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Safety of Long-term Treatment With HFA Albuterol^*

^* From the Department of Medicine (Dr. Ramsdell), University of California, San Diego Medical Center, San Diego, CA; and 3M Pharmaceuticals (Ms. Klinger, Mr. Ekholm, and Dr. Colice), St. Paul, MN.

	Abstract

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Background: Chlorofluorocarbons (CFCs) used as propellants in metered-dose inhalers deplete stratospheric ozone, which results in serious public health concerns. Albuterol has been reformulated in the non-ozone-depleting propellant, hydrofluoroalkane-134a (HFA albuterol).

Objectives: The primary objective was to compare the safety of HFA albuterol to an albuterol product formulated in chlorofluorocarbon propellants (CFC albuterol) during 1 year of treatment in asthmatics. Bronchodilator efficacy of the two products was assessed as a secondary objective.

Methods: The results from two open-label, parallel-group trials of similar design in asthmatics requiring short-acting ß-agonists for symptom control were combined. Patients took two puffs bid of either HFA albuterol or CFC albuterol for 1 year. Additional puffs of study drug were allowed as needed to control asthma symptoms. Adverse events were recorded at clinic visits. Patients self-administered study drug at quarterly visits and underwent serial spirometry during a 6-h period postdose. Bronchodilator efficacy variables, based on FEV₁ response to study drug, were proportion of responders, time to onset of effect, peak percent change, time to peak effect, duration of effect, and area under the curve. Differences between products and changes over time in efficacy variables were assessed using an analysis of variance model. Regression analyses with FEV₁ as a covariate were performed post-hoc to analyze changes in bronchodilator efficacy over time.

Results: Demographic and baseline characteristics were similar for patients receiving HFA albuterol (n = 337) and CFC albuterol (n = 132). Total reported adverse events were similar for the two treatments. Differences in only four individual adverse events were noted: the HFA albuterol group reported more gastroenteritis and dizziness; the CFC albuterol group reported more epistaxis and expectoration. Adverse events attributed to study drug use were infrequent. No serious adverse events were related to study drug use. Predose FEV₁ at quarterly visits increased to a small extent in both groups from month 0 to month 12. The bronchodilator efficacy of HFA albuterol was comparable to that of CFC albuterol at the quarterly visits, but decreased from baseline for both products over the 12 months of treatment. Use of inhaled corticosteroids, nasal corticosteroids, or theophylline did not explain the increase in predose FEV₁ over time and did not protect patients from developing reduced bronchodilator efficacy by month 12. The change in predose FEV₁ did not entirely account for the reduced bronchodilator efficacy over time.

Conclusions: HFA albuterol has a safety profile similar to that of CFC albuterol during chronic, scheduled use, and both drugs are well tolerated. HFA albuterol and CFC albuterol provided comparable bronchodilator efficacy, but bronchodilator efficacy decreased for both products with 1 year of use.

Key Words: albuterol • asthma • ß-adrenergic bronchodilator • ß-agonist • HFA-134a propellant

	Introduction

TOP Abstract Introduction Materials and Methods Results Discussion References

 
British, Canadian, and American asthma guidelines agree that short-acting ß-agonists should be used for symptom control by asthmatics.^{1 ,2 ,3} The preferred method for administering short-acting ß-agonists is use of a metered-dose inhaler (MDI). Since MDIs became commercially available in the 1950s, millions of asthmatics have used them to self-administer short-acting ß-agonists. Despite this extensive use of short-acting ß-agonists via MDIs, there is surprisingly little published, prospectively obtained information available on the safety of these products with long-term use.

Short-acting ß-agonists in MDIs have historically been formulated in MDIs with chlorofluorocarbons (CFCs) as propellants, but CFCs deplete stratospheric ozone. Loss of atmospheric ozone presents a serious public health concern.^{4 ,5} The propellant hydrofluoroalkane-134a (HFA) does not deplete stratospheric ozone and has been used to reformulate albuterol (HFA albuterol). Prior to regulatory approval of HFA albuterol, the US Food and Drug Administration (FDA) required careful documentation of its safety and efficacy compared with those of albuterol products formulated in CFCs (CFC albuterol). These regulatory requirements provided the opportunity to compile safety information and data on bronchodilator efficacy during chronic, scheduled use of short-acting ß-agonists. In this report, we present the findings from two long-term (1-year) studies, comparing the safety and bronchodilator efficacy of HFA albuterol and CFC albuterol.

	Materials and Methods

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Study Design
Results from two separate studies were combined. These studies had similar inclusion/exclusion criteria (see the section, "Patient Population"), dosing regimens, and assessment plans. Patients were enrolled in study A after completing a previously reported 12-week trial comparing the safety and efficacy of HFA albuterol, CFC albuterol, and placebo.^{6 ,7} Patients who had received either HFA albuterol or placebo in the 12-week trial were assigned to treatment with HFA albuterol in study A. Patients who had received CFC albuterol in the 12-week trial were randomized to either HFA albuterol or CFC albuterol in study A. The interval between completing the 12-week study and entering study A was about 1 week, and during this time period patients continued to take the study drug assigned to them during the 12-week study. Patients enrolled in study B were randomly assigned to either HFA albuterol or CFC albuterol. Randomization was in blocks of 12, with two patients receiving HFA albuterol for every one patient receiving CFC albuterol.

In both year-long trials, the study drugs were HFA albuterol (Proventil HFA; Key Pharmaceuticals, Schering Corporation; Kenilworth, NJ) and CFC albuterol (Ventolin; Glaxo Wellcome; Research Triangle Park, NC); dosing was two puffs bid in an open-label fashion. Patients were allowed to take additional puffs of their assigned study drug as needed to control symptoms. Use of spacers was not allowed. Patients whose asthma was stabilized on inhaled corticosteroids, nasal corticosteroids, and theophylline products could remain on these drugs through both studies. No instructions were provided for cleaning the study MDIs. The study drug was resupplied at 1- to 3-month intervals, as necessary. Returned MDIs were weighed to assess compliance with study drug use and evaluated if reported to be not operating properly.

Clinic visits took place at months 0, 3, 6, 9, and 12. Patients were instructed to withhold theophylline products for 24 h and inhaled ß-agonists and caffeine-containing products for 8 h before reporting to the clinic for these visits between 7:00 and 10:00 AM. At each clinic visit, study coordinators questioned patients in nonspecific terms (eg, had they experienced any health problems since their last visit?) about the occurrence of adverse events. Relationship of adverse events to study drug use was determined by the investigator.

Patients self-administered two puffs of their study drug in the clinic at each visit. Pulmonary function testing, using spirometers and effort reproducibility standards meeting American Thoracic Society criteria,⁸ was performed predose and serially during a 6-h period postdose. Predicted values for FEV₁ were determined by the method of Crapo et al.⁹

Patient Population
Patients 12 years of age and older with at least a 12-month history of stable asthma requiring short-acting ß-agonists for symptom control were eligible for enrollment. Asthma was considered stable if, during the month prior to study entry, there were no changes in asthma therapy and no asthma-related hospital visits. Patients had a baseline FEV₁ of 40 to 80% predicted, had at least a 15% increase in FEV₁ within 30 min of using an inhaled short-acting ß-agonist, and demonstrated satisfactory technique in the use of a placebo MDI. Women were nonpregnant, nonlactating, and using an acceptable method of contraception. Patients with significant concomitant disease (eg, cardiac arrhythmias, congestive heart failure, hypertension, nonreversible pulmonary disease, etc) were excluded. Other reasons for exclusion were a recent (within 4 weeks) upper or lower respiratory tract infection, and reported recent (within 4 weeks) use of oral corticosteroids, oral ß-agonists, monoamine oxidase inhibitors, tricyclic antidepressants, or ß-adrenergic antagonists. Prior to entry into these studies, all patients (or their parents, in the case of minors) provided written informed consent in accordance with participating Institutional Review Boards and US federal guidelines.

Data Analysis
Adverse events were summarized by the preferred terms of the World Health Organization. For these studies, an acute asthma episode was defined as an increase in asthma symptoms lasting < 24 h; increased asthma symptoms were defined as an increase in asthma symptoms lasting > 24 h. Patients with increased asthma symptoms could be treated with a short course of oral corticosteroids. The reporting rates of adverse events were compared between treatment groups using Fisher's Exact Test. Study drug use was calculated by dividing weight change of the returned MDI by shot weight of the study drug.

Bronchodilator efficacy variables were based on actual and percent change in FEV₁ from baseline after dosing at months 0, 3, 6, 9, and 12 in the intent-to-treat database (last actual value carried forward). A patient was considered a responder at a visit if the FEV₁ exceeded baseline by at least 15% within 30 min postdose at that visit. Time to onset of bronchodilator effect was determined by linear interpolation as the point at which FEV₁ first exceeded baseline by at least 15%. The peak bronchodilator response, expressed as percent change, was defined as the maximum FEV₁ within 2 h postdose. The time to peak FEV₁ effect was measured as the time point of peak response. Duration of effect was defined as the time of termination of effect minus time of onset, where time of termination equaled the point where FEV₁ fell to 15% above baseline (linear interpolation). The FEV₁ area under the curve (AUC) for bronchodilator effect was calculated using the trapezoidal rule from the time of onset of effect to termination of effect. Differences between products and changes over time in these efficacy variables were tested using an analysis of variance model with pooled center, treatment group, and interactions as factors in the model. Post-hoc regression analyses were performed using change in predose FEV₁ as a covariate to assess its influence on bronchodilator efficacy. Also tested was whether use of inhaled corticosteroids, nasal corticosteroids, or theophylline affected predose FEV₁ or bronchodilator efficacy over time.

Sample sizes for these studies were based on regulatory requirements for safety assessments of drugs intended for long-term treatment. To identify adverse events that occur in a range of 0.5% to 5%, the FDA required a sample size of 300 patients for HFA albuterol treatment. The FDA also required treatment for at least 1 year, because adverse event reporting may change over time and there may be delayed reports of adverse events.

	Results

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Four hundred sixty-four patients who completed a prior study were eligible for entry into study A. Of these 464, 160 elected to enter this year-long study; 130 were assigned to HFA albuterol and 30 to CFC albuterol. Study A was performed at 25 US sites between October 1993 and April 1995. A total of 482 patients were screened for entry into study B and 309 were selected; 207 were randomized to HFA albuterol and 102 to CFC albuterol. The most common reasons for ineligibility were baseline FEV₁ not falling within specified limits and FEV₁ reversibility < 15%. Study B was performed at 19 US sites between September 1994 and December 1995. For the two studies combined, 337 patients received HFA albuterol and 132 received CFC albuterol.

There were no significant differences in demographics and baseline lung function between the patients receiving HFA albuterol and those receiving CFC albuterol (Table 1 ). Patients were generally young adults, and most were female. The proportion of black patients in these studies was lower than the proportion in the US population. Based on FEV₁ percent predicted, many of the patients would be classified as having moderate or severe asthma. Inhaled corticosteroid and theophylline use at study entry reflects this asthma severity.

No significant differences were found between the treatment groups in terms of patients reporting at least one adverse event (86% of HFA albuterol groups vs 80% for CFC albuterol), adverse events attributed to study drug use (9% for HFA albuterol vs 7% for CFC albuterol), serious adverse events (3% for HFA albuterol vs 7% for CFC albuterol), adverse events causing study discontinuation (3% for HFA albuterol vs 5% for CFC albuterol), acute asthma episodes (23% for HFA albuterol vs 23% for CFC albuterol), and reports of increased asthma symptoms (31% for HFA albuterol vs 39% for CFC albuterol). Overall, 80 of 337 HFA albuterol–treated patients (23.7%) and 42 of 116 CFC albuterol–treated patients (36.2%) received a short course of oral prednisone for increased asthma symptoms during these two studies (p > 0.05). Adverse events were reported in similar numbers for each treatment group by quarter throughout the 1-year treatment periods (data not shown).

Adverse events relevant to ß-adrenergic bronchodilators and MDIs were not reported at different rates by patients in the HFA albuterol and CFC albuterol groups (Table 2 ). There were significant differences in the reporting rates for HFA albuterol- and CFC albuterol-treated patients for only four individual adverse events: gastroenteritis, reported by 25 HFA albuterol patients (7%) vs 3 CFC albuterol patients (2%; p = 0.048); dizziness, reported by 13 HFA albuterol patients (4%) and no CFC albuterol patients (p = 0.024); epistaxis, reported by no HFA albuterol patients vs 4 CFC albuterol patients (3%; p = 0.006); and expectoration, reported by 3 HFA albuterol patients (1%) vs 7 CFC albuterol patients (5%; p = 0.007).

View larger version (10K): [in this window] [in a new window] [Download PPT slide]   Figure 1. The predose FEV1 as percent predicted at months 0, 3, 6, 9, and 12 did not demonstrate any differences between patients who received HFA albuterol and those who used CFC albuterol. Values are given as the mean ± SE.

View larger version (18K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Serial FEV1 results obtained by spirometry during a 6-h period after dosing with HFA albuterol (top, A) and CFC albuterol (bottom, B) are shown for months 0 and 12. Note that the curves at month 12 are displaced downward compared to the month 0 curves for both HFA albuterol and CFC albuterol, illustrating the reduced bronchodilator effect for both products with regular use for 1 year. Values are given as the mean ± SE.

	Discussion

TOP Abstract Introduction Materials and Methods Results Discussion References

In open-label studies, adverse event reporting might be expected to be biased against a new product. However, the types and reporting rates of adverse events in this large cumulative year-long experience were similar for patients treated with HFA albuterol and CFC albuterol. This data reassures the clinician that reformulation of albuterol in the propellant HFA has not altered its safety profile. The significant differences between the two treatment groups in the reporting rates of four adverse events most probably occurred due to chance. This study confirms clinical experience and previous work¹⁰ that adverse events related to albuterol use (eg, tremor, nausea, palpitations, tachycardia, and nervousness) occur in far fewer patients than is suggested by current labeling material for CFC albuterol.¹¹

There was no change in reporting rates for adverse events (including respiratory-related adverse events) throughout the 1-year study in either treatment group, and the number of serious adverse events related to asthma in this large population of mostly moderate to severe asthmatics was small. Predose FEV₁ at quarterly clinic visits increased slightly at month 12 compared with month 0. These observations suggest that asthma control was not affected in these studies by regular use of albuterol, but the lack of a comparison placebo group or historical information on asthma exacerbations limits this conclusion. Previous studies have hypothesized that regular use of ß-adrenergic agonists might lead to worsened asthma control.^{12 ,13} These studies used fenoterol, a drug with pharmacologic properties different from those of albuterol.¹⁴ Results from another year-long study¹⁰ support the findings of this report, that regular albuterol use does not adversely affect asthma control.

Bronchodilator efficacy was comparable between HFA albuterol and CFC albuterol at quarterly visits throughout the 1-year treatment period. This confirms the results of previous studies^{6 ,15} showing comparable bronchodilation with HFA albuterol as with CFC albuterol. As already noted, there was a small increase in predose FEV₁ at month 12 compared with month 0 for both the HFA albuterol and CFC albuterol treatment groups. This finding differs from the results of several other studies^{16 ,17 ,18 ,19} that reported an annual decline in FEV₁ for asthmatics. The present studies were not designed to assess change in lung function over time. Consequently, these results should be confirmed by future prospective studies.

Bronchodilator efficacy at month 12 was decreased compared with month 0 for both study drugs. There has been disagreement in the medical literature on whether bronchodilator performance was maintained with regular use of short-acting ß-agonists; some work indicates a fall in effectiveness^{6 ,20} while other data reflect no change.^{21 ,22} Dosing of short-acting ß-agonists in previous studies had been two puffs qid. In these two year-long studies, patients were asked to self-administer two puffs of study drug bid, but MDI weight changes suggested use of about 6 to 8 puffs/d. The data from this report extend our previous work, which showed a decrease in bronchodilator efficacy after 4 weeks of regular use of short-acting inhaled ß-agonists.⁶ There appears to be a further gradual decline in bronchodilator efficacy with regular use of short-acting inhaled ß-agonists for 1 year. The decrease in bronchodilator efficacy seems to be a function of both a decrease in duration of effect and peak percent increase in FEV₁. Use of inhaled corticosteroids, nasal corticosteroids, or theophylline did not protect patients from developing reduced ß-agonist bronchodilator effect. The increase in predose FEV₁ may have contributed partially to the reduced bronchodilator efficacy found over time, but, after accounting for predose FEV₁ as a covariate, there was still a significant decrease in bronchodilator effect at month 12. The large sample size of this reported database provides a high degree of confidence regarding this observation. Unfortunately, these results do not yield insights into the mechanism of the reduced bronchodilator effect.

Several study design features warrent comment. Use of spacers was not allowed in these two year-long studies. Consequently, information is not available on whether spacer use would have affected either the number or pattern of reported adverse events. All patients were required to be using short-acting ß-agonists at entry into these studies. This may have influenced adverse event patterns by selecting out patients who could not tolerate these products, but finding a population of asthmatics naive to these products would have been difficult. It should be noted that recent work has shown that regular use of short-acting ß-agonists provides no added benefit over as-needed use.²² However, regular dosing was required by the FDA to allow better understanding of the relationship of adverse event reporting to study drug use. Dosing bid was thought to be a reasonable regimen for compliance in a year-long study, but patients used 6 to 8 puffs/d of their study drug, on average. Because most patients in these studies had moderate to severe asthma, this study drug use was probably appropriate for symptom control.

Patients were not instructed to clean their MDIs in these studies. Available patient instructions for using CFC albuterol advise washing the plastic case and cap at least once a day. Patient instructions for HFA albuterol advise washing these components once a week. The metal canister should not be immersed in water. If the canister does get wet, it must be adequately dried before use. If the metal canister is not dried thoroughly, water may block the exit orifice of the stem, leading to drug impaction in the stem on actuation of the MDI. During this study, four MDIs were returned from a single patient with drug particles impacted in the canister stem. This most probably occurred because the metal canister was immersed in water and not adequately dried before use of the MDI.

In summary, the combined results of two year-long studies show that reformulation of albuterol with the non-ozone-depleting propellant HFA has not altered its expected highly favorable safety and efficacy profile. HFA albuterol and CFC albuterol have similar safety profiles, and both drugs are well tolerated. HFA albuterol provided bronchodilator efficacy comparable to that of CFC albuterol during long-term use, but chronic, scheduled use of both products resulted in decreased bronchodilator efficacy.

	Footnotes

 
This work was supported by a research grant from 3M Pharmaceuticals. Ms. Klinger, Mr. Ekholm, and Dr. Colice are full-time employees of 3M Pharmaceuticals.

Correspondence to: Gene L. Colice, MD, Associate Director of Clinical Research, 3M Pharmaceuticals, 270–3A-01, St. Paul, MN 55144-1000

Abbreviations: AUC = area under the curve; CFC = chlorofluorocarbon; CFC albuterol = albuterol formulated in chlorofluorocarbon propellants: FDA = Food and Drug Administration; HFA = hydrofluoroalkane-134a; HFA albuterol = albuterol formulated in propellant hydrofluoroalkane-134a; MDI = metered-dose inhaler

Received for publication February 4, 1998. Accepted for publication November 13, 1998.

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