reduction of sUA; it is suggested that for every 1 mg/dl reduction in sUA, there is a correlating 1 ml/min improvement in GFR. Further studies need to be conducted to evaluate this finding [81,83]. Although initial concerns were raised in regard to risk of increased cardiovascular events with febuxostat use in studies where patients experienced adverse cardiovascular events, researchers concluded they were unrelated to febuxostat; cardiovascular events occurred in patients with history of atherosclerotic disease, previous myocardial infarction, baseline congestive heart failure and age older than 60 -- there was no association with HTN, stroke, DM or hyperlipidemia. Although there is an increased rate of myocardial infarction, stroke and cardiovascular death within febuxostat treatment groups when compared to allopurinol, any direct relationship has not been elucidated [1,79,82]. Subsequently, a Phase IIIB multicenter randomized active control trial is currently underway to compare cardiovascular risks with the use of febuxostat and allopurinol (Cardiovascular Safety of Febuxostat and Allopurinol in Patients With Gout and Cardiovascular Comorbidities [CARES]: NCT001101035). Clinical trials have also found that there is increased incidence of gout flares during the first 8 weeks after starting febuxostat [36,76]. Prophylactic therapy with colchicine and naproxen for a minimum of 8 weeks and up to 6 months has shown to be beneficial in reducing the number of gout flares [11,14,34,73,84]. Febuxostat is pregnancy category C; animal studies have shown increased neonatal mortality and reduction in weight gain. It is unclear whether febuxostat is safe to use with lactation, caution is advised and further studies are needed [60]. It is also suggested that dose adjustment is not needed for geriatric 754

patients; however, long-term and closer evaluation of this population is needed to have concrete evidence in this regard [60]. A retrospective analysis of a commonly encountered geriatric population with multiple comorbidities suggests febuxostat is both efficacious and well tolerated in this population [83]. Further prospective long-term data are needed to validate use in this group. 5.

Conclusion

Gout is a condition that can be particularly debilitating yet can be effectively treated. Febuxostat functions as a xanthine oxidase inhibitor that effectively decreases sUA without affecting total purine synthesis. The addition of febuxostat has provided clinicians with an efficacious and safe treatment tool for patients with gout. This is exemplified in the recent American College of Rheumatology (ACR) gout guidelines, which recommend that either allopurinol or febuxostat can be used as first-line therapy for gout [85,86]. 6.

Expert opinion

The need for safe and effective therapy for hyperuricemia with gout has been a long-term issue. Febuxostat has shown to be effective in the treatment of chronic hyperuricemia in patients with gout. Several trials, discussed throughout this paper, have shown the efficacy of febuxostat in reaching target sUA levels. Febuxostat has consistently proven effective in lowering sUA in up to 5 years of follow up, while significantly reducing the rate of flares. Efficacy and safety in the treatment of mild-to-moderate renal and hepatic impairment has been addressed with febuxostat, proving it to be a useful therapeutic agent and does not require dose adjustment. There continues to be a need for ongoing post-marketing surveillance to determine the long-term efficacy and safety with the use of febuxostat across all groups. Further data on select patient groups, such as those with severe renal and hepatic impairment and geriatric populations, need to be collected and examined. The clinical data on febuxostat however remain deficient in several key areas. Data still need to be collected to compare the use of febuxostat to higher doses of allopurinol (> 300 mg) to determine whether febuxostat has greater efficacy or is even equal to allopurinol. This issue is especially important due to the financial burden imposed on patients prescribed febuxostat that costs more than triple the generic allopurinol. Higher incidences of gout flares at initiation of febuxostat are also of concern. This requires patients to have longer prophylactic therapy (up to 8 weeks), which not only increases cost burden on patients but also raises concern for side effects that may develop. Also, studies showed a higher withdrawal rate in clinical studies due to increased gout flares, which are due to the tolerance and compliance with the medication.



Febuxostat

The major side effects of the use of febuxostat are greater incidence of elevated liver function tests, arthralgias, rash and nausea. Close monitoring of liver function tests with initiation of febuxostat is needed, and long-term examination of the effects of febuxostat on liver function needs to be gathered. Febuxostat has shown to be a safe alternative to allopurinol for the treatment of gout. Studies show that febuxostat can rapidly lower sUA and effectively treat gout. In addition, febuxostat has made headway for safe use in those patients intolerant to allopurinol. Therapies for gout are heading toward targeting small molecules and inflammatory cytokines that are of great Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

Edwards NL. Febuxostat: a new treatment for hyperuricaemia in gout. Rheumatology (Oxford) 2009;48(Suppl 2):ii15--19

2.

Ernst ME, Fravel MA. Febuxostat: a selective xanthine-oxidase/xanthinedehydrogenase inhibitor for the management of hyperuricemia in adults with gout. Clin Ther 2009;31(11):2503-18

3.

McCarty DJ. Crystals and arthritis. Dis Mon 1994;40(6):255-99

4.

Neogi T. Clinical practice. Gout. N Engl J Med 2011;364(5):443-52

5.

Nuki G, Simkin PA. A concise history of gout and hyperuricemia and their treatment. Arthritis Res Ther 2006;8(Suppl 1):S1

6.

Nuki G. Treatment of crystal arthropathy -- history and advances. Rheum Dis Clin North Am 2006;32(2):333-57; vi

7.

Richette P, Bardin T. Gout. Lancet 2010;375(9711):318-28

8.

McCarty DJ. A historical note: Leeuwenhoek’s description of crystals from a gouty tophus. Arthritis Rheum 1970;13:414-18

9.

10.

Becker MA, Jolly M. Hyperuricemia and associated diseases. Rheum Dis Clin North Am 2006;32(2):275-93; v-vi Choi HK, Mount DB, Reginato AM, American College of Physicians & American Physiological Society. Pathogenesis of gout. Ann Intern Med 2005;143(7):499-516

11.

12.

13.

interest. The advancement in treatment of gout and hyperuricemia has shown growth and success in the past few years. Ongoing research aimed to target specific pathogenic pathways is the future and has shown promise.

Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Shoji A, Yamanaka H, Kamatani N. A retrospective study of the relationship between serum urate level and recurrent attacks of gouty arthritis: evidence for reduction of recurrent gouty arthritis with antihyperuricemic therapy. Arthritis Rheum 2004;51(3):321-5

20.

Nakaya I, Namikoshi T, Tsuruta Y, Dialysis Physicians. Management of asymptomatic hyperuricaemia in patients with chronic kidney disease by Japanese nephrologists: a questionnaire survey. Nephrology (Carlton) 2011;16(5):518-21

21.

Ghaemi-Oskouie F, Shi Y. The role of uric acid as an endogenous danger signal in immunity and inflammation. Curr Rheumatol Rep 2011;13(2):160-6

22.

Martinon F, Petrilli V, Mayor A, et al. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006;440(7081):237-41

23.

Choi H. Epidemiology of crystal arthropathy. Rheum Dis Clin North Am 2006;32(2):255-73

24.

Chohan S, Becker MA. Update on emerging urate-lowering therapies. Curr Opin Rheumatol 2009;21(2):143-9

25.

Adams PF, Hendershot GE, Marano MA, Centers for Disease Control & Prevention/National Center for Health Statistics. Current estimates from the National Health Interview Survey, 1996. Vital Health Stat 1999;10(200):1-203

26.

Zhang Y, Woods R, Chaisson CE, et al. Alcohol consumption as a trigger of recurrent gout attacks. Am J Med 2006;119(9):800.e13-18

Weaver AL. Epidemiology of gout. Cleve Clin J Med 2008;75(Suppl 5):S9-12

27.

Rathmann W, Funkhouser E, Dyer AR, Roseman JM. Relations of hyperuricemia with the various components of the insulin resistance syndrome in young black and white adults: the

Kramer HM, Curhan G. The association between gout and nephrolithiasis: the National Health and Nutrition Examination Survey III, 1988-1994. Am J Kidney Dis 2002;40(1):37-42

28.

Lawrence RC, Felson DT, Helmick CG, et al.; National Arthritis Data Workgroup. Estimates of the prevalence

Firestein GS, Budd RC, Harris ED, et al. Kelley’s textbook of rheumatology. 9th edition. Saunders Elsevier, Waltham, MA, USA; 2013 Campion EW, Glynn RJ, DeLabry LO. Asymptomatic hyperuricemia. Risks and consequences in the Normative Aging Study. Am J Med 1987;82:421-6

14.

Schlesinger N. Management of acute and chronic gouty arthritis: present state-ofthe-art. Drugs 2004;64(21):2399-416

15.

Feig DI. Uric acid: a novel mediator and marker of risk in chronic kidney disease? Curr Opin Nephrol Hypertens 2009;18(6):526-30

16.

17.

18.

19.

CARDIA study. Coronary Artery Risk Development in Young Adults. Ann Epidemiol 1998;8(4):250-61

Choi HK. A prescription for lifestyle change in patients with hyperuricemia and gout. Curr Opin Rheumatol 2010;22(2):165-72 Choi HK, Ford ES, Li C, Curhan G. Prevalence of the metabolic syndrome in patients with gout: the Third National Health and Nutrition Examination Survey. Arthritis Rheum 2007;57(1):109-15


755

H. K. Grewal et al.

adherence to standards of care from a managed care perspective. Mayo Clin Proc 2006;81(7):925-34

of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum 2008;58(1):26-35


29.

Dehghan A, Kottgen A, Yang Q, et al. Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study. Lancet 2008;372(9654):1953-61

30.

Riches PL, Wright AF, Ralston SH. Recent insights into the pathogenesis of hyperuricaemia and gout. Hum Mol Genet 2009;18(R2):R177-84

31.

Emmerson BT, Nagel SL, Duffy DL, Martin NG. Genetic control of the renal clearance of urate: a study of twins. Ann Rheum Dis 1992;51(3):375-7

32.

Wilk JB, Djousse L, Borecki I, et al. Segregation analysis of serum uric acid in the NHLBI Family Heart Study. Hum Genet 2000;106(3):355-9

33.

Anderson A, Singh JA. Pegloticase for chronic gout. Cochrane Database Syst Rev 2010;(3):CD008335

34.

Zhang W, Doherty M, Bardin T, et al.; EULAR Standing Committee for International Clinical Studies Including Therapeutics. EULAR evidence based recommendations for gout. Part II: management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2006;65(10):1312-24

35.

36.

..

Jordan KM, Cameron JS, Snaith M, et al.; Audit Working Group. British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of gout. Rheumatology (Oxford) 2007;46(8):1372-4 Becker MA, Schumacher HR Jr, Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 2005;353(23):2450-61 Trial demonstrating febuxostat 80 or 120 mg is more effective in lowering serum urate than allopurinol 300 mg daily.

37.

Perez-Ruiz F, Alonso-Ruiz A, Calabozo M, et al. Efficacy of allopurinol and benzbromarone for the control of hyperuricaemia. A pathogenic approach to the treatment of primary chronic gout. Ann Rheum Dis 1998;57(9):545-9

38.

Sarawate CA, Brewer KK, Yang W, et al. Gout medication treatment patterns and

756

39.

Singh JA, Hodges JS, Asch SM. Opportunities for improving medication use and monitoring in gout. Ann Rheum Dis 2009;68(8):1265-70

40.

Dalbeth N, Stamp L. Allopurinol dosing in renal impairment: walking the tightrope between adequate urate lowering and adverse events. Semin Dial 2007;20(5):391-5

41.

Hande KR, Noone RM, Stone WJ. Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufficiency. Am J Med 1984;76(1):47-56 Literature review and case studies evaluating allopurinol toxicity with special focus on renal insufficiency.

.

42.

Riedel AA, Nelson M, Joseph-Ridge N, et al. Compliance with allopurinol therapy among managed care enrollees with gout: a retrospective analysis of administrative claims. J Rheumatol 2004;31(8):1575-81

43.

Wortmann RL. Gout and hyperuricemia. Curr Opin Rheumatol 2002;14(3):281-6

44.

Arellano F, Sacristan JA. Allopurinol hypersensitivity syndrome: a review. Ann Pharmacother 1993;27(3):337-43

45.

Reinders MK, Haagsma C, Jansen TL, et al. A randomised controlled trial on the efficacy and tolerability with dose escalation of allopurinol 300-600 mg/day versus benzbromarone 100-200 mg/day in patients with gout. Ann Rheum Dis 2009;68(6):892-7

.

anakinra in acute gout. Arthritis Res Ther 2007;9(2):R28 Open labeled pilot study evaluating IL-1 inhibition with anakinra as treatment option for gout for patients unable to take or have failed standard therapy.

51.

Mitha E, Schumacher HR, Fouche L, et al. Rilonacept for gout flare prevention during initiation of uric acid-lowering therapy: results from the PRESURGE-2 international, phase 3, randomized, placebo-controlled trial. Rheumatology (Oxford) 2013;52(7):1285-92

52.

Terkeltaub R, Sundy JS, Schumacher HR, et al. The interleukin 1 inhibitor rilonacept in treatment of chronic gouty arthritis: results of a placebo-controlled, monosequence crossover, non-randomised, single-blind pilot study. Ann Rheum Dis 2009;68(10):1613-17

53.

Chen K, Fields T, Mancuso CA, et al. Anakinra’s efficacy is variable in refractory gout: report of ten cases. Semin Arthritis Rheum 2010;40(3):210-14

54.

Schumacher HR Jr. Febuxostat: a non-purine, selective inhibitor of xanthine oxidase for the management of hyperuricaemia in patients with gout. Expert Opin Investig Drugs 2005;14(7):893-903

55.

Takano Y, Hase-Aoki K, Horiuchi H, et al. Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/ xanthine dehydrogenase. Life Sci 2005;76(16):1835-47

56.

Okamoto K, Eger BT, Nishino T, et al. An extremely potent inhibitor of xanthine oxidoreductase. Crystal structure of the enzyme-inhibitor complex and mechanism of inhibition. J Biol Chem 2003;278(3):1848-55 Preclinical study of febuxostat examining pharmacology and chemical structure of the compound.

46.

Terkeltaub R. Update on gout: new therapeutic strategies and options. Nat Rev Rheumatol 2010;6(1):30-8

47.

Gratton SB, Scalapino KJ, Fye KH. Case of anakinra as a steroid-sparing agent for gout inflammation. Arthritis Rheum 2009;61(9):1268-70

.

48.

Singh D, Huston KK. IL-1 inhibition with anakinra in a patient with refractory gout. J Clin Rheumatol 2009;15(7):366

57.

49.

McGonagle D, Tan AL, Shankaranarayana S, et al. Management of treatment resistant inflammation of acute on chronic tophaceous gout with anakinra. Ann Rheum Dis 2007;66(12):1683-4

Khosravan R, Kukulka MJ, Wu JT, et al. The effect of age and gender on pharmacokinetics, pharmacodynamics, and safety of febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase. J Clin Pharmacol 2008;48(9):1014-24

50.

So A, De Smedt T, Revaz S, Tschopp J. A pilot study of IL-1 inhibition by

58.

Mayer MD, Khosravan R, Vernillet L, et al. Pharmacokinetics and pharmacodynamics of febuxostat, a new


Febuxostat

.


59.

non-purine selective inhibitor of xanthine oxidase in subjects with renal impairment. Am J Ther 2005;12(1):22-34 Assessment of safety, pharmacokinetics and pharmacodynamics of febuxostat with normal and impaired renal function. Becker MA, Kisicki J, Khosravan R, et al. Febuxostat (TMX-67), a novel, non-purine, selective inhibitor of xanthine oxidase, is safe and decreases serum urate in healthy volunteers. Nucleosides Nucleotides Nucleic Acids 2004;23(8-9):1111-16

60.

Uloric Package insert. Takeda Pharmaceuticals America, Inc., Deerfield: Ill; 2009

61.

Bruce SP. Febuxostat: a selective xanthine oxidase inhibitor for the treatment of hyperuricemia and gout. Ann Pharmacother 2006;40:2187-94

62.

63.

64.

65.

66.

67.

Grabowski B, Khosravan R, Wu JT, et al. Effect of hydrochlorothiazide on the pharmacokinetics and pharmacodynamics of febuxostat, a nonpurine selective inhibitor of xanthine oxidase. Br J Clin Pharmacol 2010;70(1):57-64 Grabowski BA, Khosravan R, Vernillet L, Mulford DJ. Metabolism and excretion of [14C] febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase, in healthy male subjects. J Clin Pharmacol 2011;51(2):189-201 Osada Y, Tsuchimoto M, Fukushima H, et al. Hypouricemic effect of the novel xanthine oxidase inhibitor, TEI-6720, in rodents. Eur J Pharmacol 1993;241(2-3):183-8 Mukoyoshi M, Nishimura S, Hoshide S, et al. In vitro drug-drug interaction studies with febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase: plasma protein binding, identification of metabolic enzymes and cytochrome P450 inhibition. Xenobiotica 2008;38(5):496-510 Horiuchi H, Ota M, Kobayashi M, et al. A comparative study on the hypouricemic activity and potency in renal xanthine calculus formation of two xanthine oxidase/xanthine dehydrogenase inhibitors: TEI-6720 and allopurinol in rats. Res Commun Mol Pathol Pharmacol 1999;104(3):307-19

moderate hepatic impairment on pharmacokinetics, pharmacodynamics, and safety of febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase. J Clin Pharmacol 2006;46(1):88-102 Assessment of febuxostat 80 mg daily dosing safety, pharmacokinetics and pharmacodynamics in the presence of mild-to-moderate hepatic impairment.

.

..

75.

Naoyuki K, Shin F, Toshikazu H, et al. Placebo-controlled double-blind doseresponse study of the non-purine-selective xanthine oxidase inhibitor febuxostat (TMX-67) in patients with hyperuricemia (including gout patients) in Japan: late phase 2 clinical study. J Clin Rheumatol 2011;17(4 Suppl 2):S35-43

76.

Becker MA, Schumacher HR, Espinoza LR, et al. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther 2010;12(2):R63 Comparison of efficacy and safety of febuxostat 40 and 80 mg daily to allopurinol 200 and 300 mg with inclusion of patients with comorbidities.

68.

Khosravan R, Wu JT, Joseph-Ridge N, Vernillet L. Pharmacokinetic interactions of concomitant administration of febuxostat and NSAIDs. J Clin Pharmacol 2006;46(8):855-66

69.

Khosravan R, Mayer MD, Wu JT, et al. Effect of concomitant administration of febuxostat and colchicine on pharmacokinetics of febuxostat and colchicine at steady state. Arthritis Rheum 2005;52:S102-3

..

70.

Khosravan RP, Erdman KB, Vernillet LPP, et al. Effect of febuxostat on pharmacokinetics of desipramine, a CYP2D6 substrate, in healthy subjects. Clin Pharmacol Ther 2005;77:P43-3

77.

71.

Grabowski BA, Khosravan R, Wu JT, et al. Effect of hydrochlorothiazide on pharmacokinetics and pharmacodynamics of febuxostat. Arthritis Rheum 2005;52:S103-4

72.

Komoriya K, Osada Y, Hasegawa M, et al. Hypouricemic effect of allopurinol and the novel xanthine oxidase inhibitor TEI-6720 in chimpanzees. Eur J Pharmacol 1993;250(3):455-60

73.

..

74.

Becker MA, Schumacher HR Jr, Wortmann RL, et al. Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase: a twenty-eight-day, multicenter, phase II, randomized, double-blind, placebo-controlled, dose-response clinical trial examining safety and efficacy in patients with gout. Arthritis Rheum 2005;52(3):916-23 Double-blind placebo-controlled trial assessing safety and efficacy of febuxostat 40, 80 and 120 mg.

..

78.

..


Schumacher HR Jr, Becker MA, Lloyd E, et al. Febuxostat in the treatment of gout: 5-yr findings of the FOCUS efficacy and safety study. Rheumatology (Oxford) 2009;48(2):188-94 Five-year extension study assessing the clinical efficacy, safety and maintenance of sUA < 6.0 mg/dl. Becker MA, Schumacher HR, MacDonald PA, et al. Clinical efficacy and safety of successful long term urate lowering with febuxostat or allopurinol in subjects with gout. J Rheumatol 2009;36(6):1273-82 Long-term non-blinded extension study examining long-term efficacy and safety of febuxostat.

79.

Singh JA. Advances in gout: some answers, more questions. Arthritis Res Ther 2010;12(5):136

80.

Komoriya K, Hoshide S, Takeda K, et al. Pharmacokinetics and pharmacodynamics of febuxostat (TMX-67), a non-purine selective inhibitor of xanthine oxidase/xanthine dehydrogenase (NPSIXO) in patients with gout and/or hyperuricemia. Nucleosides Nucleotides Nucleic Acids 2004;23(8-9):1119-22

81.

Whelton A, Macdonald PA, Zhao L, et al. Renal function in gout: long-term

Schumacher HR Jr, Becker MA, Wortmann RL, et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind,

Khosravan R, Grabowski BA, Mayer MD, et al. The effect of mild and

parallel-group trial. Arthritis Rheum 2008;59(11):1540-8 Comparison of efficacy and safety of febuxostat, allopurinol and placebo with inclusion of renal impairment.

757

H. K. Grewal et al.

Rheumatology. American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken) 2012;64(10):1431-46 ACR gout guidelines.


treatment effects of febuxostat. J Clin Rheumatol 2011;17(1):7-13 82.

Jansen TL, Richette P, Perez-Ruiz F, et al. International position paper on febuxostat. Clin Rheumatol 2010;29(8):835-40

83.

Jackson RL, Hunt B, MacDonald PA. The efficacy and safety of febuxostat for urate lowering in gout patients >/=65 years of age. BMC Geriatr 2012;12:11

84.

85.

758

Wortmann RL, Macdonald PA, Hunt B, Jackson RL. Effect of prophylaxis on gout flares after the initiation of uratelowering therapy: analysis of data from three phase III trials. Clin Ther 2010;32(14):2386-97

..

86.

..

Khanna D, Khanna PP, Fitzgerald JD, et al. American College of Rheumatology guidelines for management of gout. Part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis. American College of Rheumatology. Arthritis Care Res (Hoboken) 2012;64(10):1447-61 ACR gout guidelines.

Khanna D, Fitzgerald JD, Khanna PP, et al. American College of


Affiliation

Harmanjot K Grewal†1 MD, Joseph R Martinez2 MD & Luis R Espinoza3 MD † Author for correspondence 1 Assistant Professor of Clinical Medicine, Louisiana State University - School of Medicine, Section of Rheumatology, New Orleans, LA, USA E-mail: [email protected] 2 First Year Fellow, Louisiana State University - School of Medicine, Section of Rheumatology, New Orleans, LA, USA 3 Chief, Professor of Medicine, Louisiana State University - School of Medicine, Section of Rheumatology, New Orleans, LA, USA

Interstitial granulomatous drug reaction due to febuxostat.

Febuxostat.

Guidelines review and update.

2015 new drug update.

Drug development update.

Teledermatology: A Review and Update.

Adrenocortical carcinoma: review and update.

Update and Review: Cystic Fibrosis.

Fibrosarcoma: a review and update.

Febuxostat-induced acute liver injury.

Update and Review: Supernumerary Marker Chromosomes.

Hypoxic Hepatitis: A Review and Clinical Update.

Antibody humanization methods - a review and update.

Gastric Hamartomatous Polyps-Review and Update.

Pulmonary nodule: a comprehensive review and update.

Eating disorders. A review and update.

Review and update: oncogenic osteomalacia-rickets.

Infant botulism: review and clinical update.

Menstrual synchrony : An update and review.

Idiopathic granulomatous mastitis: imaging update and review.

Giant coronary artery aneurysms: review and update.

Update and Review: Maternal Serum Screening.

Induction of labor: update and review.

Stroke genetics: a review and update.