1 gout management: urate lowering therapy. 2 12 recommendations were produced on the basis of...
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Gout management: urate lowering therapy
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• 12 recommendations were produced on the basis of literature evidence and expert opinion
• Ability to improve clinical practice
• Conceived in 2004-5
• The future research agenda included points to be examined further
• Update to be performed to include advances in knowledge and new drugs
Zhang W, et al. Ann Rheum Dis 2006;65:1312-1324
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EULAR recommendations 2006for the management of gout
Zhang W, et al. Ann Rheum Dis 2006;65:1312-1324.
7 Urate lowering therapy is indicated in patients with recurrent acute attacks, arthropathy, tophi,
or radiographic changes of gout.
The therapeutic goal of urate lowering therapy is to promote crystals dissolution and prevent crystal formation; this is achieved by maintaining the serum uric acid below the saturation point for monosodium urate (≤360 μmol/l).
Allopurinol is an appropriate long-term urate lowering drug; it should be started at a low dose (for example 100mg daily), and increased by 100mg every 2-4 weeks if required; the dose should be adjusted in patients with renal impairment;
if allopurinol toxicity occurs, options include other xanthine oxidase inhibitors, a uricosuric agent, or allopurinol desensitisation (the latter only in cases of mild rash).
Uricosuric agents such as probenecid and sulphinpyrazone can be used as an alternative to allopurinol in patients with normal renal function but are relatively contra-indicated in patients with urolithiasis; benzbromarone can be used in patients with mild to moderate renal insufficiency on a named patient basis but carries a small risk of hepatotoxicity.
Prophylaxis against acute attacks during the first months of urate lowering therapy can be achieved by colchicines (0.5 – 1mg daily) and/or an NSAID (with gastro-protection if indicated).
When gout associates with diuretic therapy, stop the diuretic if possible; for hypertension and hypelipidemia consider use of losartan and fenofibrate, respectively (both have modest uricosuric effects).
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Uric acid lowering therapy is indicated in gout patients with recurrent acute attacks, arthropathy, tophi or radiographic changes of gout.
Future research agenda
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Zhang W, et al. Ann Rheum Dis 2006;65:1312-1324.
The indications for initiating urate lowering treatment (for example, recurrent acute attacks, tophi,
polyarticular acute attacks, radiographic joint damage) need further evaluation.
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EULAR recommendations 2006for the management of gout
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Indications for urate-lowering therapy
• Based on risk/benefit ratio assessment
• Sparse research data to guide the decision as to when to start urate-lowering drug treatment
• Uniform agreement on this therapy in patients with severe established gout - as indicated, for example, by tophi, gouty arthropathy, radiographic changes of gout, multiple joint involvement, or associated uric acid nephrolithiasis
• Less agreement on this therapy in patients with less severe gout - for example, following clinical presentation with the first acute attack
• No agreement for patients with asymptomatic hyperuricaemia
Zhang W, et al. Ann Rheum Dis 2006;65:1301-11.Richette P, et al. Lancet 2010;375:318-328.
Terkeltaub R. Nature Rev Rheumatol 2010:6:30-38.
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Factors encouraging the use of ULT after a single attack of gout
• Presence of comorbidities
• Severe or complicated gout
• Impaired renal function
• Advanced age
• Particular benefit from prevention
• Risk associated with the treatment of acute attacks
• Patient’s wishes
Zhang W, et al. Ann Rheum Dis 2006;65:1301-1311.Richette P, et al. Lancet 2010;375:318-328.
Terkeltaub R. Nature Rev Rheumatol 2010:6:30-38.
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Urate-lowering agents currently available in most European countries
DrugDaily dose (standard)
Pharmacological characteristicsrelevant to clinical use
Uric acid synthesis inhibitors: xanthine oxidase inhibitors
Allopurinol 100-900 mg (300 mg)
Dosage adjustment to renal function Multiple drug interactions
Hypersensitivity syndrome in 0.1-0.4% of patients, sometimes life-threatening
Febuxostat 80-120 mg (80 mg)
No dosage adjustment is necessary in patients with mild or moderate renal impairment. The efficacy and safety have not been fully evaluated in patients with severe renal impairment
(creatinine clearance <30 ml/min)
Uricosuric agents
Benzbromarone 50-200 mg (100 mg)Poor efficacy in severe renal function impairment;
increases the risk of urolithiasis in acid urine; possible hepatotoxic effects
Probenecid 50-2000 mg (1000 mg)Multiple drug interactions
Poor efficacy in moderate-severe renal function; increases the risk of urolithiasis in acid urine
Sulphinpyrazone 200-400 mg (200 mg)Avoid in hypersensitivity to NSAIDs
Poor efficacy in moderate-severe renal function; increases the risk of urolithiasis in acid urine
Zhang W, et al. Ann Rheum Dis 2006;65:1301-1311. Richette P, et al. Lancet 2010;375:318-328. Perez-Ruiz F. Rheumatology 2009;48:ii9-ii14.
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Objectives of urate lowering therapy
The goal of treatment is to cure the patient by lowering the sUAenough to dissolve urate crystals and prevent further crystal formation and thus:
• prevent acute gout attacks
• resolve tophi and prevent further tophus formation
• prevent joint damage
Dissolution of urate crystal deposition from a tophus
Zhang W, et al. Ann Rheum Dis 2006;65:1312-1324.
By kind permission of L. Punzi, Rheumatology Unit, University of Padua
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The therapeutic goal of urate-lowering therapy is to promote crystal dissolution and prevent crystal formation. This is achieved by maintaining the serum uric acid below the saturation point for monosodium urate (≤360 mol/L or ≤6 mg/dl)
Future research agenda
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Zhang W, et al. Ann Rheum Dis 2006;65:1312-1324.
Further studies are required to determinethe target SUA for urate lowering treatment that ensures
crystal dissolution and eventual cure
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EULAR recommendations 2006for the management of gout
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• EULAR guidelines advocate maintaining sUA <6 mg/dl1
(<360 μmol/l)
– “The therapeutic goal of urate lowering therapy is to promote crystal dissolution and prevent crystal formation. This is achieved by maintaining the serum uric acid below the saturation point for monosodium urate (6 mg/dl or 360 μmmol/l)”
– sUA is presumed to be an indicator of levels in the joint
• BSR (UK) guidelines advocate maintaining sUA 5 mg/dl2
(<300 μmol/l)
1. Zhang W, et al. Ann Rheum Dis 2006;65:1312-1324.2. Jordan KM, et al. Rheumatol (Oxford) 2007;46(8):1372-1374
.
Treat to target
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Allopurinol is an appropriate long-term urate-lowering therapy. It should be started at a low dose (e.g. 100 mg daily) and increased by 100 mg every 2-4 weeks
if required. The dose must be adjusted in patients with renal impairment.
If allopurinol toxicity occurs, options include other xanthine oxidase inhibitors, a uricosuric agent or allopurinol desensitisation (the latter only in cases of mild rash)
Allopurinol
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Zhang W, et al. Ann Rheum Dis 2006;65:1312-1324.
EULAR recommendations 2006for the management of gout
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OxypurinolTerkeltaub R. Nature Rev Rheumatol 2010:6:30-38.
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9Allopurinol is an appropriate long-term urate-lowering therapy. It should be started at a low dose (e.g. 100 mg daily) and increased by 100 mg every 2-4 weeks if required.
The dose must be adjusted in patients with renal impairment.
If allopurinol toxicity occurs, options include other xanthine oxidase inhibitors, a uricosuric agent or allopurinol desensitisation (the latter only in cases of mild rash).
Steven-Johnson syndrome Erythema multiforme
Zhang W, et al. Ann Rheum Dis 2006;65:1312-1324.
EULAR recommendations 2006for the management of gout
By kind permission of L. Punzi,Rheumatology Unit, University of Padua
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2012 American College of RheumatologyGuidelines for Management of Gout
Significance & innovations (I)
Khanna D, et al. Arthritis Care & Research 2012;64,(10):1431-46.
“The starting dosage of allopurinol should be no greater than 100 mg/day and less than that in moderate to severe
chronic kidney disease (CKD), followed by gradual upward titration of the maintenance dose, which can
exceed 300 mg daily even in patients with CKD”
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Allopurinol safety
• Hypersensitivity reactions (2-4%)– Skin (mild to severe; fatal)– Fever, hepatitis, nephritis, hematologic– AHS (allopurinol hypersensitivity syndrome)– Mechanism: type IV ?
• Non-immunologic toxicity– renal, liver – animal toxicity: renal, liver, cardiac
• Unclear whether hypersensitivity related to allopurinol, oxypurinol or other metabolite
Zhang W, et al. Ann Rheum Dis 2006;65:1301-1311.Richette P, et al. Lancet 2010;375:318-328.
Perez-Ruiz F. Rheumatology 2009;48:ii9-ii14.
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Future research agenda for gout management
Zhang W, et al. Ann Rheum Dis 2006;65:1312-1324
Direct comparison (efficacy, side effects, cost utility) between allopurinol and alternative urate lowering
treatments are needed.
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EULAR recommendations 2006for the management of gout
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2012 American College of RheumatologyGuidelines for Management of Gout
Significance & innovations (II)
Khanna D, et al. Arthritis Care & Research 2012; 64,(10):1431-46.
“Xanthine oxidase inhibitor (XOI) therapywith either allopurinol or febuxostat is recommended
as the first-line pharmacologic urate-loweringtherapy (ULT) approach in gout.”
(Evidence Level A)
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Febuxostat: pharmacodynamics
• Non purine compound
• Selective Inhibitor of Xanthine Oxidase (SIXO)– Inhibits both (oxidized and reduced) forms of XO– Intense, dose-dependent linear reduction of serum urate
NC
S
N
CO2H
CH3
O
CH3
H3C
Febuxostat
Khosravan Clin Pharmacokinet 2006;45:821-841.
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Febuxostat: pharmacokinetics
• Bioavailability> 80% PO, Tmax: 1.0-1.5 hour, t1/2: 5-8 hours
Not influenced by food or antiacids
• MetabolismIn the liver, excretion mainly as inactive metabolites
By the kidneys and through the bile
• No clinically relevant interactions withThiazides
Warfarin
NSAIDs
Colchicine
• No clinically relevant PK changes inMild-to-moderate renal function impairment
Mild-to-moderate liver function impairment
SmPC febuxostat.
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Febuxostat: clinical trial overview
Becker MA. Arthritis Rheum 2005;52:916-923.Becker MA. N Engl J Med 2005;353:2450-2461.
Schumacher HR. Arthritis Rheum 2008;59:1540-1548.Schumacher HR. Rheumatol 2009;48:188-194.Becker MA. J Rheumatol 2009;36:1273-1282.
Becker MA. Arthrits Res Ther 2010;12:R63.
Phase II studies
Study 004153 patients
FACT760 patients
1 year
APEX1,072 patients
6 months
CONFIRMS2,269 patients
6 months
Phase III studies
FOCUSOpen-label extension study
116 patients5 years
EXCELOpen-label extension study
1,086 patients3 years
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Becker MA, et al. Arthritis Rheum 2005;52:916-923.
Febuxostat - clinical efficacy in phase II RCTPercentage of patients reaching sUA targets at day 28
56%
21%
Placebo 40 mg/day
% o
f p
atie
nts
0
10
20
30
40
50
60
70
80
100
80 mg/day 120 mg/day
0%
76%
49%
19%
94%88%
56%
<6 mg/dl (360 mcmol/l)
<5 mg/dl (300 mcmol/l)
<4 mg/dl (240 mcmol/l)
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Febuxostat - phase III studies: patients’ demographics
• Mostly male (94%)
• Average of ≥10 years with history of gout
• 63%: overweight to obese (BMI>30 Kg/m2)
• 50%: history of arterial hypertension
• 38%: history of hyperlipidaemia
• 23%: tophus at baseline
• Mean sUA at baseline: 9.97 mg/dl (600 μmol/l)
Schumacher HR. Arthritis Rheum 2008;59:1540-1548.Becker MA. N Engl J Med 2005;353:2450-2461.
Becker MA. Arthrits Res Ther 2010;12:R63.
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Becker MA, et al. N Engl J Med 2005;353:2450-61.Beara-Lasic L, et al. Int J Nephrol Renovasc Dis 2010;3:1-10.
The FACT Study
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The APEX Study
* 100 mg in patients with serum creatinine 1.5-2.0 mg/dl
Becker MA, et al. N Engl J Med 2005;353:2450-61.Beara-Lasic L, et al. Int J Nephrol Renovasc Dis 2010;3:1-10.
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Percentage of patients reaching serum urate < 6 mg/dl (360 µmol/l)ITT analysis, at last visit
Febuxostat - clinical efficacy in phase III studies
*40 mg/day not registered in EU**145/757 patients in the CONFIRMS on 200 mg/day**10/263 patients in the APEX trial on 100 mg/day
.Schumacher HR. Arthritis Rheum 2008;59:1540-1548.
Becker MA. N Engl J Med 2005;353:2450-2461.Becker MA. Arthrits Res Ther 2010;12:R63.
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EXCEL study: switch dataPatients switching due to
sUA >6.0 mg/dl (>360 μmol/l)
– Febuxostat 80 mg to febuxostat 120 mg: 22% (141/649)
– Febuxostat 120 mg to allopurinol 300 mg:8% (22/292)
– Allopurinol to febuxostat80 mg: 57% (82/145)
17%
64%
Febuxostat to allopurinol
Allopurinolto febuxostat
% o
f p
atie
nts
(n=4/24) (n=50/78)
0
10
20
30
40
50
60
70
80
Patients who reached 6.0 mg/dl(<360 μmol/l) after switching
Becker MA, et al. J Rheumatol 2009;36:1273-1282.
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Febuxostat is effective in patients with renal impairmentAPEX study (6 months):
proportion of renal impaired (1.5–2 serum creatinine [>133–177 mol/l]) subjects with last 3 sUA levels 6.0 mg/dl (<360 μmol/l)
ITT population: subjects with serum urate level 8.0 mg/dl on day -2Schumacher HR, et al. Arthritis Rheum 2008;59:1540-1548.
0%
46%44%
0%
Placebo Febuxostat 80 mg
(n=9)
Febuxostat 120 mg
(n=11)
Allopurinol 100 mg
(n=10)
% o
f p
atie
nts
(n=5)
* *
0
10
20
30
40
50
*p0.05 all febuxostat doses vs allopurinol and placebo
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Greater reduction in tophussize with lower sUA
FACT study (1 year):% change from baseline in primary tophus size at week 52
Data for ALL patients, drawn from Becker MA, et al. N Engl J Med 2005;353:2450-2461.
-45% -49% -50%
-85% -84%-80%
-60%
-40%
-20%
0%7 6-7 5-6 4-5 <4
Post-baseline
sUA (mg/dl)
-100
-80
-60
-40
-20
0
(n=15)(n=17)
(n=18) (n=13)
(n=22)
% c
han
ge
in t
op
hu
s si
ze
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Febuxostat - patients requiring treatment for a flare
Schumacher HR, et al. Rheumatology 2009;48:188-194.
FOCUS study (5 years):percentage of subjects requiring treatment for flares while receiving
maintenance treatment
‘N’ represents the total number of subjects on a final stable dose of febuxostat for the duration designated and ‘n’ is the total number of subjects that reported at least one gout flare that required treatment in the given time interval.
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Characteristics of patients in the post-hoc analysis of renal function during febuxostat treatment
Whelton A, et al. Postgrad Med 2013;125:106-14.
Variable All SubjectsN = 551
Male, n (%) 528 (95.8) Race, n (%) - Caucasian 437 (79.3)
Age, y, mean ± SD 51.3 ± 11.59 BMI- ≥ 30 kg/m2, n (%) 357 (64.8) - Mean, kg/m2 ± SD 32.7 ± 5.84 - Alcohol use, n (%) 361 (65.5)
Years with gout, mean ± SD 11.0 ± 9.04
Tophi present, n (%) 100 (18.1)
SUA level, mg/dL, mean ± SD 9.8 ± 1.26
Medical history, n (%) - Cardiovascular disease 59 (10.7) - Diabetes 32 (5.8) - Hypertension 236 (42.8)
Abbreviations: BMI = body mass indexSD = standard deviationSUA = serum uric acid
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Change in renal function over time in relation to change in serum uric acid levels
Whelton A, et al. Postgrad Med 2013;125:106-14.
32Whelton A, et al. Postgrad Med 2013;125:106-14.
Febuxostat preserved renal function
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Possible mechanisms of renal function preservation with febuxostat
• Inhibition of the deleterious effects of up-regulated xanthine oxidase in the vasculature
• Lowering blood pressure in the renal vasculature
• Progressive mobilisation of monosodium urate microdeposits from renal tissues
Whelton A, et al. Postgrad Med 2013;125:106-14.
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Becker MA, et al. N Engl J Med 2005;353:2450-61.Beara-Lasic L, et al. Int J Nephrol Renovasc Dis 2010;3:1-10.
The FACT Study
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The APEX Study
* 100 mg in patients with serum creatinine 1.5-2.0 mg/dl
Becker MA, et al. N Engl J Med 2005;353:2450-61.Beara-Lasic L, et al. Int J Nephrol Renovasc Dis 2010;3:1-10.
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EXCEL study (3 years): patients requiring treatment for gout flare
Febuxostat - fewer patients require treatment for gout flare over time
All patients receiving allopurinol without reaching the sUA target level were switched to
febuxostat. Becker MA, et al. J Rheumatol 2009;36:1273-1282.
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Percentage of patients with serious adverse events (SAE)
Febuxostat - overall safety in phase III studies
*145/757 patients in the CONFIRMS on 200 mg/day*10/263 patients in the APEX trial on 100 mg/day
.Schumacher HR. Arthritis Rheum 2008;59:1540-1548.
Becker MA. N Engl J Med 2005;353:2450-2461.Becker MA. Arthrits Res Ther 2010;12:R63.
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Main clinical differences between febuxostat and allopurinol
Febuxostat Allopurinol
Chemical structure and activity
Non-purine, selective inhibitor of xanthine oxidase
Purine, non-selective inhibitor of xanthine oxidase
EfficacyEffective at achieving <6 mg/dl (<360 μmol/l)
Minimally effective at decreasing sUA
<6 mg/dl (<360 μmol/l) at usual dose (<300 mg)
ExcretionExcreted in the faeces
and in the urinePrimarily eliminated through
the kidney
DosingEffective at the
lowest dose (80 mg)Needs to be uptitrated
(from 100 mg)
Dosing in renal insufficiency
No dosage adj. required in mild to moderate renal insufficiency
Dosage adjustment required
Dosing in elderly patients
Well tolerated at standard doses Dosage adjustment required
SmPC: allopruinol, febuxostat. Schumacher HR. Arthritis Rheum 2008;59:1540-1548. Becker MA. N Engl J Med 2005;353:2450-
2461.
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Advantages of febuxostat from the patient’s prespective
Beara-Lasic L, et al. Int J Nephrol Renovasc Dis 2010;3:1-10.
• Dosing is always once a day• Dosing simplified by the fact that only two dose levels are
available• Typically achieves target serum urate levels more rapidly than
allopurinol• More effective than usual doses of allopurinol in lowering serum
uric acid levels• No dose adjustments necessary for mild to moderate renal
impairment • No dose adjustments necessary on the basis of age or gender • The recommended dose in patients with mild hepatic impairment
is 80 mg• Appears to be a better agent for reducing tophi• An alternative to allopurinol for patients with allopurinol
hypersensitivity
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Clinical applicability of febuxostat
• Intolerance to other ULT
• Severe urate deposition– Target urate < 4-5 mg/dl
– Target urate 240-300 μmol/l
• High baseline serum urate
• Renal function impairment– Moderate (uricosurics)
– Difficult adjustment of doses (allopurinol)
Perez-Ruiz F, Future Rheumatology 2008;3(5):421-427.
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Febuxostat - clinical management (I)
• No dose adjustment needed– Elderly
– Mild to moderate renal function impairment
– Mild to moderate liver function impairment
• No dose adjustment needed while on– Colchicine, indomethacin, naproxen
– Warfarin
– Hydrochlorothiazide
– CYP 2D6 substrates
SmPC febuxostat.
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Febuxostat - clinical management (II)
• Doses registered: 80 and 120 mg PO qd
• Initial dose: 80 mg/day
• Maximum dose: 120 mg/day
• Efficacy– Evaluable already after 2-4 week’s exposure to 80 mg qd
– Increase to 120 mg if target (<6 mg/dl) sUA not achieved
• Safety– Prophylaxis to avoid flares >6 months
– Liver function tests
– Moderate ethanol intake
SmPC febuxostat.
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Febuxostat - special precautions
Febuxostat is not recommended in:• Patients with ischaemic heart disease or congestive heart
failure
• Patients being treated with mercaptopurine or azathioprine
• Patients with severe renal function impairment (no experience)
• Patients with severe liver impairment (no experience)
Caution is required when febuxostat is used in:• Patients being treated with theophylline
• Patients with thyroid disorders
SmPC febuxostat..
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Febuxostat is a non-purine inhibitor of xanthine oxidase (XO)– selective inhibition of both isoforms of XO
The urate-lowering effect of febuxostat 80 mg/day is greater than that of allopurinol 300 mg/day
Target serum urate on ULT not achieved in a significant proportion of patients on allopurinol 300 mg/day
Febuxostat is overall well tolerated and comparable in tolerability to allopurinol
Febuxostat may become an interesting choice for the treatment of hyperuricaemia of gout
Treatment with febuxostat in patients with ischaemic heart disease or congestive heart failure is not recommended
Perez-Ruiz F. Future Rheumatol 2006;3:421-7, Becker MA. N Engl J Med 2005;353:2450-61,Schumacher HR. Arthritis Rheum 2008;59:1540-8, Becker MA. Arthrits Res Ther 2010;12:R63.
SmPC febuxostat.
Febuxostat - summary