John Kottakis

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.

Effects of formoterol and salmeterol on resting inspiratory capacity in COPD patients with poor FEV1 reversibility

SUMMARY Background: Recent studies suggest that inspiratory capacity (IC) measured at rest can be used to predict improvements in dyspnea and exercise tolerance in chronic obstructive pulmonary disease (COPD) patients. In this study we compared the effect of formoterol (Foradil* Aerolizer*) and salmeterol (Sereventt Diskust) in terms of IC in patients with COPD. Methods: This was a multicentre, randomized, placebo-controlled, single-dose, double-dummy, crossover study conducted in five secondary care centres in four European countries. A total of 47 patients with Stage II and III COPD, as defined by ATS criteria, with an increase in forced expiratory volume in 1 s (FEV1) of <12% from the patients predicted normal value after salbutamol inhalation were included. Patients inhaled single doses of formoterol (12 and 24 ng), salmeterol (50 and 100 jug) or matching placebo. IC was recorded before dosing and at 5,10,15 and 30min and 1, 2, 3 and 4 h post-dose. Results: Formoterol was significantly superior to salmeterol during the first hour post-dose as indicated by notable differences at all times during the first hour post-dose and by the ANCOVA analysis of the Area Under the IC Curve (AUCMh). Conclusions: Both formoterol and salmeterol increase IC in patients with COPD, with formoterol 12|ig showing a significantly greater increase in IC over the first hour post-dose than salmeterol 50|ig, consistent with a more rapid onset of action.

Inspiratory flow rates and volumes with the Aerolizer dry powder inhaler in asthmatic children and adults

Objective: To assess the peak inspiratory flow rate (PIFR) and forced inspiratory vital capacity (FIVC) through the formoterol (Foradil*) Aerolizer* in patients with mild, moderate and severe asthma. * Foradil and Aerolizer are trade names of Novartis AG, Basel, Switzerland Research design and methods: PIFR and FIVC were assessed in 33 adults and 32 children using a spirometer alone (baseline), a spirometer with an adaptor, and a spirometer with an adaptor and the Aerolizer inhaler (placebo loaded). Results: Of adult patients using the Aerolizer inhaler, 73% had PIFR values of >100l/min and 91% had values of >60l/min. PIFR in adults was reduced from a mean baseline of 283l/min to 118l/min through the loaded Aerolizer inhaler. Similarly, 75% of children using the Aerolizer inhaler had PIFR values >80l/min and 91% had values of >60l/min. The mean PIFR in children was reduced from a baseline of 154l/min to 100l/min through the loaded Aerolizer inhaler. Only small mean decreases from baseline were observed in FIVC through the loaded Aerolizer inhaler: 8.4% in adults and 3.8% in children. FIVC values of >2.0 litre were achieved in 82% of adults, and 81% of children achieved FIVC values of >1.5 litre. Conclusion: This study, albeit in a relatively small patient population, suggests that most children and adults with asthma can generate PIFRs of >60l/min and FIVCs of >1.5litre through the Aerolizer inhaler regardless of their disease severity. Such findings compare extremely favourably with other dry powder inhalers.

A randomized, double-blind, single-dose, crossover clinical trial of the onset and duration of protection from exercise-induced bronchoconstriction by formoterol and albuterol

BACKGROUND Inhaled short-acting beta(2)-adrenoceptor agonists are the most commonly used treatment for the prevention of exercise-induced bronchoconstriction (EIB). Formoterol, a long-acting beta(2)-adrenoceptor agonist, has been demonstrated to provide protection from EIB, although the onset and duration of this protection have not been defined. OBJECTIVE The purpose of this study was to determine the onset and duration of the protective effect of a single dose of inhaled formoterol powder against EIB, comparing them with the effect of a single dose of placebo and albuterol administered via metered-dose inhaler (MDI). METHODS In this double-dummy, 4-way crossover study, patients received single doses of formoterol (12 and 24 microg) via a powder inhaler, albuterol by MDI (180 microg), and placebo. Exercise challenge tests (ECTs) were conducted at 15 minutes and at 4, 8, and 12 hours postdose. Pulmonary function studies (forced expiratory volume in 1 second [FEV(1)] and peak expiratory flow rate) were performed before and after each exercise challenge. RESULTS Twenty adolescent and adult patients (mean age, 23.8 years; range, 13-41 years; 9 male, 11 female) with asthma were enrolled in the study, and 17 completed all 4 treatment sequences. Compared with placebo, both doses of formoterol produced significantly greater inhibition of FEV(1) decreases at all time points (P < 0.01). There were no significant differences in efficacy measures between the 2 formoterol doses throughout the study. The exercise-induced decrease in FEV(1) after albuterol treatment was significantly reduced compared with placebo only at 15 minutes after dosing (P < 0.05). Formoterol and albuterol exhibited a similar rapid onset of action (<15 minutes), but formoterol continued to protect patients against EIB for at least 12 hours (P < 0.01), whereas albuterol was no longer clinically effective by the 4-hour ECT. CONCLUSIONS Formoterol and albuterol, given as single-dose inhalations, both provided protection from EIB within 15 minutes in this group of patients. The bronchoprotection afforded by formoterol lasted up to 12 hours, whereas that of albuterol was no longer significant by 4 hours.

Comparable Efficacy and Tolerability of Formoterol (Foradil®) Administered via a Novel Multi-Dose Dry Powder Inhaler (Certihaler™) or the Aerolizer® Dry Powder Inhaler in Patients with Persistent Asthma

Background: For maximum treatment compliance there is a need to provide asthma patients with devices that suit their particular preferences. The Foradil® Certihaler™ is a novel multi-dose dry powder inhaler developed to increase the choice of devices available. Objectives: To evaluate the safety and efficacy of formoterol administered via the Foradil Certihaler, or via the single-dose inhaler Foradil® Aerolizer®. Methods: This was a randomized, placebo-controlled, double-dummy, incomplete block crossover, dose-ranging and pharmacokinetic study in patients with persistent asthma. Sixty-seven patients (mean 48.0 years) were randomized to formoterol 5, 10, 15 and 30 µg twice daily via the Certihaler, 12 µg formoterol b.i.d. via the Aerolizer, or placebo in four 1-week double-blind treatment periods separated by 1-week single-blind washouts. Results: All formoterol doses delivered via the Certihaler or the Aerolizer significantly increased FEV1 compared with placebo (p < 0.0001). Formoterol demonstrated an onset of action of <3 min. All active treatments were well tolerated. Tremor was the most common adverse event and was more pronounced at high doses. At lower doses the incidence of tremor with the Certihaler was similar to that observed with placebo or the Aerolizer. The pharmacokinetic evaluation comprised 41 patients (mean 45.9 years). Urinary excretion of unchanged formoterol and total formoterol increased with dose delivered via the Certihaler. The optimum dose of formoterol via the Certihaler was 10 µg. Conclusion: Delivery of formoterol via the Certihaler or Aerolizer combines rapid relief with enduring control and provides convenient bronchodilation in patients with persistent asthma.

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

Summary Over 500 children with asthma, aged 5-12 years, have been treated with formoterol fumarate (Foradilt) 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 |ig taken twice daily, provided significant benefit in terms of lung function measurements and symptom control (a lower dose of 6 |ig twice daily appeared insufficient with this formulation). The higher, 24 |ig 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 |ig (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 patients control over dosing, while minimising the risk of under- and overdosing. These features may be especially valuable in a young patient population.

FEV1 reversibility does not adequately predict effect of formoterol via Aerolizer® in chronic obstructive pulmonary disease

Evaluation of patients with chronic obstructive pulmonary disease (COPD) often includes the use of post‐bronchodilator reversibility testing to guide treatment decisions. Recommendations for reversibility testing differ and there is no universally accepted method or outcome criterion.