Single Inhaler Device Research Articles

Triple inhaled therapy for asthma in Canada

A significant number of patients with asthma have poor control on their current inhaled therapies, typically a combination of inhaled corticosteroids (ICS) and long-acting beta-2 adrenergic bronchodilators (LABA). Adding a long-acting antimuscarinic agent (LAMA) has been shown to improve asthma control and the availability of triple therapy formulations (ICS/LABA/LAMA) in a single inhaler device or single inhaler triple therapy (SITT) mitigates the adherence concerns associated with use of multiple inhaler devices. Here, we provide an overview of the pivotal data concerning the use of triple asthma therapy in patients with poor control on ICS-LABA treatment, and present our expert approach to their application in the routine clinical management of such patients as well the appropriate sequencing of initiating triple therapy and seeking a referral for consideration of more advanced therapies.

Open and Closed Triple Inhaler Therapy in Patients with Uncontrolled Asthma.

Long-acting muscarinic antagonists (LAMAs) are a class of inhalers that has recently been included as add-on therapy in the GINA guidelines, either in a single inhaler device with inhaled corticosteroids plus long-acting β2-agonists (ICS + LABA) (closed triple inhaler therapy) or in a separate one (open triple inhaler therapy). This review summarizes the existing evidence on the addition of LAMAs in patients with persistently uncontrolled asthma despite ICS + LABA treatment based on clinical efficacy in the reduction of asthma symptoms and exacerbations, the improvement in lung function, and its safety profile.

Asthma-related hospitalizations after implementing SABA-free asthma management with a maintenance and anti-inflammatory reliever regimen

ABSTRACT Overreliance on short-acting β2-agonists (SABA) has been a common feature of asthma management globally for at least 30 years. However, given the evidence against the long-term use of SABA, including potentially increased risk of exacerbations, emergency room visits, overall healthcare resource utilization, and mortality, the latest Global Initiative for Asthma report no longer recommends SABA only therapy. Since 2014, we implemented an ICS-containing reliever strategy at our asthma center at the G Baigorria Hospital in Argentina; we only administered budesonide/formoterol via a single inhaler device across the spectrum of asthma severity and completely eliminated the use of SABA therapy. In this article, we compare hospitalization data from our center, previously reported in the EAGLE study (when inhaled corticosteroids plus as-needed SABA was administered) for the years 1999 and 2004 with data from 2017 to 2018 (when budesonide/formoterol in a single inhaler device was administered as maintenance and/or anti-inflammatory reliever therapy [MART/AIR] without any SABA) from our center, to assess the impact of two distinct asthma management strategies on asthma-related hospitalizations. MART/AIR regimens in our SABA-free center reduced asthma hospitalizations from 9 (1999 and 2004) to 1 (2017 and 2018) (Fisher’s exact test, p = 0.031; odds ratio = 0.11; 95% confidence interval [CI] = 0.013–0.98); the hospitalization rate was reduced by 92% (1.47% in 1999 and 2004 to 0.12% in 2017 and 2018). Our data provide preliminary real-world evidence that MART/AIR with budesonide/formoterol simultaneously with SABA elimination across asthma severities is an effective asthma management strategy for reducing asthma-related hospitalizations.

The Impact of 52-Week Single Inhaler Device Triple Therapy versus Dual Therapy on the Mortality of COPD Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

There are more single inhaler device triple therapy available for COPD patients now. However, the effect of long-term triple therapy fixed dose combination (FDC) on mortality remains unclear. This study aimed to evaluate the impact of one-year single inhaler device triple therapy, including long-acting β2-agonists (LABAs), long-acting muscarinic receptor antagonists (LAMAs), and inhaled corticosteroids (ICSs), with dual therapies, comprised of either LABA/LAMA or ICS/LABA, on the mortality of patients with COPD. We searched the PubMed, Cochrane library, Web of Science, Embase databases, and clinical trial registry of clinicaltrials.gov and WHO ICTRP. Randomized controlled trials (RCTs) compared single inhaler device triple and dual therapies for 52 weeks were selected for the meta-analysis. The primary endpoint was all-cause mortality. A total of 6 RCTs were selected for the meta-analysis, including 10,274 patients who received single inhaler device triple therapy (ICS/LABA/LAMA FDC) and 12,395 patients who received ICS/LABA or LABA/LAMA dual therapy. Risk of death was significantly lower in the ICS/LABA/LAMA FDC group compared to the LABA/LAMA group (RR = 0.69, 95% CI = 0.53–0.90, p = 0.007). There was no significant difference in mortality between the ICS/LABA/LAMA FDC and ICS/LABA therapy groups (RR = 0.94, 95% CI = 0.72–1.24, p = 0.66). In addition, patients receiving ICS/LABA/LAMA FDC therapy had less moderate or severe exacerbations compared with the dual therapy groups (RR = 0.76, 95% CI = 0.73–0.80, p < 0.001 for LABA/LAMA; RR = 0.84, 95% CI = 0.78–0.90, p < 0.001 for ICS/LABA). By contrast, the risk of pneumonia in the ICS/LABA/LAMA FDC group was higher than in the LABA/LAMA group (RR = 1.43, 95% CI = 1.21–1.68, p < 0.001). In conclusion, ICS/LABA/LAMA FDC therapy could help improve the clinical outcomes of patients with COPD. However, triple therapy could increase the risk of pneumonia in comparison with LABA/LAMA dual therapy.

Single inhaler triple therapy (SITT) in asthma: Systematic review and practice implications.

A significant number of patients with asthma remain uncontrolled despite treatment with inhaled corticosteroids (ICS) and long‐acting β2 adrenergic bronchodilators (LABA). The addition of long‐acting antimuscarinic agents (LAMA) can improve the management of asthma in these patients. Recently, three novel triple therapy (ICS/LABA/LAMA) formulations in a single‐inhaler device (SITT) have been investigated in patients with uncontrolled asthma despite ICS/LABA treatment. Here, we review systematically the evidence available to date in relation to SITT in patients with uncontrolled asthma despite ICS‐LABA treatment and conclude that SITT is a safe and effective therapeutic alternative in these patients. We also discuss how to position this new therapeutic alternative in their practical clinical management as well as the opportunities and challenges that it may generate for patients, physicians, and payers.

Comparative efficacy of single-inhaler triple therapies for COPD: A protocol for systematic review and network meta-analysis.

Introduction2021 Global Initiative for Chronic Obstructive Lung Disease (GOLD) Reports recommends that patients with clinically significant symptoms and exacerbations of chronic obstructive pulmonary disease (COPD) should escalate to triple therapy, a combined use of inhaled corticosteroids (ICS), long-acting muscarinic antagonists (LAMA) and long-acting b2-agonists (LABA)(ICS/LAMA/LABA). Triple therapy in fixed-dose combinations (FDCs), i.e., combining ICS, LABA with LAMA and administrating by a single inhalation device, has appeared in recent years. This study aims to compare the efficacy of triple therapy in FDCs in treating patients with moderate to severe COPD.Methods and analysesLiterature search will be conducted on PubMed, Embase and Web of science, according to pre-specified and corresponding search strategies, for relevant reports published since the inception dates of the databases. Randomised controlled trials (RCT) which compared the triple therapy in FDCs with other pharmacological therapies will be included. The Cochrane risk of bias assessment tool (RoB 2) will be used to assess the RCT quality. The outcomes will be analyzed as rate ratios and mean differences under a random-effects model in a frequentist network meta-analysis (NMA). Additional statistical analyses including subgroup analysis, sensitivity analysis, and publication bias analysis will be performed to assess the evidential heterogeneity and robustness. The strength of evidence from the NMA will be evaluated with the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) methods.Ethics and disseminationNo ethics approval is required as this systematic review and network meta-analysis do not collect confidential personal data and do not carry out interventions in treating patients.Protocol registration numberCRD42021240823.

Triple Therapy of Fluticasone Furoate, Umeclidinium, Vilanterol- A Compelling Choice in Severe Chronic Obstructive Pulmonary Disease

Trelegy Ellipta (GlaxoSmithKlineTM) is the first single inhaler triple combination therapy comprising of umeclidinium, vilanterol and fluticasone approved by the United States Food and Drug Administration (US FDA) for patients with severe COPD in 2019. Clinical trials comparing this triple combination with dual therapy including a Long Acting β2-Agonist/Long Acting Muscarinic Antagonist (LABA/LAMA) or Long Acting β2-Agonist/Inhaled Corticosteroids (LABA/ICS) were evaluated. Triple combination did show improvement through the mean Forced Expiratory Volume per second (FEV1), St. George questionnaire, and reduced hospitalisation due to acute exacerbation of COPD. This medication should be prescribed cautiously for certain populations. Although this triple combination is used only in patients with the most advanced forms of disease who have frequent exacerbations and remain uncontrolled, there are certain additional indications that may be explored in future trials. The convenience associated with using a single device for three different classes of drugs could be its biggest trump card and it will not be surprising to see its preference among patients avoiding the need for multiple dosing. Nevertheless, it remains to be seen if this improved adherence would translate into improved outcomes such as reduced mortality in real world practice among patients with severe COPD. The availability of a single inhaler device for delivering a triple combination of LABA/LAMA/ICS is a small success story in the quest to identify better therapies for patients with severe COPD, who are so prone to repeat acute exacerbations which could eventually turn fatal.

Olodaterol for the treatment of chronic obstructive pulmonary disease: a narrative review

ABSTRACTIntroduction: Inhaled bronchodilators are the key-stone of chronic obstructive pulmonary disease (COPD) management. Olodaterol 5 µg, a long-acting β2-adrenoceptor agonist (LABA) is one such bronchodilator indicated as a once-daily maintenance therapy.Areas covered: This article reviews the several trials that have assessed olodaterol as a COPD therapy. It covers safety and tolerability data and provides the reader with an expert opinion on its use as a treatment for COPD.Expert opinion: Olodaterol improves lung function for 24 h and reduces rescue medication use. It may also improve dyspnea, exercise tolerance, and health-related quality of life. It is well tolerated with an acceptable cardiovascular and respiratory adverse event profile. There is some evidence that olodaterol, as well as other LABAs, can reduce exacerbation frequency, but not FEV1 decline and death.LABAs alone are indicated in group A/B COPD subjects. Olodaterol and indacaterol are administered once-daily and may offer an adherence advantage over other LABAs with more frequent dosing schedules. Co-administration of an olodaterol/tiotropium fixed dose combination in a single inhaler device is recommended as step-up in group A/B COPD subjects not sufficiently treated by olodaterol alone or as initial therapy in those with severe exertional dyspnea.

Drug Interactions With Oral Inhaled Medications.

Objective: To evaluate the potential for drug interactions with oral inhaled medications (OIMs). OIMs include bronchodilators (β-agonists and antimuscarinics), corticosteroids, combination products (2 or more agents combined within a single inhalation device), antibiotics, prostacyclins, anesthetics, acetylcysteine, mucolytics, insulin, antivirals, nitric oxide, and nicotine replacement. Data Sources: A systemic literature search (1980 to May 2018) was performed using PubMed and EBSCO to locate relevant articles. The MESH terms used included each specific medication available as an OIM as well as "drug interactions." DAILYMED was used for product-specific drug interactions. Study Selection and Data Extraction: The search was conducted to identify drug interactions with OIMs. The search was limited to those articles studying human applications with OIMs and publications using the English language. Case reports, clinical trials, review articles, treatment guidelines, and package labeling were selected for inclusion. Data Synthesis: Primary literature and package labeling indicate that OIMs are subject to pharmacokinetic and pharmacodynamics interactions. The most frequently identified clinically significant drug interaction is an inhaled corticosteroid when combined with a potent CYP 450 inhibitor such as a protease inhibitor or antifungal. Conclusions: The available literature indicates that OIMs are associated with clinically significant drug interactions and subsequent adverse reactions. Clinicians in all practice settings should be mindful of this potential to minimize adverse effects and optimize therapy.

GFF MDI for the improvement of lung function in COPD – A look at the PINNACLE-1 and PINNACLE-2 data and beyond

ABSTRACTIntroduction: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally and incidence rates are continuing to rise. Long-acting bronchodilators are the foundation on which current pharmacological approaches to COPD management are built, with long-acting muscarinic antagonists (LAMAs) and long-acting β2-agonists (LABAs) recommended across the spectrum of the disease continuum. Combining LAMAs and LABAs provides additional lung function improvements and relief of patient symptoms compared with either therapy alone. Several options for LAMA/LABA fixed-dose combinations (FDC) delivered via a single inhaler device are available; however, only recently has a LAMA/LABA FDC become available as a pressurized metered dose inhaler (MDI).Areas covered: This article describes the rationale for the development of the LAMA/LABA FDC of glycopyrrolate and formoterol fumarate, formulated by Co-Suspension™ Delivery Technology and delivered by MDI (GFF MDI). The clinical trial program of GFF MDI, including the pivotal Phase III studies (PINNACLE-1 and PINNACLE-2) that supported regulatory approval, are reviewed, providing insights into interpretation and future directions for research.Expert commentary: LAMA/LABA FDCs are already a crucial part of the COPD treatment paradigm, but additional data are needed in order to maximize their role as maintenance therapies in patients with COPD.

The in vivo efficacy and side effect pharmacology of GS-5759, a novel bifunctional phosphodiesterase 4 inhibitor and long-acting β 2-adrenoceptor agonist in preclinical animal species.

Bronchodilators are a central therapy for symptom relief in respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma, with inhaled β2-adrenoceptor agonists and anticholinergics being the primary treatments available. The present studies evaluated the in vivo pharmacology of (R)-6-[[3-[[4-[5-[[2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino]pent-1-ynyl]phenyl]carbamoyl]phenyl]sulfonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide (GS-5759), a novel bifunctional compound with both phosphodiesterase 4 (PDE4) inhibitor and long-acting β2-adrenoceptor agonist (LABA) activity, which has been optimized for inhalation delivery. GS-5759 dose-dependently inhibited pulmonary neutrophilia in a lipopolysaccharide (LPS) aerosol challenge model of inflammation in rats with an ED50 ≤ 10 μg/kg. GS-5759 was also a potent bronchodilator with an ED50 of 0.09 μg/kg in guinea pigs and 3.4 μg/kg in dogs after methylcholine (MCh) and ragweed challenges respectively. In cynomolgus monkeys, GS-5759 was dosed as a fine-particle dry powder and was efficacious in the same dose range in both MCh and LPS challenge models, with an ED50 = 70 μg/kg for bronchodilation and ED50 = 4.9 μg/kg for inhibition of LPS-induced pulmonary neutrophilia. In models to determine therapeutic index (T.I.), efficacy for bronchodilation was evaluated against increased heart rate and GS-5759 had a T.I. of 700 in guinea pigs and >31 in dogs. In a ferret model of emesis, no emesis was seen at doses several orders of magnitude greater than the ED50 observed in the rat LPS inflammation model. GS-5759 is a bifunctional molecule developed for the treatment of COPD, which has both bronchodilator and anti-inflammatory activity and has the potential for combination as a triple therapy with a second compound, within a single inhalation device.

Fluticasone propionate-salmeterol versus inhaled corticosteroids plus montelukast: outcomes study in pediatric patients with asthma

BackgroundThe purpose of this study (GSK ADA111194) was to compare asthma-related health care utilization and costs associated with fluticasone propionate (an inhaled corticosteroid [ICS]) and salmeterol (a long-acting beta-agonist) in a single inhalation device (fluticasone propionate-salmeterol) versus the combination of ICS + montelukast in the treatment of pediatric patients with asthma.MethodsThis was a retrospective, observational cohort study using a large health insurance claims database spanning January 1, 2000 to January 31, 2008. The target population was patients aged 4–11 years with at least one pharmacy claim for fluticasone propionate-salmeterol, any ICS, or montelukast during the study period. The date of first claim for the medication of interest was deemed the index date. Patients were required to be continuously eligible to receive health care services one year prior to and 30 days after the index date, and have at least one claim with an ICD-9-CM code for asthma (493.xx) in the one-year pre-index period. Patients with prescriptions for fluticasone propionate-salmeterol, ICS + montelukast, or long-acting beta-agonists during the pre-index period were excluded. Patients were matched on a 1:1 basis according to three variables, ie, pre-index use of oral corticosteroids, ICS, and presence of pre-index respiratory-related hospitalizations/emergency department visits. The risk of asthma-related hospitalization, combined hospitalization/emergency department visit, and monthly asthma-related costs were assessed using multivariate methods.ResultsOf the 3001 patients identified, 2231 patients were on fluticasone propionate-salmeterol and 770 were on ICS + montelukast. After matching, there were 747 pairs of fluticasone propionate-salmeterol and ICS + montelukast patients, which were well matched for baseline characteristics. Patients who started fluticasone propionate-salmeterol compared with patients on ICS + montelukast had a significantly (P < 0.02) lower rate of asthma-related hospitalizations (0.3% versus 3.5%) and asthma-related hospitalizations/emergency department visits (3.5% versus 5.7%). After controlling for baseline and patient characteristics, fluticasone propionate-salmeterol users were associated with a significantly lower risk of an asthma-related hospitalization (adjusted hazard ratio 0.039; 95% confidence interval 0.004–0.408) or hospitalization/emergency department visit (hazard ratio 0.441; 95% confidence interval 0.225–0.864), and $151 (95% confidence interval 67–346) lower asthma-related monthly costs compared with ICS + montelukast.ConclusionIn patients aged 4–11 years with asthma, use of fluticasone propionate-salmeterol was associated with lower asthma-related health care utilization and costs compared with use of ICS + montelukast.

Combination Therapy in Asthma: A Review

Asthma can be defined as a chronic inflammatory disease of the airways that is reversible either spontaneously or by treatment. Despite the exponential increase in asthma research, the prevalence of asthma is on the increase, especially in children and young adults in the western societies. Inhaled therapies are the mainstay of asthma management. This is often in the form of combined therapy using two drugs in a single device to ensure adjustable maintenance dosing. Relevant literature was reviewed using available medical journals, MEDLINE, Pubmed and Science direct via the Internet. The key words employed were: asthma, combination therapy, long acting beta agonists and corticosteroids. British Thoracic Society and The National Heart, Lung and Blood Institute websites were also used in sourcing information. Several studies have shown that combination therapy using long acting beta agonists (LABA) and inhaled corticosteroids (ICS) in a single inhaler device confers complementary and synergistic effect in the management of asthma. It further improves patient compliance and reduces the complexity of treatment and morbidity associated with the disease. Recent studies have shown the combination therapy to serve not only as maintenance but also a reliever therapy with same efficacy as the short acting beta agonists (SABA). This review was able to show the advantages of using combination therapy in asthma patients. This has been a subject of review at both national and international levels as there is no single medication that is effective against both the inflammatory and bronchoconstrictive components of this disorder. Recent studies have shown that Budesonide/formoterol in a single inhaler has been found to be effective maintenance and reliever agent in both adults and children. It has also been found to be safe and more efficacious than fixed-dosing. In addition to convenience and patient compliance, combination devices also help towards individualized approach to asthma management and reduce the complexity of treatment; this appears ideal for adoption by the primary care physician with a view for the patient to effectively achieve control of his own condition.

Using a single inhaler device containing an inhaled corticosteroid plus a long-acting ??-adrenoceptor agonist is a practical approach in patients with moderate to severe asthma

Using a single inhaler device containing an inhaled corticosteroid plus a long-acting ??-adrenoceptor agonist is a practical approach in patients with moderate to severe asthma

Combination Therapy for Asthma

As treatment for moderate to severe persistent asthma, inhaled corticosteroid drugs combined with long-acting β-adrenoceptor agonists are being marketed in a single inhaler device. These combination products have important benefits (e.g. convenience, improved adherence, and improved day-to-day asthma symptom control); however, there are also problems (e.g. risk of severe asthma flares associated with long-acting β-adrenoceptor agonist therapy, high price of combination inhalers, and limited ability to titrate the dose of each component independently). Combination therapy is most likely to benefit patients with moderate to severe persistent asthma whose disease is not controlled on inhaled corticosteroids alone. Some patients may prefer this combination product to inhaled corticosteroids plus a leukotriene modifier or theophylline. For other patients with moderate to severe persistent asthma, inhaled corticosteroid adherence may be improved by use of the combination product. Combination long-acting β-adrenoceptor agonist/inhaled corticosteroid therapy is not appropriate for patients with predominantly exercise-induced asthma, patients unable to use the inhaler device, patients with either mild intermittent or mild persistent asthma, and patients whose asthma can be controlled on a low to moderate dose of inhaled corticosteroid medication alone.

Improving quality of life in asthmatic children

To assess quality of life changes in pediatric asthmatic patients switched into a single inhaler device of Budesonide/Formoterol. Thirty pediatric patients (ages 6-15 years) with moderate to severe chronic asthma previously treated with inhaled beclometasone dipropionate at a daily dose of 400 g were selected to participate in an open label study. At the baseline- phase (one month), pulmonary function tests (PFTs), indicators of asthma control, and a quality of life assessment (using a special questionnaire) were evaluated. Patients were initiated on a single inhaler device containing budesonide 160 g/formoterol 4.5 microg, one inhalation twice daily instead of their previous inhaled corticosteroid and followed for two months. PFTs, indicators of asthma control, and a quality of life assessment were evaluated at each visit. After switching to the new therapy, patients showed significant changes towards better quality of life in all aspects. The overall score dropped from 1.75+/- 0.04 to 0.80 +/- 0.07 (mean +/- SEM), p< 0.001 (Score scale varies between 0: excellent to 2: very bad Health related quality of life). There was an improvement in the PFTs, where the FEV1% improved from 62.7+/- 2.8 to 87.4 +/- 4.6 (mean +/- SEM), and the FVC% improved from 83.2 +/- 3.5 to 101.9 +/- 5.3 (mean +/-SEM), p < 0.001, and better control of asthma. Switching treatment from beclomethasone dipropionate to budesonide/formoterol combination appeared to improve quality of life in the patient population evaluated and in the appropriate clinical indices.

Bronchodilator effect of an inhaled combination therapy with salmeterol + fluticasone and formoterol + budesonide in patients with COPD

In the present trial, we compared the broncholytic efficacy of the combination therapy with 50 μg salmeterol + 250 μg fluticasone and 12 μg formoterol + 400 μg budesonide, both in a single inhaler device, in 16 patients with moderate-to-severe COPD. The study was performed using a single-blind crossover randomized study. Lung function, pulse oximetry ( S pO 2) and heart rate were monitored before and 15, 30, 60, 120, 180, 240, 300, 360, 480, 600, and 720 min after bronchodilator inhalation. Both combinations were effective in reducing airflow obstruction. FEV 1 AUC 0–12 H was 2.83 l (95% ci: 2.13–3.54) after salmeterol/fluticasone and 2.57 l (95% ci: 1.97–3.2) after formoterol/budesonide. Formoterol/budesonide elicited the mean maximum improvement in FEV 1 above baseline after 120 min (0.29 l; 95% ci: 0.21–0.37) and salmeterol/fluticasone after 300 min (0.32 l; 95% ci: 0.23–0.41). At 720 min, the increase in FEV 1 over baseline values was 0.10 l (95% ci: 0.07–0.12) after salmeterol/fluticasone and 0.10 l (95% ci: 0.07–0.13) after formoterol/budesonide. The mean peak increase in heart rate occurred 300 min after formoterol/budesonide (1.5 b/min; 95% ci —2.3 to 5.3) and 360 min after salmeterol/fluticasone (2.6 b/min; 95% ci —1.9 to 7.0). S p0 2 did not change. All differences between salmeterol/fluticasone and formoterol/budesonide were not significant ( P>0.05) except those in FEV 1 at 120 and 360 min. The results indicate that an inhaled combination therapy with a long-acting β 2-agonist and an inhaled corticosteroid appears to be effective in improving airway limitation after acute administration in patients suffering from COPD.