| 1. What are 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).
References:
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.
|
| 2. What are 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).
References:
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.
|
| 3. 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 (®).
References:
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.
|
| 4. 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).
References:
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.
|
| 5. 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:
1. Nikander K.: Drug delivery
systems. J Aerosol Med 1994; 7, Suppl 1: 386-388.
|
| 6. 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 (Nebuhaler), 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 Nebuhaler 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.
|
| 7. 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).
References:
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.
|
| 8. 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.
References:
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.
|
| 9. 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.
References:
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.
|
| 10. 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.
References:
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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