Pulmicort Respules®

What is the indications for Pulmicort Respules in children?
What is the indications for Pulmicort Respules in adults? 
In what types of nebulizers can Pulmicort Respules be used? 
Together with which other nebulized therapies can Pulmicort Respules be mixed? 
In which age groups can Pulmicort Respules be used? 
Doses of Pulmicort Respules compared with Pulmicort pMDI 
Is there a dose-response relationship for Pulmicort Respules? 
Can Pulmicort Respules be administered once daily? 
Can Pulmicort Respules be used for treatment of acute severe asthma? 
What is the safety profile of Pulmicort Respules?

What is the indications for Pulmicort Respules in children?

Pulmicort Respules is indicated in children 6 months and older requiring maintenance treatment with an inhaled corticosteroid but unable to use Turbuhaler or a pMDI with spacer (1,2). Although not approved Pulmicort Respules has been documented for the treatment of acute exacerbations of asthma.

In addition, in many countries Pulmicort Respules is also indicated for treatment of croup (3).

Reference:
1. National Institutes of Health, National Heart, Lung and Blood Institute. Pocket guide for asthma management and prevention. Bethesda: US Department of Health and Human Services, Public Health Service, National Institutes of Health, National Heart, Lung, and Blood Institute, 1998. Publication number 96-3659B.

2. Hvizdos KM, Jarvis B. Budesonide inhalation suspension. A review of its use in infants, children and adults with inflammatory respiratory disorders. Drugs 2000; 60 (5): 1141-78.

3. Ausejo et al.: The effectiveness of glucocorticoids in treating croup: a meta-analysis. Br Med J 1999; 319: 595-600.

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What is the indications for Pulmicort Respules in adults?

Pulmicort Respules is indicated for maintenance treatment of adult patients with asthma (1). Respules are especially useful in patients unable to correctly use Pulmicort Turbuhaler or Pulmicort pMDI with or without a large volume spacer.

Although not approved Pulmicort Respules has been documented for the treatment of acute exacerbations of asthma and COPD (2,3).

Reference:
1. Hvizdos KM, Jarvis B. Budesonide inhalation suspension. A review of its use in infants, children and adults with inflammatory respiratory disorders. Drugs 2000; 60 (5): 1141-78.

2. Higenbottam TW et al.: Comparison of nebulised budesonide and prednisolone in severe asthma exacerbations in adults. Bio Drugs 2000; 14: 247-254.

3. Maltais F et al.: Comparison of nebulized budesonide and oral prednisolone with placebo in the treatment of acute exacerbations of chronic obstructive pulmonary disease: A randomized controlled trial. Am J Respir Crit Care Med 2002; 165 (5): 698-703.

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In what types of nebulizers can Pulmicort Respules be used?

The choice of nebuliser/compressor system for nebulisation of budesonide is important. Ultrasonic nebulisers cannot be used for nebulisation of suspensions, as suspended particles only to a limited extent will enter the ultrasonically produced water droplets.

New types of ultrasonic nebuliser, such as Omron™ and the Pari eFlow™ (Seeman et al, 2003), which use a different technique to generate the aerosol, can produce an aerosol containing budesonide from Pulmicort suspension for nebulisation. However, the clinical efficacy and safety with Pulmicort Respules has not been established with any of these devices.

A large number of jet nebulisers have been tested. The figure shows the delivered doses in per cent of labelled dose for 29 different nebuliser/compressor systems. When an efficient nebulising system is used, more than 80% of the droplets have diameters within the respirable range of less than 5 µm (2,3).

Delivered and fine particle doses of Pulmicort Respules from different nebulizers
 

Delivered doses (as percentages of labelled dose) obtained with 29 different nebuliser/compressor systems (Smaldone et al, 1998; Nikander et al, 2003). The particle size distribution was studied with 15 of these systems: 1, Pari LC Plus/Pulmo-Aide; 2, Pari LC Plus/Pari Master; 3, Intertech/Pulmo-Aide; 4, BaxterMisty-Neb/Pulmo-Aide; 5, Hudson T Updraft II Neb-U-Mist/Pulmo-Aide; 7, Hudson T Updraft II Neb-U-Mist/Hudson; 8, Ventstream/Passport; 9, Hudson Ava-Neb/Pulmo-Aide; 10, Aiolos/CR60; 11, Ventstream/Pulmo-Aide; 13, Pari LC Jet/Pari Master; 14, Hudson Ava-Neb/Hudson; 15, Pari LC Jet/Pulmo-Aide; 16, DeVilbiss Pulmo-Neb/Pulmo-Aide Traveller; 22, DeVilbiss Pulmo-Neb/Pulmo-Aide. The names of all systems are protected by trademarks (TM) or registered trademarks (®).

Reference:
1. Smaldone GC et al.: In vitro determination of inhaled mass and particle distribution for budesonide nebulizing suspension. J Aerosol Med 1998; 11: 113-125.

2. Berlinski A, Waldrep JC. Effect of aerosol delivery system and formulation on nebulized budesonide output. J Aerosol Med 1997; 10: 307-318.

3. Nikander K, et al. Budesonide inhalation suspension delivered via Ventstream breath-enhanced jet nebulizer. Am J Respir Crit Care Med 2003; 167 (7 Suppl): A895.

4. Seemann S, Schuschnig U, Waldner R, Hug M, Keller M, Knoch M. In-vitro characteristics of the PARI eFlow(TM) electronic inhaler. American Journal of Respiratory and Critical Care Medicine 2003; 167(7 Suppl): A94.

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Together with which other nebulized therapies can Pulmicort Respules be mixed?

One advantage of nebulised therapy is the possibility of co-administration of different drugs. For Pulmicort Respules studies have been performed asserting compatibility in mixing with normal saline, albuterol, levalbuterol, terbutaline, fenoterol, cromolyn, ipratropium and acetylcysteine.

These studies have shown that mixing does not alter the physical or chemical properties of any of the drugs in the admixture under controlled laboratory conditions (1-5).

Reference:
1. Harriman AM, et al. Can we mix nebuliser solutions? Stability of drug admixtures in solutions for nebulisation. Pharmacy in Practice 1996; 6(9): 347-48

2. Roberts GW, Rossi SO. Compatibility of nebuliser solutions. Australian Journal of Hospital Pharmacy 1993; 23: 35-7.

3. Smaldone GC, et al Budesonide inhalation suspension is chemically compatible with other nebulizing formulations. Chest 2000, 118, 98S.

4. McKenzie J et al. Pulmicort Respules is chemically compatible with nebulized Xopenex. Am J Respir Crit Care Med 2001, 163, A588.

5. Grönberg S et al. Chemical compatibility of budesonide inhalation suspension (Pulmicort Respules) with other nebulization products. Am J Respir Crit Care Med 2001, 163:A588.

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In which age groups can Pulmicort Respules be used?

Already newborn babies can be given budesonide suspension for nebulisation. Like young children the infants need a facemask that has to be as tight as possible. The use of a loose-fitting mask will reduce efficiency of drug delivery and expose the facial skin to the drug. However, one advantage with nebulised therapy is that even when using a poorly fitting face mask (as can be the case in uncooperative infants), still some drug will be delivered, which is not the case when using a pMDI and spacer. The mask should be vented, allowing excess steroid to escape in a controlled way without contaminating the eyes.

Older children can use a mouthpiece instead of the facemask as inhalation through the mouthpiece maximises drug delivery.

Poorly fitting face masks with spacer and nebuliser
 

The effects of a poorly fitting facemask on aerosol delivery from a pMDI plus valved spacer and a conventional nebuliser. In contrast to spacer, a nebuliser will still provide at least some drug aerosol to the child.

Reference:
Nikander K.: Drug delivery systems. J Aerosol Med 1994; 7, Suppl 1: 386-388.

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Doses of Pulmicort Respules compared with Pulmicort pMDI

In a study in 26 adult patients with moderately severe asthma Pulmicort was administered as pMDI with a large volume spacer, 800 µg twice daily, and as 1 mg and 4 mg twice daily via a Pari Inhaler Boy jet nebuliser (1). Nebulisation was synchronised with inspiration to avoid loss of aerosol during expiration. The plasma budesonide concentrations, expressed as 2-hour AUC, were dose-dependent and independent of the delivery device (Figure). Pulmicort Respules produced significant improvements in breathlessness and wheeze compared with pMDI and similar trends were seen for other variables. The 4 mg twice-daily dose of Respules also produced significantly greater improvements in PEF and ß2-agonist use compared with administration via pMDI. However, no difference between the two Respules doses was found.

Based on this study it can be concluded that the clinical efficacy of Pulmicort administered by nebulizer or pMDI and a large volume spacer are similar (1).

Pulmicort delivered via nebulizer or pMDI with spacer
 

Plasma budesonide concentrations, expressed as 2-hour AUC in adult patients treated with Pulmicort 800 µg twice daily via pMDI plus spacer, or Pulmicort Respules 1 mg and 4 mg twice daily (Bisgaard et al, 1998). Budesonide concentrations were dose-dependent and independent of the delivery device.

Reference:
1. Bisgaard H et al. Comparative study of budesonide as a nebulized suspension vs pressurized metered-dose inhaler in adult asthmatics. Respir Med 1998; 92: 44-49.

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Is there a dose-response relationship for Pulmicort Respules?

In patients with stable asthma inhaled corticosteroids, irrespective of delivery system, have a flat dose-response curve. A factor of four is usually required in clinical studies to demonstrate a significant difference between doses.

Depending on the variability in lung deposition when using nebulizers it has been very hard to establish dose-response relationships for Pulmicort Respules. Several studies have been performed using more than one dose level and the results have been compared with placebo (1). Usually all doses, 0.25 mg once or twice daily, 0.5 mg once or twice daily, and 1 to 4 mg twice daily have been better than placebo regarding symptom control and changes in lung function. However, statistically significant differences between doses have usually not been found, and not in a consistent manner.

This is illustrated in a study in 102 children with stable asthma (age 5-47 months) who were treated with Pulmicort Respules, 0.25 or 1 mg twice daily, for 18 weeks (2). When symptom control was achieved at 5-week control intervals, the dose was reduced. The clinical effects were good with both doses. An overall minimal effective dose could not be determined but 47% of the children achieved symptom control on 0.25 mg twice daily. It was concluded that Pulmicort Respules doses should be individually adjusted to the lowest possible dose, which maintains good asthma control. Other clinical studies have shown results of similar type.

Clinical experience has shown that children with mild asthma already benefit from daily maintenance doses of 0.25-0.5 mg Pulmicort Respules. Children with moderate asthma may require 0.5-1.0 mg per day, and children with severe asthma 1.0-2.0 mg per day (3).

Reference:
1. Szefler SJ. A review of budesonide inhalation suspension in the treatment of pediatric asthma. Pharmacotherapy 2001; 21: 195-206.

2. Wennergren G et al. Nebulized budesonide for the treatment of moderate to severe asthma in infants and toddlers. Acta Paediatr 1996; 85: 183-189.

3. Hvizdos KM, Jarvis B. Budesonide inhalation suspension. A review of its use in infants, children and adults with inflammatory respiratory disorders. Drugs 2000; 60 (5): 1141-78.

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Can Pulmicort Respules be administered once daily?

The efficacy of once-daily budesonide has been investigated in two large placebo-controlled studies in children with asthma (1,2). In a 12-week study in 359 children, aged 6 months to 8 years, with mild asthma not maintained on inhaled steroids the daily doses of 0.25 mg, 0.5 mg and 1.0 mg once daily were administered. All three budesonide doses improved asthma symptoms and reduced the need for ß2-agonist reliever medication compared with placebo. No differences were found between the budesonide doses (1).

In another 12-week study in 480 infants aged 7 to 108 months with moderate persistent asthma 0.25 mg or 1.0 mg budesonide once daily were compared with placebo and 0.25 mg and 0.5 mg twice daily (2). App. 38% of the infants had earlier been on treatment with corticosteroids but that treatment was discontinued before the study. No differences were found between the 1.0 mg once-daily dose and the b.i.d. dosing regimens. The 0.25 mg once-daily dose improved only evening PEF values compared with placebo. No safety concerns were raised.

The studies thus show that budesonide inhalation suspension can be given once daily.

Asthma symptoms in children treated with once-daily Pulmicort Respules 

Once daily treatment with Pulmicort® Respules® resulted in a significant improvement in nighttime and daytime asthma symptoms compared with placebo after 12 weeks’ treatment in 359 mild, ICS-naïve children (1). The improvement was observed in all Pulmicort® Respules® dosage groups.

Reference:
1. Kemp JP et al.: Once-daily budesonide inhalation suspension for the treatment of persistent asthma in infants and young children. Ann Allergy Asthma Immunol 1999; 83: 231-239.

2. Baker JW et al.: A multiple-dosing, placebo-controlled study of budesonide inhalation suspension given once or twice daily for treatment of persistent asthma in young children and infants. Pediatrics 1999; 103: 414-421.

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Can Pulmicort Respules be used for treatment of acute severe asthma?

A number of randomised controlled clinical studies have shown that Pulmicort Respules is at least as effective as oral steroid therapy in infants and children with acute asthma (1-3). Significant effects have been reached within 1-2 hours. However, acute asthma is not an approved indication for Pulmicort Respules.

In a double-blind study in 80 children, aged 2 to 12 years, two treatments were compared:
a) a single dose of prednisolone 2 mg/kg followed by three doses of nebulised salbutamol 0.15 mg/kg and placebo for budesonide suspension at 30 min intervals, or
b) an oral placebo tablet followed by three doses of nebulised salbutamol 0.15 mg/kg and nebulised budesonide 800 µg at 30 min intervals (2).
After the three doses of nebulised therapy patients treated with budesonide showed significant improvements in oxygen saturation, respiratory rate, pulmonary index and respiratory distress score compared with prednisolone-treated patients. At 2 hours after the last dose, the proportion of patients who could be discharged from hospital was significantly higher in the budesonide group than in the prednisolone group (54% vs. 18%).

In a prospective study (1) Pulmicort Respules 0.25 mg every 6 hours or ipratropium bromide, 0.1 mg every 6 hours, was added to normal treatment with hydrocortisone and nebulized ß2-agonist (fenoterol). A clinical score was made at admission and every 12 hours. The children treated with Pulmicort had a faster clinical improvement.

 Treatment of acute severe asthma in adults 

Effects of Pulmicort Respules on lung function in children with acute asthma 

Mean improvement in FEV1 at 24 hours in 40 children (5-16 years) with acute severe asthma (1). Pulmicort Respules 2 mg every 8 hours produced a significant (p < 0.01) improvement in FEV1 from baseline, whereas oral prednisolone 2 mg/kg, at randomisation and after 24 hours, had a lesser effect.

Reference:
1. Matthews EE et al.: Nebulized budesonide versus oral steroid in severe exacerbations of childhood asthma. Acta Paediatr 1999; 88: 841-843.

2. Devidayal et al.: Efficacy of nebulized budesonide compared to oral prednisolone in acute bronchial asthma. Acta Paediatr 1999; 88: 835-840.

3. Sano F et al. Inhaled budesonide for the treatment of acute wheezing and dyspnoea in children up to 24 months old receiving intravenous hydrocortisone. J Allergy Clin Immunol 2000; 105: 699-703.

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What is the safety profile of Pulmicort Respules?

The safety of nebulized budesonide has been extensively studied. In three 12-week placebo-controlled studies in more than 1000 patients no differences were found in adverse event profiles between budesonide and placebo (1-3). Similarly, no differences between budesonide and placebo were found in tests on HPA-axis function (1-3). In a 1-year open extension study in 670 children the result was similar (4,5).

Posterior sub capsular cataract formation and increased intraocular pressure are known side-effects of treatment with oral steroids. A pooled analysis of data from 8 studies in children treated with Pulmicort Respules 0.25-2.0 mg/day revealed no cases of sub capsular or lenticular cataracts (6).

Long-term effects of Pulmicort Respules on adrenal function 

Mean basal and ACTH-stimulated plasma cortisol concentrations at baseline and week 52 of an open label study (5) in children (6 months to 8 years of age) treated with Pulmicort Respules 0.25 - 2.0 mg/day.

Reference:
1. Kemp JP et al.: Once-daily budesonide inhalation suspension for the treatment of persistent asthma in infants and young children. Ann Allergy Asthma Immunol 1999; 83: 231-239.

2. Baker JW et al.: A multiple-dosing, placebo-controlled study of budesonide inhalation suspension given once or twice daily for treatment of persistent asthma in young children and infants. Pediatrics 1999; 103: 414-421.

3. Shapiro G et al.: Efficacy and safety of budesonide inhalation suspension (Pulmicort Respules) in young children with inhaled steroid-dependent, persistent asthma. J Allergy Clin Immunol 1998; 102: 789-796.

4. Scott MB, Skoner DP.: Short-term and long-term safety of budesonide inhalation suspension in infants and young children with persistent asthma. J Allergy Clin Immunol 1999; 104: S200-S209.

5. Irani AM et al. Effects of budesonide inhalation suspension on hypothalamic-pituitary-adrenal-axis function in infants and young children with persistent asthma. J Allergy Clin Immunol 2002; 88: 306-12.

6. Szefler SJ. Budesonide inhalation suspension: a nebulized corticosteroid for persistent asthma. J Allergy Clin Immunol 2002; 109: 730-742.

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