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Introduction: The relationship between immediate symptom control, reliever medication use and exacerbation risk on treatment response and factors that modify it have not been assessed in an integrated manner. Here we apply simulation scenarios to evaluate the effect of individual baseline characteristics on treatment response in patients with moderate-severe asthma on regular maintenance dosing monotherapy with fluticasone propionate (FP) or combination therapy with fluticasone propionate/salmeterol (FP/SAL) or budesonide/formoterol (BUD/FOR)., Methods: Reduction in reliever medication use (puffs/24 h), change in symptom control scores (ACQ-5), and annualised exacerbation rate over 12 months were simulated in a cohort of patients with different baseline characteristics (e.g. time since diagnosis, asthma control questionnaire (ACQ-5) symptom score, smoking status, body mass index (BMI) and sex) using drug-disease models derived from large phase III/IV clinical studies., Results: Simulation scenarios show that being a smoker, having higher baseline ACQ-5 and BMI, and long asthma history is associated with increased reliever medication use (p < 0.01). This increase correlates with a higher exacerbation risk and higher ACQ-5 scores over the course of treatment, irrespective of the underlying maintenance therapy. Switching non-responders to ICS monotherapy to combination therapy after 3 months resulted in immediate reduction in reliever medication use (i.e. 1.3 vs. 1.0 puffs/24 h for FP/SAL and BUD/FOR, respectively). In addition, switching patients with ACQ-5 > 1.5 at baseline to FP/SAL resulted in 34% less exacerbations than those receiving regular dosing BUD/FOR (p < 0.01)., Conclusions: We have identified baseline characteristics of patients with moderate to severe asthma that are associated with greater reliever medication use, poor symptom control and higher exacerbation risk. Moreover, the effects of different inhaled corticosteroid (ICS)/long-acting beta agonist (LABA) combinations vary significantly when considering long-term treatment performance. These factors should be considered in clinical practice as a basis for personalised management of patients with moderate-severe asthma symptoms., (© 2024. The Author(s).)

Background: Asthma is a chronic respiratory disease that affects millions of children worldwide and can impair their quality of life and development. Inhaled glucocorticoids are the mainstay of asthma treatment, but some children require step-up therapy with additional drugs to achieve symptom control. Fluticasone propionate and salmeterol (FSC) has been shown to reduce asthma exacerbations and improve lung function in adults. However, the evidence for its efficacy and safety in children is limited., Objective: This study aims to provide a comprehensive basis for treatment selection by summarizing existing clinical randomized controlled trials (RCTs) on the efficacy of FSC compared to fluticasone propionate (FP) monotherapy in children with asthma who require step-up treatment., Methods: Five online databases and three clinical trial registration platforms were systematically searched. The effect size and corresponding 95% confidence interval (CI) were calculated based on the heterogeneity among the included studies., Results: Twelve RCTs were identified and a total of 9, 859 patients were involved. The results of the meta-analysis revealed that the use of FSC was associated with a greater reduction in the incidence of asthma exacerbations than FP alone when the dose of FP was the same or when the duration of treatment exceeded 12 weeks. In addition, FSC resulted in a greater proportion of time with asthma-free and without the use of albuterol compared to FP alone when the duration of treatment exceeded 12 weeks. No significant differences were observed between FSC and FP alone in the incidence of drug-related adverse events and other adverse events., Conclusion: Both FSC and FP alone are viable options for the initial selection of step-up treatment in asthmatic children. While, FSC treatment demonstrates a greater likelihood of reducing asthma exacerbations which is particularly important for reducing the personnel, social and economic burden in children requiring step-up asthma treatment., Competing Interests: Declaration of Competing Interest All the authors declare that they have no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: The assessment of future risk has become an important feature in the management of patients with asthma. However, the contribution of patient-specific characteristics and treatment choices to the risk of exacerbation is poorly understood. Here we evaluated the effect of interindividual baseline differences on the risk of exacerbation and treatment performance in patients receiving regular maintenance doses of inhaled corticosteroids (ICS) or ICS/long-acting beta-agonists (LABA) combination therapy., Methods: Exacerbations and changes to asthma symptoms 5-item Asthma Control Questionnaire (ACQ-5) were simulated over a 12-month period using a time-to-event and a longitudinal model developed from phase III/IV studies in patients with moderate-severe asthma (N = 16,282). Simulations were implemented to explore treatment performance across different scenarios, including randomised designs and real-world settings. Treatment options included regular dosing with ICS monotherapy [fluticasone propionate (FP)] and combination therapy [fluticasone propionate/salmeterol (FP/SAL) or budesonide/formoterol (BUD/FOR)]. Exacerbation rate was analysed using the log-rank test. The cumulative incidence of events was summarised stratified by treatment., Results: Being a woman, smoker, having higher baseline ACQ-5 and body mass index (BMI) and lower forced expiratory volume in the first second (FEV 1 ) are associated with increased exacerbation risk (p < 0.01). This risk is bigger in winter because of the seasonal variation effect. Across the different scenarios, the use of FP/SAL resulted in a 10% lower annual incidence of exacerbations relative to FP or regular dosing BUD/FOR, independently of baseline characteristics. Similar differences in the annual incidence of exacerbations were also observed between treatments in obese patients (BMI ≥ 25-35 kg/m 2 ) (p < 0.01) and in patients who do not achieve symptom control on FP monotherapy., Conclusions: Individual baseline characteristics and treatment choices affect future risk. Achieving comparable levels of symptom control whilst on treatment does not imply comparable risk reduction, as shown by the lower exacerbation rates in FP/SAL vs. BUD/FOR-treated patients. These factors should be considered as a basis for personalised clinical management of patients with moderate-severe asthma., (© 2023. The Author(s).)

Background: As-needed low-dose inhaled corticosteroid (ICS)-formoterol reliever is recommended in patients with asthma prescribed maintenance ICS-formoterol. Clinicians often ask whether ICS-formoterol reliever can be used with other maintenance ICS-long-acting β 2 -agonists., Objective: To evaluate the safety and effectiveness of as-needed formoterol in patients taking maintenance ICS-formoterol or ICS-salmeterol from the RELIEF study., Methods: RELIEF (SD-037-0699) was a 6-month, open-label study that randomized 18,124 patients with asthma to as-needed formoterol 4.5 μg or salbutamol 200 μg on top of maintenance therapy. This post hoc analysis included patients on maintenance ICS-formoterol or ICS-salmeterol (n = 5436). The primary safety outcome was a composite of serious adverse events (SAEs) and/or adverse events leading to discontinuation (DAEs); the primary effectiveness outcome was time-to-first exacerbation., Results: For both maintenance groups and both relievers, similar numbers of patients had ≥1 SAE and/or DAE. In patients taking maintenance ICS-salmeterol, but not ICS-formoterol, significantly more non-asthma-related and nonserious DAEs occurred with as-needed formoterol versus as-needed salbutamol (P = .0066 and P = .0034, respectively). In patients taking maintenance ICS-formoterol, there was a significantly lower risk in time-to-first exacerbation with as-needed formoterol versus as-needed salbutamol (hazard ratio [HR]: 0.82, 95% confidence interval [CI]: 0.70, 0.95; P = .007). In patients taking ICS-salmeterol maintenance, time-to-first exacerbation was not significantly different between treatment arms (HR: 0.95, 95% CI: 0.84, 1.06; P = .35)., Conclusions: As-needed formoterol significantly reduced exacerbation risk compared with as-needed salbutamol when added to maintenance ICS-formoterol, but not to maintenance ICS-salmeterol. More DAEs were seen with ICS-salmeterol maintenance therapy plus as-needed formoterol. Further research is needed to assess whether this is relevant to as-needed combination ICS-formoterol., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The Precision Interventions for Severe and/or Exacerbation-Prone Asthma clinical trials network is actively assessing novel treatments for severe asthma during the coronavirus disease (COVID-19) pandemic and has needed to adapt to various clinical dilemmas posed by the COVID-19 pandemic. Pharmacologic interactions between established asthma therapies and novel drug interventions for COVID-19 infection, including antivirals, biologics, and vaccines, have emerged as a critical and unanticipated issue in the clinical care of asthma. In particular, impaired metabolism of some long-acting beta-2 agonists by the cytochrome P4503A4 enzyme in the setting of antiviral treatment using ritonavir-boosted nirmatrelvir (NVM/r, brand name Paxlovid) may increase risk for adverse cardiovascular events. Although available data have documented the potential for such interactions, these issues are largely unappreciated by clinicians who treat asthma, or those dispensing COVID-19 interventions in patients who happen to have asthma. Because these drug-drug interactions have not previously been relevant to patient care, clinicians have had no guidance on management strategies to reduce potentially serious interactions between treatments for asthma and COVID-19. The Precision Interventions for Severe and/or Exacerbation-Prone Asthma network considered the available literature and product information, and herein share our considerations and plans for treating asthma within the context of these novel COVID-19-related therapies., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objective: This real-world observational study compared medication adherence and persistence among patients with asthma receiving the once-daily inhaled corticosteroid/long-acting β 2 -agonist (ICS/LABA) fluticasone furoate/vilanterol (FF/VI) versus the twice-daily ICS/LABAs budesonide/formoterol (B/F) and fluticasone propionate/salmeterol (FP/SAL)., Methods: This retrospective cohort study conducted using IQVIA TM Health Plan Claims Data included patients with asthma ≥18 years of age initiating ICS/LABA therapy with FF/VI, B/F, or FP/SAL between January 1, 2014 and June 30, 2016 (index date). Patients had ≥12 months and ≥3 months of continuous eligibility pre- and post-index date, respectively. Patients receiving FF/VI were separately matched 1:1 with patients receiving B/F or FP/SAL using propensity score matching (PSM) and multivariable regression to balance baseline covariates between cohorts. The primary endpoint was medication adherence, measured by proportion of days covered (PDC). Secondary endpoints included proportion of patients achieving PDC ≥ 0.5 and PDC ≥ 0.8 and persistence with index medication, measured by time to discontinuation (>45-day gap in therapy)., Results: After PSM, 3,764 and 3,339 patients receiving FF/VI were matched with patients receiving B/F or FP/SAL, respectively. Mean PDC was significantly higher for FF/VI versus B/F (0.453 vs 0.345; adjusted p  < 0.001) and FP/SAL (0.446 vs 0.341; adjusted p  < 0.001). The proportion of patients achieving PDC ≥ 0.5 or PDC ≥ 0.8, and treatment persistence were significantly higher for FF/VI versus B/F and FP/SAL (all p  < 0.001)., Conclusions: In this real-world study, patients initiating FF/VI had better adherence and lower risk of discontinuing treatment versus B/F or FP/SAL, suggesting that once-daily ICS/LABA treatment might improve adherence and persistence compared with twice-daily alternatives.

Background: Wixela ® Inhub ® is a dry powder inhaler approved as a generic equivalent to Advair ® Diskus ® (fluticasone propionate [FP]/salmeterol fixed-dose combination) for patients with asthma or chronic obstructive pulmonary disease (COPD). This study aimed at confirming the local (lung) therapeutic equivalence of both the FP and salmeterol components of Wixela Inhub (test [T]) to Advair Diskus (reference [R]) after inhalation. Methods: This randomized, double-blind, double-dummy, placebo-controlled, parallel-group study in patients ≥18 years with mild-to-moderate persistent asthma compared the local therapeutic equivalence (using forced expiratory volume in 1 second [FEV 1 ]) of FP/salmeterol (100/50 μg) after inhaled delivery via T and R. Results: Randomized patients ( N  = 1127) received T ( n  = 512), R ( n  = 512), or placebo ( n  = 103). T and R significantly increased day 1 FEV 1 area under the effect curve over 12 hours of the change from baseline (AUC [0-12] ) and day 29 trough FEV 1 over placebo, indicating that these endpoints were sufficiently sensitive for evaluation of bioequivalence. On day 1, T and R each increased FEV 1 AUC (0-12) over placebo (3.134 L•h [T], 2.677 L•h [R]; each p  < 0.0001). Following twice-daily dosing for 28 days, T and R also each increased trough FEV 1 (measured on day 29) over placebo (235 mL [T], 215 mL [R]; each p  < 0.0001). Least-squares mean T/R ratios (90% confidence intervals) for day 1 FEV 1 AUC (0-12) and day 29 trough FEV 1 were 1.120 (1.016-1.237) and 1.069 (0.938-1.220), respectively, indicating that T and R were bioequivalent for both co-primary endpoints. FP/salmeterol was well tolerated when administered via either T or R. Conclusions: These results demonstrate that the therapeutic effects of Wixela Inhub are bioequivalent to Advair Diskus in the lung. Wixela Inhub represents a therapeutically equivalent new FP/salmeterol treatment option for use in the treatment of asthma and COPD.

Objective: To evaluate the efficacy and safety of fluticasone propionate/formoterol (FP/FORM) versus fluticasone propionate/salmeterol (FP/SAL) in treating pediatric asthma during a 12-week treatment cycle., Methods: Randomized controlled trials of FP/FORM compared with FP/SAL in treating pediatric asthma were searched systematically using Medline, Embase, and the Cochrane Controlled Trials Register., Results: Two articles including 546 patients were evaluated. The FP/SAL group showed obvious improvements in pre-dose forced expiratory volume in 1 s (FEV 1 ) from day 0 to 84, asthma symptom scores, and sleep disturbance scores compared with the FP/FORM group; however, the FP/FORM group had improved peak expiratory flow rate (PEFR). In terms of 2-hour post-dose FEV 1 from day 0 to 84, 2-hour forced expiratory flow at 25%, 50%, and 75%, and 2-hour forced vital capacity, we observed no significant differences between the two groups. For safety, including patients with at least one adverse event, bronchitis, cough, or pharyngitis, both groups had similar incidences, differing only in incidence of nasopharyngitis., Conclusion: Compared with FP/FORM, FP/SAL showed a clear improvement in pre-dose FEV 1 , asthma symptom scores, and sleep disturbance scores. However, FP/FORM resulted in improved PEFR with a lower incidence of nasopharyngitis.

Background: Asthma is widely treated using inhaled corticosteroid/long-acting beta agonist (LABA) combinations, for example, fluticasone propionate/salmeterol (FPS) dry powder inhaler, marketed as Advair ® Diskus ® . Some regulators require generics to demonstrate local (lung) therapeutic equivalence (LTE) for each component of the FPS reference, ideally with a dose-response within the approved FPS dose range. We sought to develop a methacholine challenge (MeCh) LTE methodology for assessing the LABA (salmeterol) component of FPS. Methods: Forty-six patients with asthma received single doses of albuterol (active control; 90 or 180 μg), FPS (100/50 or 200/100 μg), and placebo on 5 separate study days. Spirometry and MeCh were performed 1, 6, and 10 hours after study drug inhalation. Primary endpoint was provocative concentration of methacholine producing a 20% fall in forced expiratory volume in 1 second (PC 20 ). Study entry required screening PC 20 ≤8 mg/mL, with a greater than fourfold increase (and PC 20 ≤128 mg/mL) after 180 μg albuterol. Results: Both albuterol (90 and 180 μg) and FPS (100/50 and 200/100 μg) significantly increased PC 20 compared with placebo (sustained 6 and 10 hours postdose with FPS but not albuterol). The dose-response slopes (95% confidence interval) estimated 1 hour after treatment were 0.374 (-0.068 to 0.815) and 0.310 (-0.135 to 0.754) between low and high doses of albuterol and FPS, respectively, both nonsignificant. Slopes were shallower than those available in the literature for albuterol and formoterol, but similar to those for salmeterol. Conclusions: These data confirm that the bronchoprotective effect of FPS lasts longer than that of albuterol. The shallow dose-response slope we observed for albuterol is contrary to previous reports, probably due to the measurement of PC 20 beginning at 1 hour postdose. The results suggest that use of MeCh to assess LTE for salmeterol formulations may be more difficult to accomplish than it is for albuterol and formoterol products.

Background: Loss of bronchoprotection (LOBP) with a regularly used long-acting β 2 -adrenergic receptor agonist (LABA) is well documented. LOBP has been attributed to β 2 -adrenergic receptor (B2AR) downregulation, a process requiring farnesylation, which is inhibited by alendronate., Objective: We sought to determine whether alendronate can reduce LABA-associated LOBP in inhaled corticosteroid (ICS)-treated patients., Methods: We conducted a randomized, double-blind, placebo-controlled, parallel-design, proof-of-concept trial. Seventy-eight participants with persistent asthma receiving 250 μg of fluticasone twice daily for 2 weeks were randomized to receive alendronate or placebo while initiating salmeterol for 8 weeks. Salmeterol-protected methacholine challenges (SPMChs) and PBMC B2AR numbers (radioligand binding assay) and signaling (cyclic AMP ELISA) were assessed before randomization and after 8 weeks of ICS plus LABA treatment. LOBP was defined as a more than 1 doubling dose reduction in SPMCh PC 20 value., Results: The mean doubling dose reduction in SPMCh PC 20 value was 0.50 and 0.27 with alendronate and placebo, respectively (P = .62). Thirty-eight percent of participants receiving alendronate and 33% receiving placebo had LOBP (P = .81). The after/before ICS plus LABA treatment ratio of B2AR number was 1.0 for alendronate (P = .86) and 0.8 for placebo (P = .15; P = .31 for difference between treatments). The B2AR signaling ratio was 0.89 for alendronate (P = .43) and 1.02 for placebo (P = .84; P = .44 for difference). Changes in lung function and B2AR number and signaling were similar between those who did and did not experience LOBP., Conclusion: This study did not find evidence that alendronate reduces LABA-associated LOBP, which relates to the occurrence of LOBP in only one third of participants. LOBP appears to be less common than presumed in concomitant ICS plus LABA-treated asthmatic patients. B2AR downregulation measured in PBMCs does not appear to reflect LOBP., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Fluticasone propionate 50 μg/salmeterol xinafoate 25 μg (FP/SAL) is widely used in adults and children with asthma, but there is sparse information on its use in very young children., Methods: This was a randomized, double-blind, multicentre, controlled trial conducted in children aged 8 months to 4 years. During a 2-week run-in period, they all received FP twice daily. At randomization, they commenced FP/SAL or FP twice daily for 8 weeks. All were then given FP/SAL only, in a 16-week open-label study continuation. Medications were inhaled through an AeroChamber Plus with attached face mask. The primary end-point was mean change in total asthma symptom scores from baseline to the last 7 days of the double-blind period. Analyses were undertaken in all children randomized to treatment and who received at least one dose of study medication., Results: Three hundred children were randomized 1:1 to receive FP/SAL or FP. Mean change from baseline in total asthma symptom scores was -3.97 for FP/SAL and -3.01 with FP. The between-group difference was not statistically significant (P = 0.21; 95% confidence interval: -2.47, 0.54). No new safety signals were seen with FP/SAL., Conclusion: This is the first randomized, double-blind study of this size to evaluate FP/SAL in very young children with asthma. FP/SAL did not show superior efficacy to FP; no clear add-on effect of SAL was demonstrated. No clinically significant differences in safety were noted with FP/SAL usage., (© 2018 The Authors. Pediatric Allergy and Immunology Published by John Wiley & Sons Ltd.)

Objective: There is a scarcity of studies that assessed the association between adherence to combination therapy and asthma control in pediatric patients. The authors investigated the association between adherence to fluticasone propionate/salmeterol xinafoate combination-metered aerosol and the level of asthma control in children., Methods: This was a prospective observational study of 84 patients aged 5-16 years with moderate persistent asthma, who remained uncontrolled despite the use of 1000μg/day of inhaled nonextrafine-hydrofluoric alkane-beclomethasone dipropionate in the three months prior to study enrollment. Participants were prescribed two daily doses of FP (125μg)/salmeterol xinafoate (25μg) combination by metered aerosol/spacer for six months. Adherence rates were assessed using the device's dose counter after the 2nd, 4th, and 6th months of follow up. Asthma control was assessed using a simplified Global Initiative for Asthma 2014 Report classification., Results: Mean adherence rates after the second, fourth, and sixth months were 87.8%, 74.9%, and 62.1% respectively, for controlled asthma, and 71.7%, 56.0%, and 47.6% respectively, for uncontrolled asthma (all p-values≤0.03). The proportion of children achieving asthma control increased to 42.9%, 67.9% and 89.3% after the 2nd, 4th and 6th months of follow-up, respectively (p≤0.001)., Conclusion: Adherence rates between 87.8% in the 2nd month and 62.1% in the 6th month were strong determinants of asthma control., (Copyright © 2017 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)

Aim: The aim of this study was to test the systemic pharmacodynamic effects of the salmeterol component of two pressurized metered dose inhalers that delivered a combination of salmeterol and fluticasone propionate (SM/FP)., Methods: This was a six-way crossover study in 43 adult subjects, using a single blind design (subject blinded to product and clinical assessor blinded for all measurements). Each subject received single doses of two, six, and twelve inhalations from test and reference products that delivered SM/FP as 25/125 mcg per inhalation. Heart rate, QTcB, and plasma potassium and glucose were monitored over 6 h., Results: Safety equivalence was shown by relative potency analysis for primary endpoints of maximum heart rate and maximum QTcB, since the 90% confidence intervals for both endpoints were within the acceptance limit of (0.67, 1.50). There were six secondary analyses for relative potency and equivalence was met for five of these endpoints. There were also 18 pairwise comparisons performed at each dose level. No statistical differences (95% confidence intervals included zero) among these pairwise comparisons were seen at the two-inhalation dose (therapeutic dose) or the six-inhalation dose. At the supratherapeutic dose of twelve inhalations, the test product was either comparable to or statistically less than that of the reference product for all comparisons. Overall, the results demonstrated comparable systemic safety. No differences were seen between the products in reported adverse events., Conclusion: The safety equivalence of the systemic pharmacodynamic effects of the SM component of the test and reference SM/FP products was demonstrated., (© 2017 The British Pharmacological Society.)

Background: Guidelines recommend reducing treatment in patients with well-controlled asthma after 3 months of stability. However, there is inadequate real-life data to guide physicians on therapy change in daily practice., Objective: To assess asthma control after change to and step-down of fluticasone propionate/formoterol fumarate dihydrate (FP/FOR) in real-life patients., Methods: In a randomized controlled, pragmatic, open-label trial, 225 well-controlled patients with asthma were randomized (1:2) to maintain high-dose fluticasone propionate/salmeterol xinafoate (FP/SAL, 1000/100 μg) or switch to FP/FOR (1000/40 μg) daily for 12 weeks (phase 1). One hundred sixteen patients stable on FP/FOR at week 12 were subsequently randomized (1:1) to maintain this therapy, or stepped down to FP/FOR (500/20 μg) daily for 12 weeks (phase 2). The primary end point was the 7-question Asthma Control Questionnaire (ACQ7) score., Results: In phase 1, FP/FOR (1000/40 μg) (n = 126) was noninferior to FP/SAL (1000/100 μg) (n = 73) for ACQ7 (difference in means, -0.12; 95% CI, -0.32 to 0.09). In phase 2, FP/FOR (500/20 μg) (n = 52) was noninferior to FP/FOR (1000/40 μg) (n = 52) for ACQ7 (difference in means, 0.01; 95% CI, -0.20 to 0.22). There was no significant difference in exacerbation rate between the groups in either phase. However, 1 to 2 exacerbations in 12 months before phase 1 were associated with the occurrence of an exacerbation after step-down (P = .007)., Conclusions: In patients with well-controlled asthma, a change from FP/SAL to FP/FOR did not compromise asthma control. Step-down of FP/FOR was well tolerated; however, in contrast to current guidelines, our data suggest caution in stepping down patients uncontrolled in the last 12 months. Larger step-down studies are required to confirm these findings., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Rationale: OT329 SOLIS is a generic candidate for the branded asthma treatment, ADVAIR DISKUS (fluticasone propionate/salmeterol xinafoate), and, as such, the manufacturer is required to provide evidence of clinical "bioequivalence" as a condition for regulatory approval., Objectives: The objective of the current study was to determine if SOLIS and DISKUS provided bioequivalent improvements in lung function at two time points: Day 1 and Week 4., Methods: This study was a randomized, multiple-dose, placebo-controlled, parallel-group design conducted in the United States (NCT02260492) with a 2-week run-in followed by a 4-week treatment period. Consenting patients were randomized to treatment with OT329 SOLIS 100/50, ADVAIR DISKUS 100/50, or placebo. Lung function was measured predose and 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours after the first dose to test equivalence of the β-agonist salmeterol component based on FEV 1 area under the curve (0-12 h). After 4 weeks of twice-daily dosing, trough (predose) FEV 1 was measured to evaluate equivalence of the fluticasone propionate corticosteroid component. Bioequivalence was concluded if the 90% confidence interval (CI) for the ratio of the products fell within 80-125%., Measurements and Main Results: Of the 1,524 screened, 879 patients with asthma were randomized to treatment (n = 418 SOLIS, 419 DISKUS, 42 placebo). OT329 SOLIS and ADVAIR DISKUS were bioequivalent at Day 1, with an FEV 1 area under the curve (0-12 h) test/reference ratio of 108% (90% CI = 94-122%). Likewise, the products were bioequivalent at Week 4 with a trough FEV 1 test/reference ratio of 105% (90% CI = 90-119). Both active treatments were superior to placebo (P < 0.05) at both time points., Conclusions: The data support a conclusion of clinical bioequivalence of OT329 SOLIS to ADVAIR DISKUS. Clinical trial registered with www.clinicaltrials.gov (NCT02260492).

Background: In developing countries, there is a need for access to affordable inhaled respiratory medicines. This study tested the clinical non-inferiority of fluticasone propionate/salmeterol combination (FSC) 50/250 μg Rotacaps ® /Rotahaler ® compared with FSC 50/250 μg Diskus ® ., Methods: A multi-centre, randomised, double-blind, double-dummy study evaluated 12 weeks, twice daily treatment of FSC 50/250 μg administered using Rotacaps/Rotahaler or Diskus inhaler in a crossover design in patients with asthma (pre-bronchodilator forced expiratory volume in 1 s (FEV 1 ) 40%-85% of predicted, FEV 1 reversibility ≥12%, prior stable dose with inhaled corticosteroid (ICS) or ICS/long acting beta-agonist). The primary efficacy endpoint, change from baseline in trough morning FEV 1 at Day 85, was analysed using a model for repeated measures analysis. The pre-defined criterion for non-inferiority was the lower limit of the CI (0.025, one-sided significance level) for the treatment difference (Rotacaps/Rotahaler-Diskus) in least squares (LS) mean change from baseline, being greater than -125 mL. Secondary endpoints included serial FEV 1 measurements, morning peak expiratory flow (PEF), rescue medication use, day- and night-time asthma symptoms, Asthma Control Test (ACT) scores, and serial cortisol measured over 12 h (area under the curve (AUC 0-12 ))., Results: Treatment with FSC 50/250 μg via Rotacaps/Rotahaler or Diskus resulted in a similar LS mean increase from baseline in trough FEV 1 at Day 85 (231 mL and 203 mL respectively). The difference in the model-adjusted LS mean change was 28 mL (95% CI -24 mL, 80 mL), fulfilling the criterion for non-inferiority. Data for all secondary endpoints were similar for the two treatments, supporting the primary endpoint findings. Both treatments were well tolerated and demonstrated similar safety profiles., Conclusion: This study demonstrated the clinical non-inferiority of FSC 50/250 μg when administered using Rotacaps/Rotahaler compared with administration using Diskus in patients with asthma, and suggests there is no difference in the risk:benefit profile between the two FSC inhalers., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: 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., Objective: The objective of this study was to compare persistence to salmeterol/fluticasone propionate combination treatment as AirFluSal Forspiro with persistence to Seretide Diskus in patients with asthma or COPD aged 12 years and above., Methods: This study analyzed dispensing data from a large German pharmacy database. Male and female patients who were prescribed AirFluSal Forspiro were randomly paired with those who were prescribed Seretide Diskus controlling for month of treatment initiation (to limit potential seasonality effects), age groups, and gender. Matched patient pair analysis was conducted on a total of 11,774 patients (45.1% male) to compare persistence between the 2 products., Results: The survival probability estimates at 12 months were 0.229 (0.02 standard error) for AirFluSal Forspiro versus 0.105 (0.025 standard error) for Seretide Diskus. The Renyi family of tests demonstrated a statistically significant difference (P = .01) in persistence to AirFluSal Forspiro compared with Seretide Diskus in the overall survival experience of the 2 populations., Conclusions: In this large retrospective pharmacy database analysis, patients using AirFluSal Forspiro were more likely to persist with treatment compared with those using Seretide Diskus as demonstrated by the overall survival experience of the 2 populations (12-month study period). These new data provide a basis for further research to better understand persistence behavior and to develop strategies to address poor persistence., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Unambiguously for inhaled products, PK measures are best suited for ensuring that the total systemic exposure is equivalent for two products but cannot provide regional information about lung deposition and structural changes. Functional respiratory imaging (FRI) has been demonstrated to be sensitive for distinguishing small but imperative differences related to a single treatment., Methods: In this study FRI is used in 16 asthmatic patients to assess equivalence in regional deposition for two products (fluticasone/salmeterol, test and reference) by directly measuring regional functional and structural changes within the lungs following its administration., Results: No differences were observed between the lung deposition patterns and the effects on lung structure and function of two products, having the same formulation and manufactured by different organizations using FRI., Conclusions: Results using FRI complement PK assessments. The added value of this approach to the conventional clinical methods could be significant.

Introduction: Pressurized metered-dose inhalers (pMDI) such as fluticasone propionate and salmeterol (FP/SAL) are commonly used for the treatment of asthma in the UK. Previously, a budget impact analysis demonstrated that use of FP and formoterol fumarate (FP/FORM) pMDI as an alternative to FP/SAL pMDI, would be a cost-saving option for the UK National Health Service (NHS). This budget impact analysis aimed to update the existing analysis with prescription volume data and real-world evidence since the introduction of FP/FORM to the UK market., Methods: Patient Data (IMS Information Solutions UK Ltd) moving annual total (MAT) August 2015 were used to ascertain the number of units of pMDI prescribed. Annual costs to the NHS in terms of drug, administration, monitoring and adverse event costs, were used to estimate the potential budget impact for FP/FORM and FP/SAL. Costs were calculated for current prescription volumes (12% FP/FORM, 88% FP/SAL), and for different prescription volume scenarios (FP/FORM at 0%, 25%, 50% and 100%). Real-world evidence and budget impact at a clinical commissioning group (CCG) level were also considered., Results: Total annual costs per person year were less with FP/FORM (£625) than with FP/SAL (£734). Annual costs to the NHS based on the current prescription volumes and clinical trial data were estimated at £210.0M, however, based on real-world evidence, costs were estimated at £179.8M. For all scenarios with increased FP/FORM prescription volumes, the annual total costs to the NHS decreased. This was reflected at a CCG level., Conclusion: The use of FP/FORM as an alternative to FP/SAL can result in cost savings for the NHS when assessing drug, administration, monitoring and adverse events costs. The inclusion of data released since the launch of FP/FORM within the budget impact analysis demonstrates that the potential cost savings to the NHS that were previously published are being translated to clinical practice., Funding: Mundipharma, UK.

Background: Effects of small-particle long-acting β-agonists on the small airways have been poorly documented., Objective: We used impulse oscillometry (IOS) to compare single and repeated dosing effects of small- and large-particle long-acting β-agonists., Methods: After a 1- to 2-week run-in period, patients received either 12 μg of small-particle hydrofluoroalkane 134a-formoterol solution or 50 μg of large-particle salmeterol dry powder twice daily plus inhaled corticosteroid for 1 to 2 weeks with a 1- to 2-week washout period in between. Measurements were made over 60 minutes after the first and last doses., Results: Sixteen patients completed the study as follows: mean age, 43 years; FEV1, 80%; forced midexpiratory flow between 25% and 75% of forced vital capacity (FEF(25-75)), 48%; total airway resistance at 5 Hz, 177%; peripheral airway resistance as the difference between 5 and 20 Hz, 0.18 kPa·L(-1)·s; Asthma Control Questionnaire score, 0.76; and inhaled corticosteroid dosage, 550 μg/d. There were significantly greater improvements with formoterol versus salmeterol in all IOS outcomes and FEF25-75, but not FEV1, at 5 minutes after the first dose, which were not sustained over 60 minutes. After the last dose, all IOS outcomes, but not FEV1 or FEF(25-75), were significantly better with formoterol over the entire 60 minutes: mean difference at 60 minutes between formoterol and salmeterol in total airway resistance at 5 Hz, 7.50% (95% CI, 1.56% to 13.43%, P = .02); central airway resistance at 20 Hz, 5.37% (95% CI, 0.13% to 10.62%, P = .045); peripheral airway resistance as the difference between 5 and 20 Hz, 12.76% (95% CI, 1.28% to 24.24%, P = .03); reactance area under the curve, 19.46% (95% CI, 7.56% to 31.36%, P = .003); reactance at 5 Hz, 11.19% (95% CI, 4.62% to 17.76%, P = .002); and resonant frequency, 9.34% (95% CI, 3.21% to 15.47%, P = .005). Peak expiratory flow significantly improved to a similar degree with both drugs., Conclusion: Significant improvements in IOS outcomes but not spirometry results occurred after chronic dosing with formoterol compared with salmeterol. This might reflect better deposition to the entire lung, including the small airways., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Fixed dose combinations (FDC) of inhaled corticosteroid (ICS) and long-acting beta agonist (LABA) are well established in asthma treatment. The budesonide/salmeterol (B/S) FDC is now about to reach the market. It is provided as powder in hard capsules of two strengths: 120/20μg and 240/20μg when expressed as delivered doses, equivalent to 150/25μg and 300/25μg when expressed as nominal doses. Its development involved 9 pharmacokinetic (320 subjects), 3 phase II (123 subjects) and 4 phase III (1206 patients with different asthma severity) studies. Delivery is effectuated via low resistance inhaler device, Axahaler®, generating also fine particles targeting the small airways. B/S safety, assessed in 1401 subjects, did not outline novel concerns specific for this FDC. In conclusion, the B/S dry powder FDC can be used for asthma treatment in adults not adequately controlled on ICS alone, or to maintain control of ICS/LABA treated patients, in whom switching to alternative FDC is indicated.

Chronic obstructive pulmonary disease (COPD) and asthma are common airway disorders characterized by chronic airway inflammation and airflow obstruction, and are a leading cause of morbidity and mortality in the People's Republic of China. These two diseases pose a high economic burden on the family and the whole of society. Despite evidence-based Global Initiative for Chronic Obstructive Lung Disease and Global Initiative for Asthma guidelines being available for the diagnosis and management of COPD and asthma, many of these patients are not properly diagnosed or managed in the People's Republic of China. The value of combination therapy with inhaled corticosteroids and long-acting β2-agonists has been established in the management of asthma and COPD globally. Combinations of inhaled corticosteroids and long-acting β2-agonists such as fluticasone and salmeterol, have been shown to be effective for improving symptoms, health status, and reducing exacerbations in both diseases. In this review, we discuss the efficacy and safety of this combination therapy from key studies, particularly in the People's Republic of China.

Background: The object of this study was to assess whether a capsule-based and multidose dry powder inhaler containing salmeterol (as xinafoate salt) 50 μg plus fluticasone propionate (FP) 250 μg [combination (SFC 50/250)] could be equivalent in terms of in vivo drug delivery and systemic exposure., Methods: This was a randomized, double-blind, double-dummy, replicate treatment design comparative bioavailability study of SFC 50/250 delivered in a capsule-based inhaler (Rotahaler®) and a multidose dry powder inhaler (Diskus®). Subjects with asthma or chronic obstructive pulmonary (COPD) disease (n=60) were randomized to receive twice-daily SFC 50/250 via a Rotahaler and via Diskus each for two 10-day treatment periods (GlaxoSmithKline Protocol ASR114334)., Results: For FP and salmeterol, the in vitro aerodynamic particle size profiles were within±15% of Diskus for the fine particle mass (FPM) and emitted dose (ED) using the Andersen Cascade Impactor, and ED, mass median aerodynamic diameter, and geometric standard deviation using the New Generation Impactor (NGI). This was also the case for FP but not salmeterol for FPM and fine particle dose using the NGI. For the combined asthma and COPD subjects, the plasma AUC and Cmax for FP and salmeterol were higher for Rotahaler:Rotahaler/Diskus geometric mean ratios (90% confidence intervals) for FP AUC0-τ of 1.52 (1.37-1.67) and Cmax of 1.94 (1.75-2.10) and salmeterol AUC0-τ of 1.15 (1.09-1.21) and Cmax of 1.56 (1.42-1.67). Corresponding values for the primary pharmacodynamic endpoint, weighted mean (0-12 hr) serum cortisol, were 0.928 (0.886-0.971). Inhaled FP/salmeterol via both inhalers was well-tolerated. One serious adverse event, considered possibly related to study medication, resulted in subject withdrawal from the study., Conclusions: The in vitro tests and systemic pharmacodynamic endpoints revealed no major differences between the two inhalers, but lacked predictive power and sensitivity to guide in vivo drug delivery performance and systemic exposure. Based on pharmacokinetic endpoints, the inhalers were not considered bioequivalent in terms of systemic exposure. Further studies to refine the Rotahaler performance are ongoing.

Aim: To assess the cardiovascular effects of a new inhaled long-acting β-adrenoceptor agonist PF-00610355 in COPD patients., Methods: Thirteen thousand and sixty-two heart rate measurements collected in 10 clinical studies from 579 healthy volunteers, asthma and COPD patients were analyzed. The relationship between heart rate profiles and predicted plasma concentration profiles, patient status, demographics and concomitant medication was evaluated using non-linear mixed-effects models. The median heart rate increase in COPD patients for doses of PF-00610355 up to 280 μg once daily was simulated with the final pharmacokinetic/pharmacodynamic (PKPD) model., Results: An Emax model accounting for delayed on-and off-set of the PF-00610355-induced change in heart rate was developed. The predicted potency in COPD patients was three-fold lower compared with healthy volunteers, while no difference in maximum drug effect was identified. Simulations suggested a maximum placebo-corrected increase of 2.7 (0.90-4.82) beats min(-1) in COPD patients for a PF-00610355 dose of 280 μg once daily, with 19% subjects experiencing a heart rate increase of more than 20 beats min(-1) compared with 8% in the placebo group., Conclusions: This PKPD analysis supports the clinical observation that no relevant effects of PF-00610355 on heart rate in COPD patients should be expected for doses up to 280 μg once daily., (© 2013 The Authors. British Journal of Clinical Pharmacology © 2013 The British Pharmacological Society.)

Background: Tiotropium has activity as an asthma controller. However, predictors of a positive response to tiotropium have not been described., Objective: We sought to describe individual and differential responses of asthmatic patients to salmeterol and tiotropium when added to an inhaled corticosteroid, as well as predictors of a positive clinical response., Methods: Data from the double-blind, 3-way, crossover National Heart, Lung, and Blood Institute's Asthma Clinical Research Network's Tiotropium Bromide as an Alternative to Increased Inhaled Glucocorticoid in Patients Inadequately Controlled on a Lower Dose of Inhaled Corticosteroid (ClinicalTrials.gov number, NCT00565266) trial were analyzed for individual and differential treatment responses to salmeterol and tiotropium and predictors of a positive response to the end points FEV1, morning peak expiratory flow (PEF), and asthma control days (ACDs)., Results: Although approximately equal numbers of patients showed a differential response to salmeterol and tiotropium in terms of morning PEF (n = 90 and 78, respectively) and ACDs (n = 49 and 53, respectively), more showed a differential response to tiotropium for FEV1 (n = 104) than salmeterol (n = 62). An acute response to a short-acting bronchodilator, especially albuterol, predicted a positive clinical response to tiotropium for FEV1 (odds ratio, 4.08; 95% CI, 2.00-8.31; P < .001) and morning PEF (odds ratio, 2.12; 95% CI, 1.12-4.01; P = 0.021), as did a decreased FEV1/forced vital capacity ratio (FEV1 response increased 0.39% of baseline for every 1% decrease in FEV1/forced vital capacity ratio). Higher cholinergic tone was also a predictor, whereas ethnicity, sex, atopy, IgE level, sputum eosinophil count, fraction of exhaled nitric oxide, asthma duration, and body mass index were not., Conclusion: Although these results require confirmation, predictors of a positive clinical response to tiotropium include a positive response to albuterol and airway obstruction, factors that could help identify appropriate patients for this therapy., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

High-dose and long-term use of inhaled corticosteroids may cause systemic and local side effects such as opportunistic infections. Here we report a patient with asthma who developed a giant cavity in the lung while using inhaled salmeterol plus fluticasone propionate. A 57-year-old female patient presented with a three-week history of cough, hemoptysis, and dyspnea. She had a diagnosis of asthma for 4 years and was using an inhaled salmeterol plus fluticasone treatment intermittently for 2 years. A giant cavity was detected in the patient's chest X-ray. As a result of further investigations, three different microorganisms were isolated from the samples of sputum, bronchial lavage and lung biopsy. Staphylococcus aureus was the first microorganism that was isolated from the sputum and the bronchial lavage. Afterwards, Candida albicans was detected in both the bronchial lavage fluid and the histologic examination of the tissue samples obtained by percutaneous lung biopsy. Appropriate antibiotics and antifungals were prescribed. Moderate clinical and radiological response to the treatment was obtained. During the outpatient follow-up, Mycobacterium tuberculosis growth which was sensitive to all of the major anti-tuberculosis drugs was reported in the mycobacterial culture, and the patient was started on anti-tuberculosis treatment. Tuberculosis and other opportunistic infections are a potential consequences of inhaled corticosteroids. Clinicians overseeing such patients need to be vigilant about the need for timely investigations about tuberculosis before and during prescribing medications containing inhaled corticosteroids. [ABSTRACT FROM AUTHOR]

Regular treatment with formoterol and an inhaled corticosteroid versus regular treatment with salmeterol and an inhaled corticosteroid for chronic asthma: serious adverse events. Keywords: asthma; bronchodilator agents; corticosteroids; drug side effects EN asthma bronchodilator agents corticosteroids drug side effects 491 494 4 05/10/23 20230501 NES 230501 Key messages Combined inhaled corticosteroids (ICSs) and long-acting beta-agonist therapy improve asthma outcomes compared with the long-acting beta-agonist monotherapy. Ensuring asthma treatments are safe is imperative to minimise healthcare utilisation and improve outcomes for these patient groups. [Extracted from the article]

The effectiveness of a fix-dose salmeterol/fluticasone combination therapy in asthma was previously shown for the original product. The study aim was to evaluate the clinical effectiveness and safety of a second entry DPI – dry powder inhaler (Salflumix Easyhaler) in patients with asthma in everyday clinical practice. This multicenter Investigator-Initiated Study that enrolled 2,037 adult outpatients with asthma treated with Salflumix Easyhaler, was conducted by 220 pulmonologists across Poland. Asthma control was assessed during 3 visits with 6 ± 2 weeks intervals based on the Asthma Control Test (ACT). In addition, patient Satisfaction with Asthma Treatment Questionnaire (SATQ) and adherence and adverse events (AEs) were monitored. During the observation (86 ± 30 days) the percentage of patients with controlled asthma (ACT 20-25 pts) increased from 35.5% at the first visit to 86.5% at the third visit (p < 0.001). In the subgroup analysis, there were more patients not obtaining asthma control among patients that switched from the treatment with other devices than in naive ones. Global SATQ scores increased from 5.8 ± 0.7 to 6.2 ± 0.6 during the observation. Patients' satisfaction with the use of the Salflumix Easyhaler was high. Adherence exceeded 95%. Eight AEs were reported. Salflumix Easyhaler is highly effective and well-tolerated by naïve patients with asthma and those switching from another device. In general, patients show good compliance with medical product and are satisfied with the use of this new device, and not reporting difficulties and errors related to its' use. Their physicians' overall perception of Salflumix Easyhaler use is very positive. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the impact of twice-daily inhalation of 100 µg of salmeterol (SAL) or 12 µg of formoterol (FOR) in addition to a strength- and power-training program over a 5-wk period on a 30-m sprint, strength, power, mood, stress, and skinfold thickness. Methods: In a randomized, single-blind study, 23 male and 15 female nonasthmatic, recreationally active individuals were recruited (mean [SD] age 26.3 [5.4] y, weight 76.2 [11.5] kg, height 176.9 [8.5] cm). Participants completed 3 standardized whole-body strength- and power-training sessions per week for 5 wk during which they were assigned to an SAL, FOR, or placebo group. Participants used their inhaler twice per day as instructed and completed assessments of sprint, strength, and power at baseline and 1 wk after cessation of the training program. The assessments included a 30-m sprint, vertical jump, 1-repetition-maximum (1RM) bench press, 1RM leg press, peak torque flexion and extension, anthropometric evaluation, and Rest-Q questionnaires. Results: After 5 wk of strength and power training, 30-m sprint time reduced in the FOR (0.29 [0.11] s, P = .049) and SAL (0.35 [0.05] s, P = .040) groups compared with placebo (+0.01 [0.11] s). No significant change was found in other assessments of strength, mood, or skinfold thickness. Conclusions: When strength and power training are combined with the inhalation of FOR or SAL over a 5-wk period, moderately trained individuals experience an improvement in 30-m sprint performance. [ABSTRACT FROM AUTHOR]

Background: Inhalation therapy with corticosteroids and long-acting β2-agonists has been the mainstay of asthma management. However, choosing the correct inhaler technique is essential to effectively deliver the medication to the lungs to attain good asthma control. Objective: This study aimed to evaluate asthma control and device usability with salmeterol/fluticasone fixed-dose combination (FDC) administered through Synchrobreathe®, a breath-actuated inhaler (BAI), in Indian patients with persistent asthma (EVOLVE study). Design: The present study was a prospective, open-label, non-comparative, multi-center, observational study. Methods: The study enrolled 490 patients with documented diagnoses of asthma who were treatment-naive or uncontrolled due to poor inhaler technique associated with a previous device. The primary endpoint was a change from baseline in the Asthma Control Questionnaire-6 (ACQ-6) score at week 12. Results: Mean ACQ-6 score reduced from 2.2 ± 1.07 (baseline) to 0.4 ± 0.49 (mean change: –1.9 ± 1.12, p < 0.0001) at week 12 in the intention-to-treat (ITT) population, and minimal clinically important difference of 0.5 was observed from week 4 onwards. Peak expiratory flow rate improved by 82.5 ± 75.74 ml/min (p < 0.0001) at week 12 in the ITT population. The proportion of well-controlled responders increased from 39.9% (week 4) to 77.1% (week 12). Most (91%) patients preferred the Synchrobreathe® and rated it very high for usability, portability, patient confidence, and satisfaction. Salmeterol/fluticasone FDC administered through Synchrobreathe® was well tolerated. Conclusion: Treatment with salmeterol/fluticasone FDC administered through Synchrobreathe® for 12 weeks persistently improved asthma control and lung function and was well tolerated. Most patients were satisfied with it and preferred Synchrobreathe® BAI over their previous device. Registration: The study was registered with the Clinical Trial Registry of India (CTRI/2018/12/016629). [ABSTRACT FROM AUTHOR]

PALLADIUM and IRIDIUM studies demonstrated efficacy and safety of indacaterol/mometasone (IND/MF) versus salmeterol/fluticasone (SAL/FLU). This post hoc analysis of pooled data from PALLADIUM and IRIDIUM studies evaluated efficacy and safety of IND/MF versus SAL/FLU in Asian patients with inadequately controlled asthma. Both studies were Phase III, 52-week, randomized, double-blind, active-controlled that included patients with predicted pre-bronchodilator FEV1 (PALLADIUM, ≥50%–<85%; IRIDIUM, <80%), ACQ-7 score ≥1.5. Patients treated with IND/MF high- (150/320 μg) or medium-dose (150/160 μg) or SAL/FLU high-dose (50/500 μg) were included. Lung function, asthma control, and asthma exacerbations were evaluated. In total, 323 patients (IND/MF high-dose, n = 107; IND/MF medium-dose, n = 106, SAL/FLU high-dose, n = 110) were included. IND/MF high-dose showed improvement in trough FEV1 versus SAL/FLU high-dose at Weeks 26 (Δ, 42 mL; 95% CI, −35 to 120 mL), and 52 (Δ, 41 mL; 95% CI, −37 to 120 mL). IND/MF high-dose exhibited numerically greater improvement in ACQ-7 score versus SAL/FLU high-dose at Weeks 26 (Δ, −0.215; 95% CI, −0.385 to −0.044) and 52 (Δ, −0.176; 95% CI, −0.348 to −0.005). Improvements in trough FEV1 and ACQ-7 score were comparable between IND/MF medium-dose and SAL/FLU high-dose. IND/MF high- and medium-dose showed reductions in moderate or severe (45%; 30%), severe (39%; 41%), and all (9%; 25%) exacerbations, respectively, versus SAL/FLU high-dose over 52 weeks. All treatments were well tolerated. Once-daily, single-inhaler IND/MF high-dose improved lung function with better asthma control, reduced asthma exacerbations with comparable safety versus twice-daily SAL/FLU high-dose. IND/MF medium-dose showed comparable outcomes to SAL/FLU high-dose at a reduced steroid dose. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary diseases (COPD) and asthma are fatal. The respiratory tract may be blocked, robbed of the adequate amounts of oxygen; hence, death ensues if a quick medical attention is not provided. The treatment available for the duo are inhaled corticosteroids (ICS). The ICS can work synergically with LABAS (long-acting β2-antagonists) and so many other medicines like bronchodilators. The drugs used for the treatment of asthma and COPD are metabolised once in the body system and at the same time exerting the therapeutic effect provided the concentration of the drug is within the therapeutic window. The CYP3A isoforms metabolise the ICS, in this case, salmeterol and fluticasone propionate (FP). Methods of administration are not limited to inhalation. Specific doses are prescribed accurately paying attention to factors like age, gender, race, and genetic makeup since these affect drug metabolisms. Generally, the ICS work by translocating glucocorticoid receptors to the nucleus from the cytosol. The mechanism is potentiated by the β-antagonists and this brings about an anti-inflammatory effect which is greater than either of the two drugs alone. Once this happens, it is not necessary to increase ICS dose. The ICS, in addition, cause more production of β-receptors by activating the β-receptor genes. This mode of action begets the LABAs' bronchodilator-effects. The challenge is that ICS are not limited only to "double" therapy. Analysing such therapies is daunting since coadministration interferes with pharmacology and pharmacokinetics of drugs. This work focuses on salmeterol/fluticasone propionate combination and aspects which has to do with administration, monitoring, metabolism, toxicity, and adverse effects. [ABSTRACT FROM AUTHOR]

An inhaled corticosteroid (ICS)-long-acting beta-2 agonist (LABA) combination has become the standard of care in asthma. Various ICS-LABAs are commercially available providing the clinician with many choices. A thorough understanding of the clinical efficacy and safety of various formulations will immensely benefit the prescribing doctor to decide the choice of agent. The present systematic review was undertaken to compare the clinical efficacy and safety of formoterol fluticasone (FF) to other ICS/LABA combinations in asthmatics. The review adhered to the general principles mentioned in the CRD guidance and the PRISMA statement. We searched Medline, Embase, and Cochrane Controlled Trials Register databases on the efficacy of FF in treating asthma compared with other ICS-LABAs. A total of 138 trials identified initially. Only trials comparing the efficacy and safety of FF in comparision with Salmeterol/fluticasone (SF) or Budesonide/Formoterol (BF) were selected. The outcomes compared were onset of bronchodilator action, improvement in lung function, asthma control, asthma-related quality of life and risk of pneumonia. Sixteen studies were included in the final analysis. FF therapy provided faster onset of bronchodilatation than SF. A better improvement in lung function was seen with FF inhaler use as compared with comparators in two studies. Patients using the FF inhaler had a non-inferior asthma control and asthma-related quality of life. Pneumonia risk was least with FF usage. FF provides faster onset of action, numerically superior improvement in lung function and comparable asthma control than other ICS-LABA formulations. FF has better safety evidenced by lower occurrence of pneumonia. [ABSTRACT FROM AUTHOR]

Fractional exhaled nitric oxide (FeNO) from the lower airways and nasal nitric oxide (nNO) from the upper airways are biomarkers of eosinophilic airway inflammation and are used to assess responses to corticosteroid treatment. To examine the influence of inhaled fluticasone propionate/salmeterol (FP/SAL) or fluticasone propionate (FP) treatment on the concentration of FeNO and nNO, the percentage of eosinophils, lung function, and asthma control test (ACT) scores among children with asthma, allergic rhinitis, and combined allergic rhinitis and asthma. A total of 95 steroid-naïve pediatric subjects with asthma (n = 29), asthma and allergic rhinitis (n = 30), and allergic rhinitis (n = 36) participated in this study. Initially, patients had a physical exam, baseline FeNO and nNO measurement, spirometry, blood sampling, skin tests, and an ACT questionnaire. After assessment of the baseline values, inhaled FP/SAL (100/50 µg) was administered twice daily for 4 weeks in patients with asthma; intranasal FP (100 µg) was added twice daily in cases of allergic rhinitis. Two weeks after treatment, spirometry, FeNO and nNO measurements, blood sampling, and the ACT questionnaire were repeated. A 4-week low dose combination treatment with FP/SAL in asthmatic participants or FP alone in allergic rhinitis patients is effective in reducing FeNO (p < 0.001) and/or nNO (p < 0.001) levels and reducing the percent of eosinophils in peripheral blood. Moreover, we observed improvement in lung function and an increase in ACT scores among pediatric patients. We conclude that measurements of FeNO and nNO are helpful for assessing the effectiveness of treatment with corticosteroids, especially due to the fact that these measurements are inexpensive, fast, painless, and easier to perform than spirometry, which can be a benefit for younger children. [ABSTRACT FROM AUTHOR]

Background: In the USA, drug costs associated with the inhaled corticosteroid (ICS) and long acting β agonist (LABA) combination products have been increasing since 2001. In January 2019, the first generic ICS/LABA drug product was approved by the U.S. Food and Drug Administration. Methods: We investigated retrospectively the effects of the first approved generic ICS/LABA drug from 2019 to 2020 on the wholesale cost-savings and prescription dispensing using the IQVIA data system in the USA. Results: The marketing of the first generic for fluticasone propionate and salmeterol xinafoate dry powder inhaler was associated with $941 million in drug cost-savings during the first year for this class of medications. Although the brand-name drug manufacturer concurrently introduced its authorized generic, these cost-savings were driven by the averaged unit cost of the approved generic at $115, compared to $169 for the authorized generic and $334 for the branded product. Generic initiation and substitution with the first generic were, respectively, higher compared to those with authorized generics; however, overall dispensing of the first generic was lower than that of its branded product. As in the case of budesonide and formoterol fumarate dry powder inhaler, marketing of authorized generics alone was not associated with any noticeable change in sales or prescription cost-saving. Conclusion: We estimated that more than 20% of prescription cost-saving was achieved for the ICS/LABA dry powder inhalers in the first year following the introduction of the first approved generic, even though generic utilization remained lower than that of the branded counterpart. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this review is to discuss the development of Wixela™ Inhub™, a generic equivalent of Advair Diskus®, a fixed-dose combination of fluticasone propionate/salmeterol powder for oral inhalation for patients with asthma whose symptoms are not controlled with inhaled corticosteroids alone and for those with chronic obstructive pulmonary disease (COPD) who are at a high risk for exacerbations. Summary: We provide an overview of the Inhub device and the bioequivalence studies that have been conducted to date. Briefly, the in vitro performance, improvements in forced expiratory volume in 1 s, and the fluticasone propionate/salmeterol dose strengths for Wixela Inhub and Advair Diskus were comparable. Conclusion: The bioequivalence demonstrated by the totality of clinical and in vitro data supports the use of Wixela Inhub and provides a treatment option for patients with asthma or COPD. Plain Language Summary: The Wixela™ Inhub™ device has been developed as a generic equivalent of Advair Diskus®, and provides a combination treatment for patients with asthma whose symptoms are not controlled with inhaled corticosteroids alone and for those with chronic obstructive pulmonary disease (COPD) who are at a high risk for exacerbations. We provide information about the Inhub device and studies conducted to show how Inhub and Diskus are comparable products. Based on the similar results between the two devices, Inhub can be used as a treatment option for patients with asthma or COPD. [ABSTRACT FROM AUTHOR]

Objective: To explore the clinical effects of leukotriene modulators and salmeterol in the treatment of patients with bronchial asthma and their effects on patients with fractional exhaled nitric oxide (FeNO) and serum interleukine-10 (IL-10). ) And high-sensitive C-reactive protein (hs-CRP) levels. Methods: Sixty patients with bronchial asthma who were treated in our hospital from March 2019 to March 2020 were selected and divided into study group and control group (30 patients in each group) according to the random number table method. Patients in the control group received salmeterol treatment, and patients in the study group were treated with leukotriene modifiers on the basis of the control group. The levels of FeNO, serum IL-10, hs-CRP, and forced exhalation in the first second were compared between the two groups before and after treatment. Changes in the percentage of forced expiratory volume in predicted value (FEV 1 %), peak expiratory flow (PEF) and asthma control test (ACT) and adverse effects during treatment The occurrence of the reaction. Results: After treatment, the FeNO and serum hs-CRP levels in the study group were significantly lower than those in the control group, and the serum IL-10 levels, FEV 1 %, PEF and ACT were significantly higher than those in the control group (P<0.05). There was no significant difference in the incidence of adverse reactions between the two groups during treatment (P>0.05). Conclusion: Leukotriene modifier combined with salmeterol has a good therapeutic effect on bronchitis and asthma. It can significantly improve the inflammatory state of the patient's body, while regulating the lung function of the patient, and the treatment is safer. [ABSTRACT FROM AUTHOR]

Background: Selection of the most appropriate device for a switch from one inhaler to an equivalent product is known to have a major impact on clinical outcomes in patients with asthma or chronic obstructive pulmonary disease (COPD). Salmeterol/fluticasone propionate (S/F) Easyhaler® has been demonstrated to be therapeutically equivalent with a reference product. However, no data on real-life effectiveness are currently available for patients switching to S/F Easyhaler from another S/F inhaler. Methods: The aim of this prospective, open, multicenter, non-interventional study was to assess clinical effectiveness of propionate S/F Easyhaler in adult asthma and COPD patients switched from another inhaler. The primary endpoints were Asthma Control Test (ACT) and COPD Assessment Test (CAT). Secondary endpoints included assessments of patient satisfaction and preference and physician/nurse perception on S/F Easyhaler use. The study included three visits during a 12-week follow-up. Results: A total of 211 patients (160 with asthma; 51 with COPD) were included in the analyses. In patients with asthma, there was a statistically significant increase in the mean ACT score at week 12 (20.2 ± 3.9) compared with the baseline (18.6 ± 4.1), with a mean increase of 1.6 (±3.5) points (p < 0.0001). In patients with COPD, CAT score persisted from baseline (19.9 ± 8.6) to week 12 (19.6 ± 7.0). Patients were significantly more satisfied with Easyhaler and most patients preferred Easyhaler over their previous inhaler. The physicians/nurses reported that it was 'very easy' to teach the use of Easyhaler and the training took less than 5 minutes in most cases. Conclusion: The results from this prospective real-life clinical study indicate better or at least similar treatment control of asthma and COPD after switching to S/F Easyhaler from another S/F inhaler. This study also shows that S/F Easyhaler was favored by the patients and that it is easy to teach, learn and use in a real-life setting. The reviews of this paper are available via the supplemental material section. [ABSTRACT FROM AUTHOR]

Fixed-dose combinations (FDCs) of inhaled corticosteroids (ICS) and long-acting β 2 -adrenoceptor agonists (LABA) are considered safe and efficacious in asthma management. Most available FDCs require twice-daily dosing to achieve optimum therapeutic effect. The objective of the PALLADIUM study was to assess the efficacy and safety of once-daily FDC of mometasone furoate plus indacaterol acetate (MF–IND) versus mometasone furoate (MF) monotherapy in patients with inadequately controlled asthma. This 52-week, double-blind, triple-dummy, parallel-group, phase 3 study recruited patients from 316 centres across 24 countries. Patients aged 12 to 75 years with a documented diagnosis of asthma for at least 1 year, percentage of predicted FEV 1 of 50–85%, and an Asthma Control Questionnaire 7 score of at least 1·5 despite treatment with medium-dose or high-dose ICS or low-dose ICS plus LABA were included. A history of asthma exacerbations was not a study requirement. Participants were randomily assigned (1:1:1:1:1) via interactive response technology to receive one of the following treatments for 52 weeks: high-dose MF–IND (320 μg, 150 μg) or medium-dose MF–IND (160 μg, 150 μg) once daily via Breezhaler; high-dose MF (800 μg [400 μg twice daily]) or medium-dose MF (400 μg once daily) via Twisthaler; or high-dose fluticasone propionate–salmeterol xinafoate (FLU–SAL; 500 μg, 50 μg) twice daily via Diskus. Participants received placebo via inhalation through the Breezhaler, Twisthaler, or Diskus devices in the mornings and evenings, as appropriate. The primary endpoint was improvement in trough FEV 1 with high-dose and medium-dose MF–IND versus respective MF doses from baseline at 26 weeks, analysed in the full analysis set by means of a mixed model for repeated measures. High-dose MF–IND once daily was compared with high-dose FLU–SAL twice daily for non-inferiority on improving trough FEV 1 at week 26 with a margin of −90 mL using mixed model for repeated measures as one of the secondary endpoints. Safety was assessed in all patients who had received at least one dose of study drug. This study is registered with ClinicalTrials.gov , NCT02554786 , and is completed. Between Dec 29, 2015, and May 4, 2018, 2216 patients were randomly assigned (high-dose MF–IND, n=445; medium-dose MF–IND, n=439; high-dose MF, n=442; medium-dose MF, n=444; high-dose FLU–SAL, n=446), of which 1973 (89·0%) completed the study treatment and 234 (10·6%) prematurely discontinued study treatment. High-dose MF–IND (treatment difference [Δ] 132 mL [95% CI 88 to 176]; p<0·001) and medium-dose MF–IND (Δ 211 mL [167 to 255]; p<0·001) showed superiority in improving trough FEV 1 over corresponding MF doses from baseline at week 26. High-dose MF–IND was non-inferior to high-dose FLU–SAL in improving trough FEV 1 from baseline at week 26 (Δ 36 mL [−7 to 80]; p=0·101). Overall, the incidence of adverse events was similar across the treatment groups. Once-daily FDC of ICS and LABA (MF−IND) significantly improved lung function over ICS monotherapy (MF) at week 26; high-dose MF–IND was non-inferior to twice-daily combination of ICS and LABA (high-dose FLU–SAL) for improvement in trough FEV 1. The combination of MF–IND provides a novel once-daily dry powder option for asthma control. Novartis Pharmaceuticals. [ABSTRACT FROM AUTHOR]

Background: Wixela® Inhub® was developed to deliver inhaled fluticasone propionate/salmeterol (FP/S) combination as a substitutable generic equivalent to Advair® Diskus®. These studies aimed to confirm the pharmacokinetic bioequivalence (BE) of FP/S after single doses of Wixela Inhub (test [T]) and Advair Diskus (reference [R]). Methods: Three open-label, randomized, two-way crossover, single-dose studies in healthy subjects (N = 66 each) compared the systemic exposure of FP and salmeterol after inhalation from three dose strengths of FP/S (100/50, 250/50, or 500/50 μg) delivered from T and R. Primary BE endpoints were the area under the plasma concentration-time curve from time = 0 to the last measurable concentration (AUC(0-t)) and the maximum observed plasma concentration (Cmax) for both FP and S. The BE acceptance criteria specified that the 90% confidence intervals (CIs) of the geometric mean T/R ratios for AUC(0-t) and Cmax can be contained within 0.80–1.25 for both FP and salmeterol. Results: Wixela Inhub met the acceptance criteria for BE for FP and salmeterol at each dose strength. Estimated AUC(0-t) and Cmax geometric mean ratios (T/R [90% CI]) for FP were, respectively, 1.04 (1.00–1.08) and 0.92 (0.87–0.96) for 100/50 μg FP/S, 1.07 (1.02–1.13) and 1.01 (0.95–1.07) for 250/50 μg, and 0.97 (0.92, 1.00) and 0.90 (0.86–0.93) for 500/50 μg. Estimated AUC(0-t) and Cmax ratios for salmeterol were, respectively, 1.08 (1.04–1.11) and 1.00 (0.94–1.04) for 100/50 μg FP/S, 1.03 (0.99–1.07) and 0.93 (0.87–1.00) for 250/50 μg, and 1.00 (0.96–1.04) and 0.86 (0.81–0.91) for 500/50 μg. FP/S at all doses via both T and R was comparably well tolerated. Conclusions: Wixela Inhub was bioequivalent to Advair Diskus at all three dose strengths for both FP and S, providing direct evidence of equivalent systemic safety and indirect evidence for equivalent pulmonary deposition. [ABSTRACT FROM AUTHOR]

This article, titled "Biochemical Behaviours of Salmeterol/Fluticasone Propionate in Treating Asthma and Chronic Obstructive Pulmonary Diseases (COPD)," has been retracted by Hindawi, the publisher, due to evidence of systematic manipulation of the publication process. The investigation revealed discrepancies in scope, description of the research, availability of data, inappropriate citations, incoherent content, and compromised peer review. As a result, the reliability of the article's content is undermined. The investigation also found that certain human-subject reporting requirements were not met. Wiley and Hindawi have implemented additional measures to ensure research integrity. The corresponding author has been given the opportunity to respond to the retraction. [Extracted from the article]

Background: Asthma is widely treated using inhaled corticosteroid/long-acting beta-agonist combinations, such as fluticasone propionate/salmeterol (FPS) dry powder inhaler. Some regulators require generic medications to demonstrate local therapeutic equivalence (LTE) for each component of the FPS reference product. Fractional exhaled nitric oxide (FeNO) was developed as a possible LTE endpoint for the fluticasone propionate (FP) component of FPS in a randomized, double-blind, crossover study in steroid-naive asthma patients with elevated FeNO (≥45 parts per billion). Methods: Thirty-four patients received three of five treatments: FPS 100/50 μg once daily (QD), FPS 100/50 μg twice daily (BID), FPS 250/50 μg BID, FPS 500/50 μg BID, or placebo, each for 2 weeks separated by 14-day washout. FeNO was measured on days 1, 2, 3, 5, 7, and 14 of each period, according to American Thoracic Society standards. Results: FPS treatments decreased FeNO compared with placebo, with the largest differentiation between doses noted on day 14; the mean decreases from days 1 to 14 ranged from −46.6% to −64.5% with FPS versus −9.1% with placebo. The dose–response plateaued at 200 μg/day (FPS 100/50 μg BID). Linear regression analysis revealed significant slopes between FPS doses, with the steepest between 100/50 μg QD and 100/50 μg BID (−0.0039, p = 0.020). An estimated sample size (SS) of 160 or 48 patients would be required to demonstrate LTE of generic and FPS reference products (0.80–1.25 and 0.67–1.50 bioequivalence limits, respectively). However, as the slope between BID FPS doses was shallow, a larger SS may be needed if only an approved dose regimen was used. Conclusion: FeNO could be a valid endpoint to determine LTE between the FP component of generic and reference FPS products, but only if QD dosing and wide equivalence limits are included. As QD dosing is not an approved regimen, this approach is unlikely to be acceptable. [ABSTRACT FROM AUTHOR]

Background: Morbidity from asthma is disproportionately higher among black patients than among white patients, and black patients constitute the minority of participants in trials informing treatment. Data indicate that patients with inadequately controlled asthma benefit more from addition of a long-acting beta-agonist (LABA) than from increased glucocorticoids; however, these data may not be informative for treatment in black patients.Methods: We conducted two prospective, randomized, double-blind trials: one involving children and the other involving adolescents and adults. In both trials, the patients had at least one grandparent who identified as black and had asthma that was inadequately controlled with low-dose inhaled glucocorticoids. We compared combinations of therapy, which included the addition of a LABA (salmeterol) to an inhaled glucocorticoid (fluticasone propionate), a step-up to double to quintuple the dose of fluticasone, or both. The treatments were compared with the use of a composite measure that evaluated asthma exacerbations, asthma-control days, and lung function; data were stratified according to genotypic African ancestry.Results: When quintupling the dose of fluticasone (to 250 μg twice a day) was compared with adding salmeterol (50 μg twice a day) and doubling the fluticasone (to 100 μg twice a day), a superior response occurred in 46% of the children with quintupling the fluticasone and in 46% of the children with doubling the fluticasone and adding salmeterol (P = 0.99). In contrast, more adolescents and adults had a superior response to added salmeterol than to an increase in fluticasone (salmeterol-low-dose fluticasone vs. medium-dose fluticasone, 49% vs. 28% [P = 0.003]; salmeterol-medium-dose fluticasone vs. high-dose fluticasone, 49% vs. 31% [P = 0.02]). Neither the degree of African ancestry nor baseline biomarkers predicted a superior response to specific treatments. The increased dose of inhaled glucocorticoids was associated with a decrease in the ratio of urinary cortisol to creatinine in children younger than 8 years of age.Conclusions: In contrast to black adolescents and adults, almost half the black children with poorly controlled asthma had a superior response to an increase in the dose of an inhaled glucocorticoid and almost half had a superior response to the addition of a LABA. (Funded by the National Heart, Lung, and Blood Institute; BARD ClinicalTrials.gov number, NCT01967173.). [ABSTRACT FROM AUTHOR]

• 9g and (R) -18c exhibited the most potent and higher selective in the series for β 2 -adrenoceptor activation. • 9g and (R) -18c showed the rapid onset time for 2.3 min and 1.9 min, respectively. • The duration of action of 9g and (R)-18c were more than 12 h. • 9g and (R)-18c were worthy of further investigation as lead compounds for the development of β 2 -adrenoceptor agonists. A series of novel β 2 -adrenoceptor agonists with a 5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1 H)-one moiety was designed, synthesized and evaluated for biological activity in human embryonic kidney 293 cells and isolated guinea pig trachea. Compounds 9g and (R)-18c exhibited the most excellent β 2 -adrenoceptor agonistic effects and high β 2 /β 1 -selectivity with EC 50 values of 36 pM for 9g and 21 pM for (R)-18c. They produced potent airway smooth muscle relaxant effects with fast onset of action and long duration of action in an in vitro guinea pig trachea model of bronchodilation. These results support further development of the two compounds into drug candidates. [ABSTRACT FROM AUTHOR]