| 1. What means with
versatile dosing of Pulmicort? |
Pulmicort is available in
different strengths. Pulmicort dry powder inhaler, Turbuhaler®,
100 µg,
200 µg and 400 µg
per metered dose. Pulmicort is also available as a pressurized
metered dose inhaler, pMDI, 50
µg, 100 µg
and 200 µg per metered dose.
The pMDI can be
attached to a metal spacer,
NebuChamber®, or
to a large volume spacer, NebuhalerTM
(1). Finally, Pulmicort is available as a suspension for
nebulisation; 0,125 mg/mL, 0,25 mg/mL and 0,5 mg/mL.
Pulmicort can be given to
patients via different inhalation devices depending on the patient´s
age and clinical situation: dry powder inhaler (Turbuhaler®),
pMDI with or without a large volume spacer and suspension for
nebulisation (1,2).
Pulmicort can also be
administered over a wide daily dose range: 100 µg
to 1600 µg via Turbuhaler or
pMDI, and 0.25 mg to 2.0 mg as nebulised suspension.
Pulmicort can further be
administered once daily, twice daily and sometimes four times daily.
Once-daily dosing can improve compliance in patients with
well-controlled asthma.
References:
1. Bisgaard H,
et al. Spacer devices. In: Bisgaard H,
O´Callahan C, Smaldon GC (eds.) Drug delivery to the lung.
Marcel Dekker, New York 2002: 389-420.
2. Nikander K.: Drug delivery
systems. J Aerosol Med 1994; 7, Suppl 1: 386-388.
|
| 2. Which dose range of
Pulmicort Turbuhaler can be used in clinical practice? |
Doses of Pulmicort should be
individually adjusted depending on disease severity. For adult
patients the daily doses of Pulmicort vary from 100 µg
to 1600 µg daily. For
children the dose range is 100 µg
to 800 µg daily. However,
the majority of adult and children with asthma can be treated with
maximum daily doses of 800 µg
and 400 µg, respectively
(1,2).
In a clinical study in 207
patients, reported nine years ago, the mostly used starting dose of
Pulmicort Turbuhaler was 400 µg
twice daily, i.e. 800 µg
(Table 1). After a follow-up of two years 23 patients had been able
to discontinue the treatment and the applied daily doses varied from
200 µg to 3200 µg.
Today the doses of 800 µg
and above should probably not be used as combination therapy with
inhaled long-acting ß2-agonists
is preferred.
Doses of Pulmicort Turbuhaler in a
clinical study
Daily doses of budesonide
Turbuhaler initially, when changing treatment from pMDIs to
Turbuhaler, and after mean follow-up period of 26.2 ±5.7 months.
References:
1. Pedersen S, Ramsgaard-Hansen
O.: Budesonide treatment of moderate and severe asthma in children: a
dose response study. J Allergy Clin Immunol 1995; 95: 29-33.
2. Busse WW et
al. Budesonide delivered by Turbuhaler is effective in a
dose-dependent fashion when used in the treatment of adult patients
with chronic asthma. J Allergy Clin Immunol 1998; 101: 457-463
3. Selroos O et al.: Local
side-effects during 4-year treatment with inhaled corticosteroids -
a comparison between pressurized metered-dose inhalers and
Turbuhaler. Allergy 1994; 49: 888-890.
|
| 3. Is there an upper limit
for a Pulmicort Turbuhaler daily dose? |
In most countries the highest
daily dose of Pulmicort approved by the regulatory authorities is
1600 µg. From a medical
point of view it could be stated that there is no absolute upper
limit for Pulmicort. However, when increasing the dose for adult
patients above 800 µg per
day two facts need consideration.
1) The dose-response curve for
inhaled corticosteroids is flat. Increasing the dose of Pulmicort
above 1000 µg per day will
add little to efficacy (1). In a study in Australia, 61 patients with
severe asthma were randomized to 8-week double-blind treatment with
3200 µg or 1600 µg
of Pulmicort Turbuhaler (2). For a second 8-week period all patients
received 1600 µg per day.
This was followed by a 14-month open label period when the doses of
Pulmicort were individually adjusted based on patients´ asthma
symptoms. The effects of both initial doses were quite dramatic on
both lung function and bronchial hyperresponsiveness. However,
generally speaking, no differences were found between the initial
dosing regimens although more patients in the 3200 µg
group achieved histamine PD20 values within the normal
range. At the end of the study, the mean final prescribed doses were
848 µg in the group
receiving an initial dose of 1600 µg
and 981 µg in the group
receiving an initial dose of
3200 µg.
2) Adding a long-acting inhaled ß2-agonist to the
800 µg Pulmicort dose will
result in better asthma control and airway function than increasing
the dose of Pulmicort (3).
Nevertheless, it should be
remembered that even very high doses of Pulmicort are systemically
safer than doses of oral corticosteroids giving the same degree of
asthma control.
PD20
FEV1 histamine values during treatment with high doses of
Pulmicort Turbuhaler
Changes
in airway hyperresponsiveness (AHR) in patients with severe asthma
treated with Pulmicort Turbuhaler at initial doses of 1600 µg
per day or 3200 µg per day,
followed by dose reduction. A starting dose of 1600 µg
per day was sufficient to achieve optimal control of asthma in most
patients and mean maintenance doses consecutively fell to 800-900 µg.
References:
1. Busse WW et al.: Budesonide
delivered by Turbuhaler is effective in a dose-dependent fashion when
used in the treatment of adult patients with chronic asthma. J
Allergy Clin Immunol 1998; 101: 457-463.
2. Reddel HK
et al. Optimal asthma control, starting
with high doses of inhaled budesonide. Eur Respir J 2000; 16:
226-235.
3. Pauwels RA et al.: Effect of
inhaled formoterol and budesonide on exacerbations of asthma. N
Engl J Med 1997; 337: 1405-1411.
|
| 4. Should the starting dose
of Pulmicort be high or low? |
In order to rapidly achieve best
possible asthma control the starting dose of Pulmicort should
preferably be high. A double-blind randomised study also showed that
Pulmicort 800 µg per day
resulted in statistically significantly greater reductions in blood
eosinophil counts and serum markers of inflammation (ECP and EPX)
than the low dose, and in a statistically borderline greater change
in PC20 histamine (p=0.1) (1). However, there were no
difference between the doses regarding asthma symptoms and airway
function.
Comparative studies in patients
with newly detected asthma (and usually mild disease) have shown a
low initial dose to give the same asthma control as a four times
higher starting dose (2,3). In patients with asthma of longer
duration (>2 years) 400 µg
twice daily was statistically superior to 100 µg
twice daily regarding asthma symptoms, lung function and use of
reliever medication (3).
Further support for the use of a
low starting dose in patients with newly detected mild asthma comes
from the OPTIMA study (4) where 698 patients not previously treated
with inhaled corticosteroids received Pulmicort Turbuhaler 100 µg
twice daily with or without the addition of formoterol (Oxis®)
4.5 µg twice daily.
Treatment with Pulmicort alone improved asthma control and reduced
the risk of severe asthma exacerbations. The number of severe
exacerbations (hospitalisation, emergency room treatment, or an oral
steroid course, or a decrease in morning PEF of at least 25% below
baseline on two consecutive days) and poorly controlled days (days
with morning PEF at least 20% below baseline, more than two
inhalations of reliever medication over 24 hours compared with
baseline use, or night-time awakenings due to asthma) was reduced by
60% and 48%, respectively.
Thus, in newly detected mild
asthma a low starting dose will provide as good an asthma control as
a high dose, while a delay in treatment makes a higher initial dose
more effective.
Low vs. high dose in patients with
mild asthma
In this study (2), 84 patients
with normal airway function who had not previously been treated with
inhaled steroids were randomised to receive Pulmicort Turbuhaler 100 µg or 400 µg
twice daily for 1 month, after which all patients received Pulmicort
Turbuhaler 200 µg once daily
for 2 months. After 1 month, both treatments produced similar
improvements in PEF and asthma symptom scores, which were maintained
during subsequent low-dose maintenance therapy.
References:
1.
Tukiainen H et al. Comparison of high and
low dose of the inhaled steroid, budesonide, as an initial treatment
in newly detected asthma. Respir Med 2000;
94: 678-683.
2.
van der Molen et al. Starting with a higher
dose of inhaled corticosteroid in primary care asthma treatment. Am J
Respir Crit Care Med 1998; 158: 121-125.
3.
Selroos O et al.: A double-blind, randomized,
dose-response study with budesonide in asthma patients with short or
long duration of symptoms. Am J Respir Crit Care Med 1999; 159: A627.
4.
O´Byrne PM et al. Low dose inhaled budesonide and formoterol in
mild persistent asthma. Am J Respir Crit Care Med 2001; 164:
1392-1397.
|
| 5. How to use Pulmicort
Turbuhaler to prevent patients from developing acute exacerbations? |
In the FACET study (1) patients
with moderate severe asthma were treated with Pulmicort Turbuhaler
100 µg or 400 µg
twice daily with or without the addition of formoterol (Oxis®) 9 µg twice daily. A total
of 425 severe exacerbations were identified during the 12-month study
period (2). The higher Pulmicort dose prevented patients from
developing a severe exacerbation significantly better than the low
dose Pulmicort (Figure 1) (and the addition of Oxis further reduced
the risk of having a severe exacerbation).
After treatment for an acute
severe attack of asthma in the emergency department oral prednisolone
is often prescribed for prevention of further exacerbations.
Controlled studies have shown that high doses of Pulmicort can
replace oral steroids but with improved safety (3,4).
In a double-blind, randomized
trial 188 patients discharged from an emergency department after
having experienced an acute attack of asthma were treated with
50 mg
prednisone for 7 days. They were thereafter randomized to treatment
with Pulmicort Turbuhaler 1600 µg
per day (n=94) or placebo for 3 weeks (n=94) (5). After 3 weeks no
differences were seen in lung function between the groups but
significantly fewer patients in the Pulmicort group had a relapse
(Figure 2). The Pulmicort-treated patients also had significantly
better quality of life scores, asthma symptom scores and used less
reliever medication. Using this approach as few as 9 patients would
require Pulmicort to prevent one relapse.
These studies show that in
patients at risk of developing acute exacerbations of asthma a higher
dose of Pulmicort prevents patients better than a low dose. After
experiencing an acute attack Pulmicort appears to be able to replace
oral corticosteroids, which may be associated with a greater risk of
systemic glucocorticoid side-effects.
Reduction of exacerbation frequency
with higher dose of Pulmicort
One
of the most striking results in the FACET study (1) was a 49% lower
rate of severe exacerbations in patients receiving budesonide 400 µg
b.i.d. than in those receiving 100 µg b.i.d. The prevention of
exacerbations is believed to be a good indicator of overall control
of asthma and is one of the most important aspects of management from
the patient’s point of view.
Prevention of relapses after an
acute exacerbation with Pulmicort vs. oral corticosteroids
Kaplan-Meier
Relapse curve of patients treated with Pulmicort Turbuhaler 1600 µg
or placebo for three weeks after discharge from emergency department
(5).
References:
1. Pauwels RA et al.: Effect of
inhaled formoterol and budesonide on exacerbations of asthma. N
Engl J Med 1997; 337: 1405-1411.
2.
Tattersfield AE et al. Exacerbations of asthma: a descriptive study
of 425 severe exacerbations. Am J Respir Crit Care Med 1999; 160:
594-599.
3. Nana A et
al. High-dose budesonide may substitute for oral therapy after an
acute asthma attack. J Asthma 1998; 35:
647-655.
4. FitzGerald
JM et al. A randomized, controlled trial of
high dose, inhaled budesonide versus oral prednisone in patients
discharged from emergency department following an acute asthma
exacerbation. Can Respir J 2000; 7: 61-67.
5.
Rowe BH et al. Inhaled budesonide in addition to oral corticosteroids
to prevent asthma
relapse
following discharge from the emergency department: a randomized
controlled trial.
J
Am Med Ass 1999; 281: 2119-2126.
|
| 6. Can Pulmicort be used
for treatment of acute severe attacks of asthma? |
In a 6-month study the short-term
increase in the dose of an inhaled corticosteroid was studied at the
onset of an acute exacerbation (1). A total of 213 patients with
moderate severe asthma using BDP, 500-1000 µg
daily, received Pulmicort Turbuhaler 800 µg
twice daily for four weeks. They were thereafter randomised to
double-blind treatment with Pulmicort Turbuhaler 100 µg
or 400 µg twice daily, or to
treatment with 100 µg twice
daily plus 200 µg four times
daily at onset of an exacerbation. The addition of four-times-daily
budesonide significantly reduced the number of exacerbations and days
with exacerbations compared to the low dose Pulmicort group.
A meta-analysis has been
published which included six selected, randomized controlled trials
involving children and adults treated in the emergency room for acute
severe asthma with or without the addition of inhaled corticosteroids
(2). In these six trials 352 patients were studied; 179 inhaled
steroid-treated and 173 non-inhaled-steroid-treated. Two trials
compared inhaled plus systemic steroids versus placebo plus systemic
steroids; four trials compared inhaled steroids versus placebo.
Patients receiving inhaled steroids were less likely to be admitted
to the hospital (OR 0.30; 95% CI 0.16 to 0.57) and showed small
improvements in PEF (weight mean difference 8%; 95% CI 3% to 13%. It
was concluded that there is evidence of decreased admission rates for
patients with acute severe asthma treated with inhaled
corticosteroids. However, there was insufficient evidence that
inhaled steroid therapy results in clinically important changes in
lung function when used in acute asthma, and there is insufficient
evidence that inhaled steroids alone are as effective as systemic
corticosteroids.
Increase in the dose of Pulmicort
was effective when treating an exacerbation at its onset. The role of
inhaled corticosteroids alone for treatment of acute severe asthma
has not yet been established.
Effect of temporarily increased
doses of Pulmicort on top of low dose maintenance treatment
This
study (1) shows that in patients receiving a low maintenance dose of
budesonide (200 µg/day), a temporary (7-day) increase in
budesonide dose (to 1000 µg/day) at the first sign of worsening
asthma effectively manages an exacerbation as well as regular higher
doses of budesonide (800 µg/day).
References:
1. Foresi A et al. Low-dose
budesonide with the addition of an increased dose during
exacerbations are effective in
long-term asthma control. Chest 2000; 117: 440-446.
2. Edmonds ML
et al. The effectiveness of inhaled
corticosteroids in the emergency department
treatment of
acute asthma. A meta-analysis. Ann Emerg
Med 2002; 40: 145-154.
|
| 7. When can once-daily
dosing be used? |
A large series of controlled
clinical studies have been performed investigating the use of
Pulmicort once daily. It has been found that once-daily dosing of
Pulmicort can be used as an initial dosing regimen in patients with
mild-to-moderate persistent asthma (100 µg
to 400 (800) µg in adults
and 100 µg to 400 µg
in children, and as a dosing regimen when tapering the daily dose
after achieving asthma control with higher doses given twice daily.
Reference:
1. O´Byrne PM (ed).
Once-daily corticosteroid therapy in asthma: improving compliance
with budesonide - A seminar-in-print. Drugs 1999; 58 (Suppl 4):
1-53.
Once daily Pulmicort
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