Clinically equivalent bronchodilatation achieved with formoterol delivered via Easyhaler and Aerolizer

BACKGROUND: User-friendly devices for the delivery of asthma drugs are needed to enhance treatment compliance. Formoterol inhalation powder has been developed to Easyhaler multidose powder inhaler to enable the treatment of all asthma severities with the same device. OBJECTIVES: This double-blind, double-dummy, single- dose, placebo-controlled, cross-over study aimed to demonstrate the non-inferiority of the bronchodilating effect of formoterol 12 microg delivered via Easyhaler versus via Aerolizer. In addition, dose responses following placebo, 12-microg and 48-microg doses of formoterol via Easyhaler were compared. Furthermore, onset and duration of action, and safety of formoterol inhaled using the two inhalers were compared. METHODS: Sixty-seven adult asthmatic subjects showing >or=15% increase in forced expiratory volume in 1 s (FEV(1)) after short-acting sympathomimetic inhalation were enrolled and completed the study. The study comprised screening and 4 treatment days, with each subject inhaling a single 12-mug dose of formoterol via Easyhaler, a 12-microg dose via Aerolizer, a 48-microg dose via Easyhaler or placebo. Repeat spirometry and vital sign measurements were performed for 12 h during treatment days. The primary efficacy variable was the area under the flow volume curve (AUC(0-12)) of FEV(1). Secondary efficacy variables comprised maximum FEV(1 )(FEV(1max)), forced vital capacity (FVC), and the need of rescue medication during the treatment days. Safety was evaluated by determining blood pressure, heart rate and the number of adverse events (AEs). RESULTS: Results showed the non-inferiority of the bronchodilating effect of 12 microg formoterol via Easyhaler compared to Aerolizer. The Easyhaler-Aerolizer ratio for AUC(0-12) of FEV(1 )was 0.991 (95% confidence interval from 0.969 to 1.013). No statistically significant differences emerged for secondary efficacy variables. A statistically significant dose response was seen following placebo, 12- and 48-microg doses in FEV(1). No safety differences emerged for the 12-microg dose inhaled via Easyhaler or Aerolizer, but the incidence of AEs was higher following formoterol 48 microg and placebo treatments. CONCLUSIONS: Formoterol delivered via Easyhaler was therapeutically equivalent to Aerolizerat the 12-microg dose. The 48-microg dose via Easyhaler demonstrated statistically significantly greater bronchodilation but showed an increased occurrence of AEs.     

Efficacy and safety of formoterol delivered through the Novolizer, a novel dry powder inhaler (DPI) compared with a standard DPI in patients with moderate to severe asthma

BACKGROUND & OBJECTIVE: Because of environmental concerns CFC-containing pressurised metered dose inhalers (pMDI) had to be replaced by dry powder inhalers (DPI). The Novolizer, a novel DPI has previously been shown to be as effective as the Turbuhaler in delivering budesonide. The objective of this study was to show non-inferiority of inhaled formoterol therapy delivered through the Novolizer compared to formoterol delivered through the Aerolizer in patients suffering from moderate to severe asthma. METHODS: In this double-blind, double-dummy, multicentre study 392 patients were randomised and received a dose of 12 microg formoterol twice daily for 4 weeks either through the Aerolizer or the Novolizer. FEV1 after 4 weeks of treatment was the primary variable. Secondary variables were FVC, PEF, consumption of short-acting; 2 adrenoceptor agonists, asthma symptoms, tolerability and safety. RESULTS: After 4 weeks of treatment, the mean trough FEV1 (95% CI) was 2.34 L (2.24-2.45) for the Novolizer and 2.31 L (2.21-2.41) for the Aerolizer. Non-inferiority was proven (p<0.0001, pre-defined; of 0.25 L). All secondary variables (incl. PEF) confirmed these findings. Treatment with both devices was safe and well tolerated. CONCLUSION: Inhalation of 12 microg formoterol twice daily via Novolizer was shown to be equally therapeutically effective compared to the inhalation via Aerolizer in the treatment of moderate to severe persistent asthma. Treatment via both inhalers was safe and well tolerated.     

Single-dose comparison of formoterol (Oxis) Turbuhaler 6 microg and formoterol Aerolizer 12 microg in moderate to severe asthma: a randomised,crossover study

Formoterol inhaled via Turbuhaler (Oxis) or Aerolizer (Foradil) produces fast and long-lasting bronchodilation in asthmatic patients. While formoterol Turbuhaler provides sustained efficacy for > or =12h at a metered dose of 6 microg (delivered dose 4.5 microg), the recommended metered dose for formoterol Aerolizer is 12 microg (delivered dose unknown). This difference may be attributable to improved lung deposition with the Turbuhaler. This open, randomised, crossover study compared the effects of a single metered dose of formoterol Turbuhaler 6 microg and formoterol Aerolizer 12 microg in 16 patients with stable moderate-to-severe asthma. Pulmonary function, assessed by measuring specific airway conductance (sGaw), was determined at intervals of < or =8h post-inhalation of each drug on separate study days. Both inhalers increased sGaw at all time points. There were no significant differences between the two formulations in onset of activity, maximum effect, duration of effect or area under the response curve. Furthermore, both treatments were well tolerated with no differences in adverse events, blood pressure or heart rate; thus the formoterol Turbuhaler may, therefore, have an improved therapeutic index. This pilot study indicates that the same clinical effect can be achieved with half the metered dose (6 microg) of formoterol Turbuhaler compared with formoterol Aerolizer (12 microg).     

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 microg twice daily via the Certihaler, 12 microg 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 FEV(1) 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 microg. Conclusion: Delivery of formoterol via the Certihaler or Aerolizer combines rapid relief with enduring control and provides convenient bronchodilation in patients with persistent asthma.     

Efficacy of salbutamol via Easyhaler unaffected by low inspiratory flow

The fine particle dose delivered via dry powder inhalers (DPIs) is often affected by the inspiratory flow rate generated during inhalation. This has clinical implications, since the fine particle dose determines the amount of drug reaching the lungs. With Easyhaler DPI the fine particle dose remains relatively constant over the range of inspiratory flow rates from 30-60 l min(-1). The aim of this study was to confirm that clinical efficacy is maintained even at low flow rates by comparing the bronchodilating effect of salbutamol (100 microg) delivered via Easyhaler at a target inspiratory flow of 30 l min(-1) with the same dose of salbutamol via pressurised metered-dose inhaler (pMDI) plus spacer. This was a double-blind, randomized, cross-over study with double-dummy technique. Twenty-one paediatric and adult asthmatic patients completed the study, which was conducted over 2 study days. The main outcome parameter was forced expiratory volume in 1 sec (FEV1). The patients were trained to generate a low peak inspiratory flow rate (PIFR) of 30 l min(-1), and the actual PIFR through Easyhaler was recorded. The average PIFR through Easyhaler was 28.7 l min(-1). The difference in the maximum value of FEV1 (FEV1max) between the treatments after drug inhalation was 0.01 l. The mean of FEV1max was 2.67 l after pMDI plus spacer compared to 2.69 l after Easyhaler. Improvements in FEV1 were clinically significant. No significant differences between treatments were found. A reasonably low inspiratory flow rate through Easyhaler produces an equivalent improvement in lung function to a correctly used pMDI plus spacer. Hence, Easyhaler can be used with confidence in patients who may have difficulty in generating a high inspiratory flow rate, such as children and the elderly.     

Relative therapeutic index between inhaled formoterol and salbutamol in asthma patients

A double-blind, randomized crossover study in 28 asthmatic patients assessed the relative therapeutic index for inhaled formoterol and salbutamol. Pre-drug administration FEV1 (mean 2.08 l) was 49-93% of predicted and reversibility 16-82% after inhalation of salbutamol. Patients inhaled single doses of formoterol (Oxis) (4.5,18 and 54 microg, delivered doses) via Turbuhaler, salbutamol (Ventolin) (200 and 1800 microg) via pressurized metered dose inhaler (pMDI) and placebo at intervals of 48 h or more. Individual maximum FEV1 and minimum S-K+ were calculated. Relative local (maximum FEV1) and systemic (minimum S-K+) dose potencies, and their ratio, the relative therapeutic index, were estimated using a non-linear mixed effect model. The drug effects were well tolerated and dose dependent. A log-linear approximation was used to describe the bronchodilatory effect, whereas a sigmoid approximation was more apt to describe the decrease in serum potassium concentration. A bivariate dose-response model based on these principles was fitted simultaneously to all data. The mean relative therapeutic index between formoterol 4.5-54 microg given via Turbuhaler and salbutamol 200-1800 microg given via pMDI was estimated to be 2.5 in favour of formoterol; this trend was not statistically significant.     

Safety and tolerability of high-dose formoterol (via Aerolizer) and salbutamol in patients with chronic obstructive pulmonary disease

To evaluate the safety and tolerability of high-dose formoterol and salbutamol in patients with chronic obstructive pulmonary disease (COPD). In this two-way crossover, double-blind, double-dummy study, 17 adults with mild-to-moderate COPD were randomized to receive either formoterol 24 microg (2 x 12 microg via Aerolizer), or salbutamol 600 microg (6 x 100 microg via metered-dose inhaler), and the appropriate double-dummy q.i.d. at 4-h intervals for 3 consecutive days (total daily dose: 96 and 2400 microg, respectively). After a 4-7-day washout period, patients were switched to the other treatment. Treatment with high-dose formoterol and salbutamol was equally well tolerated, with no reports of serious adverse events. Both agents were associated with decreased plasma potassium (mean minimum values: 3.4 and 3.3 mmol/l for formoterol and salbutamol, respectively; P=0.914), increased serum glucose (mean maximum values: 9.0 and 8.7 mmol/l, respectively; P=0.373), and small increases in mean QTc interval (mean maximum 439 ms with both treatments; P=0.813). No clinically relevant between-treatment differences in adverse events or laboratory values occurred. Both drugs improved lung function (mean maximum forced expiratory volume in 1s [FEV(1)] 2.6 l with both treatments; P=0.624), with the improvement being significantly greater with formoterol than with salbutamol on all 3 days of treatment (mean area under the curve [AUC](0-24 h) of FEV(1) formoterol vs. salbutamol on days 1-3, all P<0.05). High-dose formoterol via Aerolizer (up to 96 microg/day) has a comparable tolerability profile to that of salbutamol in patients with mild-to-moderate COPD.     

Safety and tolerability of high-dose formoterol (Aerolizer) and salbutamol (pMDI) in patients with mild/moderate, persistent asthma

This double-blind, double-dummy, crossover study evaluated the tolerability of high-dose formoterol and salbutamol. Sixteen adults with mild/moderate persistent asthma (FEV1 > or = 70% predicted) were randomized to receive either formoterol 36 microg three times daily (TID) at 5-h intervals via Aerolizer (total daily dose 108 microg), or salbutamol 600 microg TID via pressurized metered-dose inhaler (total daily dose 1800 microg) for 3 consecutive days. After a 3-7-day washout period patients received the other treatment. FEV1 was measured 15 min pre-dose and 2 h post-dose. Both formoterol and salbutamol were associated with decreased plasma potassium (mean of minimum values: 3.4 and 3.6 mmol/L, respectively; P<0.001), increased serum glucose (mean of maximum values: 8.3 and 7.9 mmol/L, respectively; P=0.021), and small increases in mean QTc interval (mean of maximum values: 428.8 and 417.4 ms, respectively; P<0.001). However, none of these effects was clinically significant. Both treatments increased FEV1 to a mean maximum of 4.6 L (P=0.613), but the mean FEV1 AUC(0-72)h for formoterol was significantly greater than for salbutamol (302.2 L h, vs. 277.4 L h; P<0.001). No patients discontinued due to treatment-related adverse events. High-dose formoterol via Aerolizer did not produce any clinically significant systemic effects in patients with mild/moderate asthma.     

Formoterol Delivered via the Dry Powder Aerolizer® Inhaler Versus Albuterol MDI and Placebo in Mild-to-Moderate Asthma: A Randomized,Double-Blind,Double-Dummy Trial

The objectives of this study were to compare the efficacy and tolerability of twice-daily formoterol dry powder 12 µg and 24 µg (Foradil) delivered via Aerolizer inhaler with four times daily albuterol (salbutamol) 180 µg delivered via metered dose inhaler (MDI) and placebo. A total of 554 adolescents and adults (ages 12–75 years) with mild-to-moderate asthma were randomized to this 12-week, multicenter, double-blind, double-dummy, placebo-controlled, parallel-group study. Twelve-hour spirometry measurements were taken at weeks 0, 4, 8, and 12. A total of 484 patients completed the study (122, 116, 127, and 119 given formoterol 12 µg, formoterol 24 µg, albuterol, and placebo, respectively). For the primary efficacy variable, the forced expiratory volume in 1 second (FEV₁), both formoterol 12 µg and 24 µg were statistically superior to placebo at all time points on all test days (p ≤ 0.017) and to albuterol at most time points on all test days (p ≤ 0.001). The onset of improvement in FEV₁ was rapid, with 15% increase within 5 min in 57%, 71%, and 65% of formoterol 12 µg, formoterol 24 µg, and albuterol patients, respectively. Formoterol was also superior to placebo and albuterol in terms of secondary efficacy variables: FEV₁ area under the curve, percentage of predicted FEV₁, forced vital capacity and forced expiratory flow, asthma symptom scores, and peak expiratory flows. In conclusion, both formoterol doses were superior to placebo in all lung function measurements. Overall, compared with albuterol, both formoterol doses produced superior bronchodilation. Formoterol and albuterol were safe and well-tolerated.     

A single high dose of formoterol is as effective as the same dose administered in a cumulative manner in patients with acute exacerbation of COPD

Several clinical trials have shown that the inhaled beta2-agonists with long-acting properties, formoterol and salmeterol, may be effective in acute exacerbations of chronic obstructive pulmonary disease (COPD). However, there is a great deal of controversy regarding the timing and optimal dose of inhaled beta2-agonists in this pathologic condition. In this double-blind, randomised, crossover study, we have compared the bronchodilating effect and the safety of inhaled formoterol administered via Turbuhaler using either a cumulative dose regimen or the equivalent single dose in 16 patients with acute exacerbations of COPD. On the two consecutive days, the patients received, in a randomised order, each of the following active dose regimens: (A): 9 + 9 + 18 microg of formoterol via Turbuhaler (36 microg cumulative delivered dose) or (B): 36 + 0 + 0 microg of formoterol via Turbuhaler. The three doses on each treatment day were administered at 30-mm intervals, with measurements being made 5 and 30 min after each dose. Contemporaneously, we also measured oxygen saturation by pulse oximetry (SpO2) and pulse rate. Both the high dose and the cumulative one induced a significant bronchodilation expressed as change in FEV1. The difference between the two regimens was significant (P=0.0332) only 60 min after the first inhalation. The trend of FVC and IC was similar to that of FEV1. All treatment regimens were well tolerated and no adverse events were reported. Neither the administration ofthe high dose nor that of the cumulative one modified heart rate in a significant manner. Also they did not influence SpO2. This study indicates that a single high dose offormoterol is as effective as the same dose administered in a cumulative manner in patients with acute exacerbation of COPD.     

The pulmonary and extra-pulmonary effects of high-dose formoterol in COPD: a comparison with salbutamol

OBJECTIVES: Formoterol, a beta(2) agonist with a rapid onset of effect and long duration of action, can be used as maintenance and reliever medication for asthma and COPD. We compared the pulmonary and extra-pulmonary effects of cumulative doses of formoterol and salbutamol in patients with COPD to assess efficacy and safety. METHODOLOGY: In a randomized, double-blind, cross-over study, 12 patients with moderate to severe COPD inhaled, via Turbuhaler, 10 doses of formoterol (total metered dose, 120 microg, equivalent to a 90- microg delivered dose), salbutamol (total metered dose 2000 microg) or placebo at 2-min intervals on separate days. The effects on lung function (FEV(1) and PEF), heart rate, blood pressure, oxygen saturation, corrected QT interval (QTc), T-wave height and plasma potassium were assessed before each dose, 15 min after each dose, and at half-hourly intervals for 3 h following the final dose. RESULTS: Inhalation of formoterol or salbutamol resulted in significant improvement in lung function (measured 30 min after the last dose) when compared with placebo. There were no clinically important or statistically significant changes in heart rate, QTc, T-wave height, plasma potassium, oxygen saturation, or systolic and diastolic blood pressures with formoterol or salbutamol. One patient developed ventricular trigeminy after both formoterol and salbutamol. She had had ventricular ectopics on her screening electrocardiogram. CONCLUSION: Formoterol and salbutamol both produced significant improvement in lung function and were similarly well tolerated in high doses, as might be taken by a patient for relief of COPD symptoms.     

Total reversibility testing as indicator of the clinical efficacy of formoterol in COPD

RATIONALE: The Global Initiative for Chronic Obstructive Lung Disease guidelines recommend bronchodilator reversibility testing to guide treatment decisions. This study evaluated the relationship between the change in forced expiratory volume in 1 s (FEV1) with salbutamol or formoterol and the clinical effects of a 4-week formoterol (Foradil) treatment. METHODS: At Visit 1, patients (n = 448) with stable chronic obstructive pulmonary disease took an FEV1 reversibility test using 200 microg salbutamol via a metered dose inhaler. At Visit 2 (Day 0), an FEV1 reversibility test was performed using formoterol via a dry-powder inhaler (Aerolizer). Patients then received formoterol 12 microg twice daily until Visit 3 (Day 21-30), when a further formoterol FEV1 reversibility test was performed. Clinical parameters included FEV1, symptom questionnaires and rescue medication use. RESULTS: There was no significant relationship between the immediate change in FEV1 with salbutamol and the absolute change from baseline in FEV1, symptom scores or rescue medication use after a 4-week formoterol treatment. Relative immediate change in FEV1 with formoterol was correlated with change in rescue medication use (P = 0.02) and FEV1 at Visit 3 (P < 0.001). Total reversibility in FEV1 with formoterol (post-dose Visit 3-pre-dose Visit 2) was correlated with all treatment efficacy variables (P<0.01). CONCLUSIONS: Immediate salbutamol reversibility testing, as performed under these study conditions, failed to predict the clinical efficacy of formoterol. Total reversibility after 4 weeks of formoterol treatment may be a better predictor of clinical benefits of long-term bronchodilator therapy.     

Onset and duration of action of formoterol and tiotropium in patients with moderate to severe COPD

BACKGROUND: Chronic obstructive pulmonary disease (COPD) management guidelines recommend regular treatment with one or more long-acting bronchodilators for patients with moderate to severe COPD. OBJECTIVE: To compare the onset and duration of action of formoterol and tiotropium in patients with COPD. METHODS: This randomized, multicentre, open-label crossover study in 38 patients with COPD (mean age 64 years; mean FEV(1) 55% predicted) assessed the effect of 7 days of treatment with formoterol (12 microg b.i.d. via Foradil Aerolizer) vs. tiotropium (18 microg o.d. via Spiriva HandiHaler) on lung function measured over a period of 12 h after the first dose on day 1 and the last dose on day 8. RESULTS: The primary efficacy variable, FEV(1)-AUC during the first 2 h post-dose (FEV(1)-AUC(10-120 min)), was significantly higher for formoterol compared with tiotropium, with between-treatment differences of 124 ml (p = 0.016) after the first dose and 80 ml (p = 0.036) after 7 days' treatment in favour of formoterol. FEV(1) measured 12 h after inhalation did not differ statistically significantly between treatments. Adverse events occurred in 2 (5%) patients after treatment with formoterol and in 5 (12%) patients after treatment with tiotropium. CONCLUSION: This study demonstrates faster onset of action and greater bronchodilation of formoterol vs. tiotropium for bronchodilation within the first 2 h of inhalation (FEV(1)-AUC(10-120 min)) and comparable bronchodilation 12 h post-inhalation in patients with moderate to severe COPD.     

Fluticasone/Formoterol Combination Therapy versus Budesonide/Formoterol for the Treatment of Asthma: A Randomized,Controlled, Non-Inferiority Trial of Efficacy and Safety

Objectives. The inhaled corticosteroid fluticasone propionate (fluticasone) and the long-acting β₂ agonist formoterol fumarate (formoterol) have been combined in a single aerosol inhaler fluticasone/formoterol (flutiform^®). This study compared the efficacy and safety of fluticasone/formoterol with the combination product budesonide/formoterol (Symbicort^® Turbohaler^®). Methods. A randomized, double-blind, double-dummy, multicenter, Phase 3 study comprising a 7- (±3) day screening, 2–4-week run-in, and 12-week treatment periods. Patients aged ≥12 years with moderate to severe persistent asthma for ≥6 months before screening and forced expiratory volume in one second (FEV₁) 50–80% predicted and ≥15% reversibility following salbutamol inhalation were randomized to fluticasone/formoterol 250/10 μg twice daily (n = 140) or budesonide/formoterol 400/12 μg twice daily (n = 139). Results. Fluticasone/formoterol was comparable to budesonide/formoterol with respect to the primary endpoint, change in pre-dose FEV₁ from baseline to Week 12. The LS mean treatment difference was ?0.044 L, with a lower 95% confidence interval (CI) greater than the pre-defined non-inferiority limit of ?0.2 L (95% CI: ?0.130, 0.043 L; p < 0.001). Non-inferiority was also demonstrated for the secondary endpoints mean change in FEV₁ from baseline (pre-dose) to 2 hours post-dose at Week 12, and discontinuations due to lack of efficacy. Similar results were obtained for both treatment groups for all other secondary endpoints. Fluticasone/formoterol had a good safety profile that was comparable with budesonide/formoterol. Conclusions. This study demonstrated comparable efficacy of fluticasone/formoterol to budesonide/formoterol in terms of the primary endpoint, change in pre-dose FEV₁ from baseline to Week 12. This was supported by comparable results for both treatments for all secondary endpoints.     

Assessment of the systemic effects of budesonide inhaled from Easyhaler and from Turbuhaler in healthy male volunteers.

The main objective of this study was to show dose-dependent equivalence in the systemic activity of budesonide 800 microg day(-1) and 1600 microg day(-1) delivered from either Easyhaler or Turbuhaler in healthy male subjects. This single-centre study was carried out according to a randomized, double-blind, double-dummy, five-way crossover design over a 9-week period. All subjects received 1 week of treatment with the following, in randomized order, with a washout week between each treatment: budesonide Easyhaler 800 microg day(-1) plus placebo Turbuhaler; budesonide Easyhaler 1600 microg day(-1) plus placebo Turbuhaler; placebo Easyhaler plus Pulmicort Turbuhaler 800 microg day(-1); placebo Easyhaler plus Pulmicort Turbuhaler 1600 microg day(-1); placebo Easyhaler plus placebo Turbuhaler. The final inhalation of study drug was performed at the study centre, where blood and urine samples were collected. Fifteen subjects were recruited and all completed the study. Mean serum cortisol AUC0-20 values (the primary outcome variable) were comparable for each device at the two dose levels, and met the defined criteria for equivalence (90% CI 0.8-1.25 for between-treatment difference). Budesonide 800 microg day(-1) caused minimal suppression of serum cortisol AUC0-20 values, Budesonide 1600 microg day(-1) statistically significantly suppressed serum cortisol AUC0-20 values compared with placebo. Mean morning serum cortisol values were within the reference range in al treatment groups. At a budesonide dose of 800 microg day(-1) mean urine cortisol/creatinine ratio was statistically significantly higher with Easyhaler than with Turbuhaler, but there was no significant difference between the devices at the 1600 microg day(-1) dose. Serum budesonide concentrations were equivalent for each device at both dose levels. Adverse drug reactions were infrequent and mild in nature and there were no clinically significant changes in laboratory safety variables. In conclusion, in healthy male volunteers, budesonide 800 microg day(-1) and 1600 microg day inhaled from Easyhaler had comparable systemic effects to the same doses inhaled via Turbuhaler.     

Clinical equivalence between salbutamol hydrofluoroalkane pMDI and salbutamol Turbuhaler at the same cumulative microgram doses in paediatric patients

This study aimed to demonstrate equivalent efficacy and safety between salbutamol delivered via the HFA134a pMDI (Hydrofluoroalkane 134a pressurised Metered Dose Inhaler) and the Turbuhaler dry powder inhaler in asthmatic children. This was a randomised, double-blind, double-dummy, placebo-controlled, crossover study in 10 asthmatic children aged 6-15 years who demonstrated at least 10% reversibility of FEV1 after inhaling 400 microg of salbutamol. On 5 single study days subjects received either placebo or cumulative doses of 100, 200, 400 and 800 microg of salbutamol at 30 minute intervals. Both devices were placebo on one study day while each device was active on two study days. FEV1 was measured before and 20 minutes after each dose. Heart rate was measured before spirometry. Mean FEV1 and heart rate at each time point and the area under the dose response time curve (AUC) were analysed using ANOVA. FEV1 increased similarly after cumulative doses of salbutamol on each of the study days, irrespective of device. Mean treatment difference in AUC was 0.01 L. min (95%CI -0.05 to 0.08 L). Heart did not differ at any dose. It is concluded that salbutamol delivery from a HFA pMDI and Turbuhaler is equivalenton a microgram basis in asthmatic children for efficacy and safety.     

Formoterol (OXIS) Turbuhaler as a rescue therapy compared with salbutamol pMDI plus spacer in patients with acute severe asthma

Formoterol has a similar onset of effect to salbutamol but a prolonged duration of action. However, the relative efficacy of the two drugs in acute severe asthma is not known. This double-blind, double-dummy study compared the safety and efficacy of the maximum recommended daily dose of formoterol and a predicted equivalent dose of salbutamol in 88 patients presenting to the emergency department with acute severe asthma. Patients were randomized to formoterol 54 microg via Turbuhaler or salbutamol 2400 microg via pressurized metered dose inhaler (pMDI) plus spacer in three equal doses over 1 h. Following the full dose, mean FEV1 at 75 min increased by 37% for formoterol and 28% for salbutamol (P = 0.18). The maximum increase in FEV1 over 4 h was significantly greater with formoterol compared with salbutamol (51% vs. 36%, respectively P < 0.05) and formoterol was as effective as salbutamol at improving symptoms and wellbeing. Both treatments were well tolerated. Formoterol caused a greater decrease in serum potassium (difference -0.2 mmol/l). In severe acute asthma, bronchodilator therapy with high-dose (54 microg) formoterol Turbuhaler provided equally rapid improvements in lung function of greater magnitude over 4 h than high-dose (2400 microg) salbutamol pMDI plus spacer.     

Formoterol Delivered via the Dry Powder Aerolizer® Inhaler Versus Albuterol MDI and Placebo in Mild-to-Moderate Asthma: A Randomized, Double-Blind, Double-Dummy Trial

The objectives of this study were to compare the efficacy and tolerability of twice-daily formoterol dry powder 12 µg and 24 µg (Foradil) delivered via Aerolizer inhaler with four times daily albuterol (salbutamol) 180 µg delivered via metered dose inhaler (MDI) and placebo. A total of 554 adolescents and adults (ages 12-75 years) with mild-to-moderate asthma were randomized to this 12-week, multicenter, double-blind, double-dummy, placebo-controlled, parallel-group study. Twelve-hour spirometry measurements were taken at weeks 0, 4, 8, and 12. A total of 484 patients completed the study (122, 116, 127, and 119 given formoterol 12 µg, formoterol 24 µg, albuterol, and placebo, respectively). For the primary efficacy variable, the forced expiratory volume in 1 second (FEV₁), both formoterol 12 µg and 24 µg were statistically superior to placebo at all time points on all test days (p ≤ 0.017) and to albuterol at most time points on all test days (p ≤ 0.001). The onset of improvement in FEV₁ was rapid, with 15% increase within 5 min in 57%, 71%, and 65% of formoterol 12 µg, formoterol 24 µg, and albuterol patients, respectively. Formoterol was also superior to placebo and albuterol in terms of secondary efficacy variables: FEV₁ area under the curve, percentage of predicted FEV₁, forced vital capacity and forced expiratory flow, asthma symptom scores, and peak expiratory flows. In conclusion, both formoterol doses were superior to placebo in all lung function measurements. Overall, compared with albuterol, both formoterol doses produced superior bronchodilation. Formoterol and albuterol were safe and well-tolerated.     

Improved delivery of ipratropium bromide using Respimat (a new soft mist inhaler) compared with a conventional metered dose inhaler: cumulative dose response study in patients with COPD

Respimat (RMT) is a reusable, propellant-free, soft mist inhaler (SMI), a novel device for inhalation therapy. We conducted a three-period cross-over study to evaluate the safety and efficacy of cumulative doses of ipratropium bromide inhaled from RMT (Two dose levels) or from a pressurized metered dose inhaler (MDI), in 36 patients with chronic obstructive pulmonary disease (COPD). The bronchodilator effect of ipratropium bromide was greater when administered via RMT (10 or 20 microg per puff, given double-blind within device, to total doses of 160 or 320 microg) than via MDI (20 microg per puff, total dose 320 microg). The bronchodilator effects of the 160 and 320 microg doses delivered via RMT were similar. Cumulative ipratropium bromide doses of 320 microg given via MDI or RMT and 160 microg given via RMT produced similar safety profiles. Between 45 min after the first drug inhalation and 45 min after the final dose, greater bronchodilatory effect was obtained from half the cumulative dose of ipratropium (RMT 10 microg per puff) when compared with the MDI (20 microg per puff). Therefore, ipratropium bromide delivered by RMT is as safe as, and can be more effective than, the MDI on acute administration in patients with COPD.     

Salbutamol via Easyhaler is at least as effective as salbutamol via Turbuhaler in the treatment of histamine-induced bronchoconstriction

The aim of this study was to compare the clinical efficacy and acceptability of salbutamol inhaled via Easyhaler and Turbuhaler multi-dose dry powder inhalers in the treatment of histamine-induced bronchoconstriction. Thirty-two adult patients with asthma and/or bronchial hyper-reactivity were included in the study, which was carried out according to a randomized, double-blind, double-dummy, cross-over design. Histamine challenge test was performed on 2 study days separated by at least 7 days. The challenge test was continued until a > or = 20% fall in forced expiratory volume in 1 sec (FEV1) was achieved. The patients then inhaled a single 100 microg dose of salbutamol from Easyhaler, or from Turbuhaler. FEV1 was assessed by flow-volume spirometry before and after histamine challenge and 1.5, 3, 5, 10, 15, 20, 30 and 60 min after salbutamol inhalation. The primary efficacy variable was the maximum percentage change in FEV1 from the post-challenge value. The secondary efficacy variable was area under the curve (AUC) of FEV1. At the end of the study, acceptability of salbutamol Easyhaler was evaluated using a questionnaire and Easyhaler was also compared with the inhalation device the patient had used earlier. Twenty-six patients completed the study. Both salbutamol Easyhaler and salbutamol Turbuhaler produced a rapid and significant increase in FEV1, with maximum percentage changes being 43.9% (+/-15.3) and 40.5% (+/-21.9) from the post-challenge value, respectively. There were no significant differences between the two inhalation devices in terms of changes in FEV1 or AUC of FEV1. The use of Easyhaler and getting a new dose from Easyhaler was considered to be very easy by 65% and easy by 35% of the patients. None considered it difficult. Of 16 patients who had used Turbuhaler earlier, 19% considered Easyhaler much better, 44% better, and 38% the same as Turbuhaler, and none considered it worse. In conclusion, the results show that salbutamol Easyhaler was at least as effective as salbutamol Turbuhaler in the treatment of histamine-induced bronchoconstriction. In addition, the patients considered Easyhaler very easy or easy to use. The majority of patients who reported Turbuhaler as their own inhaler considered Easyhaler better or much better than Turbuhaler.