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      Formoterol for the Treatment of Chronic Obstructive Pulmonary Disease

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          Abstract

          Bronchodilators, including long-acting β 2-agonists and long-acting muscarinic antagonists, are the mainstay for treatment of patients with chronic obstructive pulmonary disease (COPD) to prevent exacerbations or reduce symptoms. Formoterol is a highly selective and potent β 2-agonist that relaxes airway smooth muscle to significantly improve lung function. Inhaled formoterol works within 5 minutes of administration and provides improvements in spirometry measurements over 12 hours. The lipophilicity of formoterol allows it to form a depot within the smooth muscle to provide a prolonged duration of action. Following therapeutic doses, plasma concentrations are very low or undetectable. Determination of the pharmacokinetics of formoterol following high-dose administration to healthy volunteers revealed that the drug was rapidly absorbed and excreted unchanged in the urine with a half-life of 10 hours. Inhaled formoterol, as monotherapy or in combination with other agents, is an effective and safe treatment option for patients with moderate to severe COPD. Clinical studies have demonstrated improvements in lung function and COPD symptoms, particularly dyspnea; reductions in the risk of exacerbations; and improvement in patients’ health status. The adverse event profile of inhaled formoterol is similar to that of placebo, with few adverse cardiovascular events. Formoterol is a valuable bronchodilator used in the maintenance treatment of COPD. This review describes the mechanism of action, pharmacodynamics, and pharmacokinetics of inhaled formoterol. It also reviews the results of large, randomized, controlled clinical trials that evaluated the use of formoterol as monotherapy and in combination with inhaled corticosteroids, long-acting muscarinic antagonists, and triple therapy regimens in the treatment of patients with moderate to severe COPD.

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          Most cited references 53

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          Efficacy and safety of aclidinium bromide/formoterol fumarate fixed-dose combinations compared with individual components and placebo in patients with COPD (ACLIFORM-COPD): a multicentre, randomised study

          Background Aclidinium/formoterol is a twice-daily (BID) fixed-dose combination (FDC) in development for chronic obstructive pulmonary disease (COPD). The efficacy and safety of aclidinium/formoterol versus monotherapy and placebo in patients with COPD was assessed. Methods In this 24-week double-blind, parallel-group, active- and placebo-controlled, multicentre Phase III study, patients (≥40 years, post-bronchodilator forced expiratory volume in 1 second [FEV1]/forced vital capacity <70% and FEV1 ≥30% but <80% predicted normal) were randomised 2:2:2:2:1 to aclidinium/formoterol 400/12 μg (n = 385) or 400/6 μg (n = 381), aclidinium 400 μg (n = 385), formoterol 12 μg (n = 384) or placebo (n = 194) BID via Genuair®/Pressair®a. Results At Week 24, aclidinium/formoterol 400/12 μg and 400/6 μg lead to significant improvements from baseline in 1-hour post-dose FEV1 versus aclidinium (125 mL [95% CI: 90, 160; p < 0 · 001] and 69 mL [95% CI: 34, 105; p < 0.001], respectively) and trough FEV1 versus formoterol (85 mL [95% CI: 51, 119; p < 0.001] and 53 mL [95% CI: 19, 87; p < 0.01], respectively; co-primary endpoints). Additionally, aclidinium/formoterol 400/12 μg and 400/6 μg provided significant improvements in Transition Dyspnoea Index (TDI) focal score versus placebo (1.29 units [95% CI: 0.73, 1.86; p < 0.001] and 1.16 units [95% CI: 0.59, 1.73; p < 0.001], respectively; secondary endpoint). All treatments were well tolerated, with safety profiles of the FDCs similar to those of placebo and monotherapy. Conclusions Both aclidinium/formoterol BID doses significantly improved bronchodilation versus monotherapy, and dyspnoea versus placebo, with no increase in safety risk. Aclidinium/formoterol may be an effective treatment for patients with COPD. Trial registration ClinicalTrials.gov: NCT01462942. Electronic supplementary material The online version of this article (doi:10.1186/1471-2466-14-178) contains supplementary material, which is available to authorized users.
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            Efficacy and safety of budesonide and formoterol in one pressurized metered-dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease: results of a 6-month randomized clinical trial.

            The combination of an inhaled corticosteroid (ICS) and a long-acting bronchodilator is recommended in the treatment of patients with chronic obstructive pulmonary disease (COPD) who have frequent exacerbations. Budesonide/formoterol dry powder inhaler (DPI) has demonstrated efficacy and tolerability in patients with COPD. To evaluate the efficacy and tolerability of budesonide/formoterol administered via one hydrofluoroalkane pressurized metered-dose inhaler (pMDI) in patients with COPD. This was a 6-month, randomized, double-blind, double-dummy, placebo-controlled, parallel-group, multicentre study (NCT00206154) of 1704 patients aged > or =40 years with moderate to very severe COPD conducted in 194 centres in the US, Czech Republic, the Netherlands, Poland and South Africa. After 2 weeks of treatment based on previous therapy (ICSs and short-acting bronchodilators allowed during the run-in period), patients received one of the following treatments administered twice daily: budesonide/formoterol pMDI 160/4.5 microg x two inhalations (320/9 microg); budesonide/formoterol pMDI 80/4.5 microg x two inhalations (160/9 microg); budesonide pMDI 160 microg x two inhalations (320 microg) plus formoterol DPI 4.5 microg x two inhalations (9 microg); budesonide pMDI 160 microg x two inhalations (320 microg); formoterol DPI 4.5 microg x two inhalations (9 microg); or placebo. The co-primary efficacy variables were pre-dose forced expiratory volume in 1 second (FEV(1)) and 1-hour post-dose FEV(1). Budesonide/formoterol 320/9 microg demonstrated significantly greater improvements in pre-dose FEV(1) versus formoterol (p = 0.026; pre-specified primary comparator) and 1-hour post-dose FEV(1) versus budesonide (p < 0.001; pre-specified primary comparator); budesonide/formoterol 160/9 microg demonstrated significantly greater improvements versus budesonide (p < 0.001) for 1-hour post-dose FEV(1) but not versus formoterol for pre-dose FEV(1). Dyspnoea (measured using the Breathlessness Diary) and health-related quality-of-life (HR-QOL) scores (based on the St George's Respiratory Questionnaire total score) were significantly improved with both dosage strengths of budesonide/formoterol compared with budesonide, formoterol and placebo (p < or = 0.044 for all). Although not powered a priori for comparisons, the number of exacerbations per patient-treatment year requiring treatment with oral corticosteroids and/or hospitalization was numerically (20-25%) lower with the budesonide-containing treatments (0.710-0.884) versus formoterol (1.098) and placebo (1.110). This result was driven by the exacerbations requiring treatment with oral corticosteroids (79-120 events). The number of exacerbations resulting in hospitalization was very low across treatment groups (11-22); the number per patient-treatment year was significantly different for budesonide/formoterol 320/9 microg (0.158) versus other treatment groups (0.081-0.108) except budesonide/formoterol 160/9 microg (0.139), and for budesonide/formoterol 160/9 microg versus formoterol (0.081) [p < or = 0.05]. All treatments were generally well tolerated. The incidence of individual non-fatal serious adverse events was similar across all treatment groups, except COPD, which was highest in the budesonide/formoterol 320/9 microg group (6.1%) and lowest in the budesonide (3.6%) and formoterol (3.9%) groups, with a range of 4.3-4.6% in the budesonide/formoterol 160/9 microg, budesonide plus formoterol and placebo groups. Budesonide/formoterol had a safety profile comparable with that of the monocomponents and placebo. There was no increase in the incidence of pneumonia in the active treatment groups relative to placebo. Budesonide/formoterol pMDI 320/9 microg demonstrated significantly greater efficacy for pulmonary function on both co-primary endpoints versus the pre-specified comparators (formoterol DPI 9 microg for pre-dose FEV(1) and budesonide pMDI 320 microg for 1-hour post-dose FEV(1)). Budesonide/formoterol pMDI 160/9 microg demonstrated significantly greater efficacy for 1-hour post-dose FEV(1) versus budesonide pMDI 320 microg. Dyspnoea scores and HR-QOL were significantly improved with both budesonide/formoterol pMDI dosage strengths versus both monocomponents and placebo. Both budesonide/formoterol pMDI dosage strengths were well tolerated relative to the monocomponents and placebo.
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              Triple therapy with budesonide/glycopyrrolate/formoterol fumarate with co-suspension delivery technology versus dual therapies in chronic obstructive pulmonary disease (KRONOS): a double-blind, parallel-group, multicentre, phase 3 randomised controlled trial

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                Author and article information

                Journal
                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                copd
                copd
                International Journal of Chronic Obstructive Pulmonary Disease
                Dove
                1176-9106
                1178-2005
                27 November 2020
                2020
                : 15
                : 3105-3122
                Affiliations
                [1 ]Department of Medicine, David Geffen School of Medicine at UCLA , Los Angeles, CA, USA
                Author notes
                Correspondence: Donald P Tashkin David Geffen School of Medicine at UCLA , 10388 Le Conte Avenue, Los Angeles, CA90095, USATel +1 310 825 3163Fax +1 310 206 5088 Email dtashkin@mednet.ucla.edu
                Article
                273497
                10.2147/COPD.S273497
                7708267
                33273813
                © 2020 Tashkin.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 4, Tables: 11, References: 59, Pages: 18
                Categories
                Review

                Respiratory medicine

                bronchodilator, copd, long-acting β2-agonists, formoterol fumarate

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