Dr. Faisal Yunus, Ph.D, Sp.

P(K)

Dokter, FKUI, 1976

Ph.D, Hiroshima University, 1983
Dokter Spesialis Paru, FKUI, 1984

Staf Departemen Pulmonologi dan Ilmu

Kedokteran Respirasi, FKUI,
RS Persahabatan Jakarta
ADJUSTABLE THERAPY IN
ASTHMA MANAGEMENT

FAISAL YUNUS
Dept. of Pulmonology and Respiratory Medicine
Faculty of Medicine University of Indonesia
Persahabatan Hospital Jakarta
 Introduction

Asthma a global healthcare problem

Prevalence is increasing worldwide
Causes significant morbidity and mortality
Patients need continuous medical care
Major healthcare cost burden
 Introduction
The goal of asthma management is to
achieve controlled asthma
Better management could improve the
quality of life of the patients
Cost-effectiveness of treatment should be
put into consideration
 Definition of ideal asthma
control
No chronic symptoms
No need for p.r.n. 2-agonist
Infrequent exacerbations
No emergency visits
No limitations on activities, incl.
exercise
Normal PEF

GINA guidelines (abbreviated version)

Reaching ideal asthma control is challenging
due to the fact that asthma is a variable
disease

Poor
control

Increased use of reliever

Night time awakenings

Optimal
control
Time (months, weeks, days)

GINA guidelines
 Turbuhaler has characteristics of an
ideal inhaler
Ideal inhaler Turbuhaler

Easy to use Convenient, preferred by patients,

no co-ordination required

Effective High lung deposition,13 effective in

asthma in adults4,5 and children6

Safe Low oropharyngeal deposition,1,7

no propellants, no
preservatives
1
Bondesson E, et al (1996) 5
Nana A, et al (1998)
2
Thorsson L, et al (2001) 6
Pedersen S, et al (1990)
3
Borgstrm L, et al (1993) 7
Newman SP (1995)
4
Brown PH, et al (1995)
 Lung deposition with Turbuhaler

Newman SP (1995)
 Turbuhaler delivers more drug to the
lungs than Diskus
Lung deposition
(% of nominal dose)
50

40

30

20

10

0
Pulmicort Flixotide
Turbuhaler Diskus
Thorsson L, et al (2001)
 Turbuhaler clinically effective at
standard and low inspiratory flow rates
FEV1 (L)
4.0
Standard inhalation
conditions at peak
inspiratory flow of
84 L/min
Low inspiratory flow
3.5 (rate 30 L/min) through
entire inhalation

3.0
0 0.25 0.5 1 2 4
Cumulative dose of terbutaline (mg)
Adapted from Engel T, et al (1992)
 Turbuhaler is an effective delivery
device in acute severe asthmatics in the
emergency setting
60
Formoterol 3 x 18 g
50
Change in FEV 1(%)

via Turbuhaler
40
Salbutamol 3 x 800 g
30 via pMDI + spacer
20
Administration of
10 formoterol and
salbutamol
0

-10
0 40 80 120 160 200 240
Time since administration (minutes)

Boonsawat W, et al (2003)
 Is this the solution?
GINA/ NIH Guidelines Define optimum
Asthma Control
The Goal

GAP To prove optimum

asthma Control
in Asthma ICS + LABA
Control The proof

Defines current lack of

Practice Asthma Control
The problem
Asthma is a Variable Disease
Allergens Exercise
Viral infection Cold weather

Increased
Symptoms
Reliever
medication

time

Asthma
control

Decreased
Exacerbation Exacerbation
 Factors that induce asthma
variability
Allergens
Cigarette smoke
Respiratory infections
Exercise and hyperventilation
Weather changes
Air pollutants, e.g. sulphur dioxide
Food, additives, drugs
 Basic principles behind
adjustable maintenance dosing
Recognition that:
asthma is a variable disease
fixed-dosing regimens do not adequately
address this variability
an ideal treatment approach would allow an early
increase in therapy at the first sign of asthma worsening
providing patients with more flexible and effective
treatment
patients prefer fewer inhalers to control their asthma
thus a single inhaler is also desirable
Asthma is a variable disease
A traditional fixed-dose treatment approach results in
periods of poor control as well as periods of overtreatment

Undertreatment
Excessive rescue use
Courses of inhaled/oral steroids
Poor Asthma
control
control

Fixed
dosing
Optimal
control
Time
(months, weeks, days)
Overtreatment
Unnecessary drug intake
Unnecessary drug costs
+ reliever as needed
 Hypothesis :
Asthma control may be improved by providing
the right dose of drug at the right time

drug Asthma
inhalations worsening Asthma control

Quickly
gain
control
Step down to adequate
Maintain dose that maintains control
2 inh. control 4 inh.
bid bid*
1 inh. 1 inh. or 2 inh.
bid bid od

Time
+ reliever as needed (months, weeks, days)
*The dosage 4 inh. bid is within the SPC of the
monocomponents but outside the current SPC for Symbicort inh. = inhalation(s)
 Formoterol has a rapid onset of
action similar to salbutamol
Mean FEV 1 Formoterol 9 g
(% change from baseline) Formoterol 4.5 g
30 Salbutamol 200 g

25 Salbutamol 100 g
Placebo
20
15
FEV1 at 3 minutes after
10
inhalation: p<0.001 for
5 all active treatments
compared with placebo
0
0 5 10 15 20 25 30

Time after drug administration

(minutes)

Seberov E, Andersson A (2000)

 Budesonide has as rapid an onset of
action as prednisolone
Budesonide 1600 g
PEF (L/min) Budesonide 400 g
550 Prednisolone 40 mg

500

450

400

350

300
0 1 2 3 4 5 6 7 8 9 10 11 12
Time after drug administration (hours)

Ellul-Micallef R, Johansson SA (1983)

 Early intervention with an increased dose
of inhaled budesonide when asthma
worsens helps prevent severe
exacerbations
Days with oral steroids
p<0.001
120 p<0.001

100

80

60

40

20

0
BUD 400 g bid BUD 100 g bid BUD 100 g
+ placebo qid + BUD 200 g qid + placebo qid
Foresi A, et al (2000)
 Formoterol reduces severe exacerbations
more effectively than a higher dose of
budesonide in patients with mild to moderate
asthma Increasing BUD: p=0.069
Adding FORM: p<0.001
BUD 200 g + FORM vs BUD 400 g:
1.0
Exacerbations/patient/year

p<0.001

0.5

0
BUD 200 g BUD 200 g BUD 400 g BUD 400 g
+ FORM + FORM

OByrne PM, et al (2001)

Formoterol used routinely with inhaled
steroids reduces the rate of severe
exacerbations

Increasing BUD dose: p<0.001

1.0
Exacerbations/patient/year

Adding FORM: p=0.01

BUD 800 vs BUD 200 + FORM: p=0.03

0.5

0
BUD 200 g BUD 200 g BUD 800 g BUD 800 g
+ FORM + FORM

Pauwels RA, et al (1997)

 Formoterol+budesonide significantly
improves morning PEF
Morning PEF (L/min)
p<0.001 both treatments vs budesonide
400

390

380 Symbicort
Budesonide + formoterol
370
Budesonide
360

350

-10 0 10 20 30 40 50 60 70 80 90
Treatment days
Zetterstrm O, et al (2001)
 Symbicort has a faster onset

of effect than Seretide

25
* **
20 *
% increase in FEV1

15 *
10

0
* p<0.001 vs. SeretideTM ** p<0.001 vs. SeretideTM
-5
0 3 5 10 15 0.5 1 2 3
Minutes Hours
Symbicort 160/4.5 g 2 inhalations Seretide 50/250 g 1 inhalation
Symbicort 160/4.5 g 1 inhalation placebo

Palmqvist et al, Pulm Pharmacol Ther 2001

 Formoterol and
budesonide component
enables adjustable
maintenance treatment
 Formoterol+budesonide offers
tailored dosing according to the
needs of the individual patient
Quickly Asthma
gains control worsening
Asthma signs

Maintains Maintains
control control Reduce to
lowest adequate
dose that maintains
control
1x2 1x2
* 2x2 2x2 1x1

* Symbicort 160/4.5 g - 2 inhalations bid Time

+ reliever as needed
 Adjustable dosing increased the
time to first exacerbation
Fraction of patients with Adjustable dosing
no exacerbations
Fixed dosing
1.00
0.99
0.98
0.97
0.96
0.95
0.94
0.93
0.92
p=0.0501
0.91
0.90
0 30 60 90 120 150 180 210

Time after randomisation (days)

Olsson, et al. ERS 2002
 Formoterol+budesonide adjustable
dosing is more cost-effective than a
fixed dosing regimen
Costs SEK (Euro)
P<0.001
4500
4000
4124
3500
(445)
3000 3231 Adjustable dosing
2500 Fixed dosing
(349)
2000
1500
1000
500
0

Olsson, et al. ERS 2002

 Conclusions
The onset of formoterol bronchodilatory
effect is as rapid as salbutamol with a
duration of effect similar to that of
salmeterol
Budesonide has fast onset of action and
long duration of effect
Budesonide benefits in exacerbation control
with temporary dose adjustments
 Conclusions
Combination of inhaled Formoterol and
Budesonide effectively gains and maintains
control of asthma and allows patients to adjust
maintenance therapy according to the level of
their symptoms, as recommended in current
guidelines

Adjustable maintainance dosing provided greater

asthma controll and more cost-effective than
fixed dose treatment.
FY