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 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:

3 EULAR recommendations 2006 for the management of gout Zhang W, et al. Ann Rheum Dis 2006;65: 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)

4 Uric acid lowering therapy is indicated in gout patients with recurrent acute attacks, arthropathy, tophi or radiographic changes of gout. Future research agenda 7 Zhang W, et al. Ann Rheum Dis 2006;65: The indications for initiating urate lowering treatment (for example, recurrent acute attacks, tophi, polyarticular acute attacks, radiographic joint damage) need further evaluation. 7 EULAR recommendations 2006 for the management of gout

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: Richette P, et al. Lancet 2010;375: Terkeltaub R. Nature Rev Rheumatol 2010:6:30-38.

6 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: Richette P, et al. Lancet 2010;375: Terkeltaub R. Nature Rev Rheumatol 2010:6:30-38.

7 Urate-lowering agents currently available in most European countries Drug Daily dose (standard) Pharmacological characteristics relevant to clinical use Uric acid synthesis inhibitors: xanthine oxidase inhibitors Allopurinol mg (300 mg) Dosage adjustment to renal function Multiple drug interactions Hypersensitivity syndrome in % of patients, sometimes life-threatening Febuxostat 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 mg (100 mg) Poor efficacy in severe renal function impairment; increases the risk of urolithiasis in acid urine; possible hepatotoxic effects Probenecid mg (1000 mg) Multiple drug interactions Poor efficacy in moderate-severe renal function; increases the risk of urolithiasis in acid urine Sulphinpyrazone 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: Richette P, et al. Lancet 2010;375: Perez-Ruiz F. Rheumatology 2009;48:ii9-ii14.

8 Objectives of urate lowering therapy The goal of treatment is to cure the patient by lowering the sUA enough 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: By kind permission of L. Punzi, Rheumatology Unit, University of Padua

9 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 8 Zhang W, et al. Ann Rheum Dis 2006;65: Further studies are required to determine the target SUA for urate lowering treatment that ensures crystal dissolution and eventual cure 3 EULAR recommendations 2006 for the management of gout

10 EULAR guidelines advocate maintaining sUA <6 mg/dl 1 (<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/dl 2 (<300 μmol/l) 1. Zhang W, et al. Ann Rheum Dis 2006;65: Jordan KM, et al. Rheumatol (Oxford) 2007;46(8): Treat to target

11 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 9 Zhang W, et al. Ann Rheum Dis 2006;65: EULAR recommendations 2006 for the management of gout

12 Oxypurinol Terkeltaub R. Nature Rev Rheumatol 2010:6:30-38.

13 9 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). Steven-Johnson syndrome Erythema multiforme Zhang W, et al. Ann Rheum Dis 2006;65: EULAR recommendations 2006 for the management of gout By kind permission of L. Punzi,Rheumatology Unit, University of Padua

American College of Rheumatology Guidelines for Management of Gout Significance & innovations (I) Khanna D, et al. Arthritis Care & Research 2012;64,(10): “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”

15 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: Richette P, et al. Lancet 2010;375: Perez-Ruiz F. Rheumatology 2009;48:ii9-ii14.

16 Future research agenda for gout management Zhang W, et al. Ann Rheum Dis 2006;65: Direct comparison (efficacy, side effects, cost utility) between allopurinol and alternative urate lowering treatments are needed. 4 EULAR recommendations 2006 for the management of gout

American College of Rheumatology Guidelines for Management of Gout Significance & innovations (II) Khanna D, et al. Arthritis Care & Research 2012; 64,(10): “Xanthine oxidase inhibitor (XOI) therapy with either allopurinol or febuxostat is recommended as the first-line pharmacologic urate-lowering therapy (ULT) approach in gout.” (Evidence Level A)

18 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 CO 2 H CH 3 O H3CH3C Febuxostat Khosravan Clin Pharmacokinet 2006;45:

19 Febuxostat: pharmacokinetics Bioavailability > 80% PO, T max : hour, t 1/2 : 5-8 hours Not influenced by food or antiacids Metabolism In the liver, excretion mainly as inactive metabolites By the kidneys and through the bile No clinically relevant interactions with Thiazides Warfarin NSAIDs Colchicine No clinically relevant PK changes in Mild-to-moderate renal function impairment Mild-to-moderate liver function impairment SmPC febuxostat.

20 Febuxostat: clinical trial overview Becker MA. Arthritis Rheum 2005;52: Becker MA. N Engl J Med 2005;353: Schumacher HR. Arthritis Rheum 2008;59: Schumacher HR. Rheumatol 2009;48: Becker MA. J Rheumatol 2009;36: Becker MA. Arthrits Res Ther 2010;12:R63. Phase II studies Study patients FACT 760 patients 1 year APEX 1,072 patients 6 months CONFIRMS 2,269 patients 6 months Phase III studies FOCUS Open-label extension study 116 patients 5 years EXCEL Open-label extension study 1,086 patients 3 years

21 Becker MA, et al. Arthritis Rheum 2005;52: Febuxostat - clinical efficacy in phase II RCT Percentage of patients reaching sUA targets at day 28 56% 21% Placebo40 mg/day % of patients mg/day120 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)

22 Febuxostat - phase III studies: patients’ demographics Mostly male (94%) Average of ≥10 years with history of gout 63%: overweight to obese (BMI>30 Kg/m 2 ) 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: Becker MA. N Engl J Med 2005;353: Becker MA. Arthrits Res Ther 2010;12:R63.

23 Becker MA, et al. N Engl J Med 2005;353: Beara-Lasic L, et al. Int J Nephrol Renovasc Dis 2010;3:1-10. The FACT Study Cod. MCI

24 The APEX Study * 100 mg in patients with serum creatinine mg/dl Becker MA, et al. N Engl J Med 2005;353: Beara-Lasic L, et al. Int J Nephrol Renovasc Dis 2010;3:1-10. Cod. MCI

25 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: Becker MA. N Engl J Med 2005;353: Becker MA. Arthrits Res Ther 2010;12:R63.

26 EXCEL study: switch data Patients 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 febuxostat 80 mg: 57% (82/145) 17% 64% Febuxostat to allopurinol Allopurinol to febuxostat % of patients (n=4/24)(n=50/78) Patients who reached  6.0 mg/dl (<360 μmol/l) after switching Becker MA, et al. J Rheumatol 2009;36:

27 Febuxostat is effective in patients with renal impairment APEX 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 -2 Schumacher HR, et al. Arthritis Rheum 2008;59: % 46% 44% 0% PlaceboFebuxostat 80 mg (n=9) Febuxostat 120 mg (n=11) Allopurinol 100 mg (n=10) % of patients (n=5) * * *p  0.05 all febuxostat doses vs allopurinol and placebo

28 Greater reduction in tophus size 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: % -49% -50% -85%-84% -80% -60% -40% -20% 0% 776-76-75-65-64-54-5 <4 Post-baseline sUA (mg/dl) (n=15) (n=17) (n=18) (n=13) (n=22) % change in tophus size

29 Febuxostat - patients requiring treatment for a flare Schumacher HR, et al. Rheumatology 2009;48: 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.

30 Characteristics of patients in the post-hoc analysis of renal function during febuxostat treatment Whelton A, et al. Postgrad Med 2013;125: Variable All Subjects N = 551 Male, n (%) 528 (95.8) Race, n (%) - Caucasian 437 (79.3) Age, y, mean ± SD51.3 ± BMI - ≥ 30 kg/m 2, n (%) 357 (64.8) - Mean, kg/m 2 ± SD 32.7 ± 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 ± SD9.8 ± 1.26 Medical history, n (%) - Cardiovascular disease59 (10.7) - Diabetes32 (5.8) - Hypertension236 (42.8) Abbreviations: BMI = body mass index SD = standard deviation SUA = serum uric acid Cod. MCI

31 Change in renal function over time in relation to change in serum uric acid levels Whelton A, et al. Postgrad Med 2013;125: Cod. MCI

32 Whelton A, et al. Postgrad Med 2013;125: Febuxostat preserved renal function Cod. MCI

33 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: Cod. MCI

34 Becker MA, et al. N Engl J Med 2005;353: Beara-Lasic L, et al. Int J Nephrol Renovasc Dis 2010;3:1-10. The FACT Study Cod. MCI

35 The APEX Study * 100 mg in patients with serum creatinine mg/dl Becker MA, et al. N Engl J Med 2005;353: Beara-Lasic L, et al. Int J Nephrol Renovasc Dis 2010;3:1-10. Cod. MCI

36 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:

37 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: Becker MA. N Engl J Med 2005;353: Becker MA. Arthrits Res Ther 2010;12:R63.

38 Main clinical differences between febuxostat and allopurinol FebuxostatAllopurinol Chemical structure and activity Non-purine, selective inhibitor of xanthine oxidase Purine, non-selective inhibitor of xanthine oxidase Efficacy Effective at achieving <6 mg/dl (<360 μmol/l) Minimally effective at decreasing sUA <6 mg/dl (<360 μmol/l) at usual dose (<300 mg) Excretion Excreted in the faeces and in the urine Primarily eliminated through the kidney Dosing Effective 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 dosesDosage adjustment required SmPC: allopruinol, febuxostat. Schumacher HR. Arthritis Rheum 2008;59: Becker MA. N Engl J Med 2005;353:

39 Advantages of febuxostat from the patient’s prespective Beara-Lasic L, et al. Int J Nephrol Renovasc Dis 2010;3:1-10. Cod. MCI 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

40 Clinical applicability of febuxostat Intolerance to other ULT Severe urate deposition –Target urate < 4-5 mg/dl –Target urate μmol/l High baseline serum urate Renal function impairment –Moderate (uricosurics) –Difficult adjustment of doses (allopurinol) Perez-Ruiz F, Future Rheumatology 2008;3(5):

41 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: , Schumacher HR. Arthritis Rheum 2008;59:1540-8, Becker MA. Arthrits Res Ther 2010;12:R63. SmPC febuxostat. Febuxostat - summary