Fixed-dose Combination Inhalers Research Articles

Plackett–Burman and face-centered composite designs for development and optimization of chromatographic method for the simultaneous determination of glycopyrronium, indacaterol and mometasone in their fixed dose combination inhaler – Green profile assessment

A novel simple, specific, sensitive, accurate and precise reversed phase high performance liquid chromatographic method (RP-HPLC/UV) was developed and validated for the simultaneous estimation of Glycopyrronium bromide (GLY), Indacaterol acetate (IND) and Mometasone furoate (MOF) in pure form, in laboratory prepared mixtures and in pharmaceutical dosage form. Experimental design methodology was applied by using Plackett–Burman and face-centered composite designs to achieve the best resolution with minimum experimental trials. The designed model was statistically analyzed, graphically presented by surface plots and the relationships between coefficients of the derived polynomial equations were interpreted. Chromatographic separation was achieved on Inertsil ODS C18 column (250 ×4.6 mm, 5 µm) at ambient temperature using a mobile phase composed of methanol: 0.1% glacial acetic acid (pH4) in a gradient elution at a flow rate 1 mL /min. UV detection was carried out at 233 nm. Response was found to be linear in the concentration range of 20–120 µg /mL with regression coefficient (r2 = 0.999) for GLY, 50–300 µg /mL with regression coefficient (r2 = 0.9995) for IND and 50–300 µg /mL with regression coefficient (r2 = 0.9998) for MOF. The method was validated as per ICH guidelines and satisfactory results were achieved. The method was successfully applied for the analysis of the cited drugs in their fixed dose combination (FDC) pharmaceutical formulation. Statistical comparison between the results obtained by the proposed method and the reference methods for GLY, IND and MOF showed no significant difference. The developed method could be implemented in quality control aspects of the cited drugs. Four green metrics were used to evaluate the new RP-HPLC/UV method's greenness and compare it to other published techniques.

Prescription Patterns of New Use of Fixed-Dose Combination Inhalers in Patients with Chronic Obstructive Pulmonary Disease: Long-Acting β2 Agonists Plus Long-Acting Muscarinic Antagonists versus Long-Acting β2 Agonists Plus Inhaled Corticosteroids.

The clinical guideline recommends use of long-acting β2 agonists/long-acting muscarinic antagonists (LABA/LAMA) or long-acting β2 agonists/inhaled corticosteroids (LABA/ICS) combination therapies for patients with severe chronic obstructive pulmonary disease (COPD). The fixed-dose combination (FDC) inhalers of LABA/LAMA and LABA/ICS were reimbursed in Taiwan in 2015 and in 2002, respectively. This study aimed to examine prescription patterns of new use of either FDC therapy in real-world practice. We identified COPD patients who initiated LABA/LAMA FDC or LABA/ICS FDC between 2015 and 2018 from a population-based Taiwanese database with 2 million, randomly sampled beneficiaries enrolled in a single-payer health insurance system. We compared number of LABA/LAMA FDC and LABA/ICS FDC initiators in each calendar year, from different hospital accreditation levels, and cared for by different physician specialties. We also compared baseline patient characteristics between LABA/LAMA FDC and LABA/ICS FDC initiators. A total of 12,455 COPD patients who initiated LABA/LAMA FDC (n=4019) or LABA/ICS FDC (n=8436) were included. Number of LABA/LAMA FDC initiators increased apparently (n=336 in 2015 versus n=1436 in 2018), but number of LABA/ICS FDC initiators decreased obviously (n=2416 in 2015 versus n=1793 in 2018) over time. The preference of use of LABA/LAMA FDC varied across clinical environments. The proportions of LABA/LAMA FDC initiators were more than 30% in the setting of non-primary care clinics (eg, medical centers) and in the services of chest physicians; but were only less than 10% in primary care clinics and non-chest physicians' services (eg, family medicine physicians). LABA/LAMA FDC initiators appeared to be older, male, to have more comorbidities, and to utilize resources more frequently compared to LABA/ICS FDC initiators. This real-world study found evident temporal trends, variations in healthcare provider, and differences in patient characteristics among COPD patients who initiated LABA/LAMA FDC or LABA/ICS FDC.

Interclass Difference in Pneumonia Risk in COPD Patients Initiating Fixed Dose Inhaled Treatment Containing Extrafine Particle Beclometasone versus Fine Particle Fluticasone.

BackgroundInhaled corticosteroids (ICS) afford therapeutic benefits in some COPD patients, but their widespread use is cautioned due to an increased risk of developing pneumonia. Subclass variations exist, and the risk profile differs for individual ICS. Formulation particle size has been identified as a potential effect modifier. The present study compared the risk of pneumonia among new COPD users of fixed-dose combination inhalers containing fine-particle fluticasone (fp-FDC-F) versus extrafine particle beclometasone (ef-FDC-BDP).MethodsA propensity matched historical cohort study was conducted using data from the Optimum Patient Care Research Database. COPD patients aged ≥40 years with ≥1 year of continuous medical data who initiated fp-FDC-F or ef-FDC-BDP were compared. The primary outcome was time to pneumonia event, as treated, using either sensitive (physician diagnosed) or specific (physician diagnosed and x-ray or hospital admission confirmed) definitions.ResultsA total of 13,316 patients were matched. Initiation of fp-FDC-F (mean dosage furoate 99 µg; propionate 710 µg) was associated with an increased risk of pneumonia versus ef-FDC-BDP (mean beclometasone dose 395 µg), irrespective of definition (sensitive HR 1.38 95% CI 1.14–1.68; specific HR 1.31 95% CI 1.05–1.62).ConclusionIn the current investigation, we found that in comparison to extrafine beclomethasone, commencing a formulation containing fluticasone is associated with an increased risk of developing pneumonia. These observations support the idea that not all ICS are equal in their adverse effects and subclass variations exist and should be carefully considered in the treatment choice.

Combination fixed-dose β agonist and steroid inhaler as required for adults or children with mild asthma: a Cochrane systematic review

BackgroundIn people with mild asthma poor adherence to regular therapy is common and increases the risk of exacerbations, morbidity and mortality. The use of fixed-dose combination inhalers containing an inhaled...

Novel pharmacological therapies for the treatment of bronchial asthma.

Asthma has long been recognized as a chronic inflammatory disease of the airways, often in response to inhaled allergens prompting inappropriate activation of the immune response involving a range of cells including mast cells, Th2 lymphocytes and eosinophils alongside a wide range of inflammatory mediators. First-line therapy for treatment of persistent asthma involves the use of inhaled corticosteroids (ICS) in combination with inhaled β<inf>2</inf>-agonists enabling both the control of the underlying airways inflammation and a reduction of airway hyperresponsiveness. However, many patients remain symptomatic despite high-dose therapy. Therefore, there is a continued unmet clinical need to develop specifically new anti-inflammatory therapies for patients with asthma, either as an add-on therapy to ICS or as replacement monotherapies. The success of fixed dose combination inhalers containing both a bronchodilator and an anti-inflammatory drug has also led to the development of "bifunctional" drugs which are molecules specifically designed to have two distinct pharmacological actions based on distinct pharmacophores. In this review we will discuss these different pharmacological approaches under development for the treatment of bronchial asthma and the available preclinical and clinical data.

Combination fixed-dose beta agonist and steroid inhaler as required for adults or children with mild asthma.

Combination fixed-dose beta agonist and steroid inhaler as required for adults or children with mild asthma.

OP86 Exploring Public Utilization Data For Primary Care Education Programs

IntroductionNPS MedicineWise delivers nationwide educational programs to improve quality use of medicines and medical tests in Australia. Targeted horizon scanning approaches are required to detect and address emerging challenges in the healthcare landscape such as overutilization and unexpectedly high expenditure on medicines and medical tests. Publicly available utilization and expenditure data from the Australian Pharmaceutical Benefits Scheme (PBS) and Medicare Benefits Schedule (MBS) may provide insights into identifying potential areas for intervention.MethodsFive financial years (2013-18) of publicly available PBS/MBS data was extracted from Australian Government websites and clustered according to medicine class, disease groups or anatomical therapeutic chemical classification (ATC). Usage and expenditure trends were explored with signals of potential inappropriate use identified as unusual spikes or changes.ResultsPBS data showed two fixed dose combination inhalers for respiratory conditions, three direct oral anticoagulants, four analgesics (including opioids) and two blood glucose lowering agents had high volume and expenditure growths in the 2016-17 financial year. Cholesterol-reducing medicines and anti-hypertensives also commonly had high utilisation growth. The highest growth classified by ATC level two codes were for urologicals. These signals were collated into themes of stroke prevention, cardiovascular, respiratory, pain management and type two diabetes. MBS data on pathology tests showed viral and bacterial testing had the highest growth, followed by vitamin B12 testing and vitamin D testing. Magnetic resonance imaging had the highest growth in expenditure and volume of services of the various imaging modalities and X-ray of the lower leg had the highest volume of services.ConclusionsSeveral medicines and medical tests were detected as possible targets for interventions based on high volume or expenditure growth. Themes identified from the data can then be further investigated and contextualized to inform topic areas for primary care education to support quality use of medicines and medical tests.

Real-world effectiveness evaluation of budesonide/formoterol Spiromax for the management of asthma and chronic obstructive pulmonary disease in the UK

ObjectivesBudesonide/formoterol (BF) Spiromax® is an inhaled corticosteroid/long-acting β2-agonist fixed-dose combination (FDC) inhaler, designed to minimise common inhaler errors and provide reliable and consistent dose delivery in asthma and chronic obstructive...

Inhaled Triple Therapy in Severe Chronic Obstructive Pulmonary Disease (COPD)

COPD (chronic obstructive pulmonary disease) is characterised by persistent airflow obstruction caused by exposure to irritants including cigarette smoke dust, and fumes. Long-acting beta-agonist (LABA) and long-acting muscarinic antagonist (LAMA) in fixed-dose combination inhalers are the pillars of modern COPD therapy. LABA/inhaled corticosteroids (ICS) inhalers have been proved to be particularly efficient in patients with ≥ 2 exacerbations per year. Until recently, although recommended in guidelines for severe and unstable COPD patients, the clinical usefulness of the LABA/LAMA/ICS combination was a matter of debate. Recent trials with fixed-dose combination inhalers containing fluticasonfuroate/vilanterol/umeclidinium or beclometasone/formoterol/glycopyrronium significantly reduced exacerbation rates and dyspnea scores and improved lung function as well as quality of life better than the LABA/ICS, LABA/LAMA comparators or the single compounds in selected COPD trial patients. Beclometasone/formoterol/glycolpyrronium and fluticasonfuroate/umeclidinium/vilanterol are the first triple combination therapies approved in a fixed-dose inhaler for COPD patients. The domains of triple fixed-dose formulations are COPD patients in groups C andD.

Dual bronchodilator therapy for chronic obstructive pulmonary disease: evidence for the efficacy and Safety of fixed dose combination treatments in the setting of recent guideline updates.

Recent updates to the GOLD guidelines emphasize the use of combination LABA and LAMA bronchodilators for patients with chronic obstructive pulmonary disease with persistent dyspnea despite monotherapy or frequent exacerbations despite LAMA monotherapy. There are several commercially available LABA/LAMA fixed dose combination inhalers, which are likely to become the principle therapy for many patients with COPD. In the last 4 years, there have been a number of large clinical trials evaluating the efficacy and safety of combined LAMA and LABA bronchodilators. LAMA/LABA fixed dose combination therapies have consistently demonstrated clinically significant improvements to airway obstruction, dyspnea, and quality of life whenever compared with placebo, and more modest improvements compared with bronchodilator monotherapies and combined bronchodilator/inhaled corticosteroid therapy. New guidelines emphasize combination bronchodilators as a mainstay of therapy for many patients with symptomatic COPD and there are several new combination bronchodilator therapies available to patients. It is important for physicians and patients to understand the range and degree of expected clinical effects and the safety profiles of these new medications.

Role of dual and triple fixed-dose combination inhalers in the treatment of chronic obstructive pulmonary disease

Role of dual and triple fixed-dose combination inhalers in the treatment of chronic obstructive pulmonary disease

Role of dual and triple fixed-dose combination inhalers in the treatment of chronic obstructive pulmonary disease

Role of dual and triple fixed-dose combination inhalers in the treatment of chronic obstructive pulmonary disease

Maintenance therapy in COPD: time to phase out ICS and switch to the new LAMA/LABA inhalers?

Long-term maintenance therapy for COPD is evolving rapidly. Dual bronchodilation with new long-acting muscarinic antagonist and long-acting beta-agonist (LAMA/LABA) fixed dose combination inhalers were introduced over the past 2 years. In clinical trials, these inhalers significantly improved lung function (trough forced expiratory volume in 1 second), patient-reported outcomes, and quality of life measures compared with placebo, their respective monocomponents, and tiotropium. The recorded adverse events of these new inhalers were also similar to those of their monocomponents or placebo. There are concerns regarding long-term complications (weight gain, osteoporosis, cataract) and increased risk of community-acquired pneumonia with the use of inhaled corticosteroids (ICS). The new LAMA/LABA inhalers could potentially reduce the use of ICS as part and parcel of maintenance therapy in COPD. Recent studies compared these LAMA/LABA inhalers with ICS/LABA combination inhalers in moderate-to-severe COPD. The results are promising and favor the LAMA/LABA inhalers, especially in the longer duration trials. Furthermore, there is a clearer picture emerging as to the subgroup of COPD patients who may be able to successfully switch from their current ICS/LABA therapy to these new LAMA/LABA inhalers.

Fixed-dose combination inhalers compared to long-acting bronchodilators for COPD: a network meta-analysis

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:To compare the efficacy and safety of two different types of fixed-dose dual inhalers (i.e. LABA/LAMA vs ICS/LABA) as well as combination therapies versus LABA or LAMA monotherapy for patients with moderate to very severe COPD.

Long-Acting β-Agonist in Combination or Separate Inhaler as Step-Up Therapy for Children with Uncontrolled Asthma Receiving Inhaled Corticosteroids

Adding a long-acting β2-agonist (LABA) to inhaled corticosteroids (ICS) using a fixed-dose combination (FDC) inhaler is the UK guideline recommendation for children aged more than 4 years with uncontrolled asthma. The evidence of benefit of adding an FDC inhaler over a separate LABA inhaler is limited. The objective of this study was to compare the effectiveness of a LABA added as an FDC inhaler, and as a separate inhaler, in children with uncontrolled asthma. Two UK primary care databases were used to create a matched cohort study with a 2-year follow-up period. We included children prescribed their first step-up from ICS monotherapy. Two cohorts were formed for children receiving an add-on LABA as an FDC inhaler, or a separate LABA inhaler. Matching variables and confounders were identified by comparing characteristics during a baseline year of follow-up. Outcomes were examined during the subsequent year. The primary outcome was an adjusted odds ratio for overall asthma control (defined as follows: no asthma-related hospital admission or emergency room visit, prescription for oral corticosteroids or antibiotic with evidence of respiratoryconsultation, and ≤2 puffs of short-acting β-agonist daily). The final study consisted of 1330 children in each cohort (mean age 9 years; 59% male). In the separate ICS+LABA cohort, the odds of achieving overall asthma control were lower (adjusted odds ratio, 0.77 [95% confidence interval, 0.66-0.91]; P= .001) compared with the FDC cohort. The study demonstrates a small but significant benefit in achieving asthma control from an add-on LABA as an FDC, compared with a separate inhaler and this supports current guideline recommendations.

AB027. Long-acting beta-agonist in combination or separate inhaler as step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids

Background: Adding a long-acting β2-agonist (LABA) to inhaled corticosteroids (ICS) using a fixed-dose combination (FDC) inhaler containing ICS and LABA is the UK guideline-recommended step-up option for children aged >4 years with uncontrolled asthma on ICS monotherapy. The evidence of benefit of FDC inhalers over adding a separate LABA inhaler to ICS therapy is limited. Our aim was to compare outcomes for FDCversusseparate LABA + ICS inhalers for children by analyzing routinely-acquired clinical and prescribing data.

Initial step-up treatment changes in asthmatic children already prescribed inhaled corticosteroids: a historical cohort study.

Background:When standard doses of inhaled corticosteroids (ICS) fail to control symptoms in children aged >4 years, guidelines recommend the addition of a long-acting β2-agonist (LABA), with other treatment options being available if symptoms persist.Aims:To determine the proportion of initial ‘step-up’ episodes where LABAs were prescribed and to describe characteristics of individuals not stepped up with LABA.Methods:Between 1999 and 2011, initial step-up episodes from ICS monotherapy were identified in children aged 5–12 years with asthma and in receipt of ICS. Data sources were the Clinical Practice Research Datalink and Optimum Patient Care Research Database.Results:Initial step-up episodes were identified in 10,793 children. ICS dose was increased in 6,252 children (58%), LABA was introduced in 3,436 (32%; including 1,107 where fixed dose combination inhaler (FDC) replaced the ICS inhaler), and leukotriene receptor antagonist (LTRA) was added in 1,105 (10%). Compared with children stepped up to any LABA, others were younger and prescribed lower doses of ICS and reliever medication. ICS dose increase was more likely in obese children and LTRA prescribing was more likely in children with rhinitis and in receipt of antibiotics. Compared with FDC, step-up to separate LABA inhaler was more likely in younger, obese children who were using less oral steroids.Conclusions:One-third of initial step-up episodes in children with asthma treated with ICS are to add LABA. Different characteristics of children prescribed therapies other than LABA suggest that prescribers tailor treatment in some clinical settings.

Profile of a fixed-dose combination of tiotropium/olodaterol and its potential in the treatment of COPD.

Chronic obstructive pulmonary disease (COPD) is a progressive, debilitating disorder that results in frequent exacerbations and impacts quality of life. It represents a growing burden of health care cost, both from societal and economic perspectives. Short- and long-acting bronchodilators remain the mainstay of therapy in COPD patients. New fixed-dose combination inhalers with novel pharmacological combinations of long-acting β2-agonists and muscarinic antagonists and delivered once-daily through a variety of devices are currently being developed and licensed for the treatment of COPD. There is mounting research suggesting that combining a fixed dose of a β2-agonist and a muscarinic antagonist achieves better bronchodilation and clinical outcomes compared with either agent alone. These once-daily dosing inhalers are anticipated to impact favorably on patient preference and compliance. This review examines the fixed-dose combination of tiotropium bromide and olodaterol delivered by a Respimat® Soft Mist™ inhaler at doses of 2.5/5 μg and 5/5 μg in moderate-to-very-severe COPD, and its potential role in COPD compared with other long-acting β2-agonist with long-acting muscarinic antagonist combinations and delivery devices.

PRS24 - Cost-Minimization and Budget-Impact Analysis of Fixed-Dose Combination Inhalers in Treatment of Copd in Slovenia

PRS24 - Cost-Minimization and Budget-Impact Analysis of Fixed-Dose Combination Inhalers in Treatment of Copd in Slovenia

Combination formoterol and budesonide as maintenance and reliever therapy versus combination inhaler maintenance for chronic asthma in adults and children.

Combination formoterol and budesonide as maintenance and reliever therapy versus combination inhaler maintenance for chronic asthma in adults and children.