Inhalation devices for long-acting beta2-agonists: efficiency and ease of use of dry powder formoterol inhalers for use by patients with asthma and COPD.

BACKGROUND: Since the long-acting beta(2)-agonist bronchodilator, formoterol, first became available for the treatment of subjects with asthma or chronic obstructive pulmonary disease (COPD), generic forms of this agent have been launched in a variety of devices. It is timely to review the characteristics of the original dry powder delivery device, the single-dose Aerolizer, its in vitro performance and its comparability with other inhaler devices that are now available for delivery of formoterol. SCOPE: This review focuses on the performance of the formoterol Aerolizer inhaler in comparison with other inhalers. Publically available data (PubMed) on the device performance characteristics of the Aerolizer were reviewed and summarized, together with the results of comparative studies performed by the authors. Published studies (PubMed) on patient handling and inhaler technique that include the Aerolizer are described and studies comparing the clinical effect of formoterol in the Aerolizer with formoterol delivered via other devices were reviewed and are summarized. FINDINGS: The Aerolizer performs consistently in dosing efficiency across a range of inspiratory flow rates, suggesting its suitability for use by patients with differing inspiratory flow abilities. The single-dose, capsule-based nature of the device provides patients with obvious feedback on whether the drug has been taken successfully and the Aerolizer has been shown to be one of the more easily used devices in comparative patient handling studies. Studies comparing the clinical effect of formoterol delivered by different inhalation devices show that formoterol via Aerolizer has an equivalent therapeutic effect. CONCLUSION: Judged on the basis of dosing efficiency, ease of use and clinical equivalence, formoterol Aerolizer remains a useful option in the management of patients with asthma or COPD.

Effect of formoterol fumarate treatment on exercise-induced bronchoconstriction in children.

BACKGROUND: Exercise-induced bronchoconstriction (EIB) is common, particularly in children. OBJECTIVES: To compare the protective effect of single doses of formoterol fumarate via Aerolizer with placebo and albuterol in children with EIB. METHODS: In this randomized, double-blind, double-dummy, crossover trial, 23 children (aged 4-11 years) received formoterol, 12 or 24 microg; albuterol, 180 microg; or placebo at 4 separate visits. Protection against EIB was evaluated as the maximum percentage decrease in forced expiratory volume in 1 second (FEV1) from the preexercise value after exercise challenge tests (6-minute treadmill) conducted 15 minutes and 4, 8, and 12 hours after administration of the dose. RESULTS: The maximum percentage decrease in FEV1 after the 4-hour exercise test (primary efficacy variable) was significantly less for formoterol, 12 and 24 microg, vs placebo (P < .001 for both) or albuterol (P = .016 and .010, respectively); albuterol was not significantly different from placebo. Formoterol, 12 and 24 microg, differed from placebo at 8 hours (P = .002 and .001, respectively), with a smaller difference between albuterol and placebo (P = .045). Rescue medication use and a high dropout rate may have biased treatment differences at later time points. Protection against EIB (<20% maximum decrease in FEV1) across all time points was observed for 17 (77%) of 22 and 17 (74%) of 23 children with formoterol, 12 and 24 microg, respectively, compared with 8 (35%) of 23 with albuterol and 6 (27%) of 22 with placebo. CONCLUSIONS: Single doses of formoterol, 12 or 24 microg, are effective in protecting against EIB in children, affording a statistically significantly greater protective effect than placebo or albuterol.

Formoterol, 24 microg bid, and serious asthma exacerbations: similar rates compared with formoterol, 12 microg bid, with and without extra doses taken on demand, and placebo.

STUDY OBJECTIVES: The primary objective was to determine whether high-dose formoterol, 24 mug bid, was associated with more asthma exacerbations compared with lower formoterol doses in patients with stable persistent asthma. Serious asthma exacerbations (life threatening or requiring hospitalization) were the primary end point. Secondary end points included significant exacerbations requiring systemic corticosteroids, all exacerbations, and changes in FEV1. DESIGN: In a multicenter, placebo-controlled, parallel-group study, patients were randomized to 16 weeks of treatment with formoterol, 24 microg bid; formoterol, 12 microg bid, with up to two additional 12-microg doses daily on demand for worsening symptoms (12 microg bid plus on demand); formoterol, 12 microg bid; or placebo. The formoterol 12-microg-bid plus on-demand regimen was administered open label, while the other three regimens were double blind. SETTING: Outpatient clinics. PATIENTS: A total of 2,085 patients aged > or = 12 years with stable, persistent asthma were enrolled and treated; 65% (n = 1,347) received regular concomitant antiinflammatory therapy during the study. MEASUREMENTS AND RESULTS: Nine patients had respiratory-related serious adverse events (SAEs) requiring hospitalization: two patients (0.4%) in the 24-microg-bid group; one patient (0.2%) in the 12-microg-bid plus on-demand group; five patients (0.9%) in the 12-microg-bid group; and one patient (0.2%) in the placebo group. All of these events were asthma related, except for two SAEs in the 12-microg-bid group that were later considered not to be asthma related by independent reviewers who were not associated with the conduct of the study. The proportions of patients with significant asthma exacerbations (requiring systemic corticosteroids) were similar in the 24-microg-bid group (6.3%, 33 of 527 patients), 12-microg-bid group (5.9%, 31 of 527 patients) and placebo group (8.8%, 45 of 514 patients) and lower in the 12-microg-bid plus on-demand group (4.4%, 23 of 517 patients; p = 0.0057 vs placebo). All treatments were well tolerated. All formoterol treatment regimens had a significant effect on FEV1 measured 2 h after dose during the study (p < 0.0001 vs placebo); and on predose trough FEV1 measured at all visits after baseline (p < 0.002 vs placebo). CONCLUSIONS: Treatment with formoterol, 24 microg bid, was not associated with an increase in serious asthma exacerbations compared with the lower formoterol doses or placebo.

Formoterol delivered via a new multi-dose dry powder inhaler (Certihaler) is as effective and well tolerated as the formoterol dry powder inhaler (Aerolizer) in children with persistent asthma.

The Certihaler is a new multi-dose dry powder inhaler for the delivery of formoterol (Foradil), a long-acting beta(2)-agonist. This dose-ranging study compared the efficacy and safety of formoterol 5, 10, 15 and 30 microg and placebo administered via the Certihaler or formoterol 12 microg via a single-dose dry powder inhaler (Aerolizer) in children with persistent asthma. This was a randomized, placebo-controlled, double-blind, double-dummy, incomplete block crossover, dose-finding and pharmacokinetic study. Children (5-12 years, n = 77) received four of the active treatments twice weekly (BID) for 1 week separated by 1-week single-blind washouts. The primary efficacy variable was 12-h AUC of FEV(1) after 1 week's treatment. Secondary variables included serial 12-h FEV(1). A subset of patients (n = 37) participated in a pharmacokinetic analysis. All formoterol doses resulted in significant increases in 12-h AUC of FEV(1) compared with placebo, and there was no difference between active treatments. The onset of action of formoterol was <3 min for all active treatments. Doses of formoterol > or =10 microg via the Certihaler increased FEV(1) significantly for up to 12 h compared with placebo. The 5 microcg dose via the Certihaler and 12 microg dose via the Aerolizer had a significant effect up to 8 and 7 h post-dose, respectively. Urinary excretion of formoterol via the Certihaler increased in a dose-proportional manner. All formoterol doses were well tolerated, but some patients experienced tremor at the 15 and 30 microg doses. Despite the lack of significant differences between the active doses in the overall bronchodilation, formoterol 10 microg BID via the Certihaler was the dose that provided the best balance between efficacy and tolerability: its duration of action was sustained over 12 h, contrary to that the lower dose (5 microg BID), whereas its tolerability, especially with regard to tremor, was better than the higher doses (15 and 30 microg BID). Overall, Certihaler 10 microg BID was not significantly different from formoterol 12 microg BID via Aerolizer.

Faster onset of bronchodilation with formoterol than with salmeterol in patients with stable, moderate to severe COPD: results of a randomized, double-blind clinical study.

OBJECTIVES: To compare the onset and magnitude of bronchodilation after dry powder inhalations of formoterol fumarate (Foradil Aerolizer) versus salmeterol xinofoate (Serevent Diskus) with respect to normalized (*) forced expiratory volume in 1 s area under the curve 0 to 1 h after inhalation (FEV1 AUC*0-1 h). DESIGN: A double-blind, double-dummy, multicentre, randomized, placebo controlled, single-dose, five-period crossover study. SETTING: Five centres in four countries - one centre each in France, Greece and Italy, and two centres in the Netherlands. PATIENTS: Forty-seven patients aged 42 to 80 years (mean age 63.5 years) with chronic obstructive pulmonary disease (COPD) stage II and III, and mean baseline FEV1 1.17 L (range 0.56 to 1.77 L). INTERVENTIONS: Patients inhaled single doses of formoterol dry powder (12 and 24 mg), single doses of salmeterol (50 and 100 mg) and matching placebo on five separate days. MAIN RESULTS: The estimates of treatment difference in absolute terms (0.086 L) and percentage change from predose baseline (7.8%) for the primary end point, FEV1 AUC*0-1 h, showed that formoterol 12 mg was statistically significantly superior to salmeterol 50 mg (P=0.0044 and P=0.0021, respectively). In addition, both doses of formoterol were statistically superior to placebo for both absolute improvement and percentage change (P=0.0001). The analysis of secondary variables also confirmed the superiority of formoterol over salmeterol. CONCLUSIONS: Formoterol is associated with a faster onset of bronchodilation than salmeterol in patients with COPD.

Comparison of the efficacy, tolerability, and safety of formoterol dry powder and oral, slow-release theophylline in the treatment of COPD.

STUDY OBJECTIVE: To compare the efficacy, tolerability, and safety of therapy with formoterol and oral slow-release theophylline (THEO) in patients with COPD. DESIGN: A randomized, parallel-group study, with double-blind arms for formoterol and placebo (PL) and an open arm for oral slow-release THEO administered in individual doses on the basis of plasma concentrations. SETTING: Eighty-one centers worldwide. PATIENTS: Eight hundred fifty-four patients with symptomatic COPD. INTERVENTION: Comparison of twice-daily inhaled formoterol dry powder (12 or 24 microg), PL, and THEO (individualized doses) over 12 months. MEASUREMENTS AND RESULTS: Compared to PL, doses of formoterol and THEO both significantly improved the area under the curve for FEV(1) measured over a period of 12 h following the morning dose of study medication at 3 and 12 months (p < 0.001 for all comparisons). Therapy with formoterol, 12 microg, was significantly more effective than that with THEO (p < or = 0.026). Formoterol significantly reduced the percentage of "bad days" (i.e., days with at least two individual symptom scores > or = 2 and/or a reduction in peak expiratory flow from a baseline of > 20%; p < or = 0.035 vs. PL and THEO), and the use of salbutamol rescue medication (p < or = 0.003 vs PL) over the whole treatment period, while the effect of THEO was similar to that of PL. Therapy with formoterol and THEO was more effective than PL at improving quality of life for > 12 months (p < or = 0.030). Treatment-related adverse events and discontinuations were more frequent among patients receiving THEO than among those receiving formoterol. CONCLUSIONS: Long-term treatment with inhaled formoterol dry powder is more effective and better tolerated than treatment with therapeutically appropriate doses of oral slow-release THEO in symptomatic patients with COPD.

Formoterol delivered via a dry powder inhaler (Aerolizer): results from long-term clinical trials in children.

Over 500 children with asthma, aged 5-12 years, have been treated with formoterol fumarate (Foradil) delivered via the Aerolizer dry powder inhaler in clinical trials, with treatment periods of up to 15 months. In pivotal double-blind trials, two dose levels, 12 and 24 microg taken twice daily, provided significant benefit in terms of lung function measurements and symptom control (a lower dose of 6 microg twice daily appeared insufficient with this formulation). The higher, 24 microg dose appeared to provide an additional margin of benefit in a subgroup of children with more unstable/severe disease when the results from long-term follow-up (12-15 months) were analysed. Formoterol was shown to have a good safety profile when taken as regular maintenance treatment and when used as rescue medication by patients already receiving formoterol as regular maintenance treatment. In this flexible regimen, with formoterol used for rescue and maintenance, the overall daily intake of formoterol was low, with 96.1% of all treatment days (n = 2452) covered by a total daily dose (regular + rescue) of 48 microg (four doses) or less. There was no increase in the average daily intake of rescue formoterol over time. The clinical efficacy associated with this regimen was maintained over time and, in the case of morning peak expiratory flow rate, steadily improved over time. The Foradil Aerolizer inhalation system is simple to use and has a low resistance to inspiratory airflow that maximises the patient's control over dosing, while minimising the risk of under- and overdosing. These features may be especially valuable in a young patient population.