Budesonide inhalation suspension in adults with poorly controlled asthma or chronic obstructive pulmonary disease.

INTRODUCTION

Inhaled corticosteroids (ICSs) are the most effective controller therapy available for patients with persistent asthma. (1) As such, daily ICS use is recommended for all patients with persistent asthma, regardless of severity' For patients with chronic obstructive pulmonary disease (COPD), the addition of a daily ICS to inhaled long-acting bronchodilator therapy is recommended to reduce exacerbations and improve health status in patients with stage III to stage IV disease and a history of repeat exacerbations. (2)

For adult patients with asthma or COPD, important considerations in choosing an inhalation device include patient age, patient ability to use the device correctly, availability of medication(s) in a given device (eg, nebulized formulation), cost, and reimbursement. (3) Because patient satisfaction may improve adherence with therapy, patient preference also should be considered. (4)

Aerosol therapy generally is administered via a metered-dose inhaler (MDI) or dry powder inhaler (DPI); however, these devices may be a suboptimal method of inhaled drug delivery for some adult patients. Among patients with asthma or COPD, inhaler technique often is poor. (5,6) Poor technique can decrease drug deposition in the lungs (7) and lead to asthma instability. (8) Studies in adult patients show that the incorrect use of DPIs and MDIs increases with age. (5,8,9) For some elderly patients, reduced hand strength (10) or subclinical cognitive impairment or dyspraxia (11) may make proper use of an inhaler difficult, despite adequate instruction and repeated demonstration.

Administration of ICS therapy via nebulization provides a delivery system that is effective with normal breathing and requires less manual dexterity than traditional handheld inhalers. In the U.S.A., nebulized budesonide inhalation suspension (BIS) is approved for children aged 12 months to 8 years with asthma. In many countries outside of the U.S.A., BIS also is approved for use in adults. (12) A review of the few nebulized ICS studies suggested that use of BIS in adults is an effective treatment option for asthma or COPD. (12) However, these studies were conducted in limited patient populations. Early studies in adults included only patients with severe oral corticosteroid-dependent persistent asthma and showed that addition of treatment with nebulized BIS (2 - 8 mg/day) enabled oral corticosteroid treatment to be reduced or discontinued. (13,14,15) A study showing that BIS was effective in adults with noncorticosteroid-dependent moderately severe asthma uncontrolled on ICS therapy included only 26 patients. (16) A large (N=758) 12-week, randomized U.S.A. study was conducted to establish the efficacy of BIS in patients aged [greater than or equal to] 12 years with moderate to severe persistent asthma previously receiving ICSs via DPI or MDI. No difference in predose forced expiratory volume in 1 second (FEV), the primary end point, was demonstrated between BIS 2 mg twice daily and BIS 0.5 mg once daily, which may have several explanations. One possible reason is that the patients' asthma severity based on prestudy ICS dose was overestimated, resulting in the inclusion of patients with mild asthma who would have been controlled with lower doses of ICS. Therefore, definitive conclusions regarding the efficacy of BIS in U.S.A. adults could not be drawn from this study. (17) The study, however, did not include a placebo comparator. An alternate conclusion may have been that using BIS did not improve outcomes among patients previously receiving traditional ICS therapy. Finally, studies suggest that BIS is effective for treating an acute exacerbation of COPD, (18,19) but studies of daily use for COPD are lacking.

To describe the effectiveness of daily BIS therapy in a usual practice setting, I report exacerbation rates and pulmonary function outcomes for 25 adult patients with poorly controlled asthma or COPD who were initiated on BIS or transitioned from traditional ICS therapy administered via DPI or MDI to nebulized BIS. The rationale for the initiation of nebulized BIS, or the transition from other ICSs to nebulized BIS, varied based on individual patient characteristics.

METHODS

The medical charts for 25 consecutive adult patients with asthma or COPD who were initiated on ICS therapy with BIS (Pulmicort Respules[R]; AstraZeneca LP, Wilmington, DE) or transitioned from ICS therapy delivered via MDI or DPI to nebulized BIS were reviewed retrospectively. On discontinuation of any previous ICS therapy, all patients received BIS 0.5 mg administered twice daily via a jet nebulizer. Jet nebulizer/compressor systems varied among patients, with most patients using the same system that they used for as-needed administration of bronchodilators. BIS doses were not stepped up or stepped down after initiation of therapy but remained the same throughout a 1-year observation period. In some patients, changes in the dosage form of concomitant asthma or COPD therapies were made at the time of the transition to BIS. Controller medications were prescribed per labeled dosages, and rescue bronchodilator therapy was used as needed. The primary outcome was the number of exacerbations requiring the use of oral corticosteroids during the 1-year period after the initiation of BIS or transition to BIS compared with the number during the year before the transition. Pulmonary function based on [FEV.sub.1] was assessed before and 3 months after initiation of BIS treatment.

RESULTS

Patients ranged in age from 31 to 84 years (mean age, 65 years) with a similar percentage diagnosed with asthma and COPD (Table 1). More female patients (n=18) than male patients (n=7) were included. Nineteen patients were initiated on BIS or transitioned to BIS as part of their treatment regimen because of a failure of their previous therapy (Table 2) to control frequent exacerbations despite adherence checks and repeated instruction on ICS inhaler use. All 12 asthma patients previously were receiving ICS plus adjunctive therapy at step 3 or higher based on the 2002 U.S.A. asthma guidelines that were in place at the time therapy was initiated. (20) Four of the 12 asthma patients received omalizumab (Xolair[R]; Genentech Inc, South San Francisco, CA) for [greater than or equal to] 3 months before the transition to BIS but continued to experience frequent asthma symptoms. Six patients, all with COPD, were transitioned (n=4) or initiated (n=2) on BIS because they had no prescription coverage and because Medicare at that time did not have a medication benefit option to cover ICS MDI or DPI formulations. One of these patients had a tracheotomy and was unable to use any other method of ICS delivery.

During treatment with BIS, patients used as-needed rescue bronchodilator medications, including short-acting [[beta]sub.2]-adrenergic agonists (SABAs) and anticholinergics, and additive controllers, including leukotriene modifiers and long-acting [[beta].sub.2]-adrenergic agonists (LABAs) (Table 2). At the time that these patients were initiated on or transitioned to BIS, LABAs were not available as nebulized formulations. Thus, patients previously receiving ICS/LABA therapy via 1 inhaler (n=11) were switched from their previous ICS to nebulized BIS and a LABA administered via DPI. The same LABA was continued in all but 3 patients: 2 COPD patients (#13 and #14) were discontinued from LABA therapy, and 1 asthma patient (#12) had a prescription benefit formulary with a specific LABA product requirement. One COPD patient (#15) was switched from ipratropium to tiotropium DPI, and 1 COPD patient discontinued ipratropium (#18) at the time of the transition to BIS. For all other asthma and COPD patients, concomitant therapies (eg, montelukast, formoterol or salmeterol DPI, theophylline) remained the same during the transition to BIS. In 6 asthma patients and 9 COPD patients, rescue SABA therapy was continued with nebulized levalbuterol (Xopenex[C]; Sepracor Inc, Marlborough, MA) at the time of the transition to nebulized BIS. When concomitant therapy included a nebulized medication, the medication was administered simultaneously with BIS, which is not indicated in the prescribing information (21) but is commonly recommended by clinicians to reduce the time needed for nebulization.

Figure 1 shows the number of exacerbations experienced by each patient before and after the transition to BIS. The number of exacerbations decreased for all patients. The total number of exacerbations in patients with asthma decreased from 56 before the transition to BIS to 13 during BIS treatment (mean decrease, 3.6/patient or 77% overall). For patients with COPD, exacerbations decreased from 45 to 13 (mean decrease, 2.5/patient or 71 overall). Three patients with asthma had no exacerbations while receiving BIS. In 1 patient with asthma (#6), exacerbations decreased from 8 in the year before the transition to BIS to only 2 after the transition. Clinical improvements after 3 months in absolute [FEV.sub.1] values (L) of [greater than or equal to] 13% in patients with asthma and [greater than or equal to] 9% in patients with COPD were observed in 83% (10/12) of patients with asthma and 33% (4/12) of patients with COPD (Fig. 2). Patients who did not demonstrate an improvement in absolute [FEV.sub.1] after 3 months maintained similar [FEV.sub.1] values; none of the patients exhibited a significant decrease in [FEV.sub.1]. Assessment of FEV, was not performed in 1 patient with COPD (#25) because of a tracheotomy. Finally, BIS was well tolerated. None of the patients reported any adverse events.

DISCUSSION

In this series of 25 consecutive patients with poorly controlled asthma or COPD, a transition from commonly used ICS formulations administered via DPI or MDI to nebulized BIS or initiation of ICS treatment with BIS provided marked improvement in disease control for all patients and was well tolerated. Exacerbations decreased by more than 70% in patients with asthma or COPD. Moreover, despite a long-standing history of pulmonary disease, 83% of patients with asthma and 33% with COPD demonstrated clinical improvement in FEV, while receiving BIS during the 1-year observation period. Some patients continue to be treated with BIS, while others have been lost through attrition. All of the patients who still are treated actively in the practice continue to receive BIS.

These findings are in agreement with previous research of nebulized ICS use in adults. Early studies, however, focused on the addition of BIS and not replacement of traditional ICS with BIS. (13.14,15,18,22) Additionally, a retrospective cohort study of medical and pharmacy claims data showed that older adults ([greater than or equal to] 50 years) who persistently used nebulized ICS therapy required fewer courses of oral corticosteroids in the 6-month period after their first nebulized ICS prescription compared with the previous 6-month period. (18) Gawchik reported that 3 women (aged ~45 years) with uncontrolled asthma experienced decreases in the number of urgent care visits, and 2 of the 3 women required fewer oral corticosteroid courses after switching from ICSs delivered via DPI or MDI to BIS delivered via a jet nebulizer and compressor. By the end of Gawchik's 5-year observation, BIS was reduced from 1 mg twice daily to 0.5 mg twice daily in 2 patients and to 0.5 mg once daily in 1 patient while maintaining good asthma control. (22) These dosages are consistent with those reported for adults and children aged [greater than or equal to] 12 years in the international product monograph, which recommends a BIS starting dosage of 1 - 2 mg twice daily followed by a maintenance dosage of 0.5 - 1 mg/day once asthma control has been established. (23) In the present case series, administration of BIS 0.5 mg twice daily improved control of asthma and COPD in a real-world setting of older patients.

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

The efficacy of BIS in total daily doses ranging from 0.5 - 8 mg as the only ICS therapy has been assessed in 2 controlled clinical studies in adolescent and adult patients with asthma. (16,17) In a small crossover study (N=26), BIS 1- and 4-mg twice-daily dosages were at least as effective as budesonide 800 [micro]g administered twice daily via MDI with spacer in adults with moderately severe unstable asthma despite treatment with ICS. (16) A larger (N=758), more recent study demonstrated similar maintenance of asthma control in adolescents and adults with moderate to severe persistent asthma transitioned from ICS via DPI or MDI to BIS 0.5 or 1 mg once daily, BIS 1 or 2 mg twice daily, or budesonide DPI 400 [micro]g twice daily. (17) The authors also suggested that longer nebulization times for the 2-mg twice-daily BIS dosage (4 ampules of BIS 0.5 mg/2 mL twice daily) (20 - 30 minutes) compared with the 0.5-mg once-daily dosage (2 ampules of BIS 0.25 mg/2 mL once daily) (10 - 20 minutes) may have resulted in numerically lower adherence, higher withdrawal rates, and lower-than-expected [FEV.sub.1] in the higher dosage group. (17) At the time the study was conducted, the 1 mg/2 mL BIS ampule was not available; a 4-mg/day dosage can now be given twice daily as 2 ampules of BIS 1 mg/2 mL, (21) reducing nebulization time. Finally, the study population included patients who generally would not have a preference or need for nebulized ICS therapy. (17) Of the 603 patients who received BIS, approximately 5 % were aged [greater than or equal to] 65 years. (17)

In the present case series, 6 patients with COPD (mean age, 76 years) received BIS therapy because of insurance-related issues. In the U.S.A., not all ICS delivery devices (eg, spacers) may be covered by commercial insurers. Moreover, the government's health insurance program for the elderly (Medicare Part A and Part B) generally did not cover outpatient prescription drugs; however, the cost of nebulizers and the medications used in the nebulizers were covered through Part B. This reimbursement discrepancy holds true despite the introduction of Medicare Part D, which is a voluntary prescription benefit plan that includes large out-of-pocket expenses. Nebulized medications covered by Medicare Part B before the Part D prescription drug program became available still are covered under Medicare Part B, but some U.S.A. providers and patients may not be aware of this information. Although most pharmacies stock medications for nebulization, only certain pharmacies or durable medical equipment suppliers usually are able to bill for nebulized medications under Medicare Part B. Despite the limited age indication for nebulized BIS in the U.S.A., Medicare does reimburse for the branded product (code J7626; 0.5 mg/2 mL).

Mixing of nebulized medications may potentially increase the inhaled mass of medications because of increased volume in the nebulizer cup. (24) Although increased volume prolongs nebulization time, some patients may prefer 1 treatment. In the present case series, simultaneous administration of BIS with other nebulized medications (eg, levalbuterol) enabled simpler dosing of add-on therapy for those patients who required concomitant therapy. Previous data have shown BIS to be stable chemically and compatible physically when administered simultaneously with respiratory medications, including albuterol sulfate inhalation solution (Proventil[R]; Schering Corporation, Kenilworth, NJ), ipratropium bromide inhalation solution (Atrovent[R]; Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT), and levalbuterol inhalation solution. (24) Although not commercially available at the time when my patients were transitioned to BIS, arformoterol tartrate inhalation solution 15 [micro]g/2 mL (Brovana[R]; Sepracor Inc, Marlborough, MA) also has been shown to be stable physically and chemically when mixed with BIS 0.25 mg/2 mL or 0.5 mg/2 mL. (25) These studies only assessed chemical compatibility; other variables related to administration of admixing solutions, such as potential changes in inhaled mass, the emergence of new adverse events, or clinical efficacy, have not been evaluated. (24,25) The prescribing information recommends that BIS be administrated separately from other medications in the nebulizer. (21)

In the present case series, inhaler technique was reviewed and proper inhaler use was demonstrated in the clinic setting at nearly every follow-up visit. Despite these measures, many patients achieved suboptimal outcomes with ICS-based controller therapy delivered by MDT or DPI. Nebulization therapy relies on normal tidal breathing and obviates the manual dexterity needed to properly use handheld aerosol devices. These patients may have experienced improved ICS delivery to the airways with nebulizer use, contributing to the effectiveness of BIS in this patient population of older adults. In a survey of patients' views on home nebulizer treatment for chronic pulmonary disease (n=82; median age, 71.5 years) conducted by Barta et al, (26) a majority of patients reported an increased feeling of personal well-being, better symptom control, and increased confidence to be the main advantages of nebulizer use.

Approximately 75% of patients felt their nebulizer was superior to inhalers for symptom relief and that its use would keep them out of the hospital. (26) Moreover, many patients felt they would "be lost" without their nebulizers. (26) Patient preference for home nebulizer treatment and the perception of greater symptom control offer additional support for the use of nebulized therapy in older patients with asthma and COPD.

In conclusion, decreased exacerbations in patients with asthma and COPD, along with ease of use for older patients or those who have issues with other types of inhalation devices, suggest that BIS administered via a nebulizer may be a treatment option for adults with asthma or COPD who remain suboptimally controlled on ICS-based therapy administered via DPI or MDT.

ACKNOWLEDGMENTS

The author thanks Marissa Buttaro, MPH (Scientific Connexions), and Leslie Sell, PhD, for medical writing assistance. Funding for this report 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 3: Guidelines for the Diagnosis and Management of Asthma. 2007. NIH Publication no. 07-4051.

(2.) Global Initiative for Chronic Obstructive Lung Disease (GOLD)[TM]. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Updated 2008. Bethesda, MD: National Heart, Lung, and Blood Institute, National Institutes of Health; 2008.

(3.) Dolovich MB, Ahrens RC, Hess DR, Anderson P, Dhand R, Rau JL, Smaldone GC, Guyatt G; American College of Chest Physicians and American College of Asthma, Allergy, and Immunology. Device selection and outcomes of aerosol therapy: Evidence-based guidelines. Chest. 2005;127:335-371.

(4.) Thorsson L, Geller D. Factors guiding the choice of delivery device for inhaled corticosteroids in the long-term management of sta ble asthma and COPD: focus on budesonide. Respir Med. 2005;99:836-849.

(5.) Melani AS, Zanchetta D, Barbato N, Sestini P, Cinti C, Canessa PA, Aiolfi S, Neri M; for the Associazione Italiana Pneumologi Ospedalieri Educational Group. Inhalation technique and variables associated with misuse of conventional metered-dose inhalers and newer dry powder inhalers in experienced adults. Ann Allergy Asthma Immunol. 2004;93:439-446.

(6.) Cochrane MG, Bala MV, Downs KE, Mauskopf J, Ben-Joseph RH. Inhaled corticosteroids for asthma therapy: patient com pliance, devices, and inhalation technique. Chest. 2000;117:542-550.

(7.) Crompton GK, Barnes PJ, Broeders M, Corrigan C, Corbetta L, Dekhuijzen R, Dubus JC, Magnan A, Massone F, Sanchis J, Viejo JL, Voshaar T. The need to improve inhalation technique in Europe: A report from the Aerosol Drug Management Improvement Team. Respir Med. 2006;100:1479-1494.

(8.) Giraud V, Roche N. Misuse of corticosteroid metered-dose inhaler is associated with decreased asthma stability. Ear Respir.l. 2002;19:246-251.

(9.) Sestini P, Cappiello V, Aliani M, Martucci P, Sena A, Vaghi A, Canessa PA, Neri M, Melani AS; on behalf of the Associazione Italiana Pneumologi Ospedalieri Educational Group. Prescription bias and factors associated with improper use of inhalers. J Aerosol Med. 2006;19:127-136.

(10.) Gray SL, Williams DM, Pulliam CC, Sirgo MA, Bishop AL, Donohue JE Characteristics predicting incorrect metered-dose inhaler technique in older subjects. Arch Intern Med. 1996;156:984-988.

(11.) Allen SC, Ragab S. Ability to learn inhaler technique in relation to cognitive scores and tests of praxis in old age. Postgrad Med J. 2002;78:37-39.

(12.) Marcus P The role of nebulized inhaled corticosteroid therapy in adult patients with asthma and chronic obstructive pulmonary disease. Adv Ther. 2005;22:407-418.

(13.) Higenbottam TW, Clark RA, Luksza AR, Morice AH, Bateman NT, Matthews AW, Petrie GR, Taylor MD, Richardson PDI. The role of nebulised budesonide in permitting a reduction in the dose of oral steroid in persistent severe asthma. Eur J Clin Res. 1994;5:1-10.

(14.) 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.

(15.) Connolly KC, Peake MD, Halpin DMG, Golightly L, Turbitt ML, on behalf of Astra Pharmaceuticals Research Group. 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.) 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.

(17.) Murphy K, Noonan M, Silkoff PE, Uryniak T. A 12-week, multicenter, randomized, partially blinded, active-controlled, parallel-group study of budesonide inhalation suspension in adolescents and adults with moderate to severe persistent asthma previously receiving inhaled corticosteroids with a metered-dose or dry powder inhaler. Clin Ther. 2007;29:1013-1026.

(18.) Marcus P, Oppenheimer EA, Patel PA, Katz LM, Doyle JJ. Use of nebulized inhaled corticosteroids among older adult patients: an assessment of outcomes. Ann Allergy Asthma Immunol. 2006:96:736-743.

(19.) Gunen H, Hacievliyagil SS, Yetkin O, Gulbas G, Mutlu LC, In E. The role of nebulised budesonide in the treatment of exacerbations of COPD. Eur Respir J. 2007;29:660-667.

(20.) National Asthma Education and Prevention Program. Expert panel report: Guidelines for the diagnosis and management of asthma update on selected topics-2002 [published correction appears in J Allergy Clin Immunol. 2003;111:466]. J Allergy Clin Immunol. 2002;110(Suppl 5):S141-S219.

(21.) Pulmicort Respules[R] (budesonide inhalation suspension) [prescribing information]. AstraZeneca, Wilmington, DE, June 2007.

(22.) Gawchik SM. Successful treatment of previously uncontrolled adult asthma with budesonide inhalation suspension: five-year case histories. Ann Pharmacother. 2007;41:1728-1733.

(23.) Pulmicort[R] (budesonide): Active where it matters [international product monograph]. AstraZeneca, Lund, Sweden; 2002.

(24.) McKenzie JE, Cruz-Rivera M. Compatibility of budesonide inhalation suspension with four nebulizing solutions. Ann Pharmacother. 200438:967-972.

(25.) Bonasia P, Cook C, Cheng Y, Ong S. Compatibility of arformoterol tartrate inhalation solution with three nebulized drugs. Curr Med Res Opin. 2007;23:2477-2483.

(26.) Barta SK, Crawford A, Roberts CM. Survey of patients' views on domiciliary nebuliser treatment for chronic lung disease. Respir Med. 2002;96:375-381.

Corresponding Author

Dr. Philip Marcus

Chief, Division of Pulmonary Medicine

St. Francis Hospital-The Heart Center Roslyn, NY

Associate Dean, Curriculum Development

Clinical Professor of Medicine and Pharmacology

NY College of Osteopathic Medicine 

Old Westbury, NY

Telephone: [phone]

Fax: [phone]

Email: [e-mail]

Table 1. Patient characteristics.

               Age            [FEV.sub.1]
Patient        (years)        (% predicted)  Comorbidities

With asthma
1              64             64             --
2              54             20             Sjogren's syndrome
3              72             54             Coronary artery disease
4              46             63             Allergic rhinitis
5              57             67             Nasal polyps
6              65             42             Hypertension, osteoporosis
7              62             63             --
8              45             21             Pulmonary hypertension
9              58             38             Hypertension
10             52             46             --
11             31             55             --
12             58             77             Colon cancer
With COPD
13             76             35             Sleep apnea
14             67             36             Diabetes mellitus, coronary
                                               artery disease
15             74             40             Hypertension, atrial
                                               fibrillation
16             77             44             Hypertension
17             83             65             --
18             82             80             Polymyalgia rheumatica
19             83             24             Prostate cancer
20             79             70             Coronary artery disease
21             63             18             Hypertension
22             84             83             Hypertension
23             54             61             Hypertension
24             72             50             Rheumatoid arthritis
25             77             --             Laryngeal cancer

Patient        Reason for Switch to BIS

With asthma
1              Frequent exacerbations
2              Frequent exacerbations
3              Frequent exacerbations
4              Frequent exacerbations
5              Frequent exacerbations
6              Frequent exacerbations
7              Frequent exacerbations
8              Frequent exacerbations
9              Frequent exacerbations
10             Frequent exacerbations
11             Frequent exacerbations
12             Frequent exacerbations
With COPD
13             Frequent exacerbations
14             Frequent exacerbations
15             Frequent exacerbations
16             Insurance
17             Insurance
18             Frequent exacerbations
19             Frequent exacerbations
20             Frequent exacerbations
21             Insurance
22             Insurance
23             Frequent exacerbations
24             Insurance
25             Insurance, tracheotomy

BIS=budesonide inhalation suspension; COPD=chronic obstructive
pulmonary disease; [FEVsub.1] = forced expiratory volume in 1 second.

Table 2. Medications before and during BIS * treatment for patients
with asthma and COPD.

Patient                           Before

          Daily                                 As-needed
Asthma
1         Fluticasone HFA 110 [micro]g MDI      Albuterol MDI
          Montelukast, omalizumab

2         Fluticasone/salmeterol 250/50         Levalbuterol
          [micro]g DPI                          inhalation solution

3         Budesonide 200 [micro]g DPI           Levalbuterol
          Formoterol DPI, omalizumab            inhalation solution

4         Budesonide 200 [micro]g DPI           Albuterol MDI
          Formoterol DPI, montelukast,
          omalizumab

5         Beclomethasone 80 [micro]g MDI        Albuterol MDI
          Salmeterol DPI, montelukast

6         Fluticasone HFA 220 [micro]g MDI      Albuterol MDI
          Methylprednisolone 4 mg daily,
          salmeterol DPI, montelukast

7         Fluticasone HFA 220 [micro]g MDI      Levalbuterol
          Montelukast                           inhalation solution

8         Budesonide 200 [micro]g DPI           Levalbuterol
          Formoterol DPI, theohylline           inhalation solution

9         Budesonide 200 [micro]g DPI           Albuterol MDI
          Formoterol DPI, omalizumab

10        Fluticasone/salmeterol 250/50         Levalbuterol
          [micro]g DPI Montelukast              inhalation solution

11        Fluticasone/salmeterol 500/50         Levalbuterol
          [micro]g DPI Zafirlukast              inhalation solution

12        Budesonide 200 [micro]g DPI           Albuterol MDI
          Methylprednisolone 4 mg daily,
          formoterol DPI, Zafirlukast

13        Fluticasone/salmeterol 250/50         Ipratropium 0.5 mg/
          [micro]g DPI Ipratropium 0.5 mg/      albuterol 2.5 mg
          albuterol 2.5 mg inhalation           inhalation solution
          solution

14        Fluticasone/salmeterol 250/50         Levalbuterol
          [micro]g DPI Tiotropium DPI           inhalation solution

15        Fluticasone/salmeterol 250/50         Levalbuterol
          [micro]g DPI Ipratropium MDI,         inhalation solution
          theophylline

16        Budesonide 200 [micro]g DPI           Albuterol 2.5 mg
          Formoterol DPI, tiotropium DPI        inhalation solution

17        Fluticasone/salmeterol 250/50         Levalbuterol
          [micro]g DPI                          inhalation solution

18        Ipratropium 0.5 mg/albuterol          Levalbuterol
          2.5 mg inhalation solution            inhalation solution

19        Ipratropium 0.5 mg/albuterol          Levalbuterol
          2.5 mg inhalation solution            inhalation solution

20        Fluticasone/salmeterol 250/50         Levalbuterol
          [micro]g Theophylline                 inhalation solution

21        Fluticasone/salmeterol 250/50         Levalbuterol
          [micro]g Theophylline                 inhalation solution

22        Fluticasone/salmeterol 250/50         Levalbuterol
          [micro]g DPI Tiotropium DPI           inhalation solution

23        Ipratropium 0.5 mg/albuterol          Ipratropium 0.5 mg/
          inhalation solution                   albuterol 2.5 mg
                                                inhalation solution

24        Ipratropium and albuterol MDI         Ipratropium 0.5 mg/
          Theophylline                          albuterol 2.5 mg
                                                inhalation solution

25        Ipratropium 0.5 mg/albuterol          Levalbuterol inhalation
          2.5 mg inhalation solution            solution

Patient                           During

          Daily                                 As-needed
Asthma
1         BIS 0.5 mg/2 mL                       Albuterol MDI
          Montelukast, omalizumab

2         BIS 0.5 mg/2 mL                       Levalbuterol
          Salmeterol DPI                        inhalation solution

3         BIS 0.5 mg/2 mL                       Levalbuterol
          Formoterol DPI, omalizumab            inhalation solution

4         BIS 0.5 mg/2 mL                       Albuterol MDI
          Formoterol DPI, montelukast,
          omalizumab

5         BIS 0.5 mg/2 mL                       Albuterol MDI
          Salmeterol DPI, montelukast

6         BIS 0.5 mg/2 mL                       Albuterol MDI
          Methylprednisolone 4 mg daily,
          salmeterol DPI, montelukast

7         BIS 0.5 mg/2 mL                       Levalbuterol
          Montelukast                           inhalation solution

8         BIS 0.5 mg/2 mL                       Levalbuterol
          Formoterol DPI, theophylline          inhalation solution

9         BIS 0.5 mg/2 mL                       Albuterol MDI
          Formoterol DPI, omalizumab

10        BIS 0.5 mg/2 mL                       Levalbuterol
          Salmeterol DPI, montelukast           inhalation solution

11        BIS 0.5 mg/2 mL                       Levalbuterol
          Salmeterol DPI, zafirlukast           inhalation solution

12        BIS 0.5 mg/2 mL                       Albuterol MDI
          Methylprednisolone 4 mg daily,
          salmeterol DPI, zafirlukast           COPD

13        BIS 0.5 mg/2 mL                       Ipratropium 0.5 mg/
          Ipratropium 0.5 mg/albuterol          albuterol 2.5 mg
          2.5 my inhalation solution            inhalation solution

14        BIS 0.5 mg/2 mL                       Levalbuterol
          Levalbuterol HCI inhalation           inhalation solution
          solution, ([double dagger])
          tiotropium DPI

15        BIS 0.5 mg/2 mL                       Levalbuterol
          Salmeterol DPI, tiotropium DPI,       inhalation solution
          theophylline

16        BIS 0.5 mg/2 mL                       Albuterol 2.5 mg
          Formoterol DPI, tiotropium DPI        inhalation solution

17        BIS 0.5 mg/2 mL                       Levalbuterol
          Salmeterol DPI                        inhalation solution

18        BIS 0.5 mg/2 mL                       Levalbuterol
                                                inhalation solution

19        BIS 0.5 mg/2 mL                       Levalbuterol
          Ipratropium 0.5 mg/albuterol          inhalation solution
          2.5 mg inhalation solution

20        BIS 0.5 mg/2 mL                       Levalbuterol HCI
          Salmeterol DPI, theophylline          inhalation solution

21        BIS 0.5 mg/2 mL                       Levalbuterol
          Salmeterol DPI, theophylline          inhalation solution

22        BIS 0.5 mg/2 mL                       Levalbuterol
          Salmeterol DPI, tiotropium DPI        inhalation solution

23        BIS 0.5 mg/2 mL                       Ipratropium 0.5 mg/
          Ipratropium 0.5 mg/albuterol          albuterol 2.5 mg
          2.5 mM inhalation solution            inhalation solution

24        BIS 0.5 mg/2 mL                       Ipratropium 0.5 mg/
          Ipratropium 0.5 mg/albuterol          albuterol 2.5 mg
          2.5 mg inhalation solution,           inhalation solution
          theophylline

25        BIS 0.5 mg/2 mL                       Levalbuterol
          Ipratropium 0.5 mg/albuterol          inhalation solution
          2.5 mg inhalation solution

BIS=budesonide inhalation suspension, COPD=chronic obstructive
pulmonary disease; DPI=dry powder inhalation; MDI=metered dose
inhaler; HCI= hydrochloride; LABA=long-acting [[beta].sub.2]
-adrenergic agonist.

* BIS 0.5 mg/2 mL is administered twice daily.

([dagger]) Long-acting [[beta]sub.2] adrenergic agonist changed
because of formulary issues.

([double dagger]) Used instead of a LABA as daily treatment.