Symbicort®: controlling asthma in adults

(SUPPLEMENTA),

Vol.96 (2002)

Sl6-S22

Symbicort@: controlling asthma in adults u.

LALLOO

Nelson

R. Mandela

Abstract

School of Medicine,

Inhaled corticosteroids

University

of Natal,

Durban,

reduce airway inflammation

South Africa

and bronchial

hyper-responsiveness

in asthma. Their

regular use is associated with a reduction in morbidity and mortality from asthma. International guidelines recommend their use as first-line treatment in asthma and the dose should be increased stepwise in accordance with asthma severity Short-acting

Pz-agonists are recommended

for use as reliever medication

for the acute relief of symptoms. Long-acting

b2-agonists have a sustained bronchodilator action but are not recommended for use as monotherapy in asthma, particularly because they laclc clinically relevant anti-inflammatory action.The seminal observation in a controlled trial that the addition

of salmeterol

to low-dose

inhaled beclomethasone

dipropionate

was superior

to doubling the dose ofthe

be-

clomethasone dipropionate was followed by several well-controlled studies that confirmed this observationThese included multinational and multicentre trials in large numbers of patients and the use of different inhaled corticosteroids and the two long-acting

Pl-agonists,

formoterol

and salmeterol.Therefore

level Aevidence

(randomized

controlled

trials

with a rich body ofevidence) is available for this recommendation. Based on this, updated asthma guidelines recommend the addition of long-acting /&agonists for chronic asthmathat is at least moderately severe or mild asthmathat is not well controlled

with low-dose

inhaled corticosteroids.

that included inhaled corticosteroids adherence to prescribed medication. development.

Attention

was therefore

focused on developing

combination

inhalers

and long-acting /Il-agonists in order to simplify asthma treatment and improve in a single inhaler) is one such Symbicort @ Turbuhaler@ (budesonide/formoterol

Studies to date in over 800 adult patients have confirmed

to double

is superior

that budesonide/formoteroI

the dose of budesonide monotherapy and at least as effective and safe as budesonide and formoterol in separate inhalers. These studies also demonstrate thatthere are no physico-chemical interactionswhen thetwo medications are combined in a single inhaler. Symbicort @in its easy to use formulation and inhaler device represents avaluable addition tothe pharmacological management 0

2002

of asthma.

Elsevier Science Ltd

do~:10.1053/rmed.2001.1233, avaIlable online at http: //www.

ldealibrary.com

INTRODUCTION

on

IDE

inflammatory

treatment

(1,5). A stepwise Asthma

is a chronic

ways, which

inflammatory

arises from

a complex

cells, such as eosinophils, (1,2). The

inflammatory

toms

of the disorder.

interaction

Asthma

(KS),

and mortality Several

awareness

attempt

asthma

remain

national to improve

incidence

unacceptably

guidelines asthma

ICS as the

at any time 5 and 10% of

of the inflammatory

nature

and the

morbidity

high (1,2,4).

care. These

most

ity is recommended. treatment

guidelines

Institutes

of Health

effective

long-term

such (NIH) anti-

is

of normal

levels, prevention mal side-effects Short-acting well

the

are main-

normal

symptoms,

and the provision

One the

/!&,-agonists

controlled

are

or

of drugs with

prescribed

short-acting

then there

at improving of the obstacles

The

mini-

on

an ‘as

If asthma

/Iz-agonists

are

is a need to increase b2-agonist.

The

Pz-agonist

lung function

the

combiis more

and symptoms

than

the dose of ICS (6,7).

population

ment.

activity

prevention

(I).

of an ICS and a long-acting

effective

of

control

treatment

function,

dose of ICS or add a long-acting

should be addressed to: Professor Umesh Lalloo,

Durban, South Africa. Fax: +27 31 260 4420; E-mail: [email protected]

pulmonary

used too frequently nation

esca-

or step-down on

needed’ basis for the acute relief of symptoms.

Nelson R. Mandela School of Medicine, University of Natal, Private

Bag7 Congeila4013,

step-up

depending

of troublesome

of exacerbations,

increasing Correspondence

Likewise

suggested

with

with the asthma sever-

achieved. The main goals of asthma tenance

is not in an

to drug treatment

lating doses of ICS commensurate

role of inhaled corti-

have been developed

as the one from the National recommend

of many

and symp-

may develop

of the disease and the established costeroids

air-

of the disease forms the

hyper-responsiveness

during a person’s life and involves between adults (3). Despite

of the

mast cells and T lymphocytes nature

basis for the bronchial

disorder

for all grades of asthma severity

approach

is poor

reasons

for

to optimizing adherence poor

asthma

control

to prescribed

adherence

include:

in

treata) the

SYMBlCORT@: CONTROLLING

negative need

perception

of KS;

for continued

provement;

b) failure

medication

c) poor

cated treatment

ASTHMA

inhaler

regimens

IN ADULTS

to understand

the

Formoterol

symptomatic

im-

duration

after

technique;

and d) compli-

(5). Patient

education

in achieving the goals of asthma treatment adherence

to treatment

(I). Prescribing

agonist and an ICS in separate ment

and contributes of

inhaler

should improve

ICS

and

Symbicort@

terol

The

components

acting

that

a dry powder of

istered

ministered proves

de-

individual describes

of ICS with

the

In the treatment

formo-

experience

is a well-established

of chronic

persistent

local anti-inflammatory peutically

effective

mized systemic

increase the riskof control.The

desonide

persistent

for moderate

via theTurbuhaler@

is between

Formoterol

that

good

with a lower

dose of budesonide

with

courses

short

(800 pg day-‘) buhaler@

of

(II). Budesonide

is considered

to fluticasone

Inhaled

ICS reduce

for

treatment

treatment

moterol

which

can be prevented

with budesonide Patients require

be safe and well tolerated

comparable

in patients with chronic asthma formoterol

also has a

and has a tolerability /3z-agonists

profile

such as salbu-

and can be used as needed

efficacy

and tolerability

for periods response

(27).

of formoterol

of up to 5 years without or diminished

controlled

that the addition

inhaled

convincingly budesonide

years

asthma con-

4 weeks. They daily treatment

together

desonide

equipotent

reduced

has

hyper-responwithdrawal

broncho-

70-80%

of asth-

of treatment

then

randomized

the

(I2 pg) produced

alone.These sistent

volume and

twice-

100 pg of bu-

400 pg of budesonide;

reduction

for I2

(IOOpg a greater dose

the

com-

plus formo-

improvement

in forced

(FEV, ) compared

of

budesonide

with

treatment

that in subjects with per-

addition

and lung function

was achieved with

or 4OOpg)

in one second

lower

were

plus formoterol.The

findings confirmed

asthma

symptoms

to receive

was added to the lower dose

greatest

of budesonide

higher

(18-70 daily for

plus l2,~g of formoterol

formoterol

of budesonide.The bination

twice

rates of severe and mild exacerbations

when

to

doses of

patients

400,~g

with: 100 pg of budesonide;

of budesonide

expiratory of

were

the higher dose of budesonide

terol

852 adult

budesonide

dem-

of formoterol

to increased

plus I2 ,ug of formoterol;

months.The

(10,12,13).

baseline,

received

asthma

trial, Pauwelsetal.

was superior

(17). At

old)

achieved

(14). Budesonide

weeks

In a l-year randomized, onstrated

by the Tur-

exercise-induced

of

formoterol

and reduces

improves exacerbation

rates. controlled

with

Several

low-dose

therapeutic

&-agonist.

have indicated than

doses of for-

CONCURRENT USE OF BUDESONIDE AND FORMOTEROL

or 400,~g

and these include increasing

ination offers better

Daily

dose have been shown to

short-acting

and terbutaline

budesonide

as well as bronchial

by 3-6

with

long-term

budesonide

suppression

in about

of ICS or adding a long-acting

in lung function

be

of

following

in treatment.

tions are available trials

mini-

(9,16).

not adequately

step-up

controlled

doses

against bronchial

occurs

(23-26).

up to 90 ,ug delivered

of

side-ef-

moderate

administered

3 months

to be safe at

trol (23).

by DiskhalerTM (8) and has been

(15). In addition,

constriction matics

up to

sympformo-

for maintenance

has been reported

dose of bu-

(200 pg day-‘)

in asthma

been shown to protect

asthma

to salmeterol,

to and higher than those recommended

evidence of reduced

administered

could

inflammation

hyper-responsiveness siveness

with

to have less adrenal

im-

symptoms

doses equivalent

window

ICS, very high

to be approximately

propionate

demonstrated

formoterol

asthma

(21,22).

therapeutic

with

systemic

asthma

higher

bz-agonists

wide

allows thera-

optimal

control

a

ad-

has also been demonstrated

to date

400 and 8OOpg day-’ (I).

study in 213 patients

demonstrated

in contrast

well with

/Iz-agonists

and exercise-induced

to salmeterol,

dose of ICS should be

used to achieve asthma

A 6-month

activity

effects (8,9). As with other

effective

controls

In contrast

Its high ratio

doses to be administered

fects (IO) and the lowest

and

has a

ICS in the man-

asthma.

to systemic

doses of budesonide

(18). Like salmeterol,

function

(25).

EFFICACY OF BUDESONIDE AND FORMOTEROL budesonide

route. This compares

long-

of adults with asthma.

agonist that

I2 hours when admin-

has a rapid onset of action similar to that observed

The

Inhaled

orally

lung

such as nocturnal terol

flz-receptor

of action of short-acting

toms (19,20). However,

tamol

agement

by the inhaled

similar duration

the

inhaler

the

This article

the combination

and reviews

with Symbicort@

combines

PI-agonist,

safety

are well established.

Pz-agonists

in a single

is a selective

of action of approximately

with short-acting

treatment

and

behind

treat-

Thus the avail-

Pa-agonists

and the long-acting

efficacy

the rationale

fiz-

adherence.

in a single Turbuhaler?

vice.

and improving

inhalers complicates

long-acting

is a new

ICS, budesonide,

is vital

a long-acting

to non-adherence.

ability

Sl7

symptom

that

control

increasing

the

ICS op-

the dose

Several latter

wellcomb-

and improvement

the dose of ICS (6,717).

The concern

relating

to the addition

agonists to ICS compared is that the underlying this may predispose

inflammation to a more

that

exacerbation

addition of formoterol

rates

may be masked above,

were

to budesonide

pz-

the dose of ICS

severe exacerbation.

study by Pauwels et al., described strated

of long-acting

with increasing

clearly

reduced

and The

demonwith

the

(17). A recent study

RESPIRATORYMEDICINE

Sl8

used eosinophils

in induced sputum as a marker of airway

In the first of these studies (Study I) Symbicort@

(bu-

inflammation and compared low-dose budesonide (lOO,ug twice daily) and formoterol (l2pg twice daily) to

desonide/formoterol 160/4*5pg; a dose of two inhalations twice daily (b.d.)) was compared with an equiva-

a higher dose of budesonide (4OOpg twice daily). There was a 4-week run-in period during which time all pa-

rate inhalers and budesonide

tients received high-dose budesonide alone, after which they were randomized to combination treatment (low-

(Table I). In the second study (Study 2) Symbicort@ (budesonide/formoterol 80/4*5 pug; one inhalation b.d.) was

dose budesonide and formoterol)

compared with budesonide (200 pg b.d.) monotherapy (Table I). The doses of budesonide in the Symbicort@

ide alone

(28). There

was

eosinophils in either group. confirmed that the addition

and high-dose budesonno difference

in sputum

Several other studies have of a long-acting /Iz-agonist

does not compromise asthma control (6,729). Therefore, the addition of a long-acting /&-agonist preference treatment

in

to increasing the dose of ICS in ‘stepping-up’ has been shown to be beneficial without

com-

promising asthma control in terms of: a) symptoms; b) lung function; and c) airway inflammation. We may also conclude that level A evidence (randomized

control

trials

lent dose of budesonide

preparation

and formoterol

given via sepa-

(4OOpg b.d.) monotherapy

were measured as delivered

dose and were

equivalent to the metered dose of budesonide istered via separate inhaler. At baseline,

patients

were

admin-

not fully controlled

mean daily dose of approximately

400,ug

on a

ICS (31) and

lOOO,ug ICS daily (30) (Table I). All patients had experienced asthma for at least I2 years, had a low number of symptom-free days and the mean FEV, was on average 73-82% of the predicted normal, with approximately

and a rich body of evidence) exists for the recommendation that the addition of a long-acting /&-agonist is pref-

22% reversibility.

erable

tory flow (PEF), FEVr and forced vital capacity (FVC) as an objective measure of treatment efficacy. Other out-

to

increasing

asthma treatment.

the

dose of ICS in ‘stepping-up’

In this context

the combination

of

formoterol and budesonide appears to be beneficial and the development of a singleTurbuhaler inhaler combining these drugs was a logical progression.

SYMBICORT@ CONTROLLING ASTHMA IN ADULTS Symbicort @ Turbuhaler @ is a dry powder inhaler containing both budesonide and formoterol. Here we report the efficacy and safety of Symbicort@

in two

multicentre, multinational, over 800 patients (30,31).

studies involving

double-blind

l2-week,

Lung function

was assessed in terms of peak expira-

come measures included use of reliever medication,

total

asthma symptom scores, nocturnal awakenings, symptom-free days and asthma-control days. Chdnge in use of reliever medication was also assesse<:.

Symbicort@ is significantly more effective than budesonide alone In both studies, considerable tion

and outcome

patients

who

SymbicortO

improvements

measures

received

I2

were

in lung func-

observed

weeks’

treatment

compared with baselinevalues.The

in those with morning

SYMBICORT?

CONTROLLING

ASTHMA

Sl9

IN ADULTS

group

compared

studies,

the

(P
with

budesonide

difference

in Study

I. The

days was significantly with

Symbicort@

medication

was

not

(P
during

desonide

alone.These

required

*P= 0.002; **P
outcomes as no asthma

Figure I.

Between-group

PEFfollowing

difference

12weelcs’treatment

in morning and evening

with Symbicort@or

ide alone in two studies (Study I: Symbicort” moterol nide

budeson-

(budesonide/for-

160/4.5 pg, two inhalations twice daily (b.d.)) vs budeso-

2OOblg,

two

inhalations

(budesonide/formoterol

b.d.;

Study

2:

Symbicort@

80/4.5 pg b.d.) vs budesonide

200 fig

onstrate

the significant

bicort”

in adults who are poorly

and confirm

dose budesonide

these

compared

(P< 0.01) more

budesonide

results

improvement

the advantage

days medi-

In both studies, Sym-

with

(Figure

bu-

in the com-

asthma-control

awakening.

therapy

greater

no use of reliever

achieved significantly

days compared

reliever

than with

reflected

of

symptoms,

2). Overall

monother-

significantly

treatment

measure

treatment

asthma-control

was

results were

posite

in both studies

budesonide

of days when

Symbicort@

defined

bicort@

with

in both significant

of symptom-free

improved

number

cation and no nocturnal Study 2

Study 1

proportion

compared the

monotherapy statistically

(P
spy. Furthermore, 0 Morning PEF Evening PEF

being

mono-

clearly

dem-

achieved with Sym-

controlled

on ICS alone

of adding formoterol

to low-

with doubling the dose of bu-

desonide.

b. d.),

and evening

PEF increased

tent in Symbicort@ ide monotherapy were

(Figure

demonstrated

ide/formoterol pared

with

were

significant

seen after

the group

that

was

ide. Symbicort@ monotherapy measured asthma

I). In Study

pg; two alone

in

in both

symptom

(400,ug treatment

a two-fold more

all (Table

scores were

(budesonb.d.)

com-

An additional tion retain

the

in lung function

strated

with

ment

over doubling

than

budesonide

significant

outcomes

2a and b). The

total

in the Symbicort@

with

difference

days, days when

medication

symptom

no reliever

of formoas demon-

Symbicort@

budesonide

(30) there

with respect

asthma

interacmolecules

has been shown to

by the addition

et al. (17). When

separately

ing PEF, total

liever

gained

was compared

individual

complex

the dose of budesonide

by Pauwels

administered

two

device. SymbicortO

advantage

in budeson-

lower

is that a physico-chemical

by combining

into one inhaler terol

compared

concern

may occur

b.d.). In Study 2

increase

effective

improving studies

ex-

I improvements

inhalations

improvements

Symbicort@ received

greater

than in those with budeson-

in FEV, for Symbicort@

l60/4.5 budesonide

statistically

to a significantly

patients

Symbicort@ is as effective as budesonide plus formoterol administered separately

treat-

and formoterol

was no statistically

to: morning scores,

medication

and even-

symptom-free

was used and re-

usage. Thus, Symbicort@)

retains

the

RESPIRATORYMEDICIIVE

(a) Study 1 50 r 45

Study 1

g

40

$ g 5 g 4 4

35 30 25 20 15 10 5 0

Symbicort@ H Budesonide

+

formoterol ?? Budesonide

Study 2 (b) Study 2

*:p = 0.002; **P < 0.001 - Symbicort@ Figure 2. following

Between-group

difference

12 weelcs’treatment

alone in two studies

with

(Study

formoterol efkacy

80/4.5

easy-to-use

individual

patients

but has

in a single,

40

5 35 5 30 b 25 g 20 2 4

drug components,

of being administered

is well tolerated

and tolerability who

budesonide

(budesonide/

2OOpg b.d.).

-

Symbicort@ CIBudesonide

15 10 5 0

inhaler that can be used at a range of doses.

Symbicort@ Safety

(budesonide/formo-

b.d.; Study 2: Symbicort@

the added advantages

days

or budesonide

twice daily (b.d.)) vs budesonide

pg b.d.) vs budesonide

of the two

in asthma-control

Symbicort@

I: Symbicort@

terol 160/4.5 pg, two inhalations 20O,~g, two inhalations

vs budesonide

were

received

Symbicort@,

and formoterol

sonide monotherapy.

assessed

Figure 3. in a total II5 who

of 353

received

and 361 who received

Symbicort@

was well tolerated

budeand

Most frequently

weelc multinational ide/formoterol budesonide inhalations,

+ formoterol

adverse events in two 12. I: Symbicort@

Study 2: Symbicort@ budesonide

2OOpg, two inhalations

(budesonide/formoterol

200 pg b.d.

(budeson-

twice daily (b.d.)) vs

(200 pg + 4.5 pg, respectively;

b.d.) vs budesonide

groups (Figures 3a and b).The

reported

reported (a) Study

160/4.5 pg: two inhalations,

the adverse event profile was similar across all treatment most commonly

studies.

80/4.5

two

b.d.; (b)

pg b.d.) vs

SYMBICORT@: CONTROLLING

adverse

event

ations

was

due to

asthma)

respiratory

adverse

occurred

quency

(12%

inhaled

corticosteroid

of

candidiasis,

rate

were

in all groups.

(budesonide/formoterol

and no pattern

Symbiinhala-

well tolerated

as Symbicort@

80/4.5 pg b.d.) indicating

control

BJ. Systemic adverse effects of inhaled corticosteroid

1999; 159: 941-955. II.

Foresi A, Morelli MC, Catena E. Low-dose budesonide with the addition of an increased dose during exacerbations is effective in longterm asthma control.Chest 2000; 117: 440-446. Clark D, Grove A, Cargill RI, Lipworth

BJ. Comparative

adrenal

suppression with inhaled budesonide and fluticasone propionate in

it

adult asthmatic patients.Thorox 1996; 51: 266.

and formoterol

is lost due to an increase

efficacy in asthma

therapy: a systematic review and meta-analysis. Arch lniern Med

I2

that

Am ] Resplr Cn’t Care Med

pharmacological properties, and therapeutic and rhinitis. Drugs 1992; 44: 375-407.

of

effects.

Efficacy and safety of inhaled

Brogden RN, McTavish D. Budesonide. An updated review of its

IO. Lipworth

160/4.5 ,ug; two

is safe to increase the dose of budesonide if asthma

9

low fre-

Undesirable

Barnes PJ, Pedersen S, Busse WW corticosteroids. New developments. 1998; 157: SI-S53.

such as dysphonia

also rare

formoterol

tions b.d.) was as equally

such as tre-

a similar

to indicate systemic

(budesonide/

8

of

in all treatment

seen with

class effects, were

worsening

class effects,

patients)

events was observed tort@

a similar

s21

Discontinu-

(including

&agonist

mor and palpitations,

IN ADULTS

infection.

events

at

groups. Undesirable

and oral

ASTHMA

in asthma

13. Grahnen A, Jansson B, Brundi N et al. A dose-response study comparing suppression of plasma cortisol induced by fluticasone pro-

severity.

pionate

from

Diskhale?

and budesonide

from Turbuhaler?

Eur/ C/in Pharmacol 1997; 52: 261-267. 14. Juniper EF, Kline PA, Vanzieleghem MA, Ramsdale EH, O’Byrne PM,

CONCLUSION

Hargreave FE. Long-term effects of budesonide on airway responsiveness and clinical asthma severity in inhaled steroid-dependent

Modern

asthma

long-acting low-dose

guidelines

/&agonist

recommend

when asthma

ICS. Level A evidence

is available

ommendation.

Symbicort@

more effective

than budesonide

whose

is not fully controlled

asthma

ministration

of Symbicorta

ated as concurrent two

active

tort@ priately

appears

is as effective

manage the variability

budesonide after a year of increased use: a randomized controlled

lb. Vathenen AS, Knox AJ, Wisnieski KA, Tattersfield AE. Effect of in-

Ad-

haled budesonide on bronchial reactivity to histamine, exercise, and eucapnic dry air hyperventilation

and well tolerof the

and formoterol.

Symbi-

required

seen in

I% Pauwels RA, Lofdahl C-G, Postma DS et al. Effect of inhaled formoterol and budesonide on exacerbations

management

avaluable

addition

of asthma. The

are being investigated

further

logical properties

and therapeutic

efficacy in the management of

asthma.Drugs 1998; 55: 303-322. 19. Kesten S, Chapman KR, Broder I et al. A three-month of twice daily inhaled formoterol

in on-

1991; 144: 622-625. 20.

Pearlman DS, Chervinsky

P, Laforce C et 01. A comparison of

salmeterol with albuterol in the treatment

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