Transcript of patients

Gout management:
urate lowering therapy
1
• 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
2
Zhang W, et al. Ann Rheum Dis 2006;65:1312-1324
EULAR recommendations 2006
for the management of gout
7
Urate lowering therapy is indicated in patients with recurrent acute attacks, arthropathy, tophi,
or radiographic changes of gout.
8
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).
9
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).
10
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.
11
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).
12
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).
3
Zhang W, et al. Ann Rheum Dis 2006;65:1312-1324.
EULAR recommendations 2006
for the management of gout
7
Uric acid lowering therapy is indicated in gout patients with recurrent acute attacks, arthropathy,
tophi or radiographic changes of gout.
Future research agenda
7
The indications for initiating urate lowering treatment
(for example, recurrent acute attacks, tophi,
polyarticular acute attacks, radiographic joint damage)
need further evaluation.
Zhang W, et al. Ann Rheum Dis 2006;65:1312-1324.
4
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.
5
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.
6
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
Febuxostat
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
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)
50-200 mg (100 mg)
Poor efficacy in severe renal function impairment;
increases the risk of urolithiasis in acid urine;
possible hepatotoxic effects
50-2000 mg (1000 mg)
Multiple drug interactions
Poor efficacy in moderate-severe renal function;
increases the risk of urolithiasis in acid urine
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
Uricosuric agents
Benzbromarone
Probenecid
Sulphinpyrazone
7
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.
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
By kind permission of L. Punzi, Rheumatology Unit,
University of Padua
8
Dissolution of urate crystal deposition
from a tophus
Zhang W, et al. Ann Rheum Dis 2006;65:1312-1324.
EULAR recommendations 2006
for the management of gout
8
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 mmol/L or ≤6 mg/dl)
Future research agenda
3
Further studies are required to determine
the target SUA for urate lowering treatment that ensures
crystal dissolution and eventual cure
9
Zhang W, et al. Ann Rheum Dis 2006;65:1312-1324.
Treat to target
• 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)
10
1. Zhang W, et al. Ann Rheum Dis 2006;65:1312-1324.
2. Jordan KM, et al. Rheumatol (Oxford) 2007;46(8):1372-1374
.
EULAR recommendations 2006
for the management of gout
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)
Allopurinol
11
Zhang W, et al. Ann Rheum Dis 2006;65:1312-1324.
Oxypurinol
Terkeltaub R. Nature Rev Rheumatol 2010:6:30-38.
12
EULAR recommendations 2006
for the management of gout
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).
By kind permission of L.
Punzi,Rheumatology Unit,
University of Padua
Steven-Johnson syndrome
13
Erythema multiforme
Zhang W, et al. Ann Rheum Dis 2006;65:1312-1324.
2012 American College of Rheumatology
Guidelines for Management of Gout
Significance & innovations (I)
“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”
Khanna D, et al. Arthritis Care & Research 2012;64,(10):1431-46.
14
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.
15
EULAR recommendations 2006
for the management of gout
Future research agenda for gout management
4
Direct comparison (efficacy, side effects, cost utility)
between allopurinol and alternative urate lowering
treatments are needed.
16
Zhang W, et al. Ann Rheum Dis 2006;65:1312-1324
2012 American College of Rheumatology
Guidelines for Management of Gout
Significance & innovations (II)
“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)
17
Khanna D, et al. Arthritis Care & Research 2012; 64,(10):1431-46.
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
CH3
O
H3C
N
NC
CH3
S
Febuxostat
CO2H
Khosravan Clin Pharmacokinet 2006;45:821-841.
18
Febuxostat: pharmacokinetics
• Bioavailability
> 80% PO, Tmax: 1.0-1.5 hour, t1/2: 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
19
SmPC febuxostat.
Febuxostat: clinical trial overview
Phase II
studies
Study 004
153 patients
APEX
1,072 patients
6 months
Phase III
studies
FACT
760 patients
1 year
CONFIRMS
2,269 patients
6 months
20
FOCUS
Open-label extension study
116 patients
5 years
EXCEL
Open-label extension study
1,086 patients
3 years
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.
Febuxostat - clinical efficacy in phase II RCT
Percentage of patients reaching sUA targets at day 28
<6 mg/dl (360 mcmol/l)
100
<5 mg/dl (300 mcmol/l)
80
<4 mg/dl (240 mcmol/l)
94%
88%
76%
% of patients
70
60
56%
56%
49%
50
40
30
21%
19%
20
10
0%
0
Placebo
40 mg/day
80 mg/day
120 mg/day
Becker MA, et al. Arthritis Rheum 2005;52:916-923.
21
Febuxostat - phase III studies:
patients’ demographics
•
•
•
•
•
•
•
22
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.
The FACT Study
23
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 APEX Study
* 100 mg in patients with serum creatinine 1.5-2.0 mg/dl
24
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.
Febuxostat - clinical efficacy
in phase III studies
Percentage of patients reaching serum urate < 6 mg/dl (360 µmol/l)
ITT analysis, at last visit
*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
25
.
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.
EXCEL study: switch data
Patients who reached 6.0 mg/dl
(<360 μmol/l) after switching
Patients switching due to
sUA >6.0 mg/dl (>360 μmol/l)
– Febuxostat 120 mg to
allopurinol 300 mg:
8% (22/292)
– Allopurinol to febuxostat
80 mg: 57% (82/145)
80
70
% of patients
– Febuxostat 80 mg to
febuxostat 120 mg: 22%
(141/649)
64%
60
50
40
30
20
17%
10
0
Febuxostat to
allopurinol
Allopurinol
to febuxostat
(n=4/24)
(n=50/78)
Becker MA, et al. J Rheumatol 2009;36:1273-1282.
26
Febuxostat is effective in patients with
renal impairment
APEX study (6 months):
proportion of renal impaired (1.5–2 serum creatinine [>133–177 mmol/l])
subjects with last 3 sUA levels 6.0 mg/dl (<360 μmol/l)
% of patients
50
*
44%
*
46%
*p0.05 all febuxostat
doses vs allopurinol
and placebo
40
30
20
10
0
0%
0%
Placebo
Febuxostat 80 mg
Febuxostat 120 mg
Allopurinol 100 mg
(n=5)
(n=9)
(n=11)
(n=10)
ITT population: subjects with serum urate level 8.0 mg/dl on day -2
27
Schumacher HR, et al. Arthritis Rheum 2008;59:1540-1548.
Greater reduction in tophus
size with lower sUA
FACT study (1 year):
% change from baseline in primary tophus size at week 52
Post-baseline
sUA (mg/dl)
7
6-7
5-6
-45%
-49%
-50%
(n=22)
(n=17)
4-5
<4
-85%
-84%
(n=18)
(n=13)
% change in tophus size
0
0%
-20
-20%
-40
-40%
-60
-60%
-80
-80%
(n=15)
-100
Data for ALL patients, drawn from Becker MA, et al. N Engl J Med 2005;353:2450-2461.
28
Febuxostat - patients requiring
treatment for a flare
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.
Schumacher HR, et al. Rheumatology 2009;48:188-194.
29
Characteristics of patients in the post-hoc
analysis of renal function during febuxostat treatment
30
Variable
All Subjects
N = 551
Male, n (%)
Race, n (%)
- Caucasian
528 (95.8)
Age, y, mean ± SD
11.59
BMI
- ≥ 30 kg/m2, n (%)
- Mean, kg/m2 ± SD
- Alcohol use, n (%)
51.3 ±
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
- Diabetes
- Hypertension
59 (10.7)
32 (5.8)
236 (42.8)
437 (79.3)
357 (64.8)
32.7 ± 5.84
361 (65.5)
Abbreviations:
BMI = body mass index
SD = standard deviation
SUA = serum uric acid
Whelton A, et al. Postgrad Med 2013;125:106-14.
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.
31
Febuxostat preserved renal function
Whelton A, et al. Postgrad Med 2013;125:106-14.
32
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.
33
The FACT Study
34
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 APEX Study
* 100 mg in patients with serum creatinine 1.5-2.0 mg/dl
35
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.
Febuxostat - fewer patients require
treatment for gout flare over time
EXCEL study (3 years):
patients requiring treatment for gout flare
All patients receiving allopurinol without reaching the sUA target level were switched to febuxostat.
Becker MA, et al. J Rheumatol 2009;36:1273-1282.
36
Febuxostat - overall safety
in phase III studies
Percentage of patients with serious adverse events (SAE)
37
.
Schumacher HR. Arthritis Rheum 2008;59:1540-1548.
*145/757 patients in the CONFIRMS on 200 mg/day
Becker MA. N Engl J Med 2005;353:2450-2461.
*10/263 patients in the APEX trial on 100 mg/day
Becker MA. Arthrits Res Ther 2010;12:R63.
Main clinical differences between
febuxostat and allopurinol
Febuxostat
Allopurinol
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
Effective at the
lowest dose (80 mg)
Needs to be uptitrated
(from 100 mg)
No dosage adj. required in mild to
moderate renal insufficiency
Dosage adjustment required
Well tolerated at standard doses
Dosage adjustment required
Chemical structure
and activity
Dosing
Dosing in renal
insufficiency
Dosing in elderly
patients
SmPC: allopruinol, febuxostat.
Schumacher HR. Arthritis Rheum 2008;59:1540-1548. Becker MA. N Engl J Med 2005;353:2450-2461.
38
Advantages of febuxostat
from the patient’s prespective
•
•
•
•
•
•
•
•
•
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
Beara-Lasic L, et al. Int J Nephrol Renovasc Dis 2010;3:1-10.
39
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.
40
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.
41
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.
42
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..
43
Febuxostat - summary
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
44
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.