Utah Medicaid Pharmacy and Therapeutics Committee Drug ... Review Documents/2017...for the primary...

Utah Medicaid Pharmacy and Therapeutics Committee

Drug Class Review

Inhaled Corticosteroid and Long-Acting β2-Agonist Combination Inhalers

AFHS classifications: Adrenals 68:04, Selective β2-Adrenergic Agonists 12:12.08.12

Budesonide/formoterol (Symbicort)

Fluticasone propionate/salmeterol (Advair Diskus, Advair HFA, Airduo Respiclick)

Fluticasone furoate/vilanterol (Breo Ellipta)

Mometasone/formoterol (Dulera)

Final Report

October 2017 Review prepared by: Elena Martinez Alonso, B.Pharm., MSc MTSI, Medical Writer Valerie Gonzales, Pharm.D., Clinical Pharmacist Vicki Frydrych, B.Pharm., Pharm.D., Clinical Pharmacist Joanita Lake, B.Pharm., MSc EBHC (Oxon), Clinical Pharmacist Michelle Fiander, MA, MLIS, Systematic Review/Evidence Synthesis Librarian Joanne LaFleur, PharmD, MSPH, Associate Professor University of Utah College of Pharmacy University of Utah College of Pharmacy, Drug Regimen Review Center Copyright © 2017 by University of Utah College of Pharmacy Salt Lake City, Utah. All rights reserved

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Table of Contents Executive Summary ...................................................................................................................................... 2

Introduction ................................................................................................................................................... 6

Table 1. FDA Approved ICS/LABA Combination Products ........................................................... 8

Disease Overview and Clinical Guidelines 11

Table 2. Clinical Guidelines - Treatment Steps for the Management of Asthma........................... 15

Table 3. Asthma Severity and Treatment Strategies for the Management of Asthma in patients ≥12 years of age (NHLBI Guidelines) ............................................................................................ 16

Table 4. Pharmacologic treatment algorithms for the management of COPD (GOLD Guidelines) ........................................................................................................................................................ 22

Table 5. Recommendations for Initial Treatment in Patients with Asthma-COPD Overlap .......... 25

Pharmacology ............................................................................................................................................. 26

Table 6. Pharmacokinetics of ICS/LABA Combination Products ................................................ 27

Special Populations ..................................................................................................................................... 28

Table 7. Recommendations for Special Populations of ICS/LABA Combination Products .......... 29

Utah Medicaid Utilization Data .................................................................................................................. 31

Table 8. ICS/LABA treatment in Utah Medicaid FFS patients for 2013-2017 period................... 31

Methods ...................................................................................................................................................... 32

Clinical Efficacy and Safety ....................................................................................................................... 34

Safety .......................................................................................................................................................... 41

Table 9. Adverse Effects and Warnings of ICS/LABA Combination Products ............................. 42

Summary ..................................................................................................................................................... 44

References ................................................................................................................................................... 48

Appendix A. MEDLINE & EMBASE Literature Search Strategies for ICS/LABA Combination Products .................................................................................................................................................................. 54

Table 1. Medline Literature Search Strategy (via Ovid) for systematic reviews and randomized controlled trials ............................................................................................................................... 54

Table 2. EMBASE Literature Search Strategy (via EMBASE.com) ............................................. 55

Appendix B. Key Evidence: Cochrane Systematic Reviews of ICS/LABA Combination Products ......... 56

Appendix C. Key Evidence: Other Systematic Reviews Including ICS/LABA Combination Products ... 58

Appendix D. Randomized Controlled Trial Included in the Previous Systematic Reviews ...................... 59

Appendix E. Randomized Controlled Trial Not Included in the Previous Systematic Reviews ............... 60

Appendix F. List of Excluded References ................................................................................................. 66

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Executive Summary Introduction: Combination products containing inhaled corticosteroids (ICSs) and long-acting β2-agonists (LABAs) are indicated for the long-term treatment of patients with asthma. Some ICS/LABA combinations are also approved for the management of chronic obstructive pulmonary disease (COPD).

The 2007 National Heart, Lung, and Blood Institute (NHLBI) guideline and the 2017 Global Strategy for Asthma Management and Prevention (GINA) guideline recommend the use of short-acting β2-agonists (SABAs) as needed (quick relief medications) plus ICS/LABA combinations (controller medications) in certain patients with persistent moderate to severe asthma not adequately controlled with low- or medium-dose ICS. For these patients, several clinical trials demonstrated greater improvements in lung function and asthma control when LABA was added to ICS compared to increasing the ICS dose.

Regarding COPD management, the updated 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guideline recommends LABA/long-acting muscarinic antagonist (LAMA) fixed-dose combinations (FDCs) as preferred treatment options in patients with moderate to severe COPD. Combination ICS/LABA FDC products are second-line therapies. Clinical trials in COPD patients demonstrated superior efficacy of LABA/LAMA compared to LABA/ICS combinations in terms of lung function and exacerbation risk.

Currently, 6 ICS/LABA FDC products, available in a single inhaler, are approved by the Federal Drug Administration (FDA): one budesonide and formoterol (BUD/FM) metered-dose inhaler, 3 fluticasone propionate and salmeterol (FP/SAL) products (2 available as dry powder inhalers and one available as metered-dose inhaler), one fluticasone furoate and vilanterol (FF/VI) dry powder inhaler, and one mometasone and formoterol (M/FM) metered-dose inhaler. The 6 FDCs are available with different corticosteroid concentrations to accommodate different levels of asthma severity and different age groups. They are administered twice daily, with the exception of FF/VI products that are administered once daily. Device characteristics and inhalation techniques also differ between products. Single inhalers may simplify asthma/COPD management and facilitate patient adherence to treatment.

Systematic reviews/meta-analyses (SR/MA) and randomized controlled trials (RCTs) assessing head-to-head efficacy and safety comparisons between the aforementioned combination products are included in this report.

Clinical Efficacy: Comparative evidence included 26 efficacy/safety articles containing 5 SR/MA, 21 RCTs, and 2 mixed treatment comparisons (MTCs). Three safety articles containing one SR/MA and 2 RCTs were also evaluated. The majority of the evidence pertained to asthma. Limited evidence is available for COPD and asthma/COPD overlap. Nomenclature used in this

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report includes a slash ('/') to separate the different active substances contained in a FDC product and a plus sign (‘+’) to define two separate products used in combination.

For the management of asthma, 5 SR/MA, 16 RCTs and one MTC were identified:

1. BUD/FM versus BUD+FM (4 RCTs): similar efficacy and safety profiles were reported between BUD/FM pMDI (U.S product) or BUD/FM DPI (non-U.S. product) compared to BUD+FM in children 4 to 11 years, adolescents, and adults. One long-term trial (12-months) in adult patients indicated a lower withdrawal rate with BUD/FM DPI than BUD+FM.

2. FP/SAL versus FP+SAL (1 SR/MA, and 5 RCTs): Results differed among the 5 RCTs. Kawai et al demonstrated similar bronchodilator effect between FP/SAL and FP+SAL groups in adult patients. Van der Berg et al, Chapman et al, and Aubier et al reported improvements in lung function, asthma control, and symptoms at week 12 that did not significantly differ between treatment groups in patients ≥ 4 years old.

In adolescent and adult patients, Bateman et al. showed superiority of SAL/FP DPI 50/100 µg versus the same doses administered individually for lung function at week 12 (primary endpoint). Chapman et al. reported superiority of SAL/FP DPI 50/250 µg vs. SAL+FP for lung function values at other time points (week 3 and 4). One SR/MA included 4 of the 5 RCTs identified, and showed statistically significant differences between FP/SAL and the mono-components; however, a proper discussion about the clinical relevance of the results was lacking.

3. FP/SAL hydrofluoroalkane (HFA) metered-dose inhaler (MDI) versus FP/SAL dry powder inhaler (DPI) (3 RCTs): No significant differences between the two different inhalers were reported. Low-, medium- and high-doses of fluticasone plus SAL were evaluated.

4. BUD/FM versus FP/SAL (3 SR/MA, 3 RCTs): Three SR/MA reported no significant differences in terms of efficacy (reduction in exacerbations requiring oral corticosteroids or hospitalizations) and safety (asthma-related serious adverse events) between BUD/FM pMDI or DPI compared to FP/SAL MDI or DPI. Three RCTs reported faster onset of bronchodilator action and faster improvements in forced expiratory volume in one second (FEV1) with BUD/FM pMDI or DPI compared to SAL/FP DPI.

5. FF/VI versus FP/SAL (1 SR/MA containing one RCT of interest): No statistically significant differences were found between FF/VI DPI 100/25 µg compared to FP/SAL DPI 250/50 µg for the primary endpoints (change in health-related quality of life, severe asthma exacerbations, and serious adverse events), and secondary endpoints (lung function and asthma symptoms). However, authors highlighted the limited comparative efficacy and safety information available to make a robust decision about the preference of FF/VI over FP/SAL. Further research was considered required.

6. FF/VI versus FP/SAL and BUD/FM (1 MTC): One network meta-analysis included 31 RCTs to assess the probability of non-inferiority of once-daily FF/VI vs. twice-daily FP/SAL and BUD/FM in asthma patients ≥ 12 years old. Despite known limitations of network meta-

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analyses, results suggested similar lung function improvements with FF/VI 100/25 µg and FF/VI 200/25 µg compared to corresponding doses of FP/SAL and BUD/FM. Health status outcomes were comparable between once-daily FF/VI 100/25 μg compared to twice-daily FP/SAL 250/50 μg and BUD/FM 320/9 μg.

7. M/FM versus FP/SAL (1 RCT): One trial compared M/FM MDI 200/10 μg to FP/SAL DPI 250/50 μg. Non-inferiority was demonstrated for the primary endpoint (improvement in lung function) and most of the secondary endpoints (asthma control, quality of life and symptoms). The onset of bronchodilator action was faster with M/FM than FP/SAL DPI.

For the management of COPD, 4 RCTs and one MTC were identified. The main results are described below:

1. BUD/FM versus FP/SAL (1 RCTs): One trial showed faster onset of bronchodilator effect with BUD/FM compared to FP/SAL.

2. FF/VI versus FP/SAL (3 RCTs): Three trials reported statistically, but not clinically significant differences between FF/VI 100/25 µg and medium-dose FP/SAL (250/50 µg).

3. FF/VI versus FP/SAL and BUD/FM (1 MTC): One network meta-analysis included 33 RCTs to assess the probability of non-inferiority of once daily FF/VI 100/25 µg compared to twice daily FP/SAL 500/50 µg and BUD/FM 400/12 µg in COPD patients ≥ 12 years old. Despite limitations of indirect comparisons, results suggested similar lung function and health status improvements with FF/VI compared to FP/SAL and BUD/FM.

For the management of asthma-COPD overlap, only one RCT comparing FF/VI DPI 200/25 μg versus FP/SAL DPI 500/50 μg was identified. Although no between-group differences were reported, authors mentioned the need for further research due to the study limitations identified.

Adverse Drug Reactions: The majority of adverse drug reactions to LABA/ICS combinations are tolerable and manageable. The most common adverse events reported with ICS/LABA combinations are headache, upper respiratory tract infections, pharyngitis, pneumonia, dizziness, oral candidiasis, bronchitis, cough, headaches, musculoskeletal pain, nausea and vomiting. The increased risk of pneumonia in patients with COPD and adrenal suppression are related to the adverse effect profile of inhaled corticosteroids. A main safety warning and class effect for all LABAs is the increased risk of asthma-related death, and the higher risk of asthma-related hospitalizations in children and adolescents.

Summary: The identified comparative evidence indicates that the FDA-approved ICS/LABA combination products tend to be similar to each other in terms of efficacy and safety outcomes. ICS/LABA products improve lung function, increase quality of life, and reduce asthma or COPD exacerbation rates. Safety profiles remain similar and manageable when both ICS and LABA are combined.

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For the management of asthma, direct comparisons reported no significant differences for 1) FP/SAL compared to BUD/FM, FF/VI, or M/FM; and 2) FP/SAL HFA MDI compared to FP/SAL DPI. Similar efficacy and safety profiles were reported for BUD/FM compared to the mono-components administered concomitantly (BUD+FM). FP/SAL has been shown to be similar to FP+SAL; however, some studies suggest superiority of FP/SAL compared to FP+SAL. For the management of COPD, similar results were reported for FP/SAL compared to FF/VI. Nonetheless, further direct head-to-head comparisons involving ICS/LABA combinations are required to contrast the potential benefits of one FDC over another in patients with asthma, COPD, and asthma/COPD overlap.

Clinician’s decisions on one single ICS/LABA inhaler over another should be based on the specific inhaler technique and patient skills to appropriately use the prescribed ICS/LABA inhaler, the individual patient’s preference, co-morbidities, adverse events, and cost.

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Introduction

ICS/LABA combination products are indicated for the management of asthma and COPD. Asthma is a chronic inflammatory disease of the airways caused by the exposure to asthma triggers such as occupational allergens, tobacco smoke, chemical irritants, exercise and stress.1-4 It is not a curable condition but can be effectively treated with the available pharmacological options.1,4 The main goals of treatment are to control asthma symptoms and reduce the risk of exacerbations. Current clinical guidelines recommend long-term treatment for the management of asthma including reliever medications to quickly control exacerbations (i.e. inhaled short-acting β2-agonists), and controller medications as maintenance treatment to reduce inflammation and future risk of exacerbations (e.g. inhaled corticosteroids or inhaled corticosteroids and long-acting β2-agonist combinations). For patients with severe asthma, add-on therapies may be required (e.g. long-acting muscarinic antagonists, leukotriene modifiers, theophylline, anti-immunoglobulin E, anti-interleukin 5 or oral corticosteroids).1,4

Inhaled corticosteroids (ICSs) have been extensively studied and are considered by the National Heart, Lung, and Blood Institute (NHLBI) the most potent and effective long-term anti-inflammatory drugs in patients with persistent asthma, including adults and children.4 Patients discontinuing or not receiving ICS have a higher risk of asthma exacerbations and reduced lung function than those receiving ICS.5,6 Therefore, ICSs are the mainstay in the long-term control of persistent asthma. In some patients with moderate to severe asthma not responding to low doses of ICS alone, the addition of a long-acting β2-agonist (LABA) to an ICS improves asthma symptoms and lung function, while reducing the incidence of exacerbations in comparison to simply increasing the ICS dose.4

ICS/LABA combinations are also approved for the management of moderate to severe COPD. These combination products are alternative therapies to LABA/LAMA combination products (preferred therapy) because they have demonstrated superior improvement in lung function, health status and exacerbation risk than the individual components, but not versus LABA/LAMA combinations.1,4

This report evaluates the clinical efficacy and safety of the ICS/LABA combination products based on systematic reviews/meta-analyses (SR/MA) and randomized controlled trials (RCTs) assessing head-to-head comparisons between these combination products. Currently, 6 ICS/LABA fixed-dose combination products, available in a single inhaler, are approved by the Federal Drug Administration (FDA) in the United States: one budesonide and formoterol (BUD/FM7) metered-dose inhaler, 3 fluticasone propionate and salmeterol (FP/SAL8-10) products (2 available as dry powder inhalers and one available as metered-dose inhaler), one fluticasone furoate and vilanterol (FF/VI11) dry powder inhaler, and one mometasone and formoterol (M/FM12) metered-dose inhaler. The 6 FDCs are available with different corticosteroid concentrations to accommodate different levels of asthma severity and different age groups.4,7-12

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Nomenclature used in this report includes a slash ('/') to separate the different active substances contained in a FDC product and a plus sign (‘+’) to define two separate products used in combination.

Inhaler devices allow the drug to be directly delivered to the airways, increasing local concentrations and reducing the incidence of systemic adverse events.13 Several types of inhaler devices are available including pressurized metered-dose inhalers (pMDIs), dry powder inhalers (DPIs), and soft-mist inhalers (SMIs).14 Budesonide/formoterol and mometasone/formoterol are delivered with pMDIs,7,12 whereas fluticasone furoate/vilanterol is delivered via DPI.11 Fluticasone propionate/salmeterol is available in both types of devices, pMDI and DPI.8-10 Inhalers have a high impact in the efficiency of drug delivery. Although patients require skills- training for the optimal use of inhalation devices, the simplicity and intuitive use of inhalers play an important role in patient adherence to treatment, especially in children and the elderly.13,14 DPIs are deemed to be easier to use compared to MDIs.14 Yet, for an individual with severe limitations in the force they can generate to inhale a dry powder product, a MDI may be more appropriate. Inhaler device selection should be individualized in order to achieve the highest asthma improvement for each patient.1

Budesonide/formoterol7 was approved in the US in 2006 at two different dosages (80/4.5 and 160/4.5 mcg, 2 inhalations twice daily) for the treatment of asthma in patients 12 years of age and older. Later, the indication was extended to include treatment of asthma in patients 6 years of age and older, as well as treatment of patients with COPD. This FDC is formulated as a HFA-propelled pMDI.7,15 Three FDCs containing salmeterol and different concentrations of fluticasone propionate are available. Advair Diskus is a DPI approved for the management of asthma (≥ 4 years old) and COPD. Advair HFA (MDI) and Airduo Respiclick (DPI) are only approved for asthma management in adolescents and adults.8-10 Mometasone/formoterol12 (pMDI) is also indicated for asthma management in adolescents and adults. Fluticasone furoate/vilanterol11 (DPI) is approved for both asthma (only adults) and COPD management, and is the only one administered once daily (versus twice daily administration with the rest of the FDCs).11

The use of singe inhalers provides some advantages versus using separate inhalers. First, the lower dosing-frequency, the avoidance of learning two complex and different inhaler techniques, and the high level of patient satisfaction may improve patient adherence, achieve better control of asthma, and increase quality of life.16,17 Secondly, single inhalers may reduce the risk of increased asthma-related deaths associated with use of LABA inhalers alone (black box warning of LABAs).18 Lastly, the cost of a single inhaler is typically lower than separate inhalers administered together.18 A 2016 FDA safety announcement recommended use of a fixed-dose combination of ICS and LABA in one single inhaler in order to enhance adherence to asthma treatment in children and adolescents.19

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Table 1. FDA Approved ICS/LABA Combination Products7-12

Active Substances (Brand Name)

Dosage Form(s) and Strengths Mechanism of Action

Indication Recommended dose

Budesonide/ formoterol (HFA pMDI) (Symbicort) Approval date: July 2006 (AstraZeneca)

Inhalation Aerosol • 80/4.5: BUD 80 mcg and FM 4.5 mcg

(delivered doses from the actuator)* • 160/4.5: BUD 160 mcg and FM 4.5 mcg

(delivered doses from the actuator)* * Equivalent to 100/6 mcg and 200/6 mcg metered doses, respectively

Budesonide: ICS Formoterol: LABA

• Treatment of asthma in patients 6 years of age and older

• Maintenance treatment of airflow obstruction in patients with COPD including chronic bronchitis and emphysema (160/4.5 mcg dosage)

Limitation: Not indicated for relief of acute bronchospasm

• Asthma (6 to < 12 years): 2 inhalations of SYMBICORT 80/4.5 BID

• Asthma (≥12 years): 2 inhalations of SYMBICORT 80/4.5 or 160/4.5mcg BID. Starting dose depends on the severity

• COPD: 2 inhalations of SYMBICORT 160/4.5 BID

MAX: 2 inhalations BID

Fluticasone propionate/ salmeterol Advair Diskus (DPI) Approval date: August 2000 (GlaxoSmithKline)

Inhalation Powder • 100/50: FP 100 mcg and SAL 50 mcg

per blister* • 250/50: FP 250 mcg and SAL 50 mcg

per blister* • 500/50: FP 500 mcg and SAL 50 mcg

per blister* * Equivalent to 93/45 mcg, 233/45 mcg, and 465/45 mcg delivered doses per blister, respectively

Fluticasone: ICS Salmeterol: LABA

• Treatment of asthma in patients aged 4 years and older

• Maintenance treatment of airflow obstruction and reducing exacerbations in patients with COPD (250/50 mcg dosage)


• Asthma (4 to 11 years): 1 inhalation of Advair Diskus 100/50 BID

• Asthma (≥12 years): 1 inhalation of Advair Diskus 100/50, 250/50, or 500/50 BID. Starting dosage is based on asthma severity

• COPD: 1 inhalation of Advair Diskus 250/50 BID

MAX: 1 inhalation BID

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Advair HFA (pMDI) Approval date: June 2006 (GlaxoSmithKline) Airduo Respiclick (DPI) Approval date: January 2017 (Teva)

Inhalation Aerosol • 45/21: FP 45 mcg and SAL 21 mcg * • 115/21: FP 115 mcg and SAL 21 mcg* • 230/21: FP 230 mcg and SAL 21 mcg*

* Equivalent to 50/25 mcg, 125/25 mcg, and 250/25 mcg metered doses, respectively


• Treatment of asthma in patients aged 12 years and older.


Use 2 inhalations of Advair HFA 45/21, 115/21, or 230/21 BID. Starting dosage is based on asthma severity

Inhalation Powder • 55/14: FP 55 mcg and SAL 14 mcg* per

actuation • 113/14: FP 113 mcg and SAL 14 mcg*

per actuation • 232/14: FP 232 mcg and SAL 14 mcg*

per actuation

* Equivalent to 49/12.75 mcg, 100/12.75 mcg, and 202/12.75 mcg delivered doses, respectively


• Treatment of asthma in patients aged 12 years and older.


Use 1 inhalation of Airduo Respiclick 55/14 mcg, 113/14 mcg, or 232/14 mcg BID. Starting dosage is based on prior asthma therapy and disease severity

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Fluticasone furoate/ vilanterol (DPI) (Breo Ellipta) Approval date: May 2013 (GlaxoSmithKline)

Inhalation Powder • 100/25: FF 100 mcg and VI 25 mcg* • 200/25: FF 200 mcg and VI 25 mcg* * Equivalent to 92/22 mcg and 184/22 mcg delivered doses, respectively

Fluticasone: ICS Vilanterol: LABA

• Once-daily treatment of asthma in patients aged 18 years and older

• Long-term, once-daily, maintenance treatment of airflow obstruction and reducing exacerbations in patients with COPD (100/25 mcg dosage)


• Asthma: 1 inhalation of Breo Ellipta 100/25 or 200/25 QD

• COPD: 1 inhalation of Breo Ellipta 100/25 QD

Mometasone/ formoterol (pMDI) (Dulera) Approval date: June 2010 (Merck&Co., INC.)

Inhalation Aerosol • 100/5: M 100 mcg and FM 5mcg per

actuation (delivered dose)* • 200/5: M 200 mcg and FM 5mcg per

actuation (delivered dose)* * Equivalent to 115/5.5 mcg and 225/5.5 mcg metered doses, respectively

Mometasone: ICS Formoterol: LABA

• Treatment of asthma in patients 12 years of age and older

Limitation: Not indicated for the relief of acute bronchospasm Unlabeled indication: COPD

Use 2 inhalations BID of Dulera 100 mcg/5mcg or 200mcg/5mcg. Starting dosage is based on prior asthma therapy

Abbreviations: BID, twice daily; BUD, budesonide; COPD, chronic obstructive pulmonary disease; DPI, dry poder inhaler; FM, formoterol; FF, fluticasone furoate; FP, fluticasone propionate; HFA, hydrofluoroalkane; ICS, Inhaled Corticosteroids; LABA, long-acting β2-adrenergic agonist; LAMA, long-acting antimuscarinic agent; M, mometasone furoate; MAX: maximum dose; MDI, metered dose inhaler; pMDI, pressurized metered dose inhaler; SAL, salmeterol; VI, vilanterol

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Disease Overview and Clinical Guidelines

A) Asthma

Disease Overview

Asthma is a chronic inflammatory disease of the airways that affects all age groups and may be life-threatening.20 It is characterized by bronchoconstriction, airway wall thickening and increased mucus production. Asthma symptoms include wheezing, shortness of breath, chest tightness, and night or early morning cough.21 These symptoms are usually accompanied by expiratory airflow limitation.1 Asthma may be resolved spontaneously or require treatment.1 Sporadic and occasionally fatal asthma exacerbations, attacks or flares may occur, especially in those patients at high-risk or with uncontrolled asthma.21 This may result in productivity loss at work or school, family disruption and activity limitations.1 Risk factors for asthma include endogenous factors (e.g. genetic predisposition, atopy, gender), environmental factors (e.g. indoor or outdoor allergens, occupational sensitizers, passive smoking, respiratory infections, diet), and triggers (e.g. allergens such as pollution, tobacco smoke, pollen, and house dust mites, upper respiratory tract viral infections, exercise and hyperventilation, cold air, sulfur dioxide and irritant gases, stress, irritants and some drugs such as beta-blockers, aspirin and nonsteroidal anti-inflammatory drugs).20,21 Patients may have persistent or intermittent asthma, and the severity and frequency of attacks differ from person to person.2

According to the World Health Organization (WHO), it is estimated that 235 million people worldwide suffer from asthma, with children being the most affected age group.2 In December 2016, 380,000 deaths worldwide were attributed to asthma.2 The majority of deaths occurred in older adults and those living in lower and middle income countries.2 Asthma is a treatable disease whose prevalence is rising, especially in many developing countries due to the increase of people living in urban areas.20,21 In the United States, statistical data from the 2001 to 2010 period indicate an increase in asthma prevalence from 1 in 14 (7%) in 2001 to 1 in 12 (8%) in 2010.22 Data from 2015 show that around 25 million Americans were diagnosed with asthma, with a higher prevalence in children (8.4% children and 7.6% adults), females (9.1% females vs 6.5% male), black people (10.3% black, 7.8% white and 6.6% Hispanic) and those living below the federal poverty threshold.23 Among adults, women are more likely to have asthma compared to men, whereas among children, boys are diagnosed more commonly than girls.3 In the US, the number of asthma-related emergency department visits was 1.6 million in 2013.24 The number of office-based physician visits with asthma as the primary diagnosis was 10.5 million in 2012,25 and a total of 439,435 people were hospitalized in 2010.26 In 2015, the total number of asthma-deaths was 3,615 (219 children, 3,396 adults).27

In Utah, the Centers for Disease and Control (CDC) reported a prevalence in 2008 of 8.4% for adults and 6.6% for children compared to national rates of 8.5% and 9.0%, respectively.28

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The Utah prevalence in men and women was 7.4% and 9.5%, respectively. In children, the prevalence was 7.1% for boys and 6.2% for girls. The majority of hospitalizations occurred in children between 0 and 4 years, followed by children between 5 to 9 years and adults older than 65 years.28

Asthma is under-diagnosed and under-treated, causing a high health burden on the general population, with an increase in healthcare costs mainly due to hospitalizations, followed by death, emergency department visits, loss of productivity, and school absences.3,22,29 The total annual cost to society from medical expenses, loss of productivity and premature death was approximately $56 billion in 2007,3 with direct cost (mostly hospital stays due to exacerbations) accounting for $50.1 billion.13,29

Diagnosis

Diagnosis of asthma is primarily based on two features: a) a history of respiratory symptoms (i.e. wheeze, shortness of breath, chest tightness and cough), b) evidence of variable expiratory airflow limitation (forced expiratory volume in one second [FEV1] measured by spirometry test or peak expiratory flow [PEF] measured with reversibility test).30 Once a diagnosis is confirmed, treatment should be initiated as soon as possible.1

Asthma severity and control

According to NHLBI guidelines, the initiation of asthma therapy should be based on the assessment of asthma severity stratified by level of impairment (e.g. symptoms, FEV1, SABA use; etc.) and risk of exacerbations requiring oral corticosteroids. Asthma is classified in 4 levels of severity with corresponding treatment steps: intermittent asthma (treatment step 1), persistent mild asthma (treatment step 2), persistent moderate asthma (treatment step 3 or 4), and persistent severe asthma (treatment step 5 or 6). Table 3 includes asthma severity features and treatment strategies for patients ≥12 years of age.

Asthma control should be evaluated 2-6 weeks after initiation of asthma therapy with modifications made, as indicated. Once stabilized, patients should be regularly assessed (at least once a year) for asthma control, treatment-related issues (e.g. adherence, inhaler technique, adverse events), control of environmental factors, and comorbidities that may worsen asthma. This assessment approach will help health professionals to determine whether treatment remains appropriate or should be modified (step down whenever possible or step up if required).4

Asthma Management

The goal of long-term asthma management is to reduce impairment (i.e. reduce disease symptoms, reduce the use of inhaled SABAs, improve lung function and activity levels), and reduce the risk of asthma exacerbations, hospitalizations, emergency care visits, adverse effects from medications, and progressive loss of lung function.1,4 Several pathways should be

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considered in order to achieve these goals: a) administering a reliever and a controller asthma medication, b) treating modifiable risk factors, c) using non-pharmacological therapies and strategies, and d) patient training concerning asthma self-management (e.g. adherence, inhaler technique, written asthma action plan, etc.).1,4

Asthma medications are classified in 2 categories:

1. Quick-relief medications to treat acute symptoms and exacerbations (e.g. short-acting β2-agonists [SABAs], anticholinergics, systemic corticosteroids).4 According to NHLBI and GINA guidelines, SABA as needed is the preferred choice for all patients with asthma symptoms.1,4

2. Long-term control medications to achieve and control persistent asthma symptoms (e.g. inhaled or systematic corticosteroids, cromolyn sodium, immunomodulators, leukotriene modifiers, LABAs, and methylxanthines).4 Current guidelines recommend inhaled corticosteroids (ICS) or ICS/LABA combination products as preferred controller therapies.1,4 See Table 2 for further information on guideline recommendations. In general, administration of an ICS should be initiated as soon as possible, even if patients do not have asthma symptoms. The decision to use low-, medium- or high-dose ICS, a combination of ICS with a LABA, or other additional treatment(s) will depend on the frequency of symptoms, waking times per week or month and risk factors for exacerbations.1,4 Doses of ICS may be increased (step up strategy) when asthma is uncontrolled with the asthma controller initially prescribed. When asthma is well-controlled for 3 months step-down therapy may be considered.1,4

Adherence

Patient inhaler skills should be reinforced to assure a correct use of the device. Different inhalers require different techniques for effective use and adequate patient education is crucial to successfully manage asthma.1,4 Adherence to treatment should be encouraged in order to avoid uncontrolled asthma symptoms, exacerbations, and possible death.1,4

Unless asthma is appropriately managed, the number of emergency department visits, hospitalizations and deaths may increase.22 Therefore, asthma control through understanding the features of an asthma attack, avoiding the exposure to asthma triggers, and considering the instructions given from the doctor is essential.1,4

Clinical Guidelines for the Management of Asthma

Several guidelines for the treatment of asthma have been identified. The most recent evidence-based guideline is the 2017 Global Strategy for Asthma Management and Prevention (GINA),1 developed by a network of individuals, organizations, and public health officials from all around. The most relevant American guideline in clinical practice was published in 2007 by

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the National Heart, Lung, and Blood Institute (“Guidelines for the Diagnosis and Management of Asthma”).4 Comparative information including treatment recommendations of the two aforementioned guidelines is included in Table 2. Regarding ICS/LABA combination products, both guidelines consider low/medium/high-doses ICS plus LABA as preferred options in adolescents and adults with moderate to severe asthma (treatment step 3 onward). Some variations between guidelines in children of 11 years old and younger are identified. In step 3, NHLBI considers medium-dose ICS or low-dose ICS/LABA as treatment options in children aged 5 years and older, whereas the GINA guideline recommends medium-dose ICS in this population. The GINA guideline includes 4 steps for the management of asthma in children ≤ 5 years and 5 steps for children ≥ 6 years, adolescents, and adults. NHLBI guideline contains 6 steps for all age groups.

According to the NHLBI guidelines, ICS/LABA combinations demonstrated greater improvement in lung function, asthma control, and less use of SABA in comparison to ICS alone (baseline doses or increasing ICS doses), LABA alone or ICS/LTRA.4 NHLBI states: “For patients inadequately controlled on low-dose ICS, the option to increase the ICS dose should be given equal weight to the addition of a LABA. For patients who have more severe persistent asthma (i.e., those who require step 4 care or higher), the Expert Panel continues to endorse the use of a combination of LABA and ICS as the most effective therapy”.4

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Table 2. Clinical Guidelines - Treatment Steps for the Management of Asthma Asthma Severity

Preferred Reliever

Preferred Controller Choice*

NHLBI and GINA

NHLBI 2007a GINA 2017b

STEP 1 SABA PRN

None None

STEP 2 SABA PRN

All ages: low-dose ICS All ages: low-dose ICS

STEP 3

SABA PRN or

Low dose ICS/FMc

Age 0-4: medium-dose ICS Age 5-11: - Low-dose ICS + (LABA, LTRA or theophylline) OR - Medium-dose ICS Age ≥12: - Low-dose ICS + LABA OR - Medium-dose ICS * Consider consultation with asthma specialist

Age ≤5: Double “low dose” ICS Age 6-11: medium dose ICS Age ≥12: - Low-dose ICS/LABA (Evidence A31) or - Low-dose ICS/FMc

STEP 4

SABA PRN or

Low dose ICS/FMc

Age 0-4: medium-dose ICS + (LABA or montelukast) Age ≥5 to adult: medium-dose ICS + LABA * Consult with asthma specialist

Age ≤ 11: Refer for expert assessment and advice Age ≥12: - Medium dose ICS/LABA (Evidence B32) or - Low dose ICS/FMc

STEP 5

SABA PRN

Age 0-4: High-dose ICS + (LABA or montelukast) Age 5-11: High-dose ICS + LABA Age ≥12: High-dose ICS + LABA (and consider omalizumab for patients who have allergies) * Consult with asthma specialist

Children ≥ 6 years: Refer for expert advice and add-on treatment (i.e. tiotropium, anti-IgE, anti-IL5)

STEP 6

SABA PRN

Age 0-4: High-dose ICS + (LABA or montelukast) + OCS Age 5-11: High-dose ICS + LABA + OCS Age ≥12: High-dose ICS + LABA + OCS (and consider omalizumab for patients who have allergies) * Consult with asthma specialist

N/A

Other available guidelines

- Management of Asthma in Children and Adults, 2009. Department of Veterans Affairs, Department of Defense. The Management of Asthma Working Group, 200933

- British Thoracic Society Scottish Intercollegiate Guidelines Network: British guideline on the management of asthma, 201634

- Ducharme et al35 (2015): Diagnosis and management of asthma in preschoolers: A Canadian Thoracic Society and Canadian Paediatric Society position paper.

Abbreviations: FM, formoterol; ICS, inhaled corticosteroids; ICS/LABA, fixed-dose combination of inhaled corticosteroids and long acting beta2-agonists; LTRA, leukotriene receptor antagonists; N/A, not applicable; OCS, oral corticosteroids; PRN, pro re nata; SABA, short-acting β2 agonists * Only preferred options are included, but alternative options also exist (e.g. LTRA, low dose ICS +LTRA, medium dose ICS+LTRA or theophylline, anti-IgE, or refer to specialist) a NHLBI, National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program: The Expert Panel Report 3: “Guidelines for the Diagnosis and Management of Asthma”, 20074 b GINA, Global Strategy for Asthma Management and Prevention (GINA), 20171 c Low dose ICS/FM as maintenance and reliever therapy (recommended by GINA guidelines only). Not approved in the U.S. Note: - Evidence A (well-conducted RCTs with substantial number of patients)4. NHLBI: step 1, 2 and 3 (Evidence A)4 - Evidence B (RCTs with limited number of patients, post hoc or subgroup analysis)4. NHLBI: step 4 and 5 (Evidence B)4

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Table 3. Asthma Severity and Treatment Strategies for the Management of Asthma in patients ≥12 years of age (NHLBI Guidelines)4

Asthma severity

Symptoms Awakenings

at Night Use of SABA

Lung function

(FEV1)

Interference with Activity

limits

Flare-ups Quick

Reliever Preferred Controller Option Alternative Controller Options

INTERMITTENT ASTHMA STEP 1

Intermittent asthma

≤2 d/w ≤2 x/mo ≤2 d/w Normal (FEV1 >80) None 0-1/y SABA PRN No controller Consider low dose ICS

PRESISTENT ASTHMA STEP 2

Mild asthma >2 d/w 3-4 x/mo >2 d/w Normal (FEV≥80) Minor ≥2/y SABA PRN Low-dose ICS

Cromolyn, LTRA, nedocromil or theophylline

STEP 3

Moderate asthma

Daily 1 x/w Daily FEV1: 60-80%

Some limitation

≥2/y SABA PRN Low-dose ICS + LABA OR Medium-dose ICS

Low dose ICS + (LTRA, theophylline or zileuton)

STEP 4

Moderate asthma

Troughout the day 7 x/w Several

times/day FEV1< 60% Extremely limited

≥2/y SABA PRN Medium-dose ICS + LABA Medium-dose ICS + (LTRA, theophylline or zileuton)

STEP 5

Severe asthma

Troughout the day 7 x/w Several

times/day FEV1< 60% Extremely limited

≥2/y SABA PRN High-dose ICS + LABA (and consider omalizumab for patients who have allergies)

Not defined

STEP 6

Severe asthma

Not defined SABA PRN High-dose ICS + LABA + OCS (and consider omalizumab for patients who have allergies)

Not defined

Abbreviations: d, day; FEV1, forced expiratory volume in one second; FM, formoterol; ICS, inhaled corticosteroids; ICS/LABA, inhaled corticosteroids and long acting beta2-agonists; LTRA, leukotriene receptor antagonists; mo, month; NHLBI, National Heart, Lung and Blood Institute; OCS, oral corticosteroids; PRN, pro re nata (as needed); SABA, short-acting beta2 agonists; w, week; x, times; y, years

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B) Chronic Obstructive Pulmonary Disease (COPD)

Disease Overview

“Chronic Obstructive Pulmonary Disease (COPD) represents an important public health challenge and is a major cause of chronic morbidity and mortality throughout the world.”36 Around 16 million Americans have been diagnosed with COPD37 and the mortality rate due to COPD has doubled since 1969.37 COPD was the third leading cause of death in the United States in 201438 and the World Health Organization (WHO) has estimated that COPD will rise from the fourth to the third leading cause of mortality worldwide by 2030.39,40 According to the National Heart, Lung and Blood Institute and COPD National Action Plan, COPD kills more than 135,000 Americans each year41. Smoking accounts for 80% of COPD-related deaths although37 25% of cases were not related to cigarette smoking.37 Between 2000 and 2014, the overall incidence of COPD-related deaths declined for both men and women ≥25 years, but increased for the population subsets of men and women aged 45-64 and women aged ≥85.42 The number of people with COPD is increasing “because of continued exposure to risk factors and aging of the population”. Several million people are likely to have undiagnosed COPD due to patient underreporting of symptoms and under-diagnosis by practitioners. 40,41 According to estimates based on the Behavioral Risk Factor Surveillance System (BRFSS, 2015), 79,200 (3.8%) people ≥ 18 years old have COPD in Utah.37 Data provided by the Bureau of Epidemiology of the Utah Department of Health showed “a slow but steady increase in the rate of emergency department visits due to COPD, asthma, and hypersensitivity pneumonitis” from 2000 to 2011, with a monthly rate (higher during winter months) between 3 to 14 people per 100,000 Utahn’s. Monthly hospitalizations rates (4 to 15 people/100,000/month) and death rates (1 to 4 people/100,000/month) due to the above three respiratory diseases remained constant from 2000 to 2011.43

COPD is a progressive disease which includes emphysema, chronic bronchitis, and in some cases asthma.38 It is characterized by chronic coughing (most commonly daily and productive, but also intermittent and unproductive), breathlessness on exertion (initially intermittent and becoming persistent), sputum production (any pattern of sputum production may indicate COPD), and frequent exacerbations of bronchitis.40,44 In the United States, the Centers for Disease Control and Prevention (CDC) reports that tobacco smoke is a key factor in the development and progression of COPD, but other factors such as air pollutants in the home and workplace (e.g. occupational dusts, home cooking and biomass fuels), genetic factors, and respiratory infections also contribute to disease progression.38 Besides genetic factors, abnormal lung development and accelerated aging are also host factors that predispose individuals to develop COPD.40 In relation to COPD and air pollution, the Utah Department of Health recommends checking the air quality before doing any outdoor activity in order to modify the level of exertion, accordingly.43 According to the National Heart, Lung and Blood Institute,

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COPD most often occurs in people age 40 and over with a history of smoking (either current or former smokers), and several relevant sources report that tobacco smoke is the main risk factor for COPD.37,38,40,45,46 According to the CDC, groups more likely to report COPD include people aged 65–74 years, American Indians/Alaska natives and multiracial non-Hispanics, women, individuals who were unemployed, retired, or unable to work, individuals with less than a high school education, people with lower incomes, individuals who were divorced, widowed, or separated, current or former smokers, and those with a history of asthma.38 In 2010, the annual costs related to COPD for the American health care system were estimated to be more than $32 billion with additional absenteeism costs of $3.9 billion.37,47 Medical costs are projected to increase to $49 billion by 2020.47 The implementation of programs and strategies to prevent COPD are intended to reduce the economic burden of COPD and improve the quality of life of people with COPD.47

Spirometry is considered the gold standard for accurate, reproducible, and objective measurement of lung function and it is the best way of making a definitive diagnosis of asthma and COPD.40,44 However, the GOLD guidelines state that “Despite its good sensitivity, peak expiratory flow measurement alone cannot be reliably used as the only diagnostic test because of its week specificity.”40 Spirometry measures the volume of air that the patient forcibly expels from the lungs after a maximal inspiration (forced vital capacity or FVC) and the air volume exhaled during the first second (forced expiratory volume in one second or FEV1).40,44 Values are compared with predicted normal values (for age, height, sex, and ethnicity) to determine the severity of airway obstruction (e.g. mild, moderate, or severe disease levels).40 A post-bronchodilator FEV1/FVC ratio < 70% confirms the presence of airflow limitation that is not fully reversible.40 Some other measures such as the Modified Medical Research Council (mMRC) dyspnea scale for measuring breathlessness, exacerbation frequency, body mass index, quality of life assessment, and exercise capacity are used to better understand patient’s airflow status. Jones et al (2014) outlined the validated minimal clinically important differences (MCID) for the most frequently used COPD outcomes in placebo-controlled clinical trials. For the lung function outcome, a MCID of 100 ml for FEV1 was established for a COPD treatment to be considered effective. An improvement of 1 unit in the Transition Dyspnea Index (TDI) and a reduction of 4 units in the St George’s Respiratory Questionnaire were defined as MCID. No validated MCID is available for the exacerbation rate.48

COPD is a preventable disease, but once a patient has developed COPD, it is a chronic disease that is largely incurable. The goal of management is to improve a patient’s functional status and quality of life (reducing symptoms and future risk of exacerbations).40 Initially, smoking cessation or avoidance of smoke and other air pollutants is fundamental to prevent or slow disease progression.38,49 According to the WHO, smoking cessation is the single most effective and cost-effective way to reduce the risk of developing COPD and stop its progression.50 The WHO states that brief tobacco dependence treatment is effective and

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recommends that every tobacco user should be offered this treatment at every health care provider visit.50 The 2017 GOLD guideline includes several smoking cessation pharmacological strategies, such as nicotine replacement products, varenicline and bupropion, and highlights the utility of behavioral support programs.49 COPD pharmacotherapy can alleviate symptoms such as wheezing and coughing, decrease the frequency and severity of exacerbations, and increase exercise tolerance (by acting on bronchial smooth muscle contraction, bronchial mucosal congestion and edema, airway inflammation, and increased airway secretions). Currently, no treatment (aside from lung transplantation) has been shown to significantly improve long-term lung function or decrease mortality.38,40 Reduction of therapy once symptom control has been achieved is not normally possible in COPD and further worsening of lung function usually requires the introduction of additional treatments.50 Medications for the management of COPD include oral inhalation β2-agonists (SABA and LABA), oral inhalation anticholinergics (SAMA and LAMA), corticosteroids (inhaled and systemic), methylxanthines, phosphodiesterase-4 inhibitors, and combinations of short-acting bronchodilators (SABA/SAMA), long-acting bronchodilators (LABA/LAMA), and long-acting β2-agonists with inhaled corticosteroids (LABA/ICS). Bronchodilators on an as-needed basis or on a regular basis provide symptomatic relief but do not reduce disease progression.50,51 The long-term decline in lung function is one of the hallmarks of the disease.40,50 The GOLD pharmacologic treatment algorithm based on group A through D classification (using symptoms and exacerbation history) is discussed in the guideline section.

Patients with COPD often experience acute exacerbations of signs and symptoms which the WHO describes as another hallmark of COPD, and exacerbations and co-morbidities contribute to the overall severity of COPD.50 An exacerbation can be caused by several factors, but most commonly by respiratory tract infections.40 Initial recommendations for pharmacological treatment of an exacerbation include short-acting β2-agonists, with or without short-acting anticholinergics, and short courses (5-7 days) of systemic corticosteroids. Antibiotics are also considered for those with clinical signs of airway infection (e.g., increased volume and change of color of sputum, or fever).40,50 Methylxanthines, which have a narrow therapeutic index, are not recommended due to their unfavorable safety profiles.40,52 GOLD guidelines state that adequate interventions for the prevention of exacerbations should be initiated following an exacerbation, and include bronchodilators (LABAs, LAMAs, LABA+LAMA), corticosteroid-containing regimens (LABA+ICS, LABA+LAMA+ICS), non-steroid anti-inflammatory (roflumilast), anti-infectives (vaccines, long-term macrolides), mucoregulators (N-acetlcysteine, carbocysteine), and others (smoking cessation, rehabilitation, lung volume reduction).40 Selective inhibitors of isoenzyme phosphodiesterase-4 (PDE-4 inhibitors) increase cyclic adenosine monophosphate (cAMP) in inflammatory and immunomodulatory cells reducing airway inflammation.53 The only PDE-4 inhibitor currently available in the U.S. is roflumilast (Daliresp), administered orally and once-daily, to reduce the

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risk of exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations (not for the relief of acute bronchospasm).54,55 Azithromycin or erythromycin can also be used to reduce exacerbation risk. GOLD guidelines report that a reduction in the exacerbation risk has been demonstrated with the long-term use over 1 year of azithromycin or erythromycin. However, azithromycin may be linked with an increased risk of bacterial resistance and hearing impairment.49

Patient adherence to COPD treatment is a key component to achieve treatment success, improve health-related quality of life, reduce the risk of hospitalizations and diminish health system costs.56-58 Treatment adherence may increase by simplifying dosing regimens (i.e. using medications allowing for lower dosing frequencies such as once daily instead of twice daily), employing an easy-to-use59 and intuitive inhalation device, and using a single inhaler instead of multiple separate inhalers when dual- or triple-combination therapy is necessary.56,57,60

Patients with COPD may also benefit from supplemental oxygen (if blood oxygen levels are low), nonpharmacological interventions such as exercise,38,49,50 and administration of influenza and pneumococcal vaccines to decrease the impact of lower respiratory infections (infections often trigger exacerbations).38,49 Treatment programs such as pulmonary rehabilitation teach COPD management strategies on an individualized basis (e.g. breathing strategies, energy-conserving techniques, and nutritional counseling) to increase quality of life.38,40 It has been reported that COPD patients with poor nutritional status and low body weight have decreased pulmonary status, reduced diaphragmatic mass, poorer exercise capacity, increased mortality rates and reduced quality of life.61

Clinical Guidelines for the Management of COPD

Diagnosis

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) assessment guideline for guiding pharmacotherapy in COPD has progressed from a simple spirometric grading system (classified COPD severity into GOLD 1 to 4 groups according to the predicted FEV1) to the “ABCD” assessment tool in 2011 which combined spirometry, clinical symptoms, and frequency of exacerbations per year,40,62 and currently to the 2017 guideline in which some refinements were included to address concerns with the 2011 tool while “maintaining consistency and simplicity for the practicing clinician.”40,49 In the new guideline, spirometric grades are separated from symptoms and exacerbation history so that patients are first classified as GOLD grades 1-4 (disease severity based on FEV1), and then as Group A-D based on exacerbation history, assessment of symptoms, and risk of future exacerbations.40,45,49

In the current guideline, the GOLD committee recommends, after a confirmed diagnosis by spirometry (post-bronchodilator FEV1/FVC <0.7), further assessment of the patients’ condition by:

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1. Spirometry to determine the severity of airflow limitation which is graded as GOLD 1=mild (FEV1 ≥80), GOLD 2=moderate (FEV1 50-79), GOLD 3=severe (FEV1 30-49), or GOLD 4=very severe (FEV1 <30)

2. Assessment of symptoms using different questionnaires: a. the Modified Medical Research Council (mMRC) questionnaire for assessment of

dyspnea, i.e. ranging from Grade 0= “I only get breathless with strenuous exercise” to Grade 4= “I am too breathless to leave the house or I am breathless when dressing and undressing.”40

b. the COPD Assessment Test (CAT) for assessment of symptoms. 3. Recording their history of exacerbations in the previous year (0-1 or ≥2 exacerbations)

and prior hospitalizations

Labelling a patient’s COPD condition includes both a grade and a group e.g. GOLD Grade 4, group B.

As stated in the guideline: “This classification scheme may facilitate consideration of individual therapies (exacerbation prevention versus symptom relief)” and “also help guide escalation and de-escalation therapeutic strategies for a specific patient.”40

Smoking Cessation

Current Global Initiative for GOLD guidelines stress the importance of smoking cessation, and include a Cochrane systematic review reference of long-term quit success rates of up to 25% if effective resources and time are dedicated.40,63 The guideline includes a strategic framework for health care providers to help patients stop smoking. The benefit of vaccinations (influenza and pneumococcal), other non-pharmacological treatments, and recommendations for prescription of supplemental oxygen are also included as pharmacological treatments “should be complemented by appropriate non-pharmacological interventions.”40

Pharmacotherapy

The GOLD committee recommends that treatment should “be individualized and guided by severity of symptoms, risk of exacerbations, side-effects, comorbidities, drug availability and cost, and the patient’s response, preference and ability to use various drug delivery devices.”40

Pharmacologic therapy used in COPD includes β2-agonists, anticholinergics, methylxanthines, phosphodiesterase-4 inhibitors, and combinations (including corticosteroids).40 In the past, GOLD recommendations were given for initial therapy according to airflow obstruction (FEV1), symptoms and exacerbations. Currently, the 2017 GOLD guidelines include proposed pharmacologic algorithms based on patients’ symptoms and exacerbation rate (i.e. by ABCD group classification) without considering FEV1 measurement.40,64 Moreover, recommendations are proposed for initiation of therapy and for subsequent escalation and/or de-

22

escalation (considering symptoms and exacerbation risk).40 It is important to note that treatment escalation has not been systematically evaluated and de-escalation strategies only include ICS. The recommendations will be re-evaluated as additional evidence becomes available.40

GOLD guideline recommends the following pharmacologic treatment algorithms for each group (A-D):

Table 4. Pharmacologic treatment algorithms for the management of COPD (GOLD Guidelines)40

GOLD Groups

Symptom Burden

Exacerbation/previous year

Initial, escalation and de-escalation pharmacological strategiesa

A Low (mMRC 0-1,

CAT <10)

0-1 (no hospital admission)

1. Single bronchodilator (short or long-acting bronchodilator)

2. Evaluate and switch to another if necessary;

B High (mMRC ≥2, CAT ≥10)

0-1 (no hospital admission)

1. LAMA or LABA 2. If symptoms persist: LAMA+LABA

Cb Low (mMRC 0-1,

CAT <10)

≥2 or ≥1 leading to hospitalization

1. LAMA 2. If further exacerbations, switch to:

LAMA+LABA (preferred) or LABA+ICS (alternative)

Db High (mMRC ≥2, CAT ≥10)

≥2 or ≥1 leading to hospitalization

1. LABA+LAMA (preferred); some patients may start with LAMA or LABA/ICS

2. If further exacerbations and symptoms persist: TT (LABA+LAMA+ICS)

3. If further exacerbations occurs: Roflumilast (if FEV1<50 and chronic

bronchitis) Macrolide (in former smokers)c Stop ICS

Abbreviations: CAT, COPD assessment test; COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroids; LABA, long-acting β2-adrenergic agonist; LAMA, long-acting antimuscarinic agent; mMRC, modified Medical Research Council; TT, triple therapy; a Based on efficacy and safety data available. GOLD guidelines note that escalation and de-escalation have not been “systematically tested” b Treatment recommendations with lack of supporting direct evidence c Azithromycin is preferred40

The 2017 GOLD guidelines recommend a single bronchodilator for initial therapy in those

groups with lower risk of exacerbations (i.e. groups A and B). LABA/LAMA combination products are recommended as the preferred option in patients with moderate to severe COPD, when symptoms persist or further exacerbations occur on monotherapy treatment with LAMA or LABA (i.e. group B and C). For group D patients, initiate therapy with a LABA/LAMA combination product (preferred treatment) and escalate to triple therapy (LABA+LAMA+inhaled

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corticosteroids) if further exacerbations occur. Roflumilast or a macrolide may be considered, in certain severe patients if appropriate, and require evaluations and individual management.40,45,49

Comparison data LABA/ICS vs. LABA/LAMA

Recent evidence from a study published in the New England Journal of Medicine indicates that LABA/LAMA treatment is more effective at reducing exacerbations than LABA/ICS combinations.49,65 This study (Wedzicha et al. 2016) was a 52-week non-inferiority trial evaluating LABA/LAMA vs LABA/ICS (LABA indacaterol 110 mug plus the LAMA glycopyrronium 50 mug once daily or the LABA salmeterol 50 mug plus the inhaled glucocorticoid fluticasone 500 mug twice daily). The primary outcome was the annual rate of all COPD exacerbations.65 Even though this was a non-inferiority trial, the authors found that indacaterol/glycopyrronium was not only non-inferior, but more effective than salmeterol/fluticasone in decreasing COPD exacerbations in patients with a history of exacerbation during the previous year.65 The 2017 GOLD guidance reflects this evidence by including the LABA/LAMA combination as preferred over LABA/ICS combinations (but still keeping it as an alternative).40

Triple Therapy

In September 2017, the first single-triple-therapy inhaler was approved in the U.S based on 2 confirmatory trials. It contains fluticasone furoate, umeclidinium, and vilanterol. It is indicated for the long-term, once-daily, maintenance treatment of patients with COPD, including chronic bronchitis and/or emphysema, who are on a fixed-dose combination of fluticasone furoate and vilanterol for airflow obstruction and reducing exacerbations in whom additional treatment of airflow obstruction is desired or for patients who are already receiving umeclidinium and a fixed-dose combination of fluticasone furoate and vilanterol.66

Evidence presented by the GOLD guidelines supporting stepping up to triple therapy, includes (details of evidence referenced by the GOLD guidance was included to improve understanding):

• “The step up in inhaled treatment to LABA plus LAMA plus ICS (triple therapy) can occur by various approaches.”40,67 o According to Bruselle et al. (2015) “Real-world prescription pathways leading to triple

therapy (TT) (inhaled corticosteroid [ICS] plus long-acting beta2-agonist bronchodilator [LABA] plus long-acting muscarinic antagonist) differ from Global initiative for chronic Obstructive Lung Disease [GOLD] and National Institute for Health and Care Excellence treatment recommendations” and they therefore conducted a historical analysis of prescribing pathways in the UK (2002 to 2010). COPD patients without asthma that were receiving TT were identified and pathways from diagnosis to TT were then identified, and LABA plus ICS was identified as the most common

24

prescription pathway to TT. The authors concluded that “Real life UK prescription data demonstrates the inappropriate prescribing of TT and confirms that starting patients on ICS plus LABA results in the inevitable drift to overuse of TT. This study highlights the need for dissemination and implementation of COPD guidelines to physicians, ensuring that patients receive the recommended therapy.”67

• “This may improve lung function and patient reported outcomes.”40,68 o Welte et al (2009): “budesonide/formoterol added to tiotropium versus tiotropium

alone provides rapid and sustained improvements in lung function, health status, morning symptoms and activities, and reduces severe exacerbations.”68

o Singh et al (2008) states that there is little data on triple therapy with salmeterol, fluticasone propionate (SFC) and tiotropium bromide (TIO). They compared the effects of SFC 50/500 mcg twice daily in addition to TIO 18 mcg once daily versus the individual treatments alone, and found greater improvements with triple therapy in terms bronchodilation, as well as advantages in airway conductance, lung volumes, and patient related benefits (improving Transition Dyspnoea Index and use of rescue medication).”69

o Jung et al (2012) states that triple therapy with tiotropium and fluticasone propionate/salmeterol (FSC) is commonly used in COPD, “but no study had evaluated the effectiveness of tiotropium plus FSC with 250 mug of fluticasone propionate.” They therefore evaluated “whether tiotropium (18 mug once daily) plus FSC (250/50 mug twice daily) provides better clinical outcomes compared to tiotropium monotherapy” and found that “Over the course of 24 weeks, FSC (250/50 mug twice daily) added to tiotropium provided greater improvement in lung function and quality of life in patients with COPD (FEV(1) </= 65%) than tiotropium alone.”70

o Hanania et al (2012) evaluated the efficacy and safety of triple therapy: “fluticasone/salmeterol (FSC) (250/50 mcg twice daily) when added to tiotropium (18 mcg once daily) (TIO)” and found that it “significantly improves lung function without increasing the risk of adverse events.”71

• “Adding a LAMA to existing LABA/ICS improves lung function and patient reported outcomes, in particular exacerbation risk.”40 69,72-74

• “A RCT did not demonstrate any benefit of adding ICS to LABA plus LAMA on exacerbations.”40,75

• “Altogether, more evidence is needed to draw conclusions on the benefits of triple therapy LABA/LAMA/ICS compared to LABA/LAMA.”40

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C) Asthma and COPD

Disease overview

According to the updated Joint Project of GINA and GOLD (April 2017),76 “asthma-COPD overlap is characterized by persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD. Asthma-COPD overlap is therefore identified in clinical practice by the features that it shares with both asthma and COPD”. This project includes new recommendations for patients with both COPD and asthma. The correct identification of these patients and adequate treatment decisions remain a challenge. Some patients are borderline between asthma and COPD because they share asthma and COPD symptoms. This is especially common in smokers and the elderly. Given that this condition is considered a combination of asthma and COPD characteristics, the usual term used in previous guideline versions (i.e. “Asthma COPD Overlap Syndrome (ACOS)”) is no longer recommended. Currently, the Joint Project of GINA and GOLD considers that “asthma-COPD overlap” is the most appropriate term.76

Diagnosis of patients with respiratory symptoms is based on a stepwise process including: a) identification of patients with chronic airway disease by clinical history evaluation, physical examination and other investigations, b) differentiation between typical asthma, typical COPD and asthma-COPD overlap by exploring the usual features, c) assessment of airflow limitation by spirometry, and d) referral to a specialist in special situations.76

Clinical Guidelines for the Management of Asthma-COPD Overlap

The treatment recommendations outlined in table 6 are based on limited clinical evidence since studies conducted in this type of population are lacking.76

Table 5. Recommendations for Initial Treatment in Patients with Asthma-COPD Overlap76* Diagnosis Symptoms Initial Treatment

Asthma Features of asthma - Asthma drugs (adequate ICS as controller therapy)

- NO LABA monotherapy Possible Asthma Some features of asthma

Asthma-COPD Overlap Features of both asthma and COPD - Low/moderate dose ICS and consider LABA +/or LAMA

COPD Features of COPD - COPD drugs (bronchodilators or ICS/bronchodilator)

- NO ICS alone Possible COPD Some features of COPD

Abbreviations: COPD, chronic obstructive pulmonary disease; GINA, global initiative for asthma; GOLD, global initiative for chronic obstructive lung disease; ICS, inhaled corticosteroids; LABA, long-acting beta2 agonists; LAMA, long-acting muscarinic antagonist * See GINA and GOLD guidelines for further information about recommended treatments

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Pharmacology

The differing mechanism of action of medications indicated for the management of asthma allows tackling asthma through several pathophysiology aspects.77,78 β2-agonists such as albuterol, levalbuterol, formoterol, salmeterol, and vilaterol exert their pharmacologic action via relaxation of bronchial smooth muscles due to the selective activation of β2 receptors.52 These bronchodilators differ in onset of action and duration of effect. Short-acting β2-agonists (SABAs) including albuterol and levalbuterol have a fast onset of action and short duration, which make these agents useful as quick relievers for asthma attacks.4 LABAs including salmeterol, vilanterol and formoterol have slower onset of action than SABAs but provide a longer duration of effect.52 A study reported a bronchodilator effect of longer than 12 hours for salmeterol/fluticasone propionate and budesonide/formoterol,79 and longer than 24 hours for fluticasone/vilanterol.11 Among the LABAs, evidence showed that vilanterol has a faster onset of action than salmeterol.80 ICSs activate glucocorticoid receptors resulting in a delayed onset of action and extended duration of anti-inflammatory activity in the airways.81 Both LABA and ICS are classified as long-term controller medications for persistent asthma and are available as separate inhalers or may be combined into one single inhaler.52 When ICS and LABA are combined, complementary and positive benefits are shown in several studies.78,81 Regarding the recommended regimen, ICS and LABA are usually used as fixed-dose combination (once daily or twice daily) with SABA administered on as-needed basis for asthma exacerbations.52,77

ICS/LABA fixed-dose combinations are administered via inhalation, are primarily metabolized by the liver via the cytochrome P450 system, and eliminated within 4.7 to 25 hours.18 Table 6 outlines the main pharmacokinetic characteristics of ICS/LABA combination products. Although no formal drug-drug interaction have been conducted with ICS/LABAs, drug-drug interactions may occur as individual components of the combinations (i.e. glucocorticoids and LABAs) are known to be extensively metabolized by CYP3A4.7-12 For instance, vilanterol is a substrate of CYP3A4 and salmeterol hydroxylation is metabolized by the CYP3A4 isoenzyme.82 Systemic exposure to ICS and LABAs may be increased when they are administered with strong CYP3A4 inhibitors such as ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin.81 ICS/LABA combination products should be administered with caution in combination with other adrenergic drugs (LABAs’ effects may be increased), with xanthine derivatives, diuretics or non-potassium sparing diuretics (hypokalemia and electrocardiograph changes produced by LABAs may be worsened), with monoamine oxidase inhibitors, tricyclic antidepressants and QTc-prolonging drugs (LABAs’ cardiovascular events may be potentiated), and with beta blockers (reduced effect of beta-agonists and increased risk of severe bronchospasm).7-12 No pharmacokinetic interactions between the two components of the FDCs were identified in pharmacokinetic studies when both drugs were administered concomitantly.7-12

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Table 6. Pharmacokinetics of ICS/LABA Combination Products18 Active Substance

(Combination Products) Absorption Protein binding Metabolism Excretion Elimination (half-life)

Budesonide/formoterol

BUD: - Well absorbed from the lungs - Tmax (inhalation): 21 min (20

min, pediatric) FM: - Rapidly absorbed into plasma

from the GI tract - Tmax (inhalation): 10 min

BUD: 85% to 90%

FM:

31% to 64%

BUD: Liver (extensive), via CYP3A4 FM: Hepatic; via CYP2D6, CYP2C19, CYP2C9 and CYP2A6; direct glucuronidation (primary pathway), O-demethylation and glucuronide conjugation

BUD: - Fecal: as metabolites - Renal: 60% approx. FM: - Fecal: 32% to 34% - Renal: 59% to 62% as

metabolites, 6% to 10% unchanged

BUD: 4.7 hr

FM: 7.9 hr

Fluticasone propionate/salmeterol

FP: - Tmax (inhalation): 1-2 hr - BA: 18% SAL: - Tmax (inhalation): 5 min - BA: very low or undetectable

FP: 91%

SAL: 95%

FP: Complete first pass metabolism SAL: metabolized extensively via hydroxylation

FP: - Renal (<5%) - Feces (90%)

SAL: - Renal (25 to 60% in urine) - Feces (25 to 60%)

FP: 5.33 to 7.65 hr

SAL: 5.5 hr (after oral dose administration)

Fluticasone

furoate/vilanterol

FF: - Tmax (inhalation): 0.5 to 1 hr - BA: 1.3% (systemic); 15.2%

(absolute) VI: - Tmax: 10 min - BA: <2% (systemic); 27.3%

(absolute)

FF: 99.6%

VI: 93.9%

FF: Hepatic (extensive; via CYP3A4) VI: via CYP3A4

FF: - Feces: 90% (IV) to 101%

(oral) - Renal: 1% (oral) to 2% (IV) VI: - Urine (70%) - Feces (30%)

FF: 24 hr (hepatic impairment: 30.9 to

53.5 hr)

VI: 21.3 hr

Mometasone/formoterol

MOM: - Tmax (inhalation): 1 to 2 hr - BA: <1% FM: - Tmax (inhalation): 0.58 to 1.97 hr

MOM: 98% to 99%

FM: 31% to

38%

MOM/FM: Liver (extensive) MOM: - Fecal: 74% - Renal: 8% changed FM: - Fecal: 32% to 34% - Renal: 6.2% to 6.8%

unchanged

MOM: 25 hr

FM:

9 to 11 hr

Abbreviations: BA, bioavailability; BUD, budesonide; COPD, chronic obstructive pulmonary disease; FF, fluticasone furoate; FM, formoterol; FP, fluticasone propionate; GI, gastrointestinal; min, minute; hr, hour; LABA, long-acting β2-adrenergic agonist; MOM, mometasone; SAL, salmeterol; Tmax, time to peak concentration; VI, vilanterol

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Special Populations

Table 7 describes the recommendations for ICS/LABA combination product use in special populations.

Renal and hepatic impairment

No dosage adjustment is required in patients with renal impairment. Caution should be exercised in patients with hepatic impairment.

Pregnant women

No adequate and well-controlled studies of ICS/LABA FDCs are available. The use of these combinations during pregnancy and lactation should be assessed in relation to the benefit for the mother and the risk for the fetus. Beta-agonists may affect uterine contractility. Cautious use is advised when these combinations are administered during labor and delivery.7-12

Pregnant women with asthma should be monitored to avoid uncontrolled asthma. If uncontrolled asthma occurs, asthma attacks should be treated. Budesonide is the preferred ICS by NHLBI because there is more evidence available about this agent than with other ICS.4 The treatment benefits for the mother and fetus outweigh the risk of asthma medication.83

Geriatric patients

In several long-term clinical trials including COPD patients, the incidence of pneumonia in the fluticasone/salmeterol group was higher in patients older than 65 years old than in those patients younger than 65 years old.8

Comorbidities

Patients with asthma may also have comorbidities such as allergic bronchopulmonary aspergillosis, gastroesophageal reflux, obesity, obstructive sleep apnea, rhinitis and sinusitis, stress and depression. Treatment of these conditions may improve asthma control.1,4 Comorbidities associated with COPD include lung cancer, cardiovascular disease (heart failure, arrhythmias, peripheral vascular disease and hypertension), osteoporosis, depression/anxiety and gastroesophageal reflux. Each comorbid disease should be appropriately treated.40,45

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Table 7. Recommendations for Special Populations of ICS/LABA Combination Products7-12 Active Substance

(Combination Products)

Renal Impairment

Hepatic Impairment Pregnancy and lactation Pediatric Geriatric

Budesonide/ formoterol fumarate

Not studied (No dosage adjustment proposed)

Not studied. Monitor patients for signs of increased drug exposure

Pregnancy: No studies in pregnant women. Adverse events were observed in animal reproduction studies using this combination. In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal adverse outcomes such as preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control. Given that β-agonists have the potential to affect uterine contractility if administered during labor, the use of this combination during labor should be restricted to those patients in whom the benefits clearly outweigh the risks. Lactation: It is not known if formoterol is present in breast milk; budesonide is present in small amounts. Infant risk cannot be ruled out. Weigh the potential benefits of drug treatment against potential risks before prescribing this drug during breastfeeding.

Indicated for children ≥6 years. Safety and effectiveness of SYMBICORT in asthma patients <6 years of age have not been established

No adjustment required. As with other products containing β2-agonists, special caution should be exercised in elderly patients with cardiovascular disease

Fluticasone propionate/ Salmeterol


Not studied. Fluticasone and salmeterol are primarily cleared in the liver and may lead to accumulation in patients with hepatic impairment; Monitor patients for signs of increased drug exposure

Pregnancy: No studies in pregnant women. Adverse events were observed in animal reproduction studies using this combination. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. Lactation: It is not known if fluticasone or salmeterol are present in breast milk. The decision to continue or discontinue breastfeeding during therapy should take into account the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.

Indicated for children aged ≥4 years (Advair Diskus) and children aged ≥12 years (Advair HFA and Airduo Respiclick)

Limited data. Dose selection should be cautious. As with other products containing β2-agonists, special caution should be exercised in elderly patients with cardiovascular disease

Fluticasone furoate/

Vilanterol

No dosage adjustment necessary

No dosage adjustment proposed. However, systemic fluticasone exposure may be

Pregnancy: Insufficient data in pregnant women. Adverse events have not been observed in animal reproduction studies. In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal

Safety and efficacy not established in children

No adjustment required

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Active Substance (Combination

Products)

Renal Impairment

Hepatic Impairment Pregnancy and lactation Pediatric Geriatric

increased up to threefold in patients with hepatic impairment. Use with caution and monitor closely in patients with moderate to severe hepatic impairment

outcomes such as pre-eclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women should be closely monitored and medication adjusted as necessary to maintain optimal control of asthma. Given that β-agonists have the potential to affect uterine contractility if administered during labor, the use of this combination during labor should be restricted to those patients in whom the benefits clearly outweigh the risks. Lactation: It is not known if fluticasone or vilanterol are present in breast milk. The decision to continue or discontinue breastfeeding during therapy should take into account the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.

Mometasone/ Formoterol


Not studied (Mometasone exposure is increased with hepatic impairment)

Pregnancy: No studies in pregnant women. In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal adverse outcomes such as preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control. Given that β-agonists have the potential to affect uterine contractility if administered during labor, the use of this combination during labor should be restricted to those patients in whom the benefits clearly outweigh the risks. Lactation: Not known whether mometasone and formoterol are excreted in human milk. Evaluate health benefits of breastfeeding versus mother’s clinical need for therapy and any potential adverse effects on the breastfed infant from therapy or from the underlying maternal condition.

Children ≥12 years and adolescents (adult dosing)

No adjustment required. As with other products containing β2-agonists, special caution should be exercised in elderly patients with cardiovascular disease

Abbreviations: LABA, long-acting beta2 agonists; ICS, inhaled corticosteroids; COPD; chronic obstructive pulmonary disease

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Utah Medicaid Utilization Data

According to Utah Medicaid fee-for-service (FFS) data, the number of unique FFS patients with only asthma diagnosis coding from 2013 to 2017 period was 19,449. The number of patients with both asthma and COPD diagnosis coding was 2,955, and those with COPD only was 8,824. The majority of FFS patients filling prescriptions for ICS/LABA combination products were adults. The most commonly prescribed FDC for patients with asthma, COPD, or both asthma and COPD diagnosis coding during 2013-2017 period was fluticasone/salmeterol (specifically Advair Diskus), followed by budesonide/formoterol, mometasone/formoterol, and fluticasone/vilanterol. Some patients filled prescriptions for 2 separate inhalers at the same time instead of using single-inhaler, FDCs. Currently, budesonide/formoterol (Symbicort), fluticasone/salmeterol (Advair Diskus), fluticasone/vilanterol (Breo Ellipta) and mometasone/formoterol (Dulera) are preferred in the Utah Medicaid Preferred Drug List. The remaining 2 fluticasone/salmeterol FDC products (Advair HFA, Airduo Respiclick) are currently non-preferred.84

Table 8. ICS/LABA treatment in Utah Medicaid FFS patients for 2013-2017 period

Combination Products*

Unique Patients

with Medication

Fills

Unique Patients

with included

diagnoses**

Only COPD Dx Coding

(n= 8,824)

Only Asthma Dx

Coding (n= 19,449)

Asthma AND COPD Dx Coding (n=2,955)

No COPD/Asthma

Dx Coding

Fixed-dose combinations (ICS/LABA) Budesonide/formoterol 1154 1018 158 602 258 136 Fluticasone/salmeterol 2311 2073 291 1256 526 238 Fluticasone/vilanterol 65 50 9 24 17 15 Mometasone/formoterol 519 447 44 302 101 72

Separate inhalers in combination*** (ICS+LABA) Beclomethasone + formoterol 1 1 1 0 0 0 Beclomethasone + salmeterol 5 4 1 2 1 1 Budesonide + formoterol 17 16 9 1 6 1 Budesonide + salmeterol 1 1 1 0 0 0 Fluticasone + formoterol 8 8 5 0 3 0 Fluticasone + salmeterol 16 14 1 9 4 2 Mometasone + formoterol 1 1 1 0 0 0 Mometasone + salmeterol 3 3 0 2 1 0 Abbreviations: COPD, chronic obstructive pulmonary disease; Dx, diagnosis; FDC, fixed-dose combination; FFS, fee-for-service; ICS, inhaled corticosteroid; LABA, long-acting beta-2 agonist * Via FDCs or via separate inhalers ** Total unique patients with either COPD or asthma diagnosis codes submitted for 2013-2017 period *** Separate single inhalers filled within 30 days

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Methods

Literature Search

Search strategies were developed by an informational scientist for OVID Medline and EMBASE. Strategies consisted of controlled vocabulary, such as MeSH, and keyword phrases. Two methodological filters were used, one for systematic reviews and another for randomized controlled trials (RCTs). Results were limited to English language. Databases were searched from date of inception forward. In EMBASE, we excluded conference abstracts. Searches were conducted in June 2017. We searched for systematic reviews first, and then for RCTs, without any restriction date. The complete search strategies and terms are available in Appendix A.

We also screened the reference lists of related systematic reviews. Likewise, we searched other relevant websites for further information:

1. The National Institute of Health (NIH), The National Heart, Lung, and Blood Institute (NHLBI), the World Health Organization (WHO), the Centers for Disease and Control (CDC), the Global Initiative for Chronic Obstructive Lung Disease (GOLD) and the Global Initiative for Asthma (GINA) websites for the most recent asthma and COPD treatment guidelines.

2. Food and Drug Administration (Drugs@FDA: FDA Approved Drug Products: https://www.accessdata.fda.gov/scripts/cder/daf/) for prescribing information package inserts

3. Evidence-based drug information databases (Micromedex, Lexicomp, and UpToDate)

Screening

At least two review authors screened titles and abstracts. The full texts for all citations receiving two inclusion votes were retrieved; eligibility criteria for inclusion was determined by the lead author. Conflicts were resolved via discussion between reviewers or a third person. Figure 1 shows the PRISMA flow chart85 for the review process.

Inclusion and Exclusion Criteria

Systematic reviews and RCTs providing head-to-head efficacy comparisons between the ICS/LABA combination products were included. For product comparisons where a systematic review provided robust data, we examined only those trials or systematic reviews published after the search date of the robust systematic reviews.

Excluded references met the following exclusion criteria:

• Studies evaluating non-FDA-approved indications or dosages

33

• Other types of studies (e.g. non-comparative or non-randomized trials, placebo-controlled studies, phase 1 and 2 studies, observational studies, in vitro studies, animal studies, cost-effectiveness studies, etc.)

• Reviews not using a systematic review methodology

A list containing the excluded references is provided in Appendix F.

Figure 1. PRISMA Flow Diagram of the selection process

Records identified through database searching n = 1381

(221 SRs + 1160 RCTs)

Scre

enin

g In

clud

ed

Elig

ibili

ty

Iden

tific

atio

n

Records screened n = 1271

Records excluded n = 1184

Full-text articles assessed for eligibility

n = 87

Full-text articles excluded, with reasons n = 58

• Wrong comparator: 32 • Wrong outcomes: 6 • Wrong design: 5 • Wrong intervention: 2 • Review (not a SR, not a RCT): 8 • Duplicates: 4 • Full text not available: 1

Studies included in qualitative synthesis n = 29

• 26 efficacy studies • 3 safety studies

Records after duplicated removed n = 1271

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Clinical Efficacy and Safety

Clinical evidence involving head-to-head comparisons among ICS/LABA combination products is presented for the products currently available in the United States. From a total of 1,381 references identified using the developed search strategy (221 SR/MA and 1,160 RCTs), we selected 26 efficacy/safety articles containing 5 SR/MA, 21 RCTs, and 2 MTCs, and 3 safety articles containing 1 SR/MA and 2 RCTs for our qualitative synthesis. Main results are outlined in Appendixes B, C, D, and E.

Studies including ICS/LABA combinations were mainly performed in patients with persistent asthma that continue suffering symptoms and exacerbations with low- or medium-doses ICS therapy, or in patients with moderate to severe COPD. Regarding asthma management, the most common primary efficacy endpoints include: a) lung function (FEV1 or peak expiratory flow [PEF] from baseline), b) assessment of asthma symptoms (day and night time symptom score) and use of rescue medications, c) asthma exacerbations, and d) change in health-related quality of life (measured by asthma quality of life questionnaire [AQLQ]). Concerning COPD management, the most frequent primary endpoints include improvement in lung function, exacerbation rate, and health status.

Different inhaler devices delivering the same dose of BUD plus FM are internationally approved. BUD/FM pMDI is available in the U.S. BUD/FM DPI is available in Europe. Two RCTs compared the efficacy and safety of the two aforementioned inhalers showing therapeutic equivalence between them.86,87 Hence, evidence available evaluating BUD/FM DPI was also included in this report.

1. Single ICS/LABA inhaler versus separate inhalers administered concomitantly (ICS+LABA)

a) Budesonide/formoterol (BUD/FM) versus budesonide plus formoterol (BUD+FM) [4 articles: 4 RCTs]

Patients with asthma

Clinical trials including the U.S. BUD/FM inhaler (pMDI)

Noonan et al88 (2006) conducted a 12-week RCT in patients ≥12 years of age with moderate to severe persistent asthma previously receiving ICS therapy. Patients were treated with BUD/FM pMDI, BUD or FM monotherapy, placebo, or BUD+FM in separate inhalers. Results indicated similar efficacy outcomes in terms of mean changes in FEV1 and worsening or improvement in asthma symptoms between BUD/FM FDC and the concurrent administration of separate inhalers (BUD+FM). Safety profiles were also considered comparable between groups.

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Clinical trials including the non-U.S. BUD/FM inhaler (DPI)

Pohunet et al89 (2006) performed a clinical trial in children between 4 and 11 years old with asthma to compare BUD/FM DPI 80/4.5 µg, 2 inhalations twice daily (Symbicort Turbuhaler), budesonide plus formoterol (100 µg + 4.5 µg, 2 inhalations twice daily), and budesonide 100 µg 2 inhalations twice daily. No differences in efficacy outcomes (morning peak expiratory flow [PEF] and asthma symptom changes) and safety results were observed between groups.

Rosenhall et al90 2002 (6-month study, 586 patients) and Rosenhall et al91 2003 (6-month extension open label study, 321 patients) evaluated the single inhaler containing BUD/FM DPI 160/4.5 (2 inhalations twice daily) versus BUD and FM administered concomitantly in adult patients with moderate persistent asthma. The 6-month study reported that BUD/FM DPI was similarly effective in terms of lung function, exacerbation rate, asthma control, and health-related quality of life (measured by two different questionnaires) as BUD and FM administered at the same time in separate inhalers. Similar safety profiles were observed between groups. Data from a subgroup of patients completing the 12-month study showed similar efficacy and safety outcomes between groups that were constant until the end of the study. Of note, the proportion of withdrawals over 12 months was higher in the BUD+FM group than BUD/FM DPI group (19.4% vs 9.2%, respectively; p=0.008). Authors postulated a potential positive impact on adherence to inhalation therapy in those patients using one single inhaler compared to those using separate inhalers.

b) Salmeterol/fluticasone propionate (SAL/FP) versus salmeterol plus fluticasone propionate (SAL+FP) [6 articles: 1 SR/MA and 5 RCTs]


Kawai et al92 (2007) evaluated SAL/FP DPI 50/250 µg twice daily versus SAL+FP in a 14-day RCT including 18 adult Japanese and 17 Caucasian asthmatic patients. They found no significant differences in terms of FEV1 and specific airways conductance (sGaw) responses between SAL/FP and the separate inhalers administered concomitantly for total analysis. In addition, similar results were observed in Japanese and Caucasian asthmatic patients.

Van der Berg et al93 (2000) reported similar efficacy and safety results when SAL/FP DPI 50/100 µg twice daily and SAL+FP DPI administered via separate inhalers were compared in a 12-week study including asthmatic children aged from 4 to 11 years not responding to monotherapy with an ICS. Both treatment groups reported an improvement in lung function, asthma control and symptoms, without significant differences between groups. Although the authors did not measure adherence to inhalation therapy, they commented that a single inhaler may increase adherence.

36

Bateman et al94 (1998), Chapman et al95 (1999), and Aubier et al96 (1999) conducted 3 RCTs (one each) comparing SAL/FP DPI via single inhaler and FP+SAL administered via separate inhalers in patients ≥ 12 years old with asthma. Three different doses of fluticasone were tested (i.e. 100, 250 and 500 micrograms twice daily). All studies demonstrated that SAL/FP was as effective as SAL+FP with regard to the primary endpoint of lung function (measured by morning PEF rate) at week 12. In addition, Bateman et al showed superiority of SAL/FP 50/100 µg versus SAL+FP for lung function at week 12, and Chapman et al reported superiority of SAL/FP 50/250 µg for lung function values at other time points (week 3 and 4). Similar results were observed between groups for the secondary endpoints (i.e. evening PEF rate, day/night-time symptom scores, use of rescue medication, and safety outcomes).

Nelson et al97 (2003) conducted a meta-analysis to compare FP/SAL DPI versus separate inhalers administered concomitantly. Results suggested statistically significantly greater improvements in morning PEF with FP/SAL administered in one single inhaler than separate inhalers. Study limitations and a proper discussion regarding the clinical relevance of the results was lacking.

2. Fluticasone propionate/salmeterol (FP/SAL) DPI versus FP/SAL pMDI [3 articles: 3 RCTs]


• FP/SAL HFA MDI 50/25 µg vs FP/SAL Diskus 100/50 µg

Bateman et al98 (2001) directly compared two different inhalers (DPI and pMDI) containing FP/SAL in a 12-week multicenter RCT including 497 patients with asthma aged 11-79 years. The treatment arms were FP/SAL Diskus 100/50 µg (one inhalation twice daily) and FP/SAL HFA MDI 50/25 µg (two inhalations twice daily). Results demonstrated clinical equivalence between groups for the primary endpoint (increase in mean morning PEF over weeks 1 to 12), and all secondary endpoints (evening PEF, daytime and night-time symptom scores, use of rescue salbutamol and clinic FEV1).


You-Ning et al99 (2005) performed a RCT to compare FP/SAL HFA MDI 125/25 µg (two inhalations twice daily) vs FP/SAL Diskus 250/50 µg (one inhalation twice daily) in Chinese adult patients with moderate asthma. Both treatment arms reported similar improvements in the primary endpoint (morning PEF) and all secondary endpoints over weeks 1 to 4. Differences between groups were not statistically significant.


Van Noord et al100 (2001) evaluated FP/SAL HFA MDI 250/25 µg (two actuations twice daily) versus FP/SAL Diskus 500/50 µg (one actuation twice daily) in patients with asthma.

37

Clinical equivalence was demonstrated between groups for the primary endpoint (mean change in morning PEF over weeks 1 to 12) and for secondary endpoints.

Safety profiles were comparable between groups in the 3 aforementioned RCTs.

3. Budesonide/formoterol (BUD/FM) pMDI or DPI versus fluticasone propionate/salmeterol (FP/SAL) DPI or pMDI [7 articles: 3 SR/MA, 4 RCTs]


Two Cochrane reviews performed by Lasserson et al101 (2008) and Lasserson et al102 (2011) assessed the efficacy and safety between FP/SAL pMDI or DPI and BUD/FM pMDI or DPI twice daily in adolescents and adults with chronic asthma. Both reviews included the same 4 published RCTs (Aalbers 2004,103 Busse 2008,104 Kuna 2007 [COMPASS],105 and Dahl 2006106 [EXCEL]). The dose of FP/SAL was 500/100 mcg per day and doses for BUD/FM ranged from 400/12 mcg/day to 800/24 mcg/day. The meta-analysis indicated the following results:

- No statistically significant differences between groups for the primary endpoint (exacerbations requiring oral steroid treatment, exacerbations requiring admission to hospital, and asthma-related serious adverse events) at 6 months

- No statistically significant differences between groups for the secondary endpoint (lung function results, exacerbations requiring emergency department visit/hospital admission, adverse events, and rescue medication use)

Authors mentioned the results were associated with high imprecision due to the width of confidence intervals for the primary endpoint. Authors concluded the need for well-conducted RCTs, especially in children.

Edwards et al107 (2007) performed a meta-analysis to compare the effectiveness of BUD/FM versus ICS alone or other ICS/LABA in patients aged 16 years and older with moderate to severe asthma. Among the 15 studies considered for inclusion in the meta-analysis, 3 compared BUD/FM DPI versus FP/SAL MDI or DPI (Aalbers 2004,103 Kuna 2007 [COMPASS],105 and Dahl 2006106 [EXCEL]. Results for the comparisons of interest are reported below:

- No significant differences between groups for the primary endpoint of “treatment failure”, defined as 1 or more of the following outcomes: asthma-related serious adverse events, oral glucocorticosteroid treatment required, accident or emergency visit and/or admission to hospital, withdrawal due to a need for additional asthma therapy or adverse events.

- The secondary analysis showed no significant differences between groups in the number of exacerbations requiring oral steroid use. However, the risk of exacerbations requiring hospitalizations/A&E visits was statistically significantly higher with FP/SAL than BUD/FM.

38

Authors discussed several limitations, including primarily the use of an uncommon primary endpoint in this type of trial.

In addition, 3 short-term studies in asthmatic patients compared the onset of bronchodilation between single-inhaler BUD/FM pMDI or DPI and FP/SAL DPI. All showed BUD/FM had a faster onset of action measured by FEV1 at 3 minutes in comparison to FP/SAL.108-110 Moreover, improvements in FEV1 were more rapidly observed at other time points in those patients on treatment with BUD/FM than those with FP/SAL.108-110

Patients with COPD

Regarding the onset of effect of BUD/FM compared to FP/SAL, one study111 in patients with COPD reported faster onset of bronchodilator effect with BUD/FM compared to FP/SAL.

4. Fluticasone furoate/vilanterol (FF/VI) versus fluticasone propionate/salmeterol (FP/SAL) and/or BUD/FM [5 articles: 1 SR/MA, 4 RCTs, 2 MTC]


One Cochrane review, published by Dwan et al112 in 2016, evaluated the efficacy and safety of FF and VI in children and adults with chronic asthma. One 24-week study assessing FF/VI DPI 100/25 mcg once daily versus FP/SAL DPI 250/50 mcg twice daily was identified (Woodcock 2013113). A total of 806 patients with persistent asthma uncontrolled with medium-dose ICS were randomized. No statistically significant differences were found between groups for the primary endpoints (change in health-related quality of life, severe asthma exacerbations, and serious adverse events). No statistically significant differences were reported for the secondary endpoints (change in FEV1 and asthma symptoms). Authors highlighted the limited comparative efficacy and safety information available to make a robust decision about the preference of FF+VI over FP/SAL. The authors state that further research is required.

Svedsater et al114 (2016) performed a mixed treatment comparison (MTC) modelling approach, including direct and indirect comparisons (network meta-analysis), to evaluate the probability of non-inferiority of once-daily FF/VI compared to twice-daily ICS/LABA combination therapies. Thirty one RCTs including ICS/LABAs in asthma patients ≥ 12 years old were evaluated using covariate-adjusted Bayesian hierarchical models. Results suggested similar lung function improvements with FF/VI 100/25 µg and FF/VI 200/25 µg compared to corresponding doses of FP/SAL and BUD/FM. Health status outcomes were comparable between once-daily FF/VI 100/25 μg compared to twice-daily FP/SAL 250/50 μg and BUD/FM 320/9 μg. There were insufficient data to measure non-inferiority on health status of FF/VI 200/25 μg and exacerbation rates. Study limitations included: 1) indirect comparisons, 2) low number of RCTs assessing ICS/LABAs, especially those assessing exacerbation rate outcomes,

39

and 3) heterogeneity in design, outcome definition, population and region between included studies.

Patients with COPD

Dransfield et al115 (2014) conducted 3 RCTs in different centers to evaluate the efficacy and safety of FF/VI 100/25 µg once daily compared to medium-dose FP/SAL DPI (250/50 µg) twice daily over 12 weeks in adult patients with moderate to very severe COPD. The pooled analysis of the 3 trials showed statistically significant differences in favor of FF/VI for the endpoint of change in lung function at day 84; however, these results were not clinically relevant. Safety profiles were similar between groups.

Stynes et al116 (2015) performed a MTC, including direct and indirect comparisons (network meta-analysis), to evaluate the probability of non-inferiority of once-daily FF/VI compared to twice-daily ICS/LABA combination therapies. Thirty three RCTs including ICS/LABAs in COPD patients ≥ 12 years old were evaluated using covariate-adjusted Bayesian hierarchical models. Results suggested non-inferiority in terms of lung function and health-related quality of life improvements with FF/VI 100/25 µg compared to FP/SAL 500/50 µg and BUD/FM 400/12 µg. Regarding exacerbation rate outcome, non-inferiority was not demonstrated. Study limitations included: 1) indirect comparisons, 2) low number of RCTs assessing ICS/LABAs, especially those assessing exacerbation rate outcomes, and 3) heterogeneity in design, outcome definition, population and region between included studies.

Patients with asthma-COPD overlap

Ishiura et al117 (2015) conducted a 12-week, randomized, open-label cross-over study comparing FF/VI DPI 200/25 μg vs FP/SAL DPI 500/50 μg in 16 patients with asthma-COPD overlap syndrome (ACOS). This study reported the following results:

- Similar improvements in the main spirometry parameters for lung function (i.e. FEV1, forced expiratory flow, and forced vital capacity) between FF/VI once daily and FP/SAL twice daily in ACOS patients.

- No differences between groups for other parameters measured such as asthma control test and COPD assessment test.

Several limitations were identified including the controversial criteria to diagnose ACOS patients, the lack of evidence about the mechanism of the clinical benefit of FF/VI, and the use of an insufficiently validated method (forced oscillation technique) to measure the respiratory impedance. Authors propose the need of additional studies to confirm the efficacy of FF/VI in this type of patients.

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5. Mometasone/formoterol (M/FM) compared to fluticasone propionate/salmeterol (FP/SAL) [1 article: 1 RCT]


Bernstein et al118 2011 performed a multicenter, 12-week, noninferiority trial to compare the efficacy of M/FM MDI 200/10 μg twice daily versus FP/SAL DPI 250/ 50 μg twice daily in asthmatic patients aged ≥12 years uncontrolled with medium-dose ICS. This study demonstrated the below findings: - Noninferiority between treatment groups for the primary endpoint (i.e. change from baseline

in area under the curve in FEV1 measured over 0-12 hours postdose), and superiority in favor of M/FM for the secondary endpoint of onset of action (i.e change from baseline in FEV1 at 5 minutes postdose on day 1)

- No significant differences for the incidence of adverse events and for the rest of secondary efficacy endpoints such as asthma control, quality of life and day/night symptoms.

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Safety

The most common AEs reported with ICS/LABA were nasopharyngitis, upper respiratory tract infection or inflammation, dysphonia, oral candidiasis, bronchitis, cough, headaches, nausea and vomiting in patients with asthma, and pneumonia, oral candidiasis, throat irritation, bronchitis, dysphonia, cough, viral respiratory infections, headaches, and musculoskeletal pain in COPD patients.8,18 Table 9 includes complete safety information on ICS/LABA combinations. ICS/LABA combination products should not be used in patients with acute episodes of asthma or COPD due to limited clinical data available.7-12 One Cochrane review reported similar asthma-related serious adverse events between FP/SAL MDI or DPI and BUD/FM pMDI or DPI.119 Two RCTs assessed the safety of M/FM versus FP/SAL in patients with asthma: one RCT showed similar reductions in cortisol concentrations in both groups.120 The other trial reported a similar incidence of treatment-emergent and treatment-related AEs over 1 year between groups.121

A Black Box warning and a class effect of all LABAs is the increased risk of asthma-related death.7-12 This information comes from the results of a U.S. trial (SMART) comparing salmeterol versus placebo (each combined with usual asthma therapy), which showed an increased risk in death associated with asthma in the salmeterol group (13 deaths/13,176 with salmeterol vs. 3/13,179 deaths with placebo; RR: 4.37 [95% CI: 1.25, 15.34]).4,8 A post hoc analysis of SMART reported a higher risk of asthma-related hospitalizations in children and adolescents treated with salmeterol than those receiving placebo (35/1,653 with salmeterol vs 16/1,622 with placebo; RR: 2.1 [95% CI: 1.1, 3.7]).4 The product labelling specifically highlights the use of ICS/LABA only if patients have uncontrolled asthma with low- or medium-dose ICS. Once patients are controlled with ICS/LABA products, the clinician should step down therapy to ICS.8 Other important warnings associated with LABA use include paradoxical bronchospasm (a rare but life-threatening AE), and cardiovascular effects (increased heart rate, palpitations and QTc interval prolongation).4,77,122

Regarding ICS safety, pneumonia, oral candidiasis, immunosuppression, glaucoma and cataracts, hypercorticism and adrenal suppression, decrease in bone mineral density, and reduction in growth are some ICS-related warnings.7-12 An increased risk of pneumonia was observed in several long-term clinical trials (2 replicate 1-year studies and one 3-year trial) including patients with COPD.8 Yang et al123 conducted a meta-analysis comparing ICS versus placebo in COPD patients. A higher incidence of pneumonia, oral candidiasis, hoarse voice and skin bruising was reported.36 For the outcome of pneumonia in trials longer than 6 months, the odds ratio (OR) was 1.56 (95% CI 1 .30 to 1.86, 6235 participants).123 For the outcome of oropharyngeal candidiasis, a higher incidence in patients treated with ICS was reported (OR 2.65, 95% CI 2.03 to 3.46, 5586 participants).123 Nannini et al124 reported a higher incidence of pneumonia with ICS/LABA compared to salmeterol in COPD patients. A decrease in growth velocity has been reported in children and adolescents due to uncontrolled asthma or use of ICS.4 However, experts consider the benefits to outweigh the risks. As this AE is dose-dependent, patients should be treated with the lowest efficacious dose.4

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Table 9. Adverse Effects and Warnings of ICS/LABA Combination Products7-12 Combination

Product Adverse Effects Black Box, warnings and precautions

Budesonide/ formoterol fumarate

>10%: CNS: Headache (7% to 11%) Resp: Nasopharyngitis (7% to 11%), upper respiratory tract infection (4% to 11%) 1% to 10%: CNS: Dizziness (<3%) GI: Abdominal distress (1% to 7%), oral candidiasis (1% to 6%), vomiting (1% to 3%) Infection: Influenza (2% to 3%) NMS: Back pain (2% to 3%) Resp: Pharyngolaryngeal pain (6% to 9%), lower respiratory tract infection (3% to 8%), sinusitis (4% to 6%), bronchitis (5%), nasal congestion (3%)

• Black Box: ASTHMA-RELATED DEATH associated to LABA

component. This is considered a class effect among all LABAs. Available data from controlled clinical trials suggest that LABA may increase the risk of asthma-related hospitalization in pediatric and adolescent patients. When treating patients with asthma, prescribe SYMBICORT only for patients not adequately controlled on a long-term asthma-control medication, such as an inhaled corticosteroid or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g. discontinue SYMBICORT) if possible without loss of asthma control, and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid

• Not indicated in patients with acute deterioration of disease and acute episodes. Do not initiate in acutely deteriorating asthma or to treat acute symptoms

• Excessive use of the FDC or use with other LABAs may cause overdose and produce life-threatening CV effects

• Adrenal suppression: May occur with very high dosages or at the regular dosage in susceptible individuals

• Immunosuppression • Lower respiratory infections (e.g. pneumonia) • Oral candidiasis • Psychiatric manifestations (depression, euphoria, insomnia) • Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Risk of

increased systemic corticosteroid effects • Decreases in bone mineral density • Effects on growth • Glaucoma and cataracts

Fluticasone propionate/ Salmeterol

>10%: CNS: Headache (12% to 21%) Resp: Upper respiratory tract infection (16% to 27%), pharyngitis (9% to 13%) >3% to 10%: CNS: Dizziness (1% to 4%), pain (1% to 4%) GI: Nausea (3% to 6%), vomiting (3% to 6%), gastrointestinal infection (≤4%; including viral), diarrhea (2% to 4%), oral candidiasis (1% to 4%) NMS: Musculoskeletal pain (2% to 7%), myalgia (≤4%) Resp: Throat irritation (7% to 9%), bronchitis (2% to 8%), upper respiratory tract inflammation (4% to 7%), lower respiratory tract infection (1% to 7%; COPD diagnosis and age >65 years increase risk), cough (3% to 6%), sinusitis (4% to 5%), viral respiratory tract infection (3% to 5%), hoarseness (1% to 5%) 1% to 3%: CV: Cardiac arrhythmia, chest symptoms, edema, myocardial infarction, palpitations, syncope, tachycardia CNS: Migraine, mouth pain, sleep disorder Derm: Dermatitis, diaphoresis, eczema, exfoliation of skin, urticaria, viral skin infection Endo: Fluid retention, hypothyroidism, weight gain GI: Constipation, dysgeusia, oral mucosa ulcer GU: Urinary tract infection

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Combination Product Adverse Effects Black Box, warnings and precautions

Hema&onco: Hematoma Hepatic: Abnormal hepatic function tests HSR: Hypersensitivity reaction Infection: Candidiasis (≤3%), bacterial infection, viral infection NMS: Muscle injury (≤3%), arthralgia, bone disease, bone fracture, muscle cramps, muscle rigidity, muscle spasm, ostealgia, rheumatoid arthritis, tremor Ophth: Conjunctivitis, eye redness, keratitis, xerophthalmia Resp: Chest congestion, ENT infection, epistaxis, laryngitis, lower respiratory signs and symptoms (hemorrhage), nasal signs and symptoms (irritation), rhinitis, rhinorrhea, sneezing Misc: Burn, laceration, wound

• Metabolic effects: be alert to eosinophilic conditions, hypokalemia, and hyperglycemia.

• Paradoxical bronchospasm (life-threatening): Rarely occurs. • CNS depression: drowsiness, dizziness, and/or blurred vision • Immediate hypersensitivity reactions: angioedema, urticarial or

skin rash (discontinue therapy immediately) • CV effects: LABA may increase pulse rate, blood pressure, ECG

changes, prolongation of QTc interval • Use with caution in patients with: convulsive disorders,

thyrotoxico sis, diabetes mellitus, and ketoacidosis

Fluticasone furoate/

Vilanterol

1% to 10%: CV: Hypertension (≥3%), peripheral edema (≥3%), extrasystoles (≥2%), supraventricular extrasystole (≥2%), ventricular premature contractions (≥2%) CNS: Headache (5% to 8%) GI: Oropharyngeal candidiasis (2% to 5%), diarrhea (≥3%), upper abdominal pain (≥2%) Infection: Influenza (≥3%) NMS: Arthralgia (2% to ≥3%), back pain (2% to ≥3%), bone fracture (2%) Resp: Nasopharyngitis (6% to 10%), upper respiratory tract infection (≥2% to 7%), pneumonia (2% to 7%), oropharyngeal pain (2% to ≥3%), pharyngitis (2% to ≥3%), chronic obstructive pulmonary disease (≥3%), cough (1% to ≥3%), sinusitis (1% to ≥3%), bronchitis (<1% to ≥3%), acute sinusitis (≥2%), allergic rhinitis (≥2%), rhinitis (≥2%), viral respiratory tract infection (≥2%), voice disorder (2%) Misc: Fever (2% to ≥3%)

Mometasone/ Formoterol

1% to 10%: CNS: Headache (≤5%) Resp: Nasopharyngitis (5%), voice disorder (4% to 5%), sinusitis (2% to 3%)

Abbreviations: CNS, central nervous system; CV, cardiovascular system; Derm, dermatologic; ECG, electrocardiogram; Endo, endocrine; FDC, fixed-dose combinations; GI, gastrointestinal system; GU, genitourinary system; Hema&onco, hematologic and oncologic; HSR, hypersensitivity reaction; ICP, intracranial pressure; Immuno, Immunologic system; Metab, metabolic; Misc, miscellaneous; Neur, Neurologic system; NMS, neuromuscular system; Onc, oncologic; Ophth, Opthamologic system; Psy, Psychiatric; Resp, respiratory system

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Summary

The 6 FDA-approved ICS/LABA combination products are indicated for the long-term management of patients with persistent asthma. Among them, BUD/FM, FP/SAL DPI, and FF/VI are also indicated for the long-term management of COPD. The 6 FDCs are available with different corticosteroid concentrations to accommodate different levels of asthma severity and different age groups. They are administered via single inhaler twice daily, with the exception of FF/VI products that are administered once daily. Device characteristics and inhalation techniques differ between products. Patients should be adequately trained by health professionals to assure the correct use of inhalers. Single inhalers may improve patients’ convenience, adherence to controller mediation, treatment efficacy, health-related quality of life, and health system costs.

With regard to asthma disease, current U.S. and international guidelines (NHLBI and GINA guidelines, respectively) recommend the use of SABAs as needed (quick-relief medications) plus ICS/LABA combinations (controller medication) in certain patients with persistent moderate to severe asthma not adequately controlled with low- or medium-dose ICS. For these patients, several clinical trials demonstrated greater improvements in lung function and asthma control when LABA was added to ICS, rather than increasing the ICS dose.

Regarding COPD management, the updated 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guideline recommends LABA/long-acting muscarinic antagonist (LAMA) fixed-dose combinations (FDCs) as preferred treatment options in patients with moderate to severe COPD. Combination ICS/LABA FDC products are second-line therapies. Clinical trials in COPD patients demonstrated superior efficacy of LABA/LAMA compared to LABA/ICS combinations in terms of lung function and exacerbation risk. These treatment recommendations are not yet reflected in the Medicaid FFS prescription usage patterns. FFS utilization data show that ICS/LABA combinations are prescribed more frequently than LABA/LAMA combinations for moderate to severe COPD.

Comparative evidence included 26 efficacy/safety articles containing 5 SR/MA, 21 RCTs, and 2 mixed treatment comparisons (MTCs). Three safety articles containing one SR/MA and 2 RCTs were also evaluated. Studies assessed head-to-head comparisons between the FDC products, between a FDC and its mono-components administered concomitantly, or between two different inhaler devices containing the same ingredients. The majority of the evidence pertained to asthma. Limited evidence is available for COPD and asthma/COPD overlap.

For the management of asthma, 5 SR/MA, 16 RCTs and one MTC were identified:

1. BUD/FM versus BUD+FM (4 RCTs): similar efficacy and safety profiles were reported between BUD/FM pMDI (U.S product) or BUD/FM DPI (non-U.S. product) compared to BUD+FM in children 4 to 11 years, adolescents, and adults. One long-term trial (12-months) in adult patients indicated a lower withdrawal rate with BUD/FM DPI than BUD+FM.

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2. FP/SAL versus FP+SAL (1 SR/MA, and 5 RCTs): Results differed among the 5 RCTs. Kawai et al demonstrated similar bronchodilator effect between FP/SAL and FP+SAL groups in adult patients. Van der Berg et al, Chapman et al, and Aubier et al reported improvements in lung function, asthma control, and symptoms at week 12 that did not significantly differ between treatment groups in patients ≥ 4 years old. In adolescent and adult patients, Bateman et al. showed superiority of SAL/FP DPI 50/100 µg versus the same doses administered individually for lung function at week 12 (primary endpoint). Chapman et al. reported superiority of SAL/FP DPI 50/250 µg vs. SAL+FP for lung function values at other time points (week 3 and 4). One SR/MA included 4 of the 5 RCTs identified, and showed statistically significant differences between FP/SAL and the mono-components; however, a proper discussion about the clinical relevance of the results was lacking.

3. FP/SAL hydrofluoroalkane (HFA) metered-dose inhaler (MDI) versus FP/SAL dry powder inhaler (DPI) (3 RCTs): No significant differences between the two different inhalers were reported. Low-, medium- and high-doses of fluticasone plus SAL were evaluated.

4. BUD/FM versus FP/SAL (3 SR/MA, 3 RCTs): Three SR/MA reported no significant differences in terms of efficacy (reduction in exacerbations requiring oral corticosteroids or hospitalizations) and safety (asthma-related serious adverse events) between BUD/FM pMDI or DPI compared to FP/SAL MDI or DPI. Three RCTs reported faster onset of bronchodilator action and faster improvements in forced expiratory volume in one second (FEV1) with BUD/FM pMDI or DPI compared to SAL/FP DPI.

5. FF/VI versus FP/SAL (1 SR/MA containing one RCT of interest): No statistically significant differences were found between FF/VI DPI 100/25 µg compared to FP/SAL DPI 250/50 µg for the primary endpoints (change in health-related quality of life, severe asthma exacerbations, and serious adverse events), and secondary endpoints (lung function and asthma symptoms). However, authors highlighted the limited comparative efficacy and safety information available to make a robust decision about the preference of FF/VI over FP/SAL. Further research was considered required.

6. FF/VI versus FP/SAL and BUD/FM (1 MTC): One network meta-analysis included 31 RCTs to assess the probability of non-inferiority of once-daily FF/VI vs. twice-daily FP/SAL and BUD/FM in asthma patients ≥ 12 years old. Despite known limitations of network meta-analyses, results suggested similar lung function improvements with FF/VI 100/25 µg and FF/VI 200/25 µg compared to corresponding doses of FP/SAL and BUD/FM. Health status outcomes were comparable between once-daily FF/VI 100/25 μg compared to twice-daily FP/SAL 250/50 μg and BUD/FM 320/9 μg.

7. M/FM versus FP/SAL (1 RCT): One trial compared M/FM MDI 200/10 μg to FP/SAL DPI 250/50 μg. Non-inferiority was demonstrated for the primary endpoint (improvement in lung function) and most of the secondary endpoints (asthma control, quality of life and symptoms). The onset of bronchodilator action was faster with M/FM than FP/SAL DPI.

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For the management of COPD, 4 RCTs and one MTC were identified. The main results are described below:

1. BUD/FM versus FP/SAL (1 RCTs): One trial showed faster onset of bronchodilator effect with BUD/FM compared to FP/SAL.

2. FF/VI versus FP/SAL (3 RCTs): Three trials reported statistically, but not clinically significant differences between FF/VI 100/25 µg and medium-dose FP/SAL (250/50 µg).

3. FF/VI versus FP/SAL and BUD/FM (1 MTC): One network meta-analysis included 33 RCTs to assess the probability of non-inferiority of once daily FF/VI 100/25 µg compared to twice daily FP/SAL 500/50 µg and BUD/FM 400/12 µg in COPD patients ≥ 12 years old. Despite limitations of indirect comparisons, results suggested similar lung function and health status improvements with FF/VI compared to FP/SAL and BUD/FM.

For the management of asthma-COPD overlap, only one RCT comparing FF/VI DPI 200/25 μg versus FP/SAL DPI 500/50 μg was identified. Although no between-group differences were reported, authors mentioned the need for further research due to the study limitations identified.

Additional direct head-to-head comparisons involving ICS/LABA combinations are required to contrast the potential benefits of one fixed-dose combination over another in patients with asthma, COPD, and asthma/COPD overlap.

The majority of adverse drug reactions associated with ICS/LABA combinations are tolerable and manageable. The most common AEs reported with ICS/LABA were upper respiratory tract infection or inflammation, pharyngitis, dysphonia, oral candidiasis, bronchitis, cough, headaches, nausea and vomiting in patients with asthma, and pneumonia, oral candidiasis, throat irritation, dysphonia, viral respiratory infections, headaches, musculoskeletal pain in patients COPD. The increased risk of pneumonia in patients with COPD and adrenal suppression are related to the adverse effect profile of inhaled corticosteroids. A main safety warning and class effect for all LABAs is the increased risk of asthma-related death, and the higher risk of asthma-related hospitalizations in children and adolescents.

In summary, all trials concluded ICS/LABA combination products improve lung function, increase quality of life, and reduce asthma or COPD exacerbation rate. Safety profiles remain similar and manageable when both ICS and LABA are combined.

For the management of asthma, direct comparisons reported no significant differences for 1) FP/SAL compared to BUD/FM, FF/VI, or M/FM; and 2) FP/SAL HFA MDI compared to FP/SAL DPI. Similar efficacy and safety profiles were reported for BUD/FM compared to the mono-components administered concomitantly (BUD+FM). FP/SAL has been shown to be similar to FP+SAL; however, some studies suggest superiority of FP/SAL compared to FP+SAL. For the management of COPD, similar results were reported for FP/SAL compared to FF/VI.

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Studies including direct and indirect comparisons suggested similar efficacy profiles with fluticasone and vilanterol compared to fluticasone/salmeterol and budesonide/formoterol in patients with asthma or COPD.

Further direct head-to-head comparisons involving ICS/LABA combinations are required to contrast the potential benefits of one FDC over another in patients with asthma, COPD, and asthma/COPD overlap.

Clinician’s decisions on one single ICS/LABA inhaler over another should be based on the specific inhaler technique and patient skills to appropriately use the prescribed ICS/LABA inhaler, the individual patient’s preference, co-morbidities, adverse events, and cost.

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88. Noonan M, Rosenwasser LJ, Martin P, O'Brien CD, O'Dowd L. Efficacy and safety of budesonide and formoterol in one pressurised metered-dose inhaler in adults and adolescents with moderate to severe asthma: a randomised clinical trial.[Erratum appears in Drugs. 2007;67(5):759]. Drugs. 2006;66(17):2235-2254.

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91. Rosenhall L, Elvstrand A, Tilling B, et al. One-year safety and efficacy of budesonide/formoterol in a single inhaler (Symbicort Turbuhaler) for the treatment of asthma. Respiratory medicine. 2003;97(6):702-708.

92. Kawai M, Kempsford R, Pullerits T, et al. Comparison of the efficacy of salmeterol/fluticasone propionate combination in Japanese and Caucasian asthmatics. Respiratory medicine. 2007;101(12):2488-2494.

93. Van den Berg NJ, Ossip MS, Hederos CA, Anttila H, Ribeiro BL, Davies PI. Salmeterol/fluticasone propionate (50/100 microg) in combination in a Diskus inhaler (Seretide) is effective and safe in children with asthma. Pediatric Pulmonology. 2000;30(2):97-105.

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https://medicaid.utah.gov/pharmacy/PDL/files/Utah%20Medicaid%20PDL%20(10-01-17).pdf

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95. Chapman KR, Ringdal N, Backer V, Palmqvist M, Saarelainen S, Briggs M. Salmeterol and fluticasone propionate (50/250 microg) administered via combination Diskus inhaler: as effective as when given via separate Diskus inhalers. Canadian respiratory journal. 1999;6(1):45-51.

96. Aubier M, Pieters WR, Schlosser NJ, Steinmetz KO. Salmeterol/fluticasone propionate (50/500 microg) in combination in a Diskus inhaler (Seretide) is effective and safe in the treatment of steroid-dependent asthma. Respiratory medicine. 1999;93(12):876-884.

97. Nelson HS, Chapman KR, Pyke SD, et al. Enhanced synergy between fluticasone propionate and salmeterol inhaled from a single inhaler versus separate inhalers. Journal of Allergy and Clinical Immunology. 2003;112(1):29-36.

98. Bateman ED, Silins V, Bogolubov M. Clinical equivalence of salmeterol/fluticasone propionate in combination (50/100 microg twice daily) when administered via a chlorofluorocarbon-free metered dose inhaler or dry powder inhaler to patients with mild-to-moderate asthma. Respiratory medicine. 2001;95(2):136-146.

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100. Noord J.A v, H L, Diaz T C, A.P G, P D. Clinical Equivalence of a Salmeterol/Fluticasone Propionate Combination Product (50/500??g) Delivered via a Chlorofluorocarbon-Free Metered-Dose Inhaler with the Diskus??? in Patients with Moderate to Severe Asthma. Vol 212001.

101. Lasserson TJ, Cates CJ, Ferrara G, Casali L. Combination fluticasone and salmeterol versus fixed dose combination budesonide and formoterol for chronic asthma in adults and children. Cochrane Database of Systematic Reviews. 2008(3):CD004106.

102. Lasserson TJ, Ferrara G, Casali L. Combination fluticasone and salmeterol versus fixed dose combination budesonide and formoterol for chronic asthma in adults and children. Cochrane Database of Systematic Reviews. 2011(12):CD004106.

103. Aalbers R, Backer V, Kava TT, et al. Adjustable maintenance dosing with budesonide/formoterol compared with fixed-dose salmeterol/fluticasone in moderate to severe asthma. Current Medical Research & Opinion. 2004;20(2):225-240.

104. Busse WW, Shah SR, Somerville L, Parasuraman B, Martin P, Goldman M. Comparison of adjustable- and fixed-dose budesonide/formoterol pressurized metered-dose inhaler and fixed-dose fluticasone propionate/salmeterol dry powder inhaler in asthma patients. Journal of Allergy & Clinical Immunology. 2008;121(6):1407-1414, 1414.e1401.

105. Kuna P, Peters MJ, Manjra AI, et al. Effect of budesonide/formoterol maintenance and reliever therapy on asthma exacerbations. Int J Clin Pract. 2007;61(5):725-736.

106. Dahl R, Chuchalin A, Gor D, Yoxall S, Sharma R. EXCEL: A randomised trial comparing salmeterol/fluticasone propionate and formoterol/budesonide combinations in adults with persistent asthma. Respiratory medicine. 2006;100(7):1152-1162.

107. Edwards SJ, Gruffydd-Jones K, Ryan DP. Systematic review and meta-analysis of budesonide/formoterol in a single inhaler. Current Medical Research & Opinion. 2007;23(8):1809-1820.

108. van der Woude HJ, Boorsma M, Bergqvist PB, Winter TH, Aalbers R. Budesonide/formoterol in a single inhaler rapidly relieves methacholine-induced moderate-to-severe bronchoconstriction. Pulmonary pharmacology & therapeutics. 2004;17(2):89-95.

109. Palmqvist M, Arvidsson P, Beckman O, Peterson S, Lotvall J. Onset of bronchodilation of budesonide/formoterol vs. salmeterol/fluticasone in single inhalers. Pulmonary pharmacology & therapeutics. 2001;14(1):29-34.

110. Hampel FC, Martin P, Mezzanotte WS. Early bronchodilatory effects of budesonide/formoterol pMDI compared with fluticasone/salmeterol DPI and albuterol pMDI: 2 randomized controlled trials in adults with persistent asthma previously treated with inhaled corticosteroids. Journal of Asthma. 2008;45(4):265-272.

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118. Bernstein DI, Hebert J, Cheema A, et al. Efficacy and onset of action of mometasone furoate/formoterol and fluticasone propionate/salmeterol combination treatment in subjects with persistent asthma. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology. 2011;7:21.

119. Cates CJ, Lasserson TJ. Regular treatment with formoterol and an inhaled corticosteroid versus regular treatment with salmeterol and an inhaled corticosteroid for chronic asthma: serious adverse events. Sao Paulo Medical Journal = Revista Paulista de Medicina. 2010;128(5):310-311.

120. Kosoglou T, Hubbell J, Cutler DL, et al. Hypothalamic-pituitary-adrenal axis effects of mometasone furoate/formoterol fumarate vs fluticasone propionate/salmeterol administered through metered-dose inhaler. Chest. 2013;144(6):1795-1802.

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122. Mehta N, Aggarwal B, Gogtay J, Abdool-Gaffar S. Comparing the efficacy and safety of salmeterol/fluticasone pMDI versus its mono-components, other LABA/ICS pMDIs and salmeterol/fluticasone Diskus in patients with asthma. Expert opinion on drug delivery. 2015;12(6):963-975.

123. Yang IA, Clarke MS, Sim EH, Fong KM. Inhaled corticosteroids for stable chronic obstructive pulmonary disease. The Cochrane database of systematic reviews. 2012(7):Cd002991.

124. Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta(2)-agonist in one inhaler versus long-acting beta(2)-agonists for chronic obstructive pulmonary disease. The Cochrane database of systematic reviews. 2012(9):Cd006829.

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Appendix A. MEDLINE & EMBASE Literature Search Strategies for ICS/LABA Combination Products Table 1. Medline Literature Search Strategy (via Ovid) for systematic reviews and randomized controlled trials

Ovid MEDLINE(R) Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily, Ovid MEDLINE and Versions(R). Search Strategy Date: June 2017 SR Results: 130; RCT Results: 946

1 Budesonide, Formoterol Fumarate Drug Combination/ or (biresp or duoresp or vyaler or vylaer or spiromax* or (budesonid* adj3 formoterol*) or symbicort).ti,ab,kw,kf,rn. (799) 2 Fluticasone Propionate, Salmeterol Xinafoate Drug Combination/ or (Advair* or fluticason* adj5salmeterol* or Aerivio or airexar or atmadisc or (salmeterol* adj2 (xinafoat* or fluticason*)) or seretide or serflu or viani).ti,ab,kw,kf,rn. (1304) 3 ((fluticason* adj4 furoat* adj4 vilanterol*) or Breo or relovair or relvar or revinty ellipta).ti,ab,kw,kf,rn. or fluticasone furoate-vilanterol trifenatate.rs,ps. or (fluticasone and furoate-vilanterol trifenatate).nm,rn,rx,px. (133) 4 Mometasone Furoate, Formoterol Fumarate Drug Combination/ or (Dulera or ('formoterol* adj5 'mometason*) or zenhale).ti,ab,kw,kf,rn. (46) 5 1 or 2 or 3 or 4 [all 4 drug combos] (2015) 6 limit 5 to english language [All 4 drug combos, ENG] (1866) 7 Adrenergic beta-2 Receptor Agonists/ or (('adrenergic beta 2' or 'adrenergic beta2' or 'beta2 adrenergic' or 'beta 2 adrenergic' or 'beta 2 adrenoceptor*' or 'beta2 adrenoceptor*') adj3 (agonist* or stimulant* or stimulator* or stimulating)).ti,ab,kw,kf,rn. or 'beta 2 agonist*'.ti,ab. or 'beta2 agonist*'.ti,ab. (9632) 8 exp Glucocorticoids/ or (glucocorticoid* or glucocorticosteroid* or glucocortoid* or glycocorticoid*).ti,ab,kw,kf,rn. (213362) 9 7 and 8 [all 2 drug classes] (1326) 10 limit 9 to english language [All 2 drug classes, ENG] (1191) 11 exp animals/ not humans.sh. (4416452) 12 (animal? or beaver? or beef or bovine or breeding or bull or canine or castoris or cat or cattle or cats or chicken? or chimp$ or cow or dog or dogs or equine or foal or foals or fish or insect? horse or horses or livestock or mice or monkey? or mouse or murine or plant or plants or pork or porcine or protozoa? or purebred or rat or rats or rodent? or sheep or thoroughbred).ti. or veterinar$.ti,ab,kw,kf,hw. (2157596) 13 11 or 12 [animal set] (4900264) 14 ((systematic adj2 review) or (overview adj3 review?)).ti. or (metaanaly$ or meta-analy$).ti,ab,pt. or ((systematic adj2 review) or (metaanaly$ or meta-analy$)).kw,kf. [SR set] (178318) 15 (randomized controlled trial or controlled clinical trial).pt. or randomized.ab. or placebo.ab. or clinical trials as topic.sh. or randomly.ab. or trial.ti. [RCT set] (1144469) 16 6 not 13 (1831) 17 16 and 14 [Drug Combos + SR set] (88) 18 16 and 15 [Drug Combos + RCT set] (946) 19 10 not 13 (1128) 20 19 and 14 [Drug classes + SR set] (69) 21 19 and 15 [Drug classes + RCT set] (553) 22 17 or 20 [Drug combo or class -- SRs set] (130) 23 18 or 19 [Drug combo or class -- RCTs set] (1816) 24 Adrenergic beta-2 Receptor Agonists/ and exp Glucocorticoids/ (311) 25 14 and 24 (25) 26 20 not 25 (44) 27 Adrenergic beta-2 Receptor Agonists/ or (('adrenergic beta 2' or 'adrenergic beta2' or 'beta2 adrenergic' or 'beta 2 adrenergic' or 'beta 2 adrenoceptor*' or 'beta2 adrenoceptor*') adj3 (agonist* or stimulant* or stimulator* or stimulating)).ti. or 'beta 2 agonist*'.ti,ab. or 'beta2 agonist*'.ti,ab. (7888) 28 exp Glucocorticoids/ or (glucocorticoid* or glucocorticosteroid* or glucocortoid* or glycocorticoid*).ti,ab. (212735) 29 27 and 28 (1198) 30 limit 29 to english language (1070)

55

31 10 not 30 (121) 32 15 and 31 (41) 33 32 not 18 (14) Table 2. EMBASE Literature Search Strategy (via EMBASE.com)

EMBASE.com. Search Date: June 2017 SR Results: 136; RCT Results: 675

Embase Session Results (9 Jun 2017) No. Query Results #23 #18 OR #19 136 Systematic Reviews #21 #10 AND #17 NOT (#13 OR #18 OR #19 AND #20) 215 DRUG CLASSES & INDICATION & TRIALS #20 #6 AND #7 AND #17 NOT (#13 OR #18 OR #19) 675 DRUG COMBINATIONS & INDICATIONS & TRIALS #19 #10 AND #16 NOT #18 35 DRUG CLASSES & INDICATION & SR. #18 #6 AND #7 AND #16 101 DRUG COMBINATIONS & INDICATIONS & SR #17 'clinical study'/mj OR 'clinical trial'/mj OR 'controlled clinical trial'/mj OR 'controlled study'/mj OR 'major clinical study'/mj OR 'randomized controlled trial'/mj OR 'control group'/mj OR ((clinical OR randomi* OR controlled OR multicentre OR multicenter OR 'multi centre' OR 'multi center') NEAR/3 (study OR trial)):ti,ab OR placebo:ab,ti OR 'head to head':ti,ab 903390 #16 #14 OR #15 189380 #15 'systematic review'/mj OR 'meta analysis'/mj 21643 #14 metaanaly*:ti,ab OR 'meta analy*':ti,ab OR (systematic NEAR/2 review):ti 188957 #13 #11 OR #12 6675719 #12 animal*:ti OR beaver*:ti OR beef:ti OR bovine:ti OR breeding:ti OR canine:ti OR castoris:ti OR cat:ti OR cattle:ti OR cats:ti OR chicken*:ti OR cow:ti OR dog:ti OR dogs:ti OR equine:ti OR foal:ti OR foals:ti OR fish:ti OR insect*:ti OR livestock:ti OR mice:ti OR mouse:ti OR murine:ti OR plant:ti OR plants:ti OR pork:ti OR porcine:ti OR protozoa*:ti OR purebred:ti OR rabbit*:ti OR rat:ti OR rats:ti OR rodent*:ti OR sheep:ti OR thoroughbred:ti OR veterinar*:ti,ab,de 2537801 #11 'animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal tissue'/exp OR 'animal cell'/exp OR 'nonhuman'/de NOT ('animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal tissue'/exp OR 'animal cell'/exp OR 'nonhuman'/de AND ('human'/exp OR 'human cell'/de)) 6229736 #10 #7 AND #8 AND #9 AND [english]/lim NOT 'conference abstract'/it 1306 DRUG CLASSES & INDICATION #9 'beta 2 adrenergic receptor stimulating agent'/mj OR (('adrenergic beta 2' OR 'adrenergic beta2' OR 'beta2 adrenergic' OR 'beta 2 adrenergic'OR 'beta 2 adrenoceptor*' OR 'beta2 adrenoceptor*') NEAR/3 (agonist* OR stimulant* OR stimulator* OR stimulating)):ti,ab,rn OR 'beta 2 agonist*':ti,ab OR 'beta2 agonist*':ti,ab 5657 #8 'glucocorticoid'/mj OR 'corticosteroid'/mj OR corticosteroid*:ab,ti,rn OR glucocorticoid*:ab,ti,rn OR glucocorticosteroid*:ab,ti,rn OR glucocortoid*:ab,ti,rn OR glycocorticoid*:ab,ti,rn 244484 #7 'chronic obstructive lung disease'/mj OR copd:ti,ab OR 'chronic obstructive lung':ti,ab OR 'chronic obstructive pulmonary':ti,ab OR 'asthma'/exp/mj OR asthma*:ab,ti OR 'lung allergy':ab,ti OR 'lung allergies':ti,ab 303122 #6 #1 OR #2 OR #3 OR #4 OR #5 AND [english]/lim NOT 'conference abstract'/it 4175 DRUG COMBINATIONS #5 'formoterol fumarate plus mometasone furoate'/de OR dulera:ab,ti,tn OR (formoterol* NEAR/5 mometason*):ab,ti,tn,dn OR zenhale:ab,ti,tn 237 #4 'fluticasone furoate plus vilanterol'/de OR breo:ab,ti,tn OR ('fluticason*' NEAR/4 vilanterol*):ab,ti,tn OR relovair:ab,ti,tn OR relvar:ab,ti,tn OR 'revinty ellipta':ab,ti,tn 318 #3 'fluticasone propionate plus salmeterol xinafoate'/de OR aerivio:ab,ti,tn OR airexar:ab,ti,tn OR atmadisc:ab,ti,tn OR (salmeterol* NEAR/3 xinafoat*):ab,ti,tn OR seretide:ab,ti,tn OR serflu:ab,ti,tn OR viani:ab,ti,tn 1096 #2 'fluticasone propionate plus salmeterol'/de OR advair*:ab,ti,tn OR (fluticason* NEAR/5 salmeterol*):ab,ti,tn 3850 #1 'budesonide plus formoterol'/exp OR biresp:ab,ti,tn OR duoresp:ab,ti,tn OR vyaler:ab,ti,tn OR vylaer:ab,ti,tn OR spiromax*:ab,ti,tn OR (budesonid* NEAR/4 formoterol*):ab,ti,tn OR symbicort:ab,ti,tn 2455

56

Appendix B. Key Evidence: Cochrane Systematic Reviews of ICS/LABA Combination Products* Study Reference and Search

Date Objective(s) Treatment

Interventions Clinical Efficacy Clinical Safety Limitations

1. Dwan et al 2016112: Vilanterol and fluticasone furoate for asthma (Cochrane Database of Systematic Reviews 2016)

• 14 studies (Only data from 1 study and 1 conference abstract comparing VI+FF vs FP/SAL were extracted)

• Literature search up to June 2016

To compare effects of VI and FF in combination versus placebo, or versus other ICSs and/or LABAs, on acute exacerbations and on health-related quality of life (HRQoL) in adults and children with chronic asthma.

• VI + FF 100/25mcg vs FP/SAL 250/50mcg BID (1 study: Woodcock 2013113)

• VI + FF 200/25 mcg versus FP/SAL 500/50 mcg (1 conference abstract with limited information: Hojo 2015)

VI+FF 100/25mcg vs FP/SAL 250/50mcg BID Primary outcomes • Change in HRQoL (measured by AQLQ at 24

wk): MD 0.09, 95% CI -0.03 to 0.21 (no significant differences between groups)

• Severe asthma exacerbation (with hospital admission or treatment with a course of oral corticosteroid): OR 0.50, 95% CI 0.05 to 5.52

(no significant differences between groups) Secondary outcomes • Lung function (FEV1, PEF): MD -0.02, 95% CI

- 0.07 to 0.03 • Asthma symptoms: MD 0.24, 95% CI - 0.20

to 0.68 (no significant differences between groups)

VI and FF 200/25 mcg vs FP/SAL 500/50 mcg Primary outcome: the study did not include the review’s primary outcomes Secondary outcomes” • Lung function (FEV1, PEF): improvement in

AM PEF in the VI/FF group. Investigators provided no information on this outcome in relation to the FP/SAL group.

• Asthma symptoms: no significant improvement on the asthma control test with either treatment

Author’s conclusions: We found insufficient information to assess whether once-daily VI/FF was better or worse than twice-daily FP/SAL in terms of efficacy or safety

VI+FF 100/25mcg vs FP/SAL 250/50mcg BID Primary outcomes • Serious adverse events: OR

0.80, 95% CI 0.21 to 2.99 (no significant differences

between groups) Other findings: • Adverse events: 110/403

(27.30%) vs 106/403 (26.30%)

• Only one single study supporting the comparison

2. Lasserson et al 2011102: Cochrane Database of Systematic Reviews 2011. Combination fluticasone and salmeterol versus fixed dose combination

To assess the relative effects of FP/SAL and BUD/FM in adults and

• BUD/FM 400 to 800/12 to 24 mcg/day

• FP/SAL 500/100 mcg/day

Primary outcomes: • % patients with exacerbations requiring oral

steroid treatment (Mean follow-up: 6 months): OR 0.89, 95% CI 0.74 to 1.07 (4 studies)

Primary outcomes: • Asthma-related SAEs

(Mean follow-up: 6 months): OR 1.47, 95% CI 0.75 to 2.86 (3 studies)

• Wide CI for the effect estimated in primary outcomes (imprecision)

57

Study Reference and Search Date

Objective(s) Treatment Interventions

Clinical Efficacy Clinical Safety Limitations

budesonide and formoterol for chronic asthma in adults and children

• 5 studies (5537 adults

and adolescents) included in the review: Aalbers 2004,103 Busse 2008,104 COMPASS or Kuna 2007,105 EXCEL or Dahl 2006106 and one unpublished article

• Literature search conducted in June 2011

children with asthma Population included: • Adults and

adolescents taking regular inhaled steroids before the studies started and with mild or moderate chronic asthma

• % patients with exacerbations requiring admission to hospital (Mean follow-up: 6 months): OR 1.29, 95% CI 0.68 to 2.47 (4 studies)

Secondary outcomes: • Exacerbations requiring ED visit/hospital

admission (composite): OR 1.3, 95% CI 0.94 to 1.8

• Quality of life: Pooled data not available. No statistically significant differences between the treatments were reported in either study

• Diary card peak flow: No significant differences between groups (5 studies)

• FEV1: No significant differences between groups (3 studies)

• Rescue medication use: No significant differences between groups (3 studies)

• Symptoms: No significant differences between groups (3 studies)

Authors’ conclusion: Statistical imprecision in the effect estimates for exacerbations and serious adverse events, which preclude drawing conclusions. Further trials are needed to better determine the relative effects of these drug combinations)

Secondary outcomes:

• AEs: OR 1.00, 95% CI 0.88 to 1.15 (3 studies): - Headache: OR 1.08, 95%

CI 0.82 to 1.43 - Candidiasis: OR 1.64, 95%

CI 0.68 to 4.00 - Upper respiratory tract

infection: OR 1.09, 95% CI 0.81 to 1.47

- Dysphonia: OR 1.45, 95% CI 0.87 to 2.43

• Withdrawals (AEs) (Mean follow-up: 6 months): OR 0.94, 95% CI 0.6 to 1.46 (5 studies)

• Deaths: 1 death with FP/SAL and 0 deaths with DUB/FM (reported in only one study: COMPASS)

• SAEs too infrequent

• Only adults and adolescents. No data for children

3. Lasserson et al 2008101 This review includes the same studies as in Lasserson et al 2011

Abbreviations: AQLQ, asthma quality of life questionnaire; AM, morning; BID, twice daily; CI, confidence interval; ED, emergency department; FEV1, forced expiratory volume in one second; FF, fluticasone furoate; FP, fluticasone propionate; HRQoL, health-related quality of life; MD, mean difference; OR, Odds ratio; PEF, peak expiratory flow; RR, risk ratio; SAL, salmeterol; VI, vilanterol; wk, week; µg, micrograms

58

Appendix C. Key Evidence: Other Systematic Reviews Including ICS/LABA Combination Products Study Reference and Search Date

Objective(s) Treatment Intervention


4. Edwards et al 2007107: Systematic review and meta-analysis of budesonide/formoterol in a single inhaler • 15 RCTs (3

studies of BUD/FM vs SAL/FP: Aalbers 2004,103 Kuna 2007,105 and Dahl 2006106)

• Literature search up to July 2006

To compare the effectiveness of budesonide/formoterol using fixed dosing (BUD/FORM) with inhaled corticosteroid (ICS) alone or alternative ICS and long-acting β2-agonist (LABA) regimens for adults with moderate/severe asthma.

BUD/FM and SAL/FP in a single inhaler

Primary analysis: • No evidence of a difference in

treatment failure with BUD/FM compared to SAL/FP (RR 0.99; 95% CI: 0.83 to 1.16, p = 0.86)

Secondary analysis: • Use of SAL/FP compared with BUD/FM

increased the risk of exacerbations requiring hospitalizations/ A&E visits by 49% (RR 1.49; 95% CI: 1.07 to 2.08, p = 0.02)

• There is no evidence of a difference in the number of exacerbations requiring oral steroid use with BUD/FM compared to SAL/FP (RR 0.94; 95% CI: 0.79–1.11, p = 0.46).

Withdrawals due to AEs: no differences between groups

• Primary outcome not universally available

• Lack of blinding in several studies

5. Nelson et al 200397: Enhanced synergy between fluticasone propionate and salmeterol inhaled from a single inhaler versus separate inhalers • 4 double-blind

studies comparing FL/SAL vs FL+SAL at the 3 FDA-approved

This meta-analysis aimed to determine the efficacy of FP and SAL inhaled from a single inhaler (combination therapy) or from separate inhalers (concurrent therapy).

FL/SAL vs FL+SAL at the 3 FDA-approved strengths (100/50, 250/50, and 500/50)

Individual studies: Confirmed equivalence between combination and concurrent therapy on the basis of the primary efficacy measure (morning peak expiratory flow [PEF]). Each study showed a consistent trend in favor of combination therapy. Meta-analysis • A significant advantage for combination

therapy compared with concurrent therapy in morning PEF (mean difference between groups in change from baseline over 12 weeks of 5.4 L/min; P = 0.006; 95% CI = 1.5-9.2).

• No limitations explained in the article

• Letter to Editor (by Lipwoth 2003): “this information by Nelson 2003 should not be used as evidence-based

59

Study Reference and Search Date



strengths (100/50, 250/50, and 500/50): Bateman 1998,94 Chapman 1999,95 Aubier 1999,96 and van den Berg 200093)

• Odds of achieving a greater than 15 or greater than 30 L/min improvement in morning PEF with combination therapy were increased by approximately 40% compared with those after concurrent therapy (15 L/min: odds ratio = 1.42, P = .008, 95% CI = 1.11.8; 30 L/min: odds ratio = 1.40, P = .006, 95% CI = 1.1-1.8), representing an additional 7% to 9% and 5% to 14% more patients, respectively, on combination therapy responding compared with those on concurrent therapy.

medicine to support synergy for the FP/SAL combination inhaler”

Abbreviations: AE, adverse events; AQLQ, asthma quality of life questionnaire; BUD, budesonide; COPD, chronic obstructive pulmonary disease; ED, emergency department; FP, fluticasone propionate; FM, formoterol; N/A, not available; PEF, peak expiratory flow; SAE, serious adverse events; SAL, salmeterol; µg or mcg, micrograms; VI, vilanterol

Appendix D. Randomized Controlled Trial Included in the Previous Systematic Reviews Study Reference and Design



1. Woodcock et al113 2013 • 24-week phase

III, randomized, controlled, double-blinded, double-dummy, multicenter trial

To compare the effi cacy of FF/VI with fl uticasone propionate (FP)/salmeterol (SAL) in patients with persistent asthma uncontrolled on a medium dose of ICS.

• FF/VI 100/25 μg QD

• FP/SAL 250/50 μg BID

Primary endpoint:

• Change in 0 to 24-hour FEV1 after 24 weeks of treatment: FF/VI (341 mL) vs FP/S (377 mL) (not significant)

Secondary endpoints (all not significant): Exacerbation rates, ACT scores, QOL questionnaire scores, unscheduled health care use

AE (%): • Nasopharyngitis (53%

FF/VI vs. 49% FP/SAL) • Headache (34% FF/VI

vs. 41 FP/SAL) • URTI (26% FF/VI vs.

16% FP/SAL) • Cough (15% FF/VI vs.

13% FP/SAL) • Sinusitis (12% FF/VI vs.

7% FP/SAL)

• Too short-study

Abbreviations: AE, adverse events; FP, fluticasone propionate; SAL, salmeterol; µg or mcg, micrograms; VI, vilanterol

60

Appendix E. Randomized Controlled Trial Not Included in the Previous Systematic Reviews Study Reference and

Design Objective(s) Treatment Interventions Clinical Efficacy Clinical Safety

1. Ishiura et al117 2015

• 12-week, randomized, open-label cross-over study

To compare the effectiveness of once-daily FF/VI 200/25 μg vs. twice-daily FP/SAL 500/50 μg in 16 patients with stable ACOS (16 males, no females) with a mean age of 74.2 ± 6.7 (±SD) (range 59–87) years

• FF/VI 200/25 μg, DPI • FP/SAL 500/50 μg,

DPI

Mean changes values for the FEV1: • Run-in period: 1.33 (±0.29) L • After the FP/SAL treatment period: 1.38 (±0.39) L • After the FF/VI treatment period: 1.47 (±0.38) L Mean changes values for the FVC: • Run-in period: 2.85 (±0.55) L • After the FP/SAL treatment period: 2.91 (±0.56) L • After the FF/VI treatment period: 3.02 (±0.55) L Mean changes values for the FEF 25-75%: • Run-in period: 0.45 (±0.18) L/s • After the FP/SAL treatment period: 0.46 (±0.19) L/s • After the FF/VI treatment period: 0.52 (±0.21) L/s FOT parameters, FeNO levels, CAT scores, ACT scores, and other blood tests were not significantly different during the run-in period, the FP/SAL treatment period, and the FF/VI treatment period.

• The heart rate after each treatment did not differ significantly among the treatment periods

• None of the patients complained of CV or GI symptoms after the administration of FP/SAL or FF/VI

2. Dransfield et al115 2014

To compare the lung function effects of FF/VI with those of twice-daily fluticasone propionate/salmeterol (FP/SAL) in patients aged ≥40 years with moderate-to-very severe COPD

• FF/VI 100/25 μg QD in the morning via the ELLIPTA (DPI)

• FP/SAL 250/50 μg BID via the Accuhaler (DPI)

Primary efficacy end-point: • Change from baseline through 0-24 h wm FEV1 on day 84: Pooled analysis: The treatment difference was statistically but not clinically significant (P < 0.001)

• Pooled AEs (FF/VI 27%; FP/SAL 28%) and serious adverse events (FF/VI 2%; FP/SAL 3%) were similar between treatments.

3. Bernstein et al118 2011

• Multicenter, 12-week,1 open-label, evaluator-blinded, active-controlled,

To compare the noninferiority of M/FM versus FP/SAL in 722 patients aged ≥12 years with uncontrolled persistent

• M/FM MDI 200/10 μg BID (delivered as 2 inhalations of M/FM MDI 100/5 μg)

• FP/SAL 250/50 μg BID (delivered as 1 inhalation)

Primary endpoint: • Change from BL to week 12 in AUC for FEV1 measured for 0-

12 hours postdose (FEV1 AUC0-12 h): 3.43 M/FM L×h vs FP/SAL 3.24 L×h (95% CI, -0.40 to 0.76).

(M/FM was noninferior to FP/SAL) Secondary endpoints: • Onset of action: the effect of M/FM occurred significantly

faster than the effect of FP/SAL

• Incidence of AEs: M/FM: 7.8% (n = 29) FP/SAL: 8.3% (n = 29)

61

Study Reference and Design

Objective(s) Treatment Interventions Clinical Efficacy Clinical Safety

noninferiority efficacy and safety trial

asthma previously treated with medium-dose ICS with or without a LABA

Mean increase from BL in FEV1 at 5 min postdose on day 1: M/FM: 200 ml and FP/SAL: 90 ml (p<0.001)

• Asthma control, quality of life, and symptoms: similar between groups

4. Kawai et al92 2007

• 14-day randomised, double-blind, crossover study

To compare SAL/FP (SAL 50 mcg/FP 250 mcg BID) and SAL+FP (SAL 50 mcg b.i.d.+FP 250 mcg BID) in male and female Japanese (n=18) and Caucasian (n=17) asthmatics

• SAL/FP (50/250 mcg BID)

• SAL+FP (50 mcg BID+250 mcg BID)

Primary endpoint: • 0–12 h specific airways conductance (sGaw; AUC and

peak response) in Japanese patients after 14 days: SAL/FP is equivalent to SAL+FP.

Secondary endpoints: • Similar results between groups at Day 1 in Japanese patients • Similar results between groups at Day 1 and Day 14 in

Caucasian patients than in Japanese patients • No significant ethnic differences in therapeutic response

Comparable safety profiles between groups

5. Noonan et al 200688

• 12-week, double-blind, double-dummy, placebo-controlled, multicenter study

To compare the efficacy and safety of BUF/FM pMDI with BUD, FM and BUD+FM in separate inhalers in 596 patients ≥12 years of age with moderate to severe persistent asthma previously receiving ICSs.

• BUD/FM pMDI 160/4.5 µg BID

• BUD pMDI 160 µg BID

• FM DPI 4.5 µg BID • BUD pMDI 160 µg

BID + FM DPI 4.5 µg BID

• PBO

BUD/FM vs BUD+FM: Primary endpoints:

Mean change from baseline in morning predose FEV1 Mean difference between groups (95% CI): 0.05 (–0.05, 0.15)

Mean change from baseline in 12-hour FEV1 Mean difference between groups (95% CI): • At Day 1: –0.01 (–0.07, 0.06) • At week 2: 0.01 (–0.07, 0.09) • End of treatment: 0.01 (–0.08, 0.09) Secondary measures: % patients with worsening of asthma, improvements in diary variables, % of awakening-free nights, rescue medication use: • Similar results between groups

• Similar safety profile between groups

• Oral candidiasis appeared to be higher in the BUD/FM group compared with the other treatment groups

6. Pohunek et al 200689

• 12 wk, double-blind, double-dummy, randomized, parallel-group, active-controlled

To compare the efficacy and safety of BUF/FM pMDI with BUD, and BUD+FM in separate inhalers in 630 children (4–11 y) with asthma

• BUD/FM 80/4.5 µg 2 inhalations BID (Symbicort Turbuhaler, DPI)

• BUD (100 µg, 2 inhalations BID)

• BUD + FM (100 µg + 4.5 µg, 2 inhalations BID)

BUD/FM vs BUD+FM: Primary endpoints: 1. Mean change from baseline in morning PEF • No significant difference between groups (p 0.14) Secondary endpoints: change from baseline in: evening PEF; total asthma-symptom score (sum of night-time plus daytime symptom scores); night-time awakenings due to asthma symptoms; use of reliever medication; reliever free days; and symptom-free days. • Similar results between groups

Incidence of AEs: BUD/FM, 39% vs BUD+FM in separate inhalers, 37%

Discontinuations: 2 with BUD+FM and 1 with BUD

62



multi-centre study (Study 0688)

• Centers: 80 centers in 8 countries

7. You-Ning et al99 2005

• 4-week randomised, open-label, parallel-group, multicentre study

To evaluate the efficacy and safety of SAL/FP delivered via a HFA-MDI inhaler in Chinese patients (aged 18–70 years) with moderate asthma poorly controlled with ICS

• FP/SAL HFA MDI 125/25 µg (2 puffs, BID)

• FP/SAL 250/50 µg via Diskus (one puff, BID)

Primary endpoints (morning PEF): No statistically significant differences between groups regarding improvements in morning PEF Secondary endpoint (evening PEF, daytime and nighttime symptom score, use of rescue slbutamol, FEV1 and paients self-evaluation): No statistically significant differences between groups

• Incidence of AEs: No statistically significant differences between groups

8. Rosenhall et al91 2003

• 12 month open, randomized, parallel group study

• Centre: 29 Swedish centres

To compare long-term safety and efficacy of BUD/FM single inhaler with BUD+FM via separate inhalers in adults with asthma



• Fewer patients withdrew from treatment with BUD/FM compared with BUD+FM (9.2% vs 19.4%, p=0.008)

• No differences in the time to first exacerbation • Increases in FEV1 of 4-6% from BL in both groups, and

sustained during the 12-month period • Overall, no differences in lung function between groups • Reduction of approximately 30% in ACQ scores in both groups,

and sustained during the 12-month period • HRQoL: similar improvements between groups

• No differences between groups in AEs, vital signs, ECG or laboratory measurements (including morning serum cortisol)

• SAE: 3.7% in BUD/FM, 5.8% in BUD+FM

• Discontinuations due to asthma worsening: 1.4% in BUD/FM vs 4.9% BUD+FM

9. Rosenhall et al90 2002

• 6-month open, randomized, multicenter parallel group study

To compare safety and efficacy of BUD/FM single inhaler with BUD+FM via separate inhalers in adults with asthma



• A SABA was allowed as reliever

• Whithdrawal rates were low in both groups • No differences in the time to first exacerbation • Increases in FEV1 of 5-6% from BL in both groups, and

sustained during the 12-month period • Overall, no differences in lung function between groups • Reduction of approximately 30% in ACQ scores in each group • HRQoL: similar improvements between groups

• No differences between groups in AEs, vital signs, ECG or laboratory measurements (including morning serum cortisol)

63



10. Bateman et al98 2001

• 12-week multi-centre, randomized, double-blind, double-dummy, parallel-group study

• 69 centres in 10 countries

To investigate the hypothesis of equivalent efficacy and comparable safety of 2 inhaled presentations of SAL/FP combination products

• SAL/FP HFA MDI 25/50 µg (2 inhalations BID)

• SAL/FP DPI 50/100 µg (1 inhalation BID, via Diskus)

Primary endpoints (mean morning PEF over weeks 1–12) • Both groups were clinically equivalent Secondary endpoints (evening PEF, daytime and night-time symptom scores, use of as-required salbutamol and clinic FEV1) • Both groups were clinically equivalent

• AEs and serum cortisol levels: No significant difference between groups

11. Van Noord et al100 2001

• 12-week multicentre, double-blind, parallel-group study

To demonstrate equivalent efficacy and comparable tolerability of two inhaled combined formulations of SAL/FP in asthma patients (12 to 82 years)

• SAL/FP HFA MDI 25/250 µg (2 inhalations BID)

• SAL/FP DPI 50/500 µg (1 inhalation BID, via Diskus)

Primary endpoints (change in morning PEF over weeks 1 to 12): • Adjusted mean increases 50 L/min (with FP/SAL MDI) and

48 L/min (with FP/SAL DPI); treatment difference -2 L/min; 95% CI: -11 to 7 L/min (Clinical equivalence between groups)

• Similar safety profiles between groups

12. Van der Berg et al93 2000

• 12-week multicenter, randomized, double-blind, double-dummy, parallel-group study

• Centres: 35 centers in 9 countries

To compare the efficacy and safety in 257 children (4-11 years) of SAL/FP (50/100 μg BID) via a single Diskus™ inhaler (Seretide™; combination therapy) or concurrently using two separate Diskus™ inhalers (concurrent therapy)

• FP/SAL (50/100 μg BID) via Diskus™ inhaler (Seretide)

• FP+SAL (50+100 μg BID) via separate inhalers

Primary endpoint: • Adjusted change in Mean Morning PEF (week 1-12):

SAL/FP: improvement of 33 L/min SAL+FP: improvement of 28 L/min *Difference between the two treatment arms (concurrent − combination): −5 L/min (90% CI (−10, 0 L/min) was within the definition of equivalence; p=0.103). (Criterion for clinical equivalence: 90% CI between ±15 L/min)

(SAL/FM is clinically equivalent to SAL+FM) • Adjusted change in Mean Morning PEF (other time interval):

similar result to that at week 1-12, except difference between groups at week 2 that was statistically significant (−9 L/min; 90% CI, −15, −3 L/min; p=0.017) in favor of fixed dose combination

• Drug-related AEs: SAL/FP: 10% SAL+FP: 5% • Most common AEs:

candidiasis, malaise and fatigue, aggression and hostility, and lower respiratory tract events

• Withdrawals due to AEs: 4 patients (2 in SAL/FP and 2 in SAL+FP)

• Laboratory value changes (e.g. serum

64



• Adjusted mean change difference in predicted morning PEF from BL for weeks 1–12 (15% and 13% for the combination and concurrent treatment groups, respectively) (not significant treatment difference, −1%; 90% CI, −4, 1%; p=0.361)

Secondary endpoints: Similar improvements between groups in lung function, symptom score and rescue medication use

cortisol concentrations): similar between groups

13. Chapman et al95 1999

• 28-week multicentre, randomized, double-blind, double dummy, parallel group study

• 43 centers in 5 countries

To compare the efficacy and safety of a new combination Diskus inhaler containing both SAL 50 μg and FP 250 μg (Seretide) with the two drugs delivered via separate Diskus inhalers in 371 asthma patients (13 to 75 years)



Primary endpoints: • Adjusted mean improvements in morning PEFR from BL (12-

week period): SAL/FP: 43 L/min SAL+FP: 36 L/min *Difference between the two treatment arms (concurrent − combination): 6 L/min (90% CI –13 to 0 L/min; p=0.114). Criterion for clinical equivalence: 90% CI=±15 L/min

(SAL/FM is clinically equivalent to SAL+FM) • Adjusted mean improvements in morning PEFR from BL (at

week 3 and 4): • At week 3: 90% CI –16 to –2 L/min, p=0.037 • At week 4: 90% CI –16 to –2 L/min, p=0.043

(SAL/FM is statistically superior to SAL+FM at week 3 and 4) Secondary endpoints: • Adjusted mean changes in evening PEFR (12-week period):

SAL/FP: 35 L/min SAL+FP: 25 L/min *Difference between groups: –10 L/min (90% CI –16 to –4 L/min; p=0.008)

(SAL/FM is statistically superior to SAL+FM) • Daytime and night-time symptom scores, and use of

salbutamol as reliever: no differences between groups

Similar safety profile (AEs leading to withdrawal and laboratory values) between groups

14. Aubier et al96 1999

• 28-week multicentre double-blind,

To compare the efficacy and safety of a new combination Diskus inhaler containing both SAL 50 μg and FP 500 μg (Seretide) with the two




week period): SAL/FP: 35 L/min SAL+FP: 33 L/min *Difference between the two treatment arms (concurrent − combination): -3.1 L/min

Similar safety profile (AEs leading to withdrawal and laboratory values) between groups

65



double-dummy study

drugs delivered via separate Diskus inhalers in 503 asthma patients aged ≥12 years

• FP 500 μg BID • PBO

(90% CI –10 to 4 L/min; p=0.535). Criterion for clinical equivalence: 90% CI=±15 L/min

(SAL/FM is clinically equivalent to SAL+FM) Secondary endpoints: • Adjusted mean changes in evening PEFR (12-week period):

No differences between groups • Lung function (at week 28) and daytime symptom score,

night-time symptom scores, and use of salbutamol as reliever (over week 1-12): no significant differences between groups

15. Bateman et al94 1998

• 12-week multicentre, double-blind, double-dummy study

• 44 centers in 4 countries

To compare SAL 50µg and FP 100µg in a single device with the delivery of the two drugs via two separate inhalers in 244 asthma patients (12-78 years)




week period): SAL/FP: 42 L/min SAL+FP: 33 L/min *Difference between the two treatment arms (concurrent − combination): –9 L/min (90% CI: –17, 0 L/min). Criterion for clinical equivalence: 90% CI=±15 L/min

(SAL/FM is statistically superior to SAL+FM) Secondary endpoints: • Percentage predicted morning PEFR, actual and percentage

predicted evening PEFR: similar between groups • Adjusted mean changes in FEV1 from BL at week 12:

SAL/FP: 0.20L SAL+FP: 0.17L *Treatment difference=–0.03L (90% CI: –0.12, 0.05L)

• Similar improvements between groups in daytime and night-time symptom scores, percentage symptom free days and nights, and use of rescue salbutamol

• Compliance: high in both groups SAL/FP: 94 SAL+FP: 93%

• Most common AE: Headaches (12% in SAL/FM vs 4% in SAL+FP; p = 0.02)

• Withdrawals due to AEs: similar between groups

• No clinically significant changes in laboratory values, physical examinations or vital signs were observed in either treatment group

Abbreviations: ACOS, Asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS); ACQ, asthma control questionnaire; ACT, asthma control test; AE, adverse event; AUC, area under the curve; CAT, COPD assessment test; CI, confidence interval; COPD, chronic obstructive pulmonary disease; CV, cardiovascular; DPI, dry powder inhaler; HFA, hydrofluoroalkane; FEV1, forced expiratory volume in 1 second; FeNO; fractional exhaled nitric oxide; FEF, forced expiratory flow; FM, formoterol; FOT, forced oscillation technique; FP, fluticasone propionate; FVC, forced vital capacity; GI, gastrointestinal; HRQoL, health related quality of life; M, mometasone; MDI, metered-dose inhaler; MiniAQLQ, Mini Asthma Quality of Life Questionnaire; PBO, placebo; PEF, peak expiratory flow; PEFR, peak expiratory flow rate; pMDI, pressurized metered dose inhaler; SABA, short-acting beta2 agonists; SAE, serious adverse events; S or SAL, salmeterol; µg or mcg, micrograms; VI, vilanterol

66

Appendix F. List of Excluded References

Wrong comparator (monotherapy, LABA/LAMA, placebo, or non FDA-approved ICS/LABA dosages)

1. Agusti A, de Teresa L, De Backer W, et al. A comparison of the efficacy and safety of once-daily fluticasone furoate/vilanterol with twice-daily fluticasone propionate/salmeterol in moderate to very severe COPD. The European respiratory journal. 2014;43(3):763-772.

2. Bateman ED, Harrison TW, Quirce S, et al. Overall asthma control achieved with budesonide/formoterol maintenance and reliever therapy for patients on different treatment steps. Respiratory Research. 2011;12:38.

3. Cates CJ, Karner C. Combination formoterol and budesonide as maintenance and reliever therapy versus current best practice (including inhaled steroid maintenance), for chronic asthma in adults and children. Cochrane Database of Systematic Reviews. 2013(4):CD007313.

4. Cates CJ, Lasserson TJ. Combination formoterol and inhaled steroid versus beta2-agonist as relief medication for chronic asthma in adults and children. Cochrane Database of Systematic Reviews. 2009(1):CD007085.

5. Chauhan BF, Chartrand C, Ni Chroinin M, Milan SJ, Ducharme FM. Addition of long-acting beta2-agonists to inhaled corticosteroids for chronic asthma in children. Cochrane Database of Systematic Reviews. 2015(11):CD007949.

6. Chervinsky P, Baker J, Bensch G, et al. Patient-reported outcomes in adults with moderate to severe asthma after use of budesonide and formoterol administered via 1 pressurized metered-dose inhaler. Annals of Allergy, Asthma, & Immunology. 2008;101(5):463-473.

7. Cope S, Capkun-Niggli G, Gale R, Jardim JR, Jansen JP. Comparative efficacy of indacaterol 150 mug and 300 mug versus fixed-dose combinations of formoterol + budesonide or salmeterol + fluticasone for the treatment of chronic obstructive pulmonary disease--a network meta-analysis. International Journal of COPD. 2011;6:329-344.

8. Cope S, Kraemer M, Zhang J, Capkun-Niggli G, Jansen JP. Efficacy of indacaterol 75 mug versus fixed-dose combinations of formoterol-budesonide or salmeterol-fluticasone for COPD: a network meta-analysis. International Journal of COPD. 2012;7:415-420.

9. FitzGerald JM, Boulet LP, Follows RM. The CONCEPT trial: a 1-year, multicenter, randomized,double-blind, double-dummy comparison of a stable dosing regimen of salmeterol/fluticasone propionate with an adjustable maintenance dosing regimen of formoterol/budesonide in adults with persistent asthma. Clinical Therapeutics. 2005;27(4):393-406.

10. Frois C, Wu EQ, Ray S, Colice GL. Inhaled corticosteroids or long-acting beta-agonists alone or in fixed-dose combinations in asthma treatment: a systematic review of fluticasone/budesonide and formoterol/salmeterol. Clinical Therapeutics. 2009;31(12):2779-2803.

11. Horita N, Miyazawa N, Tomaru K, et al. Long-acting muscarinic antagonist-+-long-acting beta agonist versus long-acting beta agonist-+-inhaled corticosteroid for COPD: A systematic review and meta-analysis. Respirology (Carlton, Vic). 2015;20(8):1153-1159.

12. Huisman EL, Cockle SM, Ismaila AS, Karabis A, Punekar YS. Comparative efficacy of combination bronchodilator therapies in COPD: a network meta-analysis. Int J Chron Obstruct Pulmon Dis. 2015;10:1863-1881.

13. Iftikhar IH, Imtiaz M, Brett AS, Amrol DJ. Cardiovascular safety of long acting beta agonist-inhaled corticosteroid combination products in adult patients with asthma: a systematic review. Lung. 2014;192(1):47-54.

14. Kew KM, Dias S, Cates CJ. Long-acting inhaled therapy (beta-agonists, anticholinergics and steroids) for COPD: a network meta-analysis. Cochrane Database of Systematic Reviews. 2014(3):CD010844.

15. Kew KM, Karner C, Mindus SM, Ferrara G. Combination formoterol and budesonide as maintenance and reliever therapy versus combination inhaler maintenance for chronic asthma in adults and children. Cochrane Database of Systematic Reviews. 2013(12):CD009019.

16. Lee DK, Jackson CM, Currie GP, Cockburn WJ, Lipworth BJ. Comparison of combination inhalers vs inhaled corticosteroids alone in moderate persistent asthma. British journal of clinical pharmacology. 2003;56(5):494-500.

17. McKeage K, Keam SJ. Salmeterol/fluticasone propionate: a review of its use in asthma. Drugs. 2009;69(13):1799-1828.

18. Nannini L, Lasserson TJ, Poole P. Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews. 2003(4):CD003794.

19. Nannini LJ, Poole P, Milan SJ, Holmes R, Normansell R. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus placebo for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews. 2013(11):CD003794.

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20. Papi A, Mansur AH, Pertseva T, et al. Long-Term Fluticasone Propionate/Formoterol Fumarate Combination Therapy Is Associated with a Low Incidence of Severe Asthma Exacerbations. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 2016;29(4):346-361.

21. Partridge MR, Schuermann W, Beckman O, Persson T, Polanowski T. Effect on lung function and morning activities of budesonide/formoterol versus salmeterol/fluticasone in patients with COPD. Therapeutic advances in respiratory disease. 2009;3(4):1-11.

22. Peters J, Stevenson M, Beverley C, et al. The clinical effectiveness and cost-effectiveness of inhaler devices used in the routine management of chronic asthma in older children: A systematic review and economic evaluation. Health Technology Assessment. 2002;6:5.

23. Prosser TR, Bollmeier SG, Author A, et al. Fluticasone-formoterol: A systematic review of its potential role in the treatment of asthma. Therapeutics and Clinical Risk Management. 2015;11:889-899.

24. Remington TL, Heaberlin AM, DiGiovine B. Combined budesonide/formoterol turbuhaler treatment of asthma. Annals of Pharmacotherapy. 2002;36(12):1918-1928.

25. Ringdal N, Chuchalin A, Chovan L, et al. Evaluation of different inhaled combination therapies (EDICT): a randomised, double-blind comparison of Seretide (50/250 microg bd Diskus vs. formoterol (12 microg bd) and budesonide (800 microg bd) given concurrently (both via Turbuhaler) in patients with moderate-to-severe asthma. Respiratory medicine. 2002;96(11):851-861.

26. Rodrigo GJ, Castro-Rodriguez JA, Plaza V, et al. Safety and efficacy of combined long-acting β-agonists and inhaled corticosteroids vs long-acting β-agonists monotherapy for stable COPD: A systematic review. Chest. 2009;136(4):1029-1038.

27. Rodrigo GJ, Neffen H, Author A, et al. A systematic review with meta-analysis of fluticasone furoate/vilanterol combination for the treatment of stable COPD. Pulmonary Pharmacology and Therapeutics. 2017;42:1-6.

28. Rojas-Reyes MX, Garcia Morales OM, Dennis RJ, Karner C. Combination inhaled steroid and long-acting beta2-agonist in addition to tiotropium versus tiotropium or combination alone for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews. 2016(6):CD008532.

29. Sin DD, Man J, Sharpe H, Gan WQ, Man SF. Pharmacological management to reduce exacerbations in adults with asthma: a systematic review and meta-analysis. Jama. 2004;292(3):367-376.

30. Sin DD, McAlister FA, Man SF, Anthonisen NR. Contemporary management of chronic obstructive pulmonary disease: scientific review. Jama. 2003;290(17):2301-2312.

31. Tricco AC, Strifler L, Veroniki AA, et al. Comparative safety and effectiveness of long-acting inhaled agents for treating chronic obstructive pulmonary disease: a systematic review and network meta-analysis. BMJ Open. 2015;5(10):e009183.

32. Zhu Y, Zhang T, Li H, et al. Discovering the relative efficacy of inhaled medications for chronic obstructive pulmonary disease: Multiple treatment comparisons. Cellular Physiology and Biochemistry. 2017;41(4):1532-1546.

Wrong outcome

33. Diong B, Singh K, Menendez R. Effects of two inhaled corticosteroid/long-acting beta-agonist combinations on small-airway dysfunction in mild asthmatics measured by impulse oscillometry. Journal of asthma and allergy. 2013;6:109-116.

34. Hozawa S, Terada M, Hozawa M. Comparison of budesonide/formoterol Turbuhaler with fluticasone/salmeterol Diskus for treatment effects on small airway impairment and airway inflammation in patients with asthma. Pulmonary pharmacology & therapeutics. 2011;24(5):571-576.

35. Lotvall J, Langley S, Woodcock A. Inhaled steroid/long-acting beta 2 agonist combination products provide 24 hours improvement in lung function in adult asthmatic patients. Respiratory Research. 2006;7:110.

36. Main C, Shepherd J, Anderson R, et al. Systematic review and economic analysis of the comparative effectiveness of different inhaled corticosteroids and their usage with long-acting beta2 agonists for the treatment of chronic asthma in children under the age of 12 years. Health Technology Assessment (Winchester, England). 2008;12(20):1-174, iii.

37. Mapel DW, Roberts MH. Management of asthma and chronic obstructive pulmonary disease with combination inhaled corticosteroids and long-acting beta-agonists: a review of comparative effectiveness research. Drugs. 2014;74(7):737-755.

38. Shepherd J, Rogers G, Anderson R, et al. Systematic review and economic analysis of the comparative effectiveness of different inhaled corticosteroids and their usage with long-acting beta2 agonists for the treatment of chronic asthma in adults and children aged 12 years and over. Health Technology Assessment (Winchester, England). 2008;12(19):iii-iv, 1.

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Wrong study design

39. Aalbers R. Fixed or adjustable maintenance-dose budesonide/formoterol compared with fixed maintenance-dose salmeterol/fluticasone propionate in asthma patients aged >or=16 years: post hoc analysis of a randomized, double-blind/open-label extension, parallel-group study. Clinical Drug Investigation. 2010;30(7):439-451.

40. Adachi M, Goldfrad C, Jacques L, Nishimura Y. Efficacy and safety comparison: Fluticasone furoate and fluticasone propionate, after step down from fluticasone furoate/vilanterol in Japanese patients with well-controlled asthma, a randomized trial. Respiratory medicine. 2016;120:78-86.

41. Adachi M, Goldfrad C, Jacques L, et al. Corrigendum to “Efficacy and safety comparison: Fluticasone furoate and fluticasone propionate, after step down from fluticasone furoate/vilanterol in Japanese patients with well-controlled asthma, a randomized trial” [Respir. Med. (2016) 120 (78–86)] (S0954611116302517)(10.1016/j.rmed.2016.09.018). Respiratory medicine. 2017;126:25.

42. Akamatsu T, Shirai T, Kato M, et al. Switching from salmeterol/fluticasone to formoterol/budesonide combinations improves peripheral airway/alveolar inflammation in asthma. Pulmonary pharmacology & therapeutics. 2014;27(1):52-56.

43. Hagedorn, C., Kässner, F., Banik, N., Ntampakas, P., & Fielder, K. (2013). Influence of salmeterol/fluticasone via single versus separate inhalers on exacerbations in severe/very severe COPD. Respiratory medicine, 107(4), 542-549.

Wrong intervention

44. Edwards SJ, Von Maltzahn R, Naya IP, et al. Budesonide/formoterol for maintenance and reliever therapy of asthma: A meta analysis of randomised controlled trials. International Journal of Clinical Practice. 2010;64(5):619-627.

45. Kaiser H, Parasuraman B, Boggs R, Miller CJ, Leidy NK, O'Dowd L. Onset of effect of budesonide and formoterol administered via one pressurized metered-dose inhaler in patients with asthma previously treated with inhaled corticosteroids.[Erratum appears in Ann Allergy Asthma Immunol. 2009 Feb;102(2):175]. Annals of Allergy, Asthma, & Immunology. 2008;101(3):295-303.

Review (not a systematic review, not a randomized controlled trials)

46. Berger WE, Noonan MJ. Treatment of persistent asthma with Symbicort (budesonide/formoterol inhalation aerosol): an inhaled corticosteroid and long-acting beta2-adrenergic agonist in one pressurized metered-dose inhaler. Journal of Asthma. 2010;47(4):447-459.

47. Bollmeier SG, Prosser TR. Patient perspectives on fluticasone-vilanterol versus other corticosteroid combination products for the treatment of asthma. Patient preference & adherence. 2016;10:825-836.

48. Goldsmith DR, Keating GM. Budesonide/formoterol: a review of its use in asthma. Drugs. 2004;64(14):1597-1618.

49. Korenblat PE, Rosenwasser LJ. Budesonide/formoterol pressurized metered-dose inhaler for patients with persistent asthma. Allergy & Asthma Proceedings. 2010;31(3):190-202.

50. Lipworth BJ, Fardon TC. Enhanced synergy between fluticasone propionate and salmeterol inhaled from a single inhaler versus separate inhalers. Journal of Allergy & Clinical Immunology. 2004;113(1):178; author reply 178-179.

51. O'Connor RD. Treatment with budesonide/formoterol pressurized metered-dose inhaler in patients with asthma: a focus on patient-reported outcomes. Patient Related Outcome Measures. 2011;2:41-55.

52. Shivashankar M, Mani D, Author A, et al. A systematic review on asthma. Research Journal of Pharmaceutical, Biological and Chemical Sciences. 2015;6(1):679-687.

53. Vestbo J, Leather D, Diar Bakerly N, et al. Effectiveness of Fluticasone Furoate-Vilanterol for COPD in Clinical Practice. New England Journal of Medicine. 2016;375(13):1253-1260.

Full text not available

54. Metcalfe S, Moodie P. Seretide meta-analysis missed important features and overstates any advantages over

concurrent LABA/ICS devices. Journal of Allergy & Clinical Immunology. 2004;113(3):568-569; author reply 569.

Note: Duplicates (n=4) are not included in this list.

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