Nama : Dr. dr. I Dewa Putu Pramantara S.

SpPD,K Ger, FINASIM

Tempat / Tgl. Lahir : Bangli (Bali)/ 18 November 1957
No. HP: 0811282768

JABATAN : 1. Kepala Divisi Geriatri, Depart. Ilmu Penyakit Dalam FKKMK UGM / KSM
Geriatri RSUP Dr. Sardjito Yogyakarta
2. Ketua SubKomite Kredensial, Komite Medik RSUP Dr. Sardjito Yogyakarta
3. Kepala Poli Herbal RSUP Dr. Sardjito Yogyakarta
4. Kepala Divisi Pelayanan, Pusat Pengembangan Obat Herbal RSUP
Dr. Sardjito Yogyakarta
5. Dosen Klinik S1 dan S2 Gizi UGM
6. Dosen dan Pembimbing Klinik S2 Farmasi Klinik UGM
7. Konsulen Unit Home Care RSUP Dr. Sardjito Yogyakarta

ORGANISASI : 1. PAPDI CAB YOGYAKARTA

2. PERGEMI CAB YOGYAKARTA
3. SP3T DIY
 TATALAKSANA FARMAKOLOGIK
TERBARU HIPERURISEMIA DAN GOUT
USIA LANJUT: FOKUS PADA
PEMAKAIAN FEBUXOSTAT

Dewa P. Pramantara S.
Divisi Geriatri, Depart. Ilmu Penyakit Dalam FKKMK UGM/KSM Geriatri
RSUP Dr Sardjito
Yogyakarta
 ALUR PRESENTASI
1. DEFINISI
2. KEJADIAN PADA USIA LANJUT
3. DIAGNOSIS
4. TATA LAKSANA
5. KAJIAN “ FEBOXOSTAT” PADA USIA LANJUT
6. KESIMPULAN
Hyperuricemia
Type of Hyperuricemia

5
PENYAKIT GOUT :
Spektrum klinis akibat deposit kristal
mono-sodium urat di sendi dan jaringan
berupa artritis, tofus, batu saluran kemih
yang kesemuanya berkaitan dengan
hiperurisemia kronis dan terutama diderita
pria (IRA,2018)
Gout: the most common arthritis
and a growing epidemic Japan
China South
2005: Korea (Wakayam
England 0.9% 2008 a)
1992: 0.34% 2014: 0.4% 2003
1999: 1.39% 1.4% 0.51%
2012: 2.49%

Hong Kong
2001: 6.1%

USA
1990: 0.29%
1999: 0.52% Taiwan
(NHIA)
2004: 4.92%
2010: 6.24%

New Zealand
Singapore (European/Maori)
1998 4.1% 1958: 0.3% / 2.7%
1992: 2.9% / 6.4%

Kuo C-F, et al. Nat Rev Rheumatol. 2015 Nov;11(11):649-62

Pathophysiology
of Gout
 Sign and
Symptom
• Clinical spectrum of
disease:
– Hyperuricemia
– Recurrent acute arthritis attacks due http://www.healthinplainenglish
.com/health/musculoskeletal/g
to monosodium urate (MSU) crystals out/

in synovial fluid
– Deposition of MSU into articular and
extra-articular space (tophi)
– Interstitial renal disease
– Uric acid nephrolithiasis

• Primarily caused by
elevated SUA levels, but
can occur in patients with
normal SUA levels.
http://www.assh.org/Public/HandCo
nditions/Pages/GoutandPseudogou
t.aspx
Course of Gout

11
 Theoretical
Constructs
(1)
Vascular injury
Kidney Injury
CV Disease
Uric Acid Chronic Kidney
Disease

(2)
Hypertensi CV Disease
on Chronic Kidney
Uric Acid Diabetes Disease
Metabolic
Syndrome

Kang DH and Nakagawa T. Semin Nephrol 2005; 25:43-49

 DIAGNOSIS
GOUT menurut ACR/ EULAR 2015
“Pedoman Diagnosis dan Pengelolaan Gout “
“Pedoman Diagnosis dan Pengelolaan Gout “
Prinsip Tata Laksana Hiperurisemia & Gout

1. Pasien harus mendapat informasi yang jelas

2. Modifikasi gaya hidup penting
3. Harus dilakukan penapisan penyakit
komorbiditas
4. Tujuan terapi : - menghentikan serangan akut
- mencegah serangan kembali
- mencegah komplikasi

DepKes, 2006; IRA, 2018

 TERAPI FARMAKOLOGIK
HIPERURISEMIA
1. Urikostatik ( Inhibitor Xantin Oksidase )

2. Urikosurik ( Probenecid )

3. Urikolitik ( Uric oxidase )

Goals of Pharmacology
Treatment in Gout
 Mechanism of Action of ULTs

G. Fenech et al. / Joint Bone Spine 81 (2014) 392–397

ULTs (Urate Lowering Therapy) Option
Kelas Agen Considerations
XO inhibitors Allopurinol1,2 • Perlu penyesuaian dosis pada gagal ginjal
• Interaksi obat ; memerlukan penyesuaian
dosis
• Tidak selalu mencapai target sUA;
kadang diperlukan dosis yang lebih tinggi
• Potensi untuk gejala hipersensitivitas
berat
Febuxostat3 • Lebih signifikan mencapai target sUA
dibanding Allopurinol
• Hati hati ketika digunakan pada pasien
dengan gangguan ginjal berat, dan
dengan gangguan hati sedang sampai
berat
 Uricosuric agents Probenecid dan • Tidak efektif pada pasien dengan
Sulhinpyrazone4 gangguan ginjal
• Interaksi obat (mis:aspirin)
• Target sUA tidak selalu tercapai
• Risiko nefrolitiasis pada kondisi over-
produksi asam urat
Benzbromarone5 • Risiko hepatotoksik
Urate oxidase Pegloticase6 • Flare akut karena onset of action yang
cepat
• Hindari pada pasien yang memiliki
antibody anti-pegloticase, pada pasien
ini tidak ada respon obat

Benzbromarone5 • Risiko hepatotoksik

Urate oxidase Pegloticase6 • Flare akut karena onset of action yang
cepat
• Hindari pada pasien yang memiliki
antibody anti-pegloticase, pada pasien
ini tidak ada respon obat

1. Harris MD,et al. Am Fam Physician 1999;59:925-934. 2. Schumacher HR,Jr.,et al. Cleve Clin J Med 2008;75 9Suppl,5):522-525. 3. Yu KH. Recent Pat
Inflamm Allergy Drug Discover 2007;1:69-75. 4. Edwards NL. Rheumatology (Oxford)2009;48 (Suppl.2):Il 5_Il. 5. European Medicines Agency.
Adenuric:EPAR-Product information (Annex):Summary of product characteristics) 2012. 6. Rider TG,et al. Rheumatology (Oxford) 2010;49:5-
14.7Schlesinger N, et al.Nat Rev Drug Discov 2011:10:17-18
Allopurinol
 First indicated in gout patients in 1963.
 Dose adjustment required in renal impaired
patients
 Purine-base structure and excreted mainly through
kidneys
 May induce severe allergic reactions that are life
threatening, like toxic epidermal necrolysis and
Stevens–Johnson Syndrome
 Risk factors: HLA-B*5801(+), renal impairment and
age>65yr drug-drug interaction：may play a role in
triggering allergic reactions, such as ampicillin,
thiazide or ACEI
Hung SI, et al. Proc Natl Acad Sci USA. 2005; 102:4134–9.
Remarkable Regional Differences of Prevalence of
HLA-B*58:01 Hot Spot covers Southeast Asia

Fernando SL & Broadfoot AJ. CMAJ 2010, 182(5): 476-480. Middleton D, et al. Tissue
Antigens. 2003;61(5):403-407
Tassaneeyakul W, et al. Pharmacogenet Genomics. 2009; 19:704–
9.
 Risiko tinggi Allopurinol: Severe Allergic
Reactions (SJS, TEN and DRESS)
Risiko tinggi Severe Allergic
Reactions (SJS, TEN and
DRESS).
Faktor risiko:
• HLA-B*8501 (+) terutama
pada suku Han Chinese,
Thai, Koreans dengan
CKD3 atau lebih
• Renal impairment
• Elderly (usia >65)
Dosis Allopurinol harus
dimulai dari dosis rendah
untuk meminimalkan flares
dan hypersensitivity
Multiple drug-drug
interactions (e.g. ampicillin,
thiazide, ACE inhibitors) –
dapat memicu reaksi alergi
30
TEN: Topic Epidermal necrolysis DRESS: Drug Reaction with Eosinophilia and Systemic symptom
 HLA-B*5801: What the guidelines
Say?
 Allopurinol dosing and
pharmacogenetics
− Prior to initiation of allopurinol,
HLA-B*5801 testing should be
considered in selected patients
sub-populations at elevated risk for
AHS (Evidence A). Those with
HLA-B*5801 and of Korean
descent with stage 3 or worse CKD
(HLA-B*5801 allele frequency
~12%), or of Han Chinese or Thai
extraction irrespective of renal
(HLA-B*5801 allele frequency ~6–
8%)
2012 American College of Rheumatology Guidelines for Management of Gout
 A nonpurine selective inhibitor of
xanthine oxidase

Potent, minimal effects on other

enzymes in purine and pyrimidine

Febuxostat metabolisms

Metabolised in the liver

Serum UA lowering effect of febuxostat

was unaltered by renal impairment

Am J Ther 2005;12:22
The new non-purine XOI: Febuxostat
Potent Inhibition of XO
Febuxostat
Center of enzyme Hydrophobic interaction
reaction Ion bond
Hydrogen bond
Van der Waals
XO interaction
(oxidized π-π interaction
form, reduced
form)

Allopurinol
Center of enzyme
酵素
酵素反 Covalent
reaction
Oxypurinol 反応
応の中 bonding
水素結
の中心 合
心

π-π相互
作用 ファンデル
XO ワールス力
(reduced form)
Okamoto K. et al.: J Biol Chem. 278(3) 1848, 2003, Okamoto K.：Yakuri to Chiryo．38
Rumus Molekul

Jordan & Gresser, 2018

 Mechanism of XO Inhibition of
Febuxostat: Biochemical Characteristics
 XO accelerates the production of uric acid as it converts between its oxidized and reduced
forms.
 Oxypurinol , a metabolite of Allopurinol, can inhibit only the reduced form. In addition,
oxypurinol-inhibited enzyme is reactivated relatively quickly by spontaneous reoxidation of
the molybdenum cofactor. Therefore, high dose Allopurinol is necessary for inhibition.
 Febuxostat can strongly inhibit both forms of XO. So even low doses can effectively inhibit XO.

Febuxostat
inhibition inhibition
xanthine Uric acid

Xanthine Xanthin
e
oxidase
(oxidized) oxidase
(reduce)
H2O2,O2- O2 inhibition
Xanthine oxidase
Allopurinol Oxypurinol
Hyperuricemia & Gout Training Text; Teijin
Main Differences in the Elimination Pathways
between Febuxostat and Allopurinol
Febuxostat Allopurinol

hepatic Metabolism
metabolism in systemic
organs

Hyperuricemia & Gout Training Text; Teijin

Metabolites Metabolite (Oxyprinol)

Biliary Urinary Urinary

excretion excretion excretion
After inactivated in the liver, Active metabolite, oxyprinol is
Febuxostat is eliminated via multiple excreted primarily by the kidneys
pathways including bile and the (Single excretion pathway)
kidneys.
No dose adjustments for patients with Dose adjustment is required
mild to moderate renal impairment. for patients with renal
impairment.
Clinical Differences Between Febuxostat
vs Allopurinol
Febuxostat Has Been Extensively Studied in
a Number of Clinical Trials
Phase 2
studies
FOCUS2
Study 0041 Open-label extension
153 patients
study
116 patients
5 years
Phase 3
studies
APEX3
1072 patients EXCEL4
6 months
Open-label
FACT 5
extension study
760 patients 1086 patients
1 year 3 years

CONFIRMS6
2269 patients
6 months

1. Becker MA, et al. Arthritis Rheum. 2005;52(3):916-923. 2. Schumacher HR Jr, et al. Rheumatology (Oxford).
2009;48(2):188-194. 3. Schumacher HR Jr, et al. Arthritis Rheum. 2008;59(11):1540-1548. 4. Becker MA, et al. J
Rheumatol. 2009;36(6):1273-1282. 5. Becker MA, et al. N Engl J Med. 2005;353(23):2450-2461. 6. Becker MA, et al.
Arthritis Res Ther. 2010;12(2):R63.
Penelitian Phase 3 FOCUS
Selama penelitian, persentase pasien yang membutuhkan
pengobatan untuk serangan akut menurun sampai
dengan 0 (nol).

Schumacher HR et al. Rheumatology 2009; 48:188-194

 Penelitian Phase 3 EXCEL
Febuxostat efektif mengurangi Flares
“Recommended oral dose of feburic is 80 mg once daily. If sUA is >6 mg/DL
after 2-4 weeks and risk factor modification has failed, feburic 120 mg
once daily may be considered” 2
 Penelitian Phase 3 EXCEL
Febuxostat mengurangi ukuran
tophi
“Recommended oral dose of feburic is 80 mg once daily. If sUA is >6 mg/DL after 2-4
weeks and risk factor modification has failed, feburic 120 mg once daily may be
considered” 2
 EXCEL study: switch data1
Patients switching Patients who reached  6.0
due to sUA >6.0 mg/dl
mg/dl (>360 μmol/l) (<360 μmol/l) after
switching
– Febuxostat 80 mg to 80
febuxostat 120 mg: 70
22% (141/649) 64%
60

% of patients
– Febuxostat 120 mg
to allopurinol 300 mg: 50
8% (22/292) 40

– Allopurinol to 30
febuxostat 20 17%
80 mg: 57% (82/145)
10
“Recommended oral dose of feburic is 80 mg
once daily. If sUA is >6 mg/DL after 2-4 0
weeks and risk factor modification has failed, Febuxostat to Allopurinol
feburic 120 mg once daily may be allopurinol to febuxostat
considered” 2 (n=4/24) (n=50/78)
1. Becker MA, et al. J Rheumatol 2009;36:1273-1282.. 2. Indonesia,
Feburic Package Insert
 Greater reduction in tophus
size with lower sUA1
FACT study (1 year):
% change from baseline in primary tophus size at week 52

7 6-7 5-6 4-5 <4

0
0%
Post- “Recommended
% change in tophus size

baseline oral dose of

-20
-20% feburic is 80
sUA
(mg/dl) mg once
-40 -45% -49% daily. If sUA
-40% -50%
is >6 mg/DL
(n=1 after 2-4
-60
-60% (n=2 (n=1
5) weeks and
2) 7)
-85% -84% risk factor
-80
-80% modification
(n= (n=1 has failed,
-100 18) 3) feburic 120
mg once
1. Data for ALL patients, drawn from Becker MA, et al. N Engl J Med 2005;353:2450-2461. 2. daily may be
Indonesia, feburic package insert
considered” 2
 APEX: Febuxostat is effective in patients with renal
impairment
APEX study (28 weeks)
Proportion of renal impairment subjects
(serum creatinine of >1.5 to ≤2 mg/dL) with
last three sUA levels <6.0 mg/dL (<0.36 mmol/L)

60%
*

44% 45%
* *
“Recommended oral dose of
feburic is 80 mg once daily. If
sUA is >6 mg/DL after 2-4
weeks and risk factor
modification has failed, feburic
0% 120
0% mg once daily may be

considered” 2
(n = 5)
(n = 9) (n = 11) (n = 10)

*p<0.05 vs allopurinol
† Allopurinol patients with serum creatinine level >1.5 and ≤2.0 mg/dL received

allopurinol 100 mg (n=10)

Schumacher HR, et al. Arthritis Rheum 2008;59:1540-1548 Indonesia , Feburic Package Insert].
“Recommended
oral dose of
feburic is 80
mg once
daily. If sUA
is >6 mg/DL
after 2-4
weeks and
risk factor
modification
has failed,
feburic 120
mg once daily
may be
considered” 2
Indonesia, Feburic Package Insert
Penelitian Phase 3 CONFIRMS
Febuxostat 80 mg secara signifikan lebih efektif daripada
Allopurinol 300 mg dalam menurunkan sUA
100%
Subjects with sUA < 6 mg/dl at 6 months
Percentage of Patients *
80%
67%
“Recommended
60% oral dose of
45% feburic is 80
42% mg once daily.
40% If sUA is >6
mg/DL after
2-4 weeks and
20% risk factor
modification
has failed,
0%
feburic 120
Febuxostat Febuxostat Allopurinol mg once daily
40 mg 80 mg 200/300 mg may be
considered” 2
Becker MA et al. Arthritis Research & Therapy 2010; 12:1-12. 2. Indonesia,
48
Feburic Package Insert
Penelitian Phase 3 CONFIRMS
Efek Febuxostat pada pasien dengan gangguan
ginjal 100% Renal Impaired Subjects with sUA < 6 mg/dl
at 6 months
Percentage of Patients 80% *
72%
“Recommended
¶ oral dose of
60% feburic is 80
50%
42% mg once daily.
40% If sUA is >6
mg/DL after
2-4 weeks and
20% risk factor
modification
0% has failed,
feburic 120
Febuxostat Febuxostat Allopurinol mg once daily
2010; 12:1-12
40 mg 80 mg 200/300 mg may be
(n=238/479) (n=360/503) (n=212/501) considered” 2
Becker MA et al. Arthritis Research & Therapy 2010; 12:1-12. 2. Indonesia,
Feburic Package Insert;
 Take home message…
Pharmacology Treatment for Gout initiate Urate Lowering Therapy to achieve the
target SuA ,6mg/dL to control flares, normalize SUA and attack prevention 1
Allopurinol first indicated in gout patients in 1963, but the target serum
urate level is not always achieve 2
Allopurinol may induce severe allergic reactions that are life threatening, like toxic
epidermal necrolysis and Stevens–Johnson Syndrome, for risk factors: HLA-
B*5801(+), renal impairment and age>65yr 2
Febuxostat is a new treatment option for hyperuricemia & gout with
its proven efficacy , well tolerance profile and convenience at use 3
Febuxostat offers simple, once-daily dosing with 80 mg tablets, may
improve patient adherence3
Febuxostat more effectively lowered and maintained serum urate levels
<6.0 mg/dl than
Allopurinol (300 or 100 mg) or placebo in subjects with hyperuricemia
and gout, including those with mild to moderately impaired renal
function3
Febuxostat administered in mild to moderate renal or mild hepatic impairment
without dosage adjustment 3
TERIMA
KASIH