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Concept: Salmeterol

63

Background The safe and appropriate use of long-acting beta-agonists (LABAs) for the treatment of asthma has been widely debated. In two large clinical trials, investigators found a potential risk of serious asthma-related events associated with LABAs. This study was designed to evaluate the risk of administering the LABA salmeterol in combination with an inhaled glucocorticoid, fluticasone propionate. Methods In this multicenter, randomized, double-blind trial, adolescent and adult patients (age, ≥12 years) with persistent asthma were assigned to receive either fluticasone with salmeterol or fluticasone alone for 26 weeks. All the patients had a history of a severe asthma exacerbation in the year before randomization but not during the previous month. Patients were excluded from the trial if they had a history of life-threatening or unstable asthma. The primary safety end point was the first serious asthma-related event (death, endotracheal intubation, or hospitalization). Noninferiority of fluticasone-salmeterol to fluticasone alone was defined as an upper boundary of the 95% confidence interval for the risk of the primary safety end point of less than 2.0. The efficacy end point was the first severe asthma exacerbation. Results Of 11,679 patients who were enrolled, 67 had 74 serious asthma-related events, with 36 events in 34 patients in the fluticasone-salmeterol group and 38 events in 33 patients in the fluticasone-only group. The hazard ratio for a serious asthma-related event in the fluticasone-salmeterol group was 1.03 (95% confidence interval [CI], 0.64 to 1.66), and noninferiority was achieved (P=0.003). There were no asthma-related deaths; 2 patients in the fluticasone-only group underwent asthma-related intubation. The risk of a severe asthma exacerbation was 21% lower in the fluticasone-salmeterol group than in the fluticasone-only group (hazard ratio, 0.79; 95% CI, 0.70 to 0.89), with at least one severe asthma exacerbation occurring in 480 of 5834 patients (8%) in the fluticasone-salmeterol group, as compared with 597 of 5845 patients (10%) in the fluticasone-only group (P<0.001). Conclusions Patients who received salmeterol in a fixed-dose combination with fluticasone did not have a significantly higher risk of serious asthma-related events than did those who received fluticasone alone. Patients receiving fluticasone-salmeterol had fewer severe asthma exacerbations than did those in the fluticasone-only group. (AUSTRI ClinicalTrials.gov number, NCT01475721 .).

Concepts: Asthma, Intubation, Salmeterol, Long acting beta-adrenoceptor agonist, Fluticasone

27

Asthma is an increasing pathology with poor compliance. Achievement of control is possible but under intensive treatment. In this setting, fluticasone/salmeterol association delivered by dry powder inhalers is a valuable and proved option. A prospective, parallel, open-label, phase IV, multicentre non-inferiority study was conducted to determine therapeutic similarity between 2 different inhalers: Generic DPI and Diskus®, which both deliver a fluticasone/salmeterol association (CAS 80474-14-2/CAS 89365-50-4). A 103 uncontrolled asthmatic patients were randomly assigned in 2 groups, Generic (G) and Diskus® (D), and received the association for 18 weeks through the appropriate device. They were evaluated according to Asthma Quality of Life Questionnaire and GINA/NIH guidelines. To demonstrate non-inferiority, the estimation of the Relative Risk between the Global Score Rate per group with its 95% confidence interval was calculated and compared against a non-inferiority margin obtained from a previous study. The Global Score Rate was 82% for G Group and 83% for D Group. The RR was 1.0124 (95% CI: 0.847-1.210). The margin set at 0.832 was not reached by the lower 95% CI (z=-2.097; p=0.018) pointing out non-inferiority. The results have demonstrated non-inferiority between groups. Thus, the 2 products are therapeutically similar.

Concepts: Asthma, Relative risk, Dry powder inhaler, Inhaler, Nebulizer, Phase IV, Salmeterol, Fluticasone/salmeterol

22

The potential of the force control agent (FCA) magnesium stearate (MgSt) to enhance the aerosol performance of lactose-based dry powder inhaled (DPI) formulations was investigated in this study. The excipient blends were investigated with analytical techniques including time-of-flight secondary ion mass spectrometry (ToF-SIMS) and Single Particle Aerosol Mass Spectrometry (SPAMS) and particle size, morphology and surface properties were evaluated. Excipient-blends were manufactured either by high-shear or low-shear blending lactose carrier with different amounts of MgSt in the range from 0-10% (w/w). Fluticasone propionate (FP) and salmeterol xinafoate (SX) used as model APIs were added by low-shear mixing. The in vitro aerosol performance in terms of aerodynamic particle size distribution (APSD) and fine particle fraction (FPF) of the FP and SX DPI formulations was evaluated with the Next Generation Impactor (NGI) and also with SPAMS using a Breezhaler® inhalation device. The distribution of MgSt on the lactose carrier in the blends was visualized and found to depend strongly on the blending method. This affected drug particle detachment from the carrier and thus impacted aerosol performance for FP and SX. Compared to blends without FCA, low-shear blending of MgSt increases the FPF of the model drug SX, while high shear blending significantly increased FPF of both SX and FP. The interactions between drug and carrier particles were substantially affected by the choice of blending technique of MgSt with lactose. This allows detailed control of aerosol performance of a DPI by an adequate choice of the blending technique. SPAMS successfully demonstrated that it is capable to distinguish changes in DPI formulations blended with different amounts of MgSt and additional information in terms of dispersibility of fine particles could be generated.

Concepts: Asthma, Mass spectrometry, Particle size distribution, Particulate, Particulates, Global dimming, Salmeterol, Fluticasone/salmeterol

20

Background Most guidelines recommend either a long-acting beta-agonist (LABA) plus an inhaled glucocorticoid or a long-acting muscarinic antagonist (LAMA) as the first-choice treatment for patients with chronic obstructive pulmonary disease (COPD) who have a high risk of exacerbations. The role of treatment with a LABA-LAMA regimen in these patients is unclear. Methods We conducted a 52-week, randomized, double-blind, double-dummy, noninferiority trial. Patients who had COPD with a history of at least one exacerbation during the previous year were randomly assigned to receive, by inhalation, either the LABA indacaterol (110 μg) plus the LAMA glycopyrronium (50 μg) once daily or the LABA salmeterol (50 μg) plus the inhaled glucocorticoid fluticasone (500 μg) twice daily. The primary outcome was the annual rate of all COPD exacerbations. Results A total of 1680 patients were assigned to the indacaterol-glycopyrronium group, and 1682 to the salmeterol-fluticasone group. Indacaterol-glycopyrronium showed not only noninferiority but also superiority to salmeterol-fluticasone in reducing the annual rate of all COPD exacerbations; the rate was 11% lower in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group (3.59 vs. 4.03; rate ratio, 0.89; 95% confidence interval [CI], 0.83 to 0.96; P=0.003). The indacaterol-glycopyrronium group had a longer time to the first exacerbation than did the salmeterol-fluticasone group (71 days [95% CI, 60 to 82] vs. 51 days [95% CI, 46 to 57]; hazard ratio, 0.84 [95% CI, 0.78 to 0.91], representing a 16% lower risk; P<0.001). The annual rate of moderate or severe exacerbations was lower in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group (0.98 vs. 1.19; rate ratio, 0.83; 95% CI, 0.75 to 0.91; P<0.001), and the time to the first moderate or severe exacerbation was longer in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group (hazard ratio, 0.78; 95% CI, 0.70 to 0.86; P<0.001), as was the time to the first severe exacerbation (hazard ratio, 0.81; 95% CI, 0.66 to 1.00; P=0.046). The effect of indacaterol-glycopyrronium versus salmeterol-fluticasone on the rate of COPD exacerbations was independent of the baseline blood eosinophil count. The incidence of adverse events and deaths was similar in the two groups. The incidence of pneumonia was 3.2% in the indacaterol-glycopyrronium group and 4.8% in the salmeterol-fluticasone group (P=0.02). Conclusions Indacaterol-glycopyrronium was more effective than salmeterol-fluticasone in preventing COPD exacerbations in patients with a history of exacerbation during the previous year. (Funded by Novartis; FLAME ClinicalTrials.gov number, NCT01782326 .).

Concepts: Asthma, Pneumonia, Chronic obstructive pulmonary disease, Emphysema, Pulmonary hypertension, Inhalation, Formoterol, Salmeterol

17

After the introduction of the long-acting beta-agonist (LABA) salmeterol for the treatment of asthma, two large trials - the Salmeterol Multicenter Asthma Research Trial (SMART),(1) which was mandated by the Food and Drug Administration (FDA) and involved 26,000 patients, and the Serevent Nationwide Surveillance (SNS) trial(2) in the United Kingdom, which involved 25,000 patients - showed a higher risk of asthma-related death among patients receiving salmeterol than among those receiving placebo. A second LABA, formoterol, was introduced some years later, and although no such large studies were available for this drug, the aggregate evidence showed that patients taking this drug . . .

Concepts: Asthma, United Kingdom, Chronic obstructive pulmonary disease, Introduction, Formoterol, Salmeterol, Long acting beta-adrenoceptor agonist, Beta-adrenergic agonists

4

The combination of aclidinium bromide, a long-acting anticholinergic, and formoterol fumarate, a long-acting beta2-agonist (400/12 μg twice daily) achieves improvements in lung function greater than either monotherapy in patients with chronic obstructive pulmonary disease (COPD), and is approved in the European Union as a maintenance treatment. The effect of this combination on symptoms of COPD and exacerbations is less well established. We examined these outcomes in a pre-specified analysis of pooled data from two 24-week, double-blind, parallel-group, active- and placebo-controlled, multicentre, randomised Phase III studies (ACLIFORM and AUGMENT).

Concepts: Pulmonology, Asthma, Lung, Pneumonia, Chronic obstructive pulmonary disease, Emphysema, Formoterol, Salmeterol

4

Inhaled long-acting bronchodilators are the mainstay of pharmacotherapy for chronic obstructive pulmonary disease (COPD). Both the twice-daily long-acting β(2)-adrenoceptor agonists (LABAs) salmeterol and formoterol and the once-daily LABA indacaterol are indicated for use in COPD. This review examines current evidence for the safety of LABAs in COPD, focusing on their effect on exacerbations and deaths.

Concepts: Asthma, Pneumonia, Chronic obstructive pulmonary disease, Formoterol, Salmeterol, Long acting beta-adrenoceptor agonist, Beta-adrenergic agonists

3

Low adherence and persistence to inhaled therapy result in poor outcomes in patients with asthma and chronic obstructive pulmonary disease (COPD). Although adherence has been widely studied, growing awareness of the large number of patients who abandon their asthma treatment suggests that persistence to treatment may be more relevant for longer term outcomes.

Concepts: Medicine, Asthma, Pneumonia, Chronic obstructive pulmonary disease, Spirometry, Salmeterol

2

Effects of small-particle long-acting β-agonists on the small airways have been poorly documented.

Concepts: Asthma, Chronic obstructive pulmonary disease, Formoterol, Salmeterol

2

Chronic obstructive pulmonary disease (COPD) is the result of persistent and progressive pathologic abnormalities in the small airways, most often associated with alveolar loss. Smoking cessation is the most effective intervention to slow down the progression of COPD. Long-acting inhaled bronchodilators are prescribed for the symptomatic relief at any stage of disease severity. For patients whose COPD cannot be not sufficiently controlled with long-acting bronchodilator monotherapy, international guidelines suggest the possibility of associating a long-acting beta2 agonist (LABA) with a long-acting muscarinic antagonist (LAMA), ie, dual bronchodilation. This is not a new concept as the combination of short-acting agents has been popular in the past. In recent years, several fixed-dose combinations containing a LAMA and a LABA in a single inhaler have been approved by regulatory authorities in several countries. Among the new LAMA/LABA combinations, the fixed-dose combination of indacaterol 110 µg/glycopyrronium 50 µg (QVA149) has been shown in a series of clinical trials to be as safe as the single components and placebo, and more effective than placebo and the single components with regard to lung function, symptoms, and patient-oriented outcomes. Furthermore, QVA149 achieved better bronchodilation than salmeterol 50 µg/fluticasone 500 µg twice daily. Compared with tiotropium, a well-recognized treatment for COPD, the percentage of patients that exceed the minimal clinical important difference for dyspnea and health-related quality of life measurements was superior with QVA149. Other patient-oriented outcomes, such as daily symptoms, night-time awakening, and use of rescue medication consistently favored QVA149. Finally, QVA149 was significantly superior to LAMAs for reducing all types of exacerbation. In conclusion, several years after introduction of dual bronchodilation, the fixed-dose combination of indacaterol 110 µg/glycopyrronium 50 µg in a single inhaler for once-daily administration via the Breezhaler(®) device (QVA149) has been demonstrated to be a safe and effective treatment for COPD patients.

Concepts: Clinical trial, Asthma, Lung, Chronic obstructive pulmonary disease, Obstructive lung disease, Bronchodilator, Salmeterol, Long acting beta-adrenoceptor agonist