Pulmicort versatile dosing

What means with versatile dosing of Pulmicort?" ]
Which dose range of Pulmicort Turbuhaler can be used in clinical practice?" ]
Is there an upper limit for a Pulmicort Turbuhaler daily dose?" ]
Should the starting dose of Pulmicort be high or low?" ]
How to use Pulmicort Turbuhaler to prevent patients from developing acute exacerbations?" ] 
Can Pulmicort be used for treatment of acute severe attacks of asthma?" ] 
When can once-daily dosing be used?" ] 

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 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.

Reference:
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.

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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-agoanists 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.

Reference:
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.

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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.

Reference:
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.

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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.

Reference:
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.

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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).

Reference:
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.

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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).

Reference:
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.

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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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