1 Gout management: urate lowering therapy. 2 12 recommendations were produced on the basis of literature evidence and expert opinion Ability to improve

1

Gout management: urate lowering therapy

2

• 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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9

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12

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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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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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5

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


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


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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Further studies are required to determinethe target SUA for urate lowering treatment that ensures

crystal dissolution and eventual cure

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10

• 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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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



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


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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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)



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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


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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


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


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The FACT Study

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The APEX Study

* 100 mg in patients with serum creatinine 1.5-2.0 mg/dl


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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.

42

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.

43

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..

44

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

Documents

1 Gout management: urate lowering therapy. 2 12 recommendations were produced on the basis of literature evidence and expert opinion Ability to improve