Advances in Therapy®

Volume 22 No. 4 July/August 2005

The Role of Nebulized Inhaled Corticosteroid Therapy in Adult Patients With Asthma and Chronic Obstructive Pulmonary Disease Philip Marcus, MD, MPH Clinical Professor of Medicine and Associate Dean, Curriculum Development New York College of Osteopathic Medicine of New York Institute of Technology Old Westbury, NY Chief, Division of Pulmonary Medicine St. Francis Hospital Roslyn, NY

ABSTRACT Conventional metered-dose inhalers and dry powder inhalers are used by most adult patients with asthma and chronic obstructive pulmonary disease who receive inhaled corticosteroid therapy. There are circumstances, however, in which nebulized inhaled corticosteroid delivery may provide greater clinical benefit to these patients. This review discusses the efficacy and safety of nebulized inhaled corticosteroid therapy in adult patients with asthma or chronic obstructive pulmonary disease for whom nebulized therapy may be preferable.

Keywords: asthma; COPD; inhaled corticosteroids; nebulized ICS therapy

INTRODUCTION National Asthma Education and Prevention Program guidelines recommend long-term treatment with inhaled corticosteroids (ICS) for the control of mild to severe persistent asthma in adults.1 According to the American Thoracic Society and the Global Initiative for Chronic Obstructive Lung Disease, ICS treatment also can reduce the frequency of exacerbations and ©

2005 Health Communications Inc Transmission and reproduction of this material in whole or part without prior written approval are prohibited.

0827

Address reprint requests to Philip Marcus, MD, MPH Nassau Chest Physicians PC 233 East Shore Road, Suite 112 Great Neck, NY 11023

407

improve the health of patients with severe (stage III or IV) symptomatic chronic obstructive pulmonary disease (COPD).2,3 When prescribing ICS, the type of inhalation delivery system warrants careful consideration. Adult patients generally use conventional metered-dose inhalers and dry powder inhalers; however, there are situations in which nebulized treatment may be preferable. In older patients, for example, cognitive impairment or decreased hand strength may compromise the use of conventional inhalation devices (Table 1).4-7 Table 1. Adult Patients Who May Benefit From ICS Treatment by Nebulization • Patients unable to use a metered-dose inhaler despite instruction and demonstration • Patients with an inspired vital capacity <1.5 times the predicted tidal volume of 7 mL/kg, inspired flow <30 L/min, or breath-hold capacity <4 s • Patients with severe disease or acute exacerbations who would benefit from the OCS-sparing effect of high-dose ICS • Patients with severe persistent asthma that is suboptimally controlled using other treatments • Patients with asthma and chronic sinusitis or nasosinusoidal polyps OCS=oral corticosteroids

Budesonide inhalation suspension (BIS) (Pulmicort Respules®, AstraZeneca LP, Wilmington, Del) is currently approved for nebulization by the US Food and Drug Administration (FDA) for use in children 12 months to 8 years of age. Although current approval in the United States and France is limited to children, BIS is approved for the maintenance treatment of asthma in adults in 71 other countries. In the United States, BIS is sometimes prescribed for older patients, and Medicare covers budesonide treatment when administered by nebulizer. Nebulized fluticasone propionate (FP) (Flixotide™ Nebules™; Glaxo Wellcome UK Ltd, Uxbridge, Middlesex, UK) is not approved for use in the United States but is approved in the United Kingdom and several other countries for adult patients with severe persistent asthma who require high-dose ICS or OCS treatment.

Pharmacokinetics of Nebulized ICS Lung deposition of 14% to 16% of the labeled dose and 36% to 78% of the received dose (delivered dose minus amount lost through exhalation and mouth rinsing) has been reported for BIS in healthy adults, depending on the nebulizer used.8,9 In comparison, 34% of the metered dose of budesonide administered via dry powder inhaler is deposited in the lungs of healthy adults.10 The terminal half-life of BIS is about 2.3 hours in children (4 to 6 years of age) with asthma. Although blood levels decrease rapidly, budesonide is retained in the airways as esters.11 Prolonged retention in

408

P. Marcus Nebulized ICS Therapy in Adults With Asthma or COPD

the lungs may contribute to the efficacy of once-daily BIS dosing. Peak plasma concentrations of budesonide occur 10 to 30 minutes after the start of nebulization.12 After adjustment for body weight, the systemic clearance of 0.5 L/min in children is about 50% greater than in healthy adults.12 The absolute bioavailability of FP ranges from about 10% to 30% of the labeled dose, depending on the nebulizer used.13 Lung deposition of FP delivered via nebulization has been shown to be almost 7-fold lower than the same nominal dose of FP delivered via pressurized metered-dose inhaler with large volume spacer in healthy adults.14 The terminal half-life of FP is about 8 hours.13

Effectiveness of Nebulized ICS Therapy in Adults Persistent Asthma In patients with severe persistent asthma who rely on systemic corticosteroids, the use of nebulized ICS may allow tapering or elimination of systemic agents and decrease the potential for systemic adverse events. Studies support the use of nebulized ICS, especially BIS, to treat severe OCS-dependent asthma in adults (Table 2).15-19 In adult patients with persistent asthma who have not responded to other therapies, the use of nebulized ICS may enable better disease control. In a case series, Gawchik20 reported that in 3 women with asthma suboptimally controlled with other ICS, leukotriene modifiers, and long-acting β2-adrenergic agonists, initiation of BIS therapy decreased exacerbation frequency, improved peak expiratory flow, and reduced the need for OCS (Table 2). Adult patients unable to master inhaler technique with conventional devices despite instruction and those physically incapable of using these devices also may benefit from nebulized therapy. Nebulized corticosteroids may be administered through a face mask or a mouthpiece, allowing for effective drug delivery with minimal patient effort and coordination. Clinical efficacy of BIS was demonstrated in a 30-year-old patient with moderate to severe persistent asthma and cerebral palsy who was unable to use a pressurized metered-dose inhaler (Table 2).21 The patient’s prior asthma treatments included nebulized cromolyn sodium and albuterol, delivered via an intermittent positive-pressure breathing machine 3 or 4 times daily, intermittent OCS, and an oral long-acting β2-adrenergic agonist.

Acute Exacerbations of Asthma Patients with acute exacerbations of asthma who require short-term use of OCS likewise may benefit from nebulized ICS. Studies of adults with acute asthma using nebulized ICS are limited to those using BIS. One randomized study comparing the efficacy of BIS therapy and oral prednisolone in adult patients hospitalized for severe asthma exacerbations demonstrated more effective control of asthma symptoms with BIS than with prednisolone (Table 2).22

Advances in Therapy® Volume 22 No. 4, July/August 2005

409

410

P. Marcus Nebulized ICS Therapy in Adults With Asthma or COPD

49 patients (≥18 y) receiving ≥10 mg/d prednisolone or equivalent plus ICS

18 patients (19–62 y) receiving ≥7.5 mg/d prednisolone plus ICS

Otulana et al16

Higenbottam et al17

118 patients (16–65 y) receiving ≥5 mg/d prednisolone plus ICS

Population

Connolly et al15

Persistent asthma

Study

BIS 2 mg/d × 12 wk

BIS, average, 5.7±2.1 mg/d (range, 4–8 mg/d) × 12–18 mo

BIS 4 mg/d × 15 wk

Nebulized Treatment

Table 2. Studies in Adult Patients With Asthma and COPD

Discontinuation in 17% of patients

Mean 59% reduction in 55% of patients (P<.0001)

Discontinuation in 78% of patients

Mean reduction from 17.6±10 to 3.2±6.7 mg/d (P<.001)

Reduction by a third or a half in 17% of patients

Reduction in 68% of patients

OCS Dose Reduction/ Discontinuation

AM

and

PM

PEF

cont’d

Reduction in activity limitations (P<.05)

Improvement in clinical assessment (P<.01)

Stable

Increase in AM PEF from 238±119 to 286±130 L/min (P<.05)

Increase in FEV1 from 1.9±0.9 to 2.2±0.9 L (P=.06)

Reduction in exacerbations requiring hospitalization, from 1.5±1.8 to 0.9±1.1/y (P=.05)

Improvement in cough, breathlessness (P<.05 for both), and sleep disturbance (P<.01) vs placebo

Fewer exacerbations with BIS than with placebo (0.35 vs 1.1; P<.05)

Additional Outcomes

Advances in Therapy® Volume 22 No. 4, July/August 2005

411

37 patients (27–75 y) receiving ≥7.5 mg/d prednisolone or equivalent plus ICS

360 patients (≥17 y) with a 5–30 mg/d OCS dose requirement16

3 patients with asthma uncontrolled with other ICS, leukotriene modifiers, LABAs

Westbroek et al19

Gawchik20

Population

O’Connor et al18

Study

BIS 2 mg bid to 1 mg bid with improvement

FP 1 or 4 mg/d × 12 wk

BIS 1 or 8 mg/d until OCS dose reduction to 0 (or asthma exacerbation)

Nebulized Treatment

Table 2. Studies in Adult Patients With Asthma and COPD, cont’d

Discontinuation in 37% of patients with FP 4 mg/d vs 26% with FP 1 mg/d (P=.038) and 18% with placebo (P<.001)

cont’d

Reduced exacerbation frequency in all patients

Improved PEF

Significantly higher percentage of days without daytime (P=.036) and nighttime (P=.021) wheezing with FP 4 mg/d than with placebo

No change in clinical lung function

Discontinuation in 41% and 60% of patients receiving BIS 1 and 8 mg, respectively Mean reduction of 5.0±7.5 mg/d with FP 4 mg/d and 3.9±8.3 mg/d with FP 1 mg/d

No loss of asthma control

Additional Outcomes

Reduction in all patients

OCS Dose Reduction/ Discontinuation

412

P. Marcus Nebulized ICS Therapy in Adults With Asthma or COPD

Higenbottam et al 22

Acute asthma

Berman et al 21

Study

13 patients (mean age, 37.1 y) hospitalized for an asthma exacerbation

1 cerebral palsy patient unable to use a pressurized metereddose inhaler

Population

BIS 4 mg tid × 48–72 h, followed by budesonide dry powder inhaler 1600 µg × 7 d, then 800 µg bid × 21 d or prednisolone 40 mg/d × 9–11 d, followed by budesonide dry powder inhaler 800 µg bid × 21 d

BIS 0.5 mg qid

Nebulized Treatment

Table 2. Studies in Adult Patients With Asthma and COPD, cont’d OCS Dose Reduction/ Discontinuation

cont’d

Lower severity of wheezing with BIS than with prednisolone at 24 h (P=.0336) and 48 h (P=.0326)

Reduction in albuterol use, from daily to as needed

No emergency department visits or hospitalizations

Reduction in asthma exacerbations, from several/y to 2 in 3 y

During 3 y after BIS start, improvement in percent predicted FEV1, from ≤62% to 70%–80%

Additional Outcomes

Advances in Therapy® Volume 22 No. 4, July/August 2005

413

199 patients with an exacerbation of COPD

Maltais et al24 BIS 2 mg qid, prednisolone 30 mg bid, or placebo × 72 h, followed by budesonide dry powder inhaler, prednisolone, or placebo, respectively, ×7d

BIS 2 mg bid or prednisolone 30 mg/d ×5d

Nebulized Treatment

PEF=peak expiratory flow; LABA=long-acting β2-adrenergic agonist

19 patients with severe acute airway obstruction

Population

Morice et al23

COPD

Study

Table 2. Studies in Adult Patients With Asthma and COPD, cont’d OCS Dose Reduction/ Discontinuation

No significant difference in FEV1 between BIS and prednisolone

Faster improvement in FEV1 in both the BIS and prednisolone groups than in the placebo group

Greater improvement in FEV1 in both the BIS and prednisolone groups than in the placebo group

No significant difference in change in FEV1 between BIS and prednisolone

Additional Outcomes

COPD Extensive data support international recommendations for the addition of ICS treatment to bronchodilator therapy in symptomatic patients with stage III or IV COPD and recurrent exacerbations.2 Although systemic corticosteroids may be valuable in the short-term treatment of acute exacerbations to speed recovery, treatment with nebulized ICS may be a safer alternative. Morice et al23 showed no significant difference in response to treatment, based on forced expiratory volume in 1 second (FEV1), in 19 patients with severe acute airway obstruction randomly assigned to receive 5 days of treatment with BIS versus prednisolone. A larger study conducted in 199 patients experiencing acute exacerbations of COPD demonstrated similar improvements in postbronchodilator FEV1 with BIS and prednisolone regimens.24

Safety of Nebulized ICS Therapy in Adults For adult patients, especially the elderly, the potential for adverse effects from ICS treatment may differ from that in children. Elderly patients may be more prone to develop cataracts or osteoporosis due to the cumulative effects of long-term, highdose ICS treatment or prior OCS use.1 Data regarding ICS effects on bone mineral density in adults are inconsistent. One recent meta-analysis demonstrated no significant decrease in bone mineral density in adult patients with asthma treated with ICS for at least 3 years,25 and a second meta-analysis of studies conducted in cohorts of patients with asthma or COPD reported no effect of 2 to 3 years of ICS treatment at conventional doses on bone mineral density or the development of fractures.26 In a meta-analysis by Richy et al,27 reductions in bone mineral density with ICS were significant but smallest with budesonide. To avoid confounding effects of prior or concomitant medications, this meta-analysis included studies in patients who did not use ICS or OCS for at least 6 months before the study.27 High doses of ICS administered via nebulization appear to be well tolerated in adult patients and might offer a safety advantage over OCS. In patients experiencing exacerbations of COPD, treatment with nebulized budesonide 2 mg twice daily has resulted in improvement in biochemical markers of bone metabolism compared with conventional oral prednisolone.23 Moreover, a randomized, double-blind, placebo-controlled crossover study comparing the systemic activity profiles of BIS (1, 2, and 4 mg/d) and oral prednisolone (5, 10, and 20 mg/d) in adults with asthma demonstrated significant dose-related suppression with prednisolone, but not BIS, in morning plasma cortisol, osteocalcin, and blood eosinophil counts.28 Clinical study and postmarketing surveillance data for BIS in adult and geriatric populations demonstrate the safety profile of BIS.29,30 In clinical studies involving patients 65 years of age or older, adverse events were less frequent with BIS than with prednisolone and placebo. Additionally, the frequency of reported adverse events was low in US postmarketing surveillance reports. There were no reports of cataracts and few reports of other local adverse events in adults, including those 65 years of age or older. No differences were observed in safety profiles between adult patients younger than 65 and those 65 or older, and there were no apparent trends in adverse events unique to the elderly.

414

P. Marcus Nebulized ICS Therapy in Adults With Asthma or COPD

BIS can also be used safely in women who are pregnant. Based on extensive pregnancy safety data for the ICS budesonide, BIS carries a Pregnancy Category B rating.31,32 All other ICS carry a Pregnancy Category C rating because of lack of adequate and well-controlled studies in pregnant women and either lack of animal reproduction studies or a demonstrated risk in animals.

Administration of Nebulized ICS The effectiveness of nebulized ICS therapy depends on the pharmacology of the drug as well as the extent of lung deposition.33 BIS is indicated for use with a jet nebulizer.12,13,34 Among currently available jet nebulizers, there are marked differences in output and particle size for a given ICS8,35,36; nevertheless, lung deposition, as a percentage of labeled dose, appears to be similar among the various jet nebulizers.8,35 In children, recommended daily BIS doses range from 0.5 mg (once daily or in divided doses) in children previously receiving bronchodilators alone or ICS to 1 mg (once daily or in divided doses) in children with OCS-dependent asthma.12 Neither budesonide nor fluticasone are FDA approved for nebulized administration in adults in the United States. In adults with moderately severe unstable asthma, budesonide 1 mg and 4 mg twice daily administered via nebulizer has been shown to be at least as effective as budesonide 0.8 mg twice daily administered via pressurized metereddose inhaler plus spacer.37 The form of budesonide currently approved for use by adults in the United States is that administered in a dry powder inhaler (Pulmicort Turbuhaler®, AstraZeneca LP, Wilmington, Del). For nebulized FP, a dose of 0.5 to 2 mg twice daily is recommended for adults.13 BIS labeling recommends separate administration of BIS and concomitant medications administered via the nebulizer; however, patients with asthma or COPD often receive multiple inhaled medications, particularly during acute exacerbations. BIS has been shown to be chemically stable and physically compatible when mixed for simultaneous administration with other common nebulized respiratory medications, including albuterol sulfate inhalation solution (Proventil®, Schering Corporation, Kenilworth, NJ), cromolyn sodium inhalation solution (Intal®, Aventis Pharmaceuticals, Parsippany, NJ), levalbuterol inhalation solution (Xopenex®, Sepracor, Inc, Marlborough, Mass), and ipratropium bromide inhalation solution (Atrovent®, Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Conn).38 Because stability and physical compatibility of admixtures have been shown only for commercially available agents, these results cannot be extrapolated to other compounded mixtures for which no efficacy or safety data are available.

CONCLUSION Inhaled corticosteroids are the mainstay of treatment for persistent asthma of all severities and an important component of treatment for severe, symptomatic COPD. An expanding role for nebulized delivery of ICS among certain adult populations in the United States is a consequence of demonstrated efficacy and tolerability. Delivery of ICS via nebulization enables patients who are unable to use conventional inhalation devices or master inhaler technique to improve ICS delivery and achieve greater benefit from therapy. Moreover, in adults with severe OCS-dependent

Advances in Therapy® Volume 22 No. 4, July/August 2005

415

asthma and acute exacerbations of asthma and COPD, BIS treatment provides a means to easily administer high-dose ICS therapy that may reduce requirements for OCS and the potential for adverse systemic effects associated with long-term and intermittent OCS use.

ACKNOWLEDGMENTS The author thanks Sudha Vemuri, PhD, and Leslie Sell, PhD, for their assistance in the preparation of this manuscript. Funding for this review was provided by AstraZeneca LP, Wilmington, Delaware. Dr. Marcus is on the Speakers Bureau for AstraZeneca LP and has received research support from AstraZeneca LP.

REFERENCES 1. National Asthma Education and Prevention Program. Expert panel report: guidelines for the diagnosis and management of asthma. Update on selected topics—2002. J Allergy Clin Immunol. 2002;110(5 suppl):S141-S219. 2. Global Initiative for Chronic Obstructive Lung Disease™. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Executive Summary. Bethesda, MD: National Heart, Lung, and Blood Institute, National Institutes of Health; 2003. 3. American Thoracic Society. Management of Stable COPD: Pharmacological Therapy. Available at: http://www.thoracic.org/COPD/6/glucocorticoids.asp. Accessed on: August 23, 2004. 4. Allen SC, Jain M, Ragab S, Malik N. Acquisition and short-term retention of inhaler techniques requiring intact executive function in elderly subjects. Age Ageing. 2003;32:299-302. 5. Gray SL, Williams DM, Pulliam CC, Sirgo MA, Bishop AL, Donohue JF. Characteristics predicting incorrect metered-dose inhaler technique in older subjects. Arch Intern Med. 1996;156:984-988. 6. O’Donohue WJ and the National Association for Medical Direction of Respiratory Care Consensus Group. Guidelines for the use of nebulizers in the home and at domiciliary sites. Report of a consensus conference. Chest. 1996;109:814-820. 7. Demoly P, Jaffuel D, Sahla H, Bousquet J, Michel F-B, Godard P. The use of home nebulizers in adult asthma. Respir Med. 1998;92:624-627. 8. Dahlström K, Thorson L, Larsson P, Nikander K. Systematic availability and lung deposition of budesonide via three different nebulizers in adults. Ann Allergy Asthma Immunol. 2003;90: 226-232. 9. Szefler SJ, Eigen H. Budesonide inhalation suspension: a nebulized corticosteroid for persistent asthma. J Allergy Clin Immunol. 2002;109:730-742. 10. Pulmicort Turbuhaler® [package insert]. Wilmington, Del: AstraZeneca LP; September 2004. 11. Edsbacker S, Brattsand R. Budesonide fatty-acid esterification: a novel mechanism prolonging binding to airway tissue. Review of available data. Ann Allergy Asthma Immunol. 2002;88:609-616. 12. Pulmicort Respules® [package insert]. Wilmington, Del: AstraZeneca LP; September 2004. 13. Flixotide™ Nebules™ [package insert]. Uxbridge, Middlesex, UK: Glaxo Wellcome UK Ltd; March 2003. 14. Dempsey OJ, Humphreys M, Coutie WJR, Lipworth BJ. Relative lung delivery of fluticasone propionate via large volume spacer or nebuliser in healthy volunteers. Eur J Clin Pharmacol. 2001;57:637-641.

416

P. Marcus Nebulized ICS Therapy in Adults With Asthma or COPD

15. Connolly KC, Peake PD, Halpin DMG, Golightly L, Turbitt ML. Challenging current asthma treatment guidelines. Improved control of asthma symptoms with nebulized budesonide in patients with severe asthma receiving continuous oral steroids. Dis Manag Health Outcomes. 2000;7:217-225. 16. Otulana BA, Varma N, Bullock A, Higenbottam T. High dose nebulized steroid in the treatment of chronic steroid-dependent asthma. Respir Med. 1992;86:105-108. 17. Higenbottam TW, Clark RA, Luksza AR, et al. The role of nebulized budesonide in permitting a reduction in the dose of oral steroid in persistent severe asthma. Eur J Clin Res. 1994;5:1-10. 18. O’Connor BJ, Barsan GS, O’Connell F, O’Shaughnessy KM. Oral steroid sparing effect of nebulized budesonide in chronic severe asthma. Am J Respir Crit Care Med. 1996;153:A341. 19. Westbroek J, Saarelainen S, Laher M, O’Brien J, Barnacle H, Efthimiou J. Oral steroid-sparing effect of two doses of nebulized fluticasone propionate and placebo in patients with severe chronic asthma. Respir Med. 1999;93:689-699. 20. Gawchik SM. Successful treatment of previously uncontrolled adult asthma with budesonide inhalation suspension (Pulmicort Respules®) [abstract]. Ann Allergy Asthma Immunol. 2002;88:97. Abstract 75. 21. Berman GD, Rockey C. Nebulized budesonide inhalation suspension (Pulmicort Respules®) improves asthma control and quality of life in an adult cerebral palsy patient unable to use metered-dose inhalers [abstract]. Ann Allergy Asthma Immunol. 2003;90:103. Abstract 26. 22. Higenbottam TW, Britton J, Lawrence D, et al, on behalf of the Pulmicort Respules Versus Oral Steroids: A Prospective Clinical Trial in Acute Asthma (PROSPECTS): ADULT study team. Comparison of nebulized budesonide and prednisolone in severe asthma exacerbations in adults. Bio Drugs. 2000;14:247-254. 23. Morice AH, Morris D, Lawson-Matthew P. A comparison of nebulized budesonide with oral prednisolone in the treatment of exacerbations of obstructive pulmonary disease. Clin Pharmacol Ther. 1996;60:675-678. 24. Maltais F, Ostinelli J, Bourbeau J, et al. Comparison of nebulized budesonide and oral prednisolone with placebo in the treatment of acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2002;165:698-703. 25. Sharma PK, Malhotra S, Pandhi P, Kumar N. Effect of inhaled steroids on bone mineral density: a meta-analysis. J Clin Pharmacol. 2003;43:193-197. 26. Jones A, Fay JK, Burr M, Stone M, Hood K, Roberts G. Inhaled corticosteroid effect on bone metabolism in asthma and mild chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2002; CD003537. 27. Richy F, Bousquet J, Ehrlich GE, et al. Inhaled corticosteroids effects on bone in asthmatic and COPD patients: a quantitative systematic review. Osteoporos Int. 2003;14:179-190. 28. Wilson AM, McFarlane LC, Lipworth BJ. Systemic bioactivity profiles of oral prednisolone and nebulized budesonide in adult asthmatics. Chest. 1998;114:1022-1027. 29. Cruz-Rivera M, Lyzell E, Fitzpatrick S. Low frequency of adverse events reported through postmarketing surveillance for Pulmicort Respules® (budesonide inhalation suspension) in the US adult population [abstract]. J Allergy Clin Immunol. 2002;109(suppl):S292. Abstract 895. 30. Lyzell E, Cruz-Rivera M, Fitzpatrick S. Safety of Pulmicort Respules® (budesonide inhalation suspension) in geriatric patients: postmarketing surveillance and clinical study data [abstract]. J Allergy Clin Immunol. 2002;109(suppl):S292. Abstract 894. 31. Källén B, Rydhstroem H, Åberg A. Congenital malformations after the use of inhaled budesonide in early pregnancy. Obstet Gynecol. 1999;93:392-395.

Advances in Therapy® Volume 22 No. 4, July/August 2005

417

32. Ericson A, Källén B. Use of drugs during pregnancy-unique Swedish registration method that can be improved. Information From the Swedish Medical Products Agency. 1999;1:8-11. 33. Barnes PJ, Pedersen S. Efficacy and safety of inhaled corticosteroids in asthma. Am Rev Respir Dis. 1993;148:S1-S26. 34. Nikander K, Turpeinen M, Wollmer P. The conventional ultrasonic nebulizer proved inefficient in nebulizing a suspension. J Aerosol Med. 1999;12:47-53. 35. Smaldone GC, Crus-Rivera M, Nikander K. In vitro determination of inhaled mass and particle distribution for budesonide nebulizing suspension. J Aerosol Med. 1998;11:113-125. 36. Barry PW, O’Callaghan C. An in vitro analysis of the output of budesonide from different nebulizers. J Allergy Clin Immunol. 1999;104:1168-1173. 37. Bisgaard H, Nikander K, Munch E. Comparative study of budesonide as a nebulized suspension vs pressurized metered-dose inhaler in adult asthmatics. Respir Med. 1998;92:44-49. 38. McKenzie JE, Cruz-Rivera M. Compatibility of budesonide inhalation suspension with four nebulizing solutions. Ann Pharmacother. 2004;38:967-972.

418

P. Marcus Nebulized ICS Therapy in Adults With Asthma or COPD