Not all ICS/LABA are the same.

Chairil A Siregar
I
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

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
 Apa yang dirasakan oleh pasien asma?

Gejala yang terus muncul

• Sensitif terhadap cuaca
dingin
• Batuk-batuk
• Sesak napas
• Aktifitas fisik terbatas
• Sering terbangun dimalam
Yulia, 55 Thn, Pensiunan*
hari karena gejala asmanya
• Penurunan kegiatan sosial

*Hanya untuk keperluan ilustrasi

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 Walaupun sudah mendapatkan pengobatan,
pasien asma masih merasakan gejala yang
menurunkan kualitas hidupnya1,2
Lebih dari separuh pasien asma
yang tidak terkontrol
menggunakan obat pelega mereka
secara teratur paling tidak sehari
sekali1

Seperti juga Yulia, banyak sekali

pasien asma yang mengalami
gejala-gejala asma dan
menerimanya sebagai bagian dari
kondisi mereka2

1. Demoly P et al. Eur Respir Rev 2010; 19(116):150–157

2. Bellamy D, Harris T Prim Care Respir J 2005; 14:252–258
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 Apa tujuan jangka panjang
pengobatan asma ? 1

1. Mencapai dan mempertahankan asma terkontrol pada

tingkatan aktifitas yang normal

2. Meminimalkan resiko masa depan seperti eksaserbasi

berulang, keterbatasan saluran napas yang permanen
dan efek samping pengobatan

 Hidup bebas & normal

 Tetap produktif

1. Global Strategy for Asthma Management and Prevention, GINA Up Dated 2016, Page 36 Downloaded from
www.ginasthma.org
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 Tingkatan Kontrol Asma
pada Dewasa, Remaja dan Anak Usia 6-11 Tahun1
Karakteristik Gejala yang Dialami Pasien Asma:
1. Gejala harian lebih dari 2 kali seminggu
2. Terbangun dimalam hari karena asma
3. Penggunaan pelega lebih dari 2 kali seminggu untuk mengatasi gejala
4. Keterbatasan aktifitas karena asma

Kriteria Kontrol Pasien Asma:

 Pasien Asma Tidak terkontrol: mengalami 3-4 gejala diatas
 Pasien Asma Terkontrol Sebagian: mengalami 1-2 gejala diatas
 Pasien Asma Terkontrol dengan Baik: tidak alami satupun gejala diatas

1. Adapted from Global Strategy for Asthma Management and Prevention, GINA Up Dated 2016 Page. 31 Downloaded from www.ginasthma.org
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 Bagaimana cara mencapai
Asma Terkontrol?
Berikan pelatihan mengenai teknik penggunaan inhaler

Arahkan pasien untuk menggunakan obat secara teratur 

kegagalan pengobatan umumnya karena ketidak-patuhan memakai
obat pengontrol

Berikan pelatihan kepada pasien mengenai manajemen asma dan

monitor status kontrol asmanya untuk dapat terus mengontrol gejala
asma dan mengurangi risiko terjadinya eksaserbasinya.
Cek status & perbaikan asmanya dengan

Adapted from Global Strategy for Asthma Management and Prevention, GINA Up Dated 2016, Page. 42 Downloaded from www.ginasthma.org
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www.asthmacontroltest.com ID/SFC/0024/14(1) –
Asthma Control Test is a trademark of Quality Metric Incorporated AD. 20/01/2017 ED. 20/01/2019-
For HCP only
www.asthmacontroltest.com
Asthma Control Test is a trademark of Quality Metric Incorporated

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Asthma Medication

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

 Reliever
– Bronkodilator
– Dipakai saat serangan
 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
Step 1 Step 2 Medium- treatment
CONTROLLER e.g.
dose
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. 12
© 2016 Global Initiative for Asthma, all rights reserved. Use is by express license from the owner
The Difference in Outcomes:
Fixed Vs. Variable

13
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 Scicch O’Bryne Rabe Vogelme Kuna Bousque Weighted

et a 2 itano et al 4 et al 5 ier et al et al 7 t Averages
et al 3 6 et al8
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
day
Activity limitation
Exacerbation No No
due to asthma
What it is
Reliever ≤2x
No mean? Reliever
usage per
usage
week
Emergency visit No
Night awakening
morning PEF  No
normal due to asthma
80%
Asthma control
Drug related
adverse event
No cannot be
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

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
The Difference in Devices

22
Evaluating Drug Delivery

Inspiratory Flow

Ease of use &

critical error

Device Resistance Fine Particle Mass

Evaluating Drug Delivery

Inspiratory Flow

Ease of use &

critical error

Device Resistance Fine Particle Mass

Resistance of Various 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

Inspiratory Effort Needed

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
Evaluating Drug Delivery

Inspiratory Flow

Ease of use &

critical error

Device Resistance
Fine Particle Mass
 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
0 100 90 80 70 60 50 40 30 20 10 0
% doses remaining
200
DiskusTM consistently delivers the
180
160
medicine throughout itsTotal
working life
Emitted Dose
% Label

140
120 through Life
100
80
and over a wide range of flow rates
Delivered at 90 L/min
60 DISKUS™
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
Evaluating Drug Delivery

Inspiratory Flow

Ease of use &

critical error

Device Resistance
Fine Particle Mass
 Turbuhaler requires high Inspiratory flow rate to
deliver the correct amount of fine particle mass

25

20

Fine
Particle
15
Mass Diskus
(%) 10 Turbuhaler

0
28 L/min 60 L/min

Hill S., Slater A., A comparison of the performance of two modern multidose dry powder asthma inhalers, Respiratory Medicine (1998) 92,Pg
105-110
Evaluating Drug Delivery

Inspiratory Flow

Ease of use &

critical error

Device Resistance
Fine Particle Mass
 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
Handling inhaler devices in real life (observational
study)

Number of errors compromising treatment efficacy:

Molimard et al, J. Aer. Med. 2003, vol 16, 249 – 254

Device Conclusion

 Drug delivery will be affected by device performance in

related to: device resistance, inspiratory flow, FPM, ease of
use & critical error rate
– High resistance device need high inspiratory flow that will be difficult
to achieved by some patients such as old patients.

– Total emitted dose affected by different inspiratory flow rate in

turbuhaler, while Diskus consistently delivers the medicine throughout
its working life and over a wide range of flow rate

– Data show that Diskus is lower resistance, easy to use and have
lower critical error compare to Turbuhaler

Presentation title 34
Summary

 ICS/LABA combination are available, however mainly with 2 concepts:

– Fixed dose combination
– Adjustable dose combination

 Achievement of ASTHMA CONTROL defined by GINA guideline by the 2

concept: 71% by fixed dose vs 17% by adjustable dose
 The medicine are available in different kind of device. Knowledge and
understanding of device characteristic will benefit when you choose an
appropriate device for the patients.

– Turbuhaler need a high inspiratory flow to ensure reliable drug

delivery
– While DISKUS provide consistent drug delivery irrespective of
inspiratory flow rate

Presentation title 35
Thank you