Differentiation of

ICS/LABAc
Not all ICS/LABA are the same
Definisi Asma

• Asma merupakan penyakit

heterogen, umumnya dengan
karakteristik inflamasi saluran
napas kronik

• Asma ditandai dengan riwayat

gejala pernapasan seperti mengi,
sesak napas, rasa tertekan di
dada dan batuk yang waktu dan
intensitasnya dapat berubah-
ubah, bersamaan dengan variasi
hambatan aliran ekspirasi.

Adapted from GINA Updated 2016 2

 Obat apa yang harus dipakai pada asma?

Bronkodilator

Anti inflamasi
Syslová K et al. (2012). Determination of Biomarkers in Exhaled Breath Condensate: A Perspective Way in Bronchial Asthma Diagnostics, Bronchial
Asthma - Emerging Therapeutic Strategies, Dr. Elizabeth Sapey (Ed.), InTech
GINA: long-term goals of asthma management

Long-term goals of
asthma management

To achieve good To minimise future

control of symptoms risk of exacerbations,
and maintain normal fixed airflow limitation
activity levels and side effects

It is also important to elicit the patients’ own goals regarding their asthma

From the Global Strategy for Asthma Management and Prevention 2016, ©
Global Initiative for Asthma (GINA) all rights reserved. Available from
http://www.ginasthma.org
GINA assessment of asthma control

From the Global Strategy for Asthma Management and Prevention 2016, ©
Global Initiative for Asthma (GINA) all rights reserved. Available from
http://www.ginasthma.org
www.asthmacontroltest.com ID/SFC/0024/14(1) –
AD. 20/01/2017 ED. 20/01/2019-
Asthma Control Test is a trademark of Quality Metric Incorporated For HCP only
www.asthmacontroltest.com
Asthma Control Test is a trademark of Quality Metric Incorporated
 Preferred choice of pharmacotherapy: 6-11 years,
adolescents, adult

Disease severity
Severe
asthma
Moderate
asthma Step 5
Mild asthma Step 4 Refer for
add-on
PREFERRED Step 3 Medium- treatment
CONTROLLER Step 1 Step 2
dose e.g.
CHOICE Low-dose ICS/LABA tio*, oma,
Low-dose ICS ICS/LABA mepo

Med/high-dose Add tio*

Other Consider ICS; low-dose High-dose Add low-
controller low-dose LTRA
ICS+LTRA ICS+LTRA dose OCS
options ICS Low-dose theoph (or + theoph) (or + theoph)
As-needed SABA or low dose
RELIEVER As-needed SABA
ICS/formoterol

*Tiotropium by mist inhaler is an add-on treatment for patients with a history of exacerbations.
GINA, Global Initiative for Asthma; ICS, inhaled corticosteroid; LABA, long-acting beta2-agonist; LTRA, leukotriene
receptor antagonist; mepo, mepolizumab; OCS, oral corticosteroid; oma, omalizumab; SABA, short-acting beta2-agonist;
theoph, theophylline; tio, tiotropium.
Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2016. Available from: https://www.ginasthma.org. 8
© 2016 Global Initiative for Asthma, all rights reserved. Use is by express license from the owner
Asthma Medication

 Controller
– Anti-inflamasi
– Dipakai rutin setiap hari
– Lama penggunaan sesuai dengan parameter
kontrol asma

 Reliever
– Bronkodilator
– Dipakai saat serangan
Salmeterol/Fluticasone memberikan kontrol asma
dengan dosis steroid yang lebih rendah

40
% pasien yang mencapai Total Kontrol

p<0.0001

30 500

20 250
High
(FP 500 mcg b.d)

10 Medium
( FP 250 mcg b.d)

100
Low
(FP 100 mcg b.d)
0
FP SFC
n=577 n=583

Bateman ED et al. Am J Respir Crit Care Med 2004; 170: 836–844.

The Difference in Outcomes:
Fixed Vs. Variable
Asthma control: fixed vs variable

• Managing the challenge of residual asthma symptoms in

adults using ICS/LABA has been managed in two ways:1
- REGULAR DOSING (ICS/LABA as a controller)
- VARIABLE DOSING (ICS/LABA as a controller and reliever)2
• Variable dosing suggested to offer convenience and better
improvements in outcomes with lower ICS dosing3

Does evidence support the use of this strategy?

1. Bousquet J, et al. Respir Med 2007. 2. Chapman KR, et al. Thorax 2010.
3. Humbert M, et al. Allergy 2008.
 Reliever used in Variable Dosing study1

Asthma control by SMART study

(formoterol/budesonide as reliever and controller)

Rabe Scicchi O’Bryne Rabe Vogelme Kuna Bousquet Weighted

et a 2 tano et et al 4 et al 5 ier et al 6 et al 7 et al8 Averages
al 3
N 354 947 925 1107 1067 1052 1151
(SMART arm)
Length of study 6 12 12 12 12 6 6 N/A
bulan bulan bulan bulan bulan bulan bulan
Usage of
reliever 1.04 0.9 1.01 1.02 0.59† 1.02 0.95 0.92
inhalation /day

Usage formoterol/budesonide as reliever & controller

showing that patient add almost one puff every day
1.K. Czarnecka and K. Chapman. ‘The clinical impact of single inhaler therapy in asthma’ Clin Exp Allergy 2012. 2. Rabe KF et al. Budesonide/Formoterol in a Single Inhaler for Maintenance and
Relief in Mild-to-Moderate Asthma. A Randomised, Double-Blind Trial. CHEST 2006; 129: 246 - 256.3. Scicchitano R. et al. Efficacy and safety of budesonide/formoterol single inhaler therapy
versus a higher dose of budesonide in moderate to severe asthma. Curr Med Res Opin 2004; 20: 1403-18.4. O’Byrne PM et al. Budesonide/formoterol combination therapy as both maintenance
and reliever medication in asthma.5. Rabe KF et al. Effect of budesonide in combination with formoterol for reliver therapy in asthma exacerbations: a randomised controlled, double-blind study.
Lancet 2006; 368: 744 - 753.6. Vogelmeier C et al. Budesonide/formoterol maintenance And reliever therapy: an effective asthma treatment option?Eur Respir J 2005; 26: 819-28.
7. Kuna et al. Effect of budesonide/formoterol maintenance and reliever therapy on asthma exacerbations. Int J Clin Pract 2007; 61:725-36.8. Bousquet et al. Budesonide/formoterol for
maintenance and relief in uncontrolled asthma vs. high-dose salmeterol/fluticasone. Respir Med 2007; 101: 2437-46.
 TOTAL CONTROL WELL-CONTROL
(GOAL )1 (GINA) 2
Night awakening Use of reliever ≤2x per
No Daily symptoms
due to asthma almost every week

Exacerbation No day
Activity limitation
No
due to asthma
Reliever What it is
No
usage mean? ≤2x per
Reliever usage
week
Emergency visit No

morning PEF  Night awakening

No
normal due to asthma
80%
Drug related
Asthma control
No cannot be
adverse event
achieved using
variable dosing

1. Bateman ED et al. Am J Respir Crit Care Med 2004; 170(8):836–844.

2. Global Strategy for Asthma Management and Prevention, GINA 2016 page 29. Downloaded from www.ginasthma.org
How Many Patients can Achieved GINA
Defined Asthma Control?
 Achieving GINA guideline-defined control by fixed
dose Salm/FP (GOAL study)
100

80 78%* 75%**
70%

60% 62%**
60

47%

40
CONTROLLED
% of patients

20

Well Well Well Well Well Well

Controlled Controlled Controlled Controlled Controlled Controlled
0
Steroid naïve (S1) Low dose ICS (S2) Moderate dose ICS (S3)

Fp

*p=0.003 Sal/Fp
Bateman et al ARJCCM 2004
**p<0.001
 Level of patients’ asthma control that treated by
Variable dosing concept
Studies analyzed:

17.1%
44.2%

37.8%

n = 5,246

Controlled Partly Controlled

Uncontrolled

Only 17% of asthma patients can be controlled by Form/Bud (Variable dosing)

Czarnecka & Chapman. Clinical & Experimental Allergy, 1–8, 2012

Primary Endpoint – Persentase rata-rata
hari bebas gejala pada minggu 1-4 dan minggu 1-52

Fase Variable dimana Bud/For diberikan

dengan konsep AMD pada minggu ke 5-52

80 74 p=0.03

70 65
% Hari bebas gejala

60
50 Fase stabilisasi dengan
fixed-doses pada minggu 1-4
40
30 25 25
20
10 n = 344 n = 343 n = 305 n = 299
0
SERETIDE™
SERETIDE Bud/Form SERETIDE™
SERETIDE FD Bud/Form AMD
Fitzgerald, et al Clin Ther 2005; 27 (4): 1-14
REGULAR DOSING (ICS/LABA as a controller) VS.
VARIABLE DOSING (ICS/LABA as a controller and reliever)

– BIOPSY INFLAMMATORY CE LLS

120 +
100
80
60
% 40
change 20 **
from
0
baseline
-20 Total Cells Mast Cells** CD4+ Eosinophils+
-40
-60
Regular Dosing Variable Dosing

n = 127
+ p < 0.001
** p = 0.0012

Pavord et al J Allergy Clin Immunol 2009;123:1083-1089

 Asthma control: fixed vs variable

Conclusion
• Based on Chapman review, the reliever used in Variable
dosing study show that the patient use additional almost one
puff per day1

• GINA defined asthma control achieved by:

- 71% fixed dose Salm/FP2 (regular dosing)
- 17% adjustable dose For/Bud1 (variable dosing)

1. Chapman KR et al. Thorax 2010

2. Bateman et al ARJCCM 2004
Diskus ®
 Tingkat aliran inhalasi bervariasi antar populasi pasien

120
Rata-rata puncak tingkat aliran inhalasi

100 105
94.7
80
82.3
(L/min)

60 70

40

20

0 2 3 3
Dewasa dengan asma Dewasa dengan Pasien anak asma Pasien anak asma
berat 1 PPOK usia 4 tahun usia 8 tahun

1. Tarsin WY et al. Int J Pharm. 2006; 19:316:131–137

2. Burnell PKP et al. Resp Med. 2001;95:324–330;
3. Bisgaard H et al. Eur Respir J. 1998;11:1111–1115
 Diskus memberikan penghantaran dosis yang konsisten dan
tidak bergantung pada kekuatan hirupan / inhalasi

100 90 92
87 Diskus (FP)
Dosis yang terhantarkan

80
(% labelled dose)

58
60 Turbuhaler
46 (BUD)
40
40

20

0
30 L/min 60 L/min 90 L/min

Tingkat aliran inhalasi (L/min)

Dibandingkan dengan Turbuhaler, dosis yang dihantarkan Diskus lebih tidak

sensitif terhadap kekuatan hirupan

Adapted from Prime D et al. Am J Respir Crit Care Med. 1996;153:A62.

Resistensi alat-alat DPI

20
Spiriva Handihaler
Symbicort Turbuhaler
16 Pulmicort Turbuhaler
Seretide Diskus

12

0
0 20 40 60 80 100 120
Inhalation Flow Rate (L/min)

Raid.A.M, et.al. Respiratory Medicine 2007; 101: 2395-2401

Usaha Inspirasi yang Dibutuhkan

mouthpiece

EFFORT

location
of drug

The narrower the gap between the site of drug and the inhaler mouthpiece,
the less the effort needed to get the drug
 100
90
80
% Label

70
60
Total Emitted Dose
50
40
through Life
30
20 DISKUS™ Delivered at 30 L/min
10 Turbuhaler™
0
100 90 80 70 60 50 40 30 20 10 0
% doses remaining
100
90
% Label

80
70
Total Emitted Dose
60
50 through Life
40 DISKUS™
30
20 Turbuhaler™ Delivered at 60 L/min
10 TM consistently delivers the medicine throughout
Diskus
0 100
90 80 70 60 50 40 30 20 10 0
% doses remaining
its working life and over a wide range of flow rates
200
180
160 Total Emitted Dose
% Label

140
120
100
through Life
80
60 DISKUS™ Delivered at 90 L/min
40 Turbuhaler™
20
0
100 90 80 70 60 50 40 30 20 10 0
% doses remaining Malton A, et al. J Pharm Med 1996; 6: 35–48
 Banyak pasien asma dan PPOK yang masih keliru
dalam penggunaan inhaler
Jumlah pasien yang melakukan kesalahan1
80
70 DPI inhalers
60
Pasien(%)

50
40
30
20
10
0
MDI Aerolizer (n=83) Diskus/ Turbuhaler (n=146)
(n=193) Accuhaler (n=103)

• Sekitar 75% pasien yang menggunakan MDIs melakukan kesalahan minimal 1x1,2
• Berdasarkan studi, hampir 90% pasien tidak menggunakan MDI dengan benar 3
• GINA: Jika asma yang diderita pasien tidak terkontrol dengan baik, hal pertama yang perlu
dilakukan adalah memeriksa teknik inhalasinya 4
1. Khassawneh BY et al. Respir Care. 2008;53;324–328; 2. Molimard M et al. J Aerosol Med. 2003;16;249–254; 3. Lavorini F et al. Respir Med. 2008;102:593–604; 4. Global Initiative for
Asthma. Global Strategy for Asthma Management and Prevention. 2016. Available from: https://www.ginasthma.org.
 Banyak pasien asma dan PPOK yang masih tidak dapat
menggunakan inhaler dengan benar

Proporsi pasien asma dan PPOK yang melakukan kesalahan fatal (critical error)†

40
<30 tahun 31–64 tahun ≥65 tahun
35
kesalahan penggunaan yang fatal
30 (critical error) lebih umum terjadi pada
penggunaan MDI dan Turbuhaler, dan
25 tingkat kesalahannya meningkat
Pasien(%)

berdasarkan usia
20

15

10

0
Aerolizer Autohaler Diskus/Accuhaler pMDI Turbuhaler
– †Kesalahan fatal adalah ketika kesalahan penggunaan berpengaruh pada dosis yang terhantarkan ke paru-paru,; n=3811 patients.
– COPD, chronic obstructive pulmonary disease; pMDI, pressurised metered dose inhaler

Molimard M et al. J Aer Med. 2003;16:249–254.

 Diskus Easy To Use & Easy To Teach

Van der Palen, J., Klein J., Schildkamp M., Comparison of a New Multidose Powder Inhaler (Diskus/Accuhaler) and the Turbuhaler Regarding Preference
and Ease pof Use, Journal of Asthma, 35(2), 1998. Pg. 147-152
Diskus: Mudah digunakan
 78% pasien memilih Diskus dan
hanya 16% yang memilih Turbuhaler2
 Mudah digenggam1
 Tidak terlalu besar
 Tidak terlalu berat
 Bentuk yang menarik
 Mudah digunakan (hanya 3 langkah)
 Mudah dalam pemeliharaan (tetap
bersih)
 Memiliki penutup untuk setiap
dosisnya
 Memiliki dose counter untuk melihat
dosis yang tersisa
 Mouthpiece yang nyaman
 Mudah untuk diajarkan kepada pasien

ID/SFC/0014/16(1) AD: 16/03/2017 ED:16/03/2019

1. Chrystyn H. Clin Drug Invest 1999; 18: 287–296. 2. Luyt D et al. J Aerosol Med 1995; 8: 105.