Hydrofluoroalkane-134a Beclomethasone Dipropionate, 400 μg, Is as Effective as Chlorofluorocarbon Beclomethasone Dipropionate, 800 μg, for the Treatment of Moderate Asthma

doi:10.1378/chest.115.2.343

Chest

Volume 115, Issue 2, February 1999, Pages 343-351

https://doi.org/10.1378/chest.115.2.343 Get rights and content

Objective

The improved lung deposition of hydrofluoroalkane-134a beclomethasone dipropionate (HFA-BDP) extrafine aerosol compared with chlorofluorocarbon beclomethasone dipropionate (CFC-BDP) suggests that lower doses of HFA-BDP may be required to provide equivalent asthma control. The present study was undertaken to test this hypothesis.

Design

A 10- to 12-day run-in period confirmed that patients met established criteria of at least moderate asthma and the asthma was inadequately controlled by current therapy (inhaled β-agonist and CFC-BDP [≤ 400 μg/d]). A short course of oral prednisone, 30 mg/d for 7 to 12 days, was followed to establish the patients were steroid responsive and to provide an“ in-study” baseline of “optimal” asthma control.

Patients

A total of 347 patients were then randomized to HFA-BDP 400 μg/d, CFC-BDP 800 μg/d, or HFA-placebo for 12 weeks.

Results

Morning peak expiratory flow (am PEF) measurements showed that HFA-BDP 400 μg/d achieved equivalent control of asthma to CFC-BDP 800 μg/d at all time intervals after oral steroid treatment. All other efficacy variables supported the am PEF results and both active treatments were more effective than placebo. The safety profile of HFA-BDP compared favorably with that of CFC-BDP with no unexpected adverse events reported.

Conclusions

These findings demonstrate that HFA-BDP provides equivalent control of moderate or moderately severe asthma as CFC-BDP in the population studied, but at half the total daily dose.

Section snippets

Study Design and Population

This was a 12-week, placebo-controlled, parallel-group, randomized, blinded, multicenter study. The study population included nonsmoking adults, aged 18 to 65 years, with at least moderate asthma who were symptomatic despite current treatment with bronchodilators and inhaled steroid of 0 to 400 μg/d (Table 1). Additional qualification criteria were concurrent use of β-agonists for symptom relief and reversibility of FEV₁ of ≥ 15% in response to pirbuterol (400 μg). Eligible patients entered a

Demographics

A total of 347 patients were entered into this study, of whom 113 received HFA-BDP, 117 received CFC-BDP, and 117 received HFA-placebo. The three treatment groups were similar in all baseline patient characteristics, including lung function (Table 1). The use of inhaled steroids and the proportions of steroid-naive patients before randomization were also comparable between treatment groups.

Sixty-one patients (17.6%) withdrew prematurely from the study, with a total of 286 patients completing

Discussion

The imminent phasing out of CFC propellants in pharmaceutical aerosols has made it important to assess the comparable efficacy and safety of alternative CFC-free formulations to the original products. HFA-134a has been identified as a substitute for CFCs in pressurized MDIs.⁸ Preclinical studies have shown it to be well tolerated and to present no safety concerns.¹⁷ HFA formulations of salbutamol and fluticasone propionate have been shown previously to be as effective and well tolerated as CFC

Appendix

The Study Group includes the following: Eugene Bleecker, MD; Baltimore, MD; Dick Briggs, MD, Birmingham, AL; Edwin Bronsky, MD, Salt Lake City, UT; Stuart Brooks, MD, Tampa, FL; A. Sonia Buist, MD; Portland, OR; Paul Chervinsky, MD, North Dartmouth, MA; Edward, Diamond, MD, Elk Grove Village, IL; Robert Dockhorn, MD, Lenexa, KS; Thomas Edwards, MD, Albany, NY; Stanley Galant, MD, Orange, CA; Gary Gross, MD, Dallas, TX; Jay Grossman, MD, Tucson, AZ; F. Charles Hiller, MD, Little Rock, AR; Harold

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Role of Small Airways in Asthma
2016, Immunology and Allergy Clinics of North America
Can 'extrafine' dry powder aerosols improve lung deposition?
2015, European Journal of Pharmaceutics and Biopharmaceutics
Citation Excerpt :
The origin of this idea may have been the findings in the literature when chlorofluorocarbon (CFC)-based pressurized metered dose inhalers (pMDIs) containing beclometasone dipropionate (BDP) were replaced by hydrofluoroalkane (HFA)-based pMDIs, as a response to environmental concerns about the ozone layer in the 1990s [7]. It was shown that with the HFA pMDI only half the BDP dose is needed compared with CFC pMDI for effective treatment of moderate asthma [8,9]. The effect was attributed to the much finer aerosol from the HFA pMDI of which the particles had a mass median aerodynamic diameter (MMAD) of 1.1 μm versus 3.5–4 μm for the CFC pMDI.
There is increasing interest in the use of so-called ‘extrafine’ aerosols to target the small airways in the management of asthma and COPD. Using previously presented deposition data, we assessed whether submicron (<1 μm) particles can improve central and deep lung deposition. Our data show instead that particles in the range 1–3 μm are much more relevant in this respect. Based on this finding the Symbicort Turbuhaler, Seretide Diskus, Rolenium Elpenhaler and Foster (Fostair) NEXThaler ICS/LABA combination DPIs were tested in vitro as a function of the pressure drop (2, 4 and 6 kPa) across the inhaler. Obtained fine particle fractions (FPFs) <5 μm (as percent of label claim) were divided into subfractions <1, 1–3 and 3–5 μm. Differences of up to a factor of 4 were found between the best (Turbuhaler) and worst performing DPI (Elpenhaler), particularly for the FPF in the size range 1–3 μm. The NEXThaler, described as delivering ‘extrafine’ particles, did not appear to be superior in this size range. The marked differences in amount and size distribution of the aerosols between the devices in this study must cause significant differences in the total lung dose and drug distribution over the airways.
Childhood asthma hospital discharge medication fills and risk of subsequent readmission
2015, Journal of Pediatrics
Citation Excerpt :
With respect to inhaled steroids, prior studies suggest that the anti-inflammatory effects of inhaled steroids on pulmonary function may not be experienced for 7-14 days after initiation.18-20 At least 1 prior study demonstrated sustained pulmonary function improvement with inhaled steroids following treatment with systemic steroids compared with placebo.21 Given that inhaled steroid fills immediately follow asthma hospitalization in the current study and that nearly 100% of children receive systemic steroids during asthma hospitalization,3 our finding of a protective effect on immediate readmission may reflect sustained pulmonary function improvement.
To assess the relationship between posthospitalization prescription fills for recommended asthma discharge medication classes and subsequent hospital readmission.
This was a retrospective cohort analysis of Medicaid Analytic Extract files from 12 geographically diverse states from 2005-2007. We linked inpatient hospitalization, outpatient, and prescription claims records for children ages 2-18 years with an index hospitalization for asthma to identify those who filled a short-acting beta agonist, oral corticosteroid, or inhaled corticosteroid within 3 days of discharge. We used a multivariable extended Cox model to investigate the association of recommended medication fills and hospital readmission within 90 days.
Of 31 658 children hospitalized, 55% filled a beta agonist prescription, 57% an oral steroid, and 37% an inhaled steroid. Readmission occurred for 1.3% of patients by 14 days and 6.3% by 90 days. Adjusting for patient and billing provider factors, beta agonist (hazard ratio [HR] 0.67, 95% CI 0.51, 0.87) and inhaled steroid (HR 0.59, 95% CI 0.42, 0.85) fill were associated with a reduction in readmission at 14 days. Between 15 and 90 days, inhaled steroid fill was associated with decreased readmission (HR 0.87, 95% CI 0.77, 0.98). Patients who filled all 3 medications had the lowest readmission hazard within both intervals.
Filling of beta agonists and inhaled steroids was associated with diminished hazard of early readmission. For inhaled steroids, this effect persisted up to 90 days. Efforts to improve discharge care for asthma should include enhancing recommended discharge medication fill rates.
Real-life comparison of beclometasone dipropionate as an extrafine- or larger-particle formulation for asthma
2013, Respiratory Medicine
Beclometasone dipropionate is an inhaled corticosteroid (ICS) available in both extrafine and larger-particle hydrofluoroalkane formulations. Extrafine beclometasone has greater small airway distribution and inhalation technique tolerance than larger-particle beclometasone; therefore, its use may be associated with improved asthma outcomes at population levels. The study objective was to compare real-life effectiveness of extrafine and larger-particle beclometasone.
Retrospective matched cohort study including primary care patients with asthma (ages 12–60 and non-smokers 61–80 years) prescribed extrafine or larger-particle beclometasone by metered-dose inhaler. We studied patients receiving their first ICS (initiation population, n = 11,289) or switched from another ICS without dose change (switch population, n = 19,065). The extrafine and larger-particle beclometasone cohorts were matched in each population for demographic and database measures of asthma control during a baseline year; and endpoints assessed during 1 outcome year were adjusted for residual confounding factors.
The odds of no loss of asthma control (no asthma-related hospital attendance, consultation for lower respiratory tract infection, or oral corticosteroids) were significantly higher in the extrafine beclometasone cohorts of both initiation population (adjusted odds ratio [aOR] 1.12; 95% CI 1.02–1.23) and switch population (aOR 1.10; 95% CI 1.01–1.19). The odds of better adherence to ICS therapy were also significantly higher in both extrafine beclometasone cohorts (initiation population, aOR 1.64; 95% CI 1.52–1.75 and switch population, aOR 1.35; 95% CI 1.27–1.43).
These findings are consistent with the hypothesis that delivery of beclometasone in extrafine particle size produces real-life asthma treatment benefits.
Clinical trials no. NCT01400217.
Characterization of respiratory deposition of fluticasone-salmeterol hydrofluoroalkane-134a and hydrofluoroalkane-134a beclomethasone in asthmatic patients
2012, Annals of Allergy, Asthma and Immunology
Fixed combination fluticasone-salmeterol is the most used anti-inflammatory asthma treatment in North America, yet no studies report the actual respiratory tract dose or the distribution of drug within the lungs. Inflammation due to asthma affects all airways of the lungs, both large and small. Inhaled steroid delivery to airways results from a range of drug particle sizes, with emphasis on smaller drug particles capable of reaching the peripheral airways. Previous studies suggested that smaller drug particles increase pulmonary deposition and decrease oropharyngeal deposition.
To characterize the dose of fluticasone-salmeterol hydrofluoroalkane-134a (HFA) (particle size, 2.7 μm) delivered to asthmatic patients and examine the drug distribution within the lungs. The results were compared with the inhalation delivery of HFA beclomethasone (particle size, 0.7 μm).
A crossover study was conducted in asthmatic patients with commercial formulations of fluticasone-salmeterol and HFA beclomethasone radiolabeled with technetium Tc 99m. Deposition was measured using single-photon emission computed tomography/computed tomography gamma scintigraphy.
Two-dimensional planar image analysis indicated that 58% of the HFA beclomethasone and 16% of the fluticasone-salmeterol HFA were deposited in the patient's lungs. The oropharyngeal cavity and gut analyses indicated that 77% of the fluticasone-salmeterol HFA was deposited in the oropharynx compared with 35% of the HFA beclomethasone.
The decreased peripheral airway deposition and increased oropharyngeal deposition of fluticasone-salmeterol HFA was a result of its larger particle size. The smaller particle size of HFA beclomethasone allowed a greater proportion of lung deposition with a concomitant decrease in oropharyngeal deposition.
Effect of inhaled corticosteroids on small airways in asthma: Investigation using impulse oscillometry
2009, Pulmonary Pharmacology and Therapeutics
Citation Excerpt :
Baseline characteristics were assessed during a one-week run-in period during which patients were allowed to use only short-acting β2-agonists. Patients were then randomly assigned to receive either HFA-BDP (400 μg daily) or CFC-BDP (800 μg daily) [18] at a ratio of 2:1 [19]. This was due to an ethical reason based on the predominance in the efficacy of HFA-BDP over that of CFC-BDP already shown by several studies [20,21].
Small airways appear to have an important role in asthma. Hydrofluoroalkane-134a beclomethasone dipropionate (HFA-BDP) has ultrafine particles and accordingly greater deposition in the small airways than chlorofluorocarbon (CFC)-BDP. Impulse oscillometry systems (IOS), a new and non-invasive measure of pulmonary function, can examine the resistance of total (R5), large (R20), and small airways (R5–R20) separately, and low-frequency reactance area (AX), also considered a measure of small airways dysfunction.
Mild-to-moderate asthmatics who were inhaled corticosteroid naïve were randomized to receive 200 mcg HFA-BDP bid (n = 26) or 400 mcg CFC-BDP bid (n = 12) for 12 weeks in an open-label manner. Following baseline measurements, IOS and spirometry were repeated every 4 weeks, and methacholine challenge to separately assess airway sensitivity and airway reactivity and lung volumes at 12 weeks.
Moderate correlations were found between R5–R20 or AX and spirometry and lung volume indices of small airways, and between R20 and peak expiratory flow at baseline. The two groups did not significantly differ in baseline clinical or functional parameters. At 12 weeks, all IOS indices improved in the HFA-BDP group, whereas all but R5–R20 improved with CFC-BDP. R5–R20 and AX progressively improved with HFA-BDP; these changes achieved statistical significance at 12 weeks versus the CFC-BDP group. Other IOS and spirometry indices failed to show such trends. HFA-BDP significantly attenuated methacholine airway sensitivity; the degree of this attenuation strongly correlated with R5–R20 and AX baseline values, and with improvement of AX with treatment.
HFA-BDP is an effective treatment of small airways in asthma. Prolonged treatment provides a progressive effect over time, which is associated with an attenuation of airway responsiveness.

View all citing articles on Scopus

: This study was supported by a grant from 3M Pharmaceuticals.

^†: A complete list of Study Group participants is located in the Appendix.

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Chest

Clinical InvestigationsASTHMAHydrofluoroalkane-134a Beclomethasone Dipropionate, 400 μg, Is as Effective as Chlorofluorocarbon Beclomethasone Dipropionate, 800 μg, for the Treatment of Moderate Asthma

Objective

Design

Patients

Results

Conclusions

Section snippets

Study Design and Population

Demographics

Discussion

Appendix

J Allergy Clin Immunol

J Allergy Clin Immunol

Respir Med

Respir Med

Pharmacol Ther

Expert panel report 2: guidelines for the diagnosis and management of asthma. NIH publication No. 97-4051

Optimizing inhaled drug delivery in patients with asthma

Br J Gen Pract

Improving the bronchial deposition of pressurized aerosols

Chest

Drug delivery to the small airways

Am J Respir Crit Care Med

Effects of drugs on small airways

Am J Respir Crit Care Med

In vivo measurements of aerosol dose and distribution: clinical relevance

J Aerosol Med

Approaches and challenges to use freon propellant replacements

Aerosol Sci Technol

Improved lung deposition and decreased oropharyngeal deposition with a new CFC-free beclomethasone metered dose inhaler

Am J Respir Crit Care Med

A conceptual model for the delivery of pressurized metered-dose hydrofluoroalkane-based inhalation aerosols

Pharm Technol

Improved performance characteristics of CFC-free aerosol MDIs

J Aerosol Med

Enhanced drug delivery through reformulating MDIs with HFA propellants—drug deposition and its effect on preclinical and clinical programs

Efficient lung deposition of beclomethasone dipropionate via a novel multidose dry powder inhaler compared to a conventional pressurized metered dose inhaler

Pharm Res

Clinical Investigations
ASTHMA
Hydrofluoroalkane-134a Beclomethasone Dipropionate, 400 μg, Is as Effective as Chlorofluorocarbon Beclomethasone Dipropionate, 800 μg, for the Treatment of Moderate Asthma