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New Treatment Option for Chronic Obstructive Pulmonary Disease: Two Long-Acting Bronchodilators in a Single Metered-Dose Inhaler

      Abstract

      Combination long-acting inhaled bronchodilators are central to the management of patients with moderate to very severe chronic obstructive pulmonary disease. Glycopyrrolate is a long-acting muscarinic antagonist (LAMA), and formoterol fumarate is a long-acting beta2 agonist (LABA). In randomized controlled trials, this LAMA/LABA combination in a metered-dose inhaler was shown to be effective in improving pulmonary function and quality of life. Clinicians now have the availability of 3 delivery systems for LAMA/LABA therapy, including metered-dose inhaler, dry-powder inhaler, and Soft Mist inhaler. On the basis of numerous patient factors, such as cognitive ability, manual strength/dexterity, and peak inspiratory flow, clinicians may select the most appropriate inhalation device. For each inhalation device, persistent patient education is absolutely essential, including observation of patient use. International evidence-based guidelines stress the critical importance of ensuring correct use of inhalation devices.

      Keywords

      Clinical Significance
      • Long-acting muscarinic antagonist/long-acting beta2 agonist combination therapy is a key component in the management of moderate to very severe chronic obstructive pulmonary disease, and tailoring the type of inhaler to the patient is clinically relevant.
      • When prescribing long-acting muscarinic antagonist/long-acting beta2 agonist via metered-dose inhaler, dry-powder inhaler, or Soft Mist inhaler, ensuring correct inhalation technique is essential for optimal patient response.
      Chronic obstructive pulmonary disease (COPD) is now the third leading cause of death in the United States and causes enormous human suffering and economic loss worldwide.
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of COPD (2017 report).
      Long-acting inhaled bronchodilators are an important component in the maintenance treatment of COPD.
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of COPD (2017 report).
      Although many of these agents are available in a variety of delivery systems, such as dry-powder or Soft Mist inhalers, having the combination of 2 long-acting bronchodilators in a pressurized metered-dose inhaler (MDI) is novel (see Table). Depending on patient preference and ability to use an inhalation device correctly, availability of multiple options to patients and prescribers may be helpful.
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of COPD (2017 report).
      Thus, this combination of long-acting bronchodilators in an MDI is more than simply a “new product.” In April 2016 the US Food and Drug Administration approved a glycopyrrolate/formoterol fumarate (GFF) fixed-dose combination MDI under the brand name Bevespi Aerosphere (AstraZeneca Pharmaceuticals, Wilmington, Del) for the long-term maintenance treatment of airflow obstruction in patients with COPD.
      • AstraZeneca Pharmaceuticals LP
      Bevespi Aerosphere (package insert).
      Glycopyrrolate is a long-acting muscarinic antagonist (LAMA), and formoterol fumarate is a long-acting beta2 agonist (LABA).
      TableInhaled LAMA/LABA Combination Products Available in the United States for Management of COPD
      Product (Generic and Brand Name)FrequencyDelivery Device
      See product literature for full information; observe patients use devices to verify correct technique.
      Aclidinium/formoterolTwice dailyDPI
      Duaklir Genuair
      Glycopyrrolate/indacaterolOnce dailyDPI
      Utibron Neohaler
      Glycopyrrolate/formoterolTwice dailyMDI
      Bevespi Aerosphere
      Tiotropium/olodaterolOnce dailySoft Mist
      Stiolto Respimat
      Umeclidinium/vilanterolOnce dailyDPI
      Anoro Ellipta
      For all inhalation devices, first exhale gently and fully; for DPIs, inhale rapidly/deeply, for MDI and SoftMist, inhale slowly/deeply; then, hold breath for a few seconds as long as comfortable (10 sec is best; ≤4-5 sec is more realistic for many COPD patients).
      COPD = chronic obstructive pulmonary disease; DPI = dry-powder inhaler; LABA = long-acting beta2 agonist; LAMA = long-acting muscarinic antagonist; MDI = metered-dose inhaler.
      * See product literature for full information; observe patients use devices to verify correct technique.

      Place in Therapy

      The updated 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of COPD (2017 report).
      state that the goals for treatment of stable COPD include reducing symptoms (relieve symptoms, improve exercise tolerance, and improve health status) and reducing risk (prevent disease progression, prevent and treat exacerbations, and reduce mortality). In addition to smoking cessation and reducing indoor/outdoor pollution as well as occupational exposures to inhaled irritants, pharmacologic treatment is central to COPD management in achieving these goals. The GOLD guidelines propose a revised combined COPD assessment to guide long-term management,including drug therapy. After spirometry to evaluate the severity of airflow limitation, patients should be assessed by a dyspnea score or symptom score using validated questionnaires.
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of COPD (2017 report).
      In addition, a history of exacerbations and comorbidities helps to guide long-term therapy.
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of COPD (2017 report).
      The GOLD guidelines
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of COPD (2017 report).
      summarize several key points regarding long-acting bronchodilators:
      • 1.
        LAMAs and LABAs are preferred over short-acting bronchodilators, except in patients who have occasional dyspnea only.
      • 2.
        LAMAs improve symptoms and health status, increase effectiveness of pulmonary rehabilitation, and decrease exacerbations and related hospitalizations.
      • 3.
        LAMAs are superior to LABAs in decreasing the rate of exacerbations and have fewer adverse effects.
      • 4.
        LAMA/LABA combination products have better patient-reported outcomes and improved symptoms and health status, as well as decreased rates of exacerbations compared with single-agent bronchodilator therapy or inhaled corticosteroid (ICS) plus LABA.
      • 5.
        Adding an ICS to LABA/LAMA has not been shown to reduce exacerbations. (We note COPD patients with elevated blood eosinophils may benefit more from ICS, but available data are conflicting.
        • Global Initiative for Chronic Obstructive Lung Disease
        Global strategy for the diagnosis, management, and prevention of COPD (2017 report).
        • Wedzicha J.A.
        • Banerju D.
        • Chapman K.R.
        • et al.
        Indacaterol-glycopyrronium versus salmeterol-fluticasone for COPD.
        ) Furthermore, ICS therapy in COPD patients is associated with increased risk of pneumonia.
        • Suissa S.
        • Coulombe J.
        • Ernst P.
        Discontinuation of inhaled corticosteroids in COPD and the risk reduction of pneumonia.
        • Crim C.
        • Dransfiled M.T.
        • Bourbeau J.
        • et al.
        Pneumonia risk with inhaled fluticasone furoate and vilanterol compared with vilanterol alone in patients with COPD.
        Therefore, it is logical to initiate LABA/LAMA therapy in many COPD patients before a trial of ICS/LABA or LAMA/LABA/ICS. Triple therapy with LAMA/LABA/ICS in a single inhaler has recently been evaluated in 2 trials.
        • Singh D.
        • Papi A.
        • Corradi M.
        • et al.
        Single inhaler triple therapy versus inhaled corticosteroid plus long-acting beta2 agonist therapy for chronic obstructive pulmonary disease (TRILOGY): a double-blind, parallel group, randomized controlled trial.
        • Vestbo J.
        • Papi A.
        • Corradi M.
        • et al.
        Single inhaler extrafine triple therapy versus long-acting muscarinic antagonist therapy for chronic obstructive pulmonary disease (TRINITY): a double-blind, parallel group, randomized controlled trial.
        Although some benefits were found, the authors point out that neither trial answered the question regarding the value of adding ICS to LAMA/LABA.
        • Singh D.
        • Papi A.
        • Corradi M.
        • et al.
        Single inhaler triple therapy versus inhaled corticosteroid plus long-acting beta2 agonist therapy for chronic obstructive pulmonary disease (TRILOGY): a double-blind, parallel group, randomized controlled trial.
        • Vestbo J.
        • Papi A.
        • Corradi M.
        • et al.
        Single inhaler extrafine triple therapy versus long-acting muscarinic antagonist therapy for chronic obstructive pulmonary disease (TRINITY): a double-blind, parallel group, randomized controlled trial.

      Clinical Evidence of GFF Efficacy

      A dose-ranging study determined optimal doses of GFF MDI to improve forced expiratory volume in the first second (FEV1) area under the curve (AUC) from 0 to 12 hours (FEV1 AUC 0-12h) to be glycopyrrolate 18 µg and formoterol 9.6 µg.
      • Tashkin D.P.
      • Martinez F.J.
      • Rodriguez-Roisin R.
      • et al.
      A multicenter, randomized, double-blind dose ranging study of glypyrrolate/formoterol fumarate fixed-dose combination metered dose inhaler compared to the monocomponents and open-label tiotropium dry powder inhaler in patients with moderate to severe COPD.
      The GFF MDI delivers glycopyrrolate 9 µg and formoterol 4.8 µg at the mouthpiece with a dose of 2 puffs twice daily. Adverse effects associated with the fixed-dose combination were similar to those reported with other doses, as well as tiotropium, and most commonly included dry mouth and tremor. A subsequent randomized double-blind investigation compared the safety and efficacy of the GFF MDI with single components (glycopyrrolate MDI, formoterol MDI, placebo MDI), open-label tiotropium dry-powder inhaler (DPI), and formoterol DPI.
      • Reisner C.
      • Fabbri L.M.
      • Kerwin E.M.
      • et al.
      A randomized, seven-day study to assess the efficacy and safety of a glycopyrrolate/formoterol fumarate fixed-dose combination metered dose inhaler using novel Co-suspension Delivery Technology in patients with moderate-to-very severe chronic obstructive pulmonary disease.
      In these patients with moderate to very severe COPD, GFF was superior to placebo in efficacy per FEV1 AUC 0-12h, monocomponent MDIs, and monocomponent DPIs. In this 7-day study, no difference in adverse effects was observed.
      • Reisner C.
      • Fabbri L.M.
      • Kerwin E.M.
      • et al.
      A randomized, seven-day study to assess the efficacy and safety of a glycopyrrolate/formoterol fumarate fixed-dose combination metered dose inhaler using novel Co-suspension Delivery Technology in patients with moderate-to-very severe chronic obstructive pulmonary disease.
      The efficacy and safety of GFF MDI were evaluated in 2 phase 3, double-blind, randomized, placebo-controlled trials.
      • Martinez F.J.
      • Rabe K.F.
      • Ferguson G.T.
      • et al.
      Efficacy and safety of glycopyrrolate/fomoterol metered dose inhaler formulated usingco-suspension delivery technology in patients with COPD.
      Patients with moderate to very severe COPD were assessed over 24 weeks. In one study (PINNACLE-1), 2103 patients were randomized to GFF MDI, glycopyrrolate MDI, formoterol MDI, placebo, or open-label tiotropium. The same methods were used in PINNACLE-2 (n = 1615) but without a tiotropium group. At week 24, change from baseline in morning predose trough FEV1 was the primary endpoint, and GFF MDI treatment resulted in better improvement (P < .0001) compared with the monocomponent MDIs.
      • Martinez F.J.
      • Rabe K.F.
      • Ferguson G.T.
      • et al.
      Efficacy and safety of glycopyrrolate/fomoterol metered dose inhaler formulated usingco-suspension delivery technology in patients with COPD.
      Adverse events across groups were similar to those with placebo and included nasopharyngitis, sinusitis, cough, dyspnea, and upper respiratory tract infection. In a 28-week safety extension study of these 2 24-week trials, 892 patients were further evaluated for adverse events and efficacy.
      • Hanaia N.A.
      • Tashkin D.P.
      • Kerwin E.M.
      • et al.
      Long-term safety and efficacy of glycopyrrolate/formoterol metered dose inhaler using novel Co-suspension Delivery Technology in patients with chroncic obstructive pulmonary disease.
      Quality of life and pulmonary function improvement were sustained over the 1-year total study, with no unexpected safety findings.
      • Hanaia N.A.
      • Tashkin D.P.
      • Kerwin E.M.
      • et al.
      Long-term safety and efficacy of glycopyrrolate/formoterol metered dose inhaler using novel Co-suspension Delivery Technology in patients with chroncic obstructive pulmonary disease.
      Consistent with GOLD guidelines, GFF MDI is a viable treatment option for patients who continue to have poor control ofmoderate to very severe COPD despite monotherapy with a LAMA or LABA.

      Administration: A Critical Concern

      Patient-specific instructions for use of GFF are not technically different from those for other MDIs; importantly, however, the anticipated benefit from GFF is dependent upon administration technique. Since the initial report of incorrect inhalation technique with MDI in 1965, voluminous documentation of this problem, which may result in poor clinical outcomes, has continued.
      • Saunders K.B.
      Misuse of inhaled bronchodilators.
      • Melani A.S.
      • Bonavia M.
      • Cilenti V.
      • et al.
      Inhaler mishandling remains common in real life and is associated with reduced disease control.
      • Sanchis J.
      • Gich I.
      • Pedersen S.
      Systematic review of errors in inhaler use: has patient technique improved over time?.
      Evidence-based COPD GOLD guidelines state, “Education and training in inhaler technique cannot be overemphasized.”
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of COPD (2017 report).
      Such education must include observation of the patient using the inhaler device(s). Common technique errors include 1) failure to gently exhale for a few seconds before inhalation, 2) not inhaling at the appropriate inspiratory flow (eg, slow with an MDI but fast for most DPIs), and 3) not breath-holding after a full inhalation.
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of COPD (2017 report).
      • Melani A.S.
      • Bonavia M.
      • Cilenti V.
      • et al.
      Inhaler mishandling remains common in real life and is associated with reduced disease control.
      • Sanchis J.
      • Gich I.
      • Pedersen S.
      Systematic review of errors in inhaler use: has patient technique improved over time?.
      In patients who struggle with MDI technique, a valved holding chamber “spacer” has been shown to be helpful for other MDIs.
      • Singh D.
      • Collarini S.
      • Poli G.
      • et al.
      Effect of AeroChamber Plus on the lung and systemic bioavailability of beclomethasone dipropionate/formoterol pMDI.
      For time efficiency and owing to the lack of placebo teaching devices in many settings, it is helpful to have the patient view correct technique via YouTube videos available from National Jewish Health (www.nationaljewish.org/health-insights/multimedia/asthma-inhalers).
      Although we were unable to identify any primary literature examining pulmonary deposition with the GFF MDI, studies with other hydrofluoroalkane (HFA) MDI products offer some insight.
      • Leach C.L.
      • Davidson P.J.
      • Hasselquist B.E.
      • Boudreau R.J.
      Influence of particle size and patient dosing technique on lung deposition of HFA-beclomethasone from a metered dose inhaler.
      • De Backer W.
      • Devolder A.
      • Poli G.
      • et al.
      Lung deposition of BDP/formoterol HFA pMDI in healthy volunteers, asthmatic, and COPD patients.
      In general, pulmonary deposition associated with HFA MDIs is much higher than with the discontinued propellant chlorofluorocarbon MDIs. For example, with HFA-beclomethasone MDI, asthma patients with good inhalation technique, under controlled study conditions, had lung deposition of 59%, contrasted with <10% deposition in previous studies with chlorofluorocarbon MDI.
      • Leach C.L.
      • Davidson P.J.
      • Hasselquist B.E.
      • Boudreau R.J.
      Influence of particle size and patient dosing technique on lung deposition of HFA-beclomethasone from a metered dose inhaler.
      The combination of beclomethasone/formoterol HFA-MDI was shown to have 33% pulmonary deposition in COPD patients.
      • De Backer W.
      • Devolder A.
      • Poli G.
      • et al.
      Lung deposition of BDP/formoterol HFA pMDI in healthy volunteers, asthmatic, and COPD patients.
      Manufacturer instructions for the GFF MDI include “While breathing in deeply and slowly, press down….” Unfortunately, it is well documented that 5%-18% (ie, several million) of COPD and asthma patients will inhale to total lung capacity before pressing down on the MDI.
      • Melani A.S.
      • Bonavia M.
      • Cilenti V.
      • et al.
      Inhaler mishandling remains common in real life and is associated with reduced disease control.
      • Giraud V.
      • Roche N.
      Misuse of corticosteroid metered-dose inhaler is associated with decreased asthma stability.
      Many COPD patients are elderly with several comorbidities and cannot inhale for several seconds. Therefore, instructing them to first inhale deeply and slowly enhances the likelihood of inhaling to total lung capacity before pressing down on the MDI. Consequently, clinicians are urged to teach their patients the technique that is consistent with national/international guidelines: to press down on the MDI at the start of inhalation.
      • Self T.H.
      • Hoth L.M.
      • Bolin J.M.
      • Stewart C.
      Metered-dose inhaler technique per the Global Initiative for Asthma and Expert Panel Report 3: why do pharmaceutical companies have one critical difference.
      Physicians working with respiratory therapists, as well as pharmacists and nurses who are skilled in use of inhalation devices, will help to ensure optimal response to the GFF MDI and other aerosol therapies.
      Although there are several concerns with MDIs specifically, patients face technique-related obstacles with all available inhaler types. Rogliani et al
      • Rogliani P.
      • Calzetta L.
      • Coppola A.
      • et al.
      Optimizing drug delivery in COPD: the role of inhaler devices.
      have recently reviewed the role of various inhaler devices in COPD patients. With most DPIs the medication is administered by the patient inhaling quickly and forcefully. Dry-powder inhalers do not require the coordination of pressing down on the MDI while beginning to inhale. However, because of the inspiratory flow required, a DPI may not be ideal for many elderly COPD patients with comorbidities or for use during an acute exacerbation in which airflow is limited. The level of coordination that is required of MDIs and the inspiratory flow required of DPIs are not limitations when using a Soft Mist inhaler, but patients must still remember to exhale first and be able to inhale slowly and deeply when the medication is released and then breathhold. It is imperative to weigh all considerations, including inspiratory ability, inhalation coordination, age, manual strength/dexterity, visual acuity, cognitive ability, and cost, when discussing appropriate therapy with each COPD patient.

      Conclusion

      The GFF MDI offers clinicians and patients another option in the long-term management of COPD. Although the safety and efficacy of GFF MDI are comparable to those with other available LAMA/LABA combination inhalers, head-to-head randomized controlled trials are needed to further assess clinical outcomes.

      References

        • Global Initiative for Chronic Obstructive Lung Disease
        Global strategy for the diagnosis, management, and prevention of COPD (2017 report).
        (Available at)
        • AstraZeneca Pharmaceuticals LP
        Bevespi Aerosphere (package insert).
        AstraZeneca Pharmaceuticals, Wilmington, DE2016
        • Wedzicha J.A.
        • Banerju D.
        • Chapman K.R.
        • et al.
        Indacaterol-glycopyrronium versus salmeterol-fluticasone for COPD.
        N Engl J Med. 2016; 374: 2222-2234
        • Suissa S.
        • Coulombe J.
        • Ernst P.
        Discontinuation of inhaled corticosteroids in COPD and the risk reduction of pneumonia.
        Chest. 2015; 148: 1177-1183
        • Crim C.
        • Dransfiled M.T.
        • Bourbeau J.
        • et al.
        Pneumonia risk with inhaled fluticasone furoate and vilanterol compared with vilanterol alone in patients with COPD.
        Ann Am Thorac Soc. 2015; 12: 27-34
        • Singh D.
        • Papi A.
        • Corradi M.
        • et al.
        Single inhaler triple therapy versus inhaled corticosteroid plus long-acting beta2 agonist therapy for chronic obstructive pulmonary disease (TRILOGY): a double-blind, parallel group, randomized controlled trial.
        Lancet. 2016; 388: 963-973
        • Vestbo J.
        • Papi A.
        • Corradi M.
        • et al.
        Single inhaler extrafine triple therapy versus long-acting muscarinic antagonist therapy for chronic obstructive pulmonary disease (TRINITY): a double-blind, parallel group, randomized controlled trial.
        Lancet. 2017; 389: 1919-1929
        • Tashkin D.P.
        • Martinez F.J.
        • Rodriguez-Roisin R.
        • et al.
        A multicenter, randomized, double-blind dose ranging study of glypyrrolate/formoterol fumarate fixed-dose combination metered dose inhaler compared to the monocomponents and open-label tiotropium dry powder inhaler in patients with moderate to severe COPD.
        Respir Med. 2016; 120: 16-24
        • Reisner C.
        • Fabbri L.M.
        • Kerwin E.M.
        • et al.
        A randomized, seven-day study to assess the efficacy and safety of a glycopyrrolate/formoterol fumarate fixed-dose combination metered dose inhaler using novel Co-suspension Delivery Technology in patients with moderate-to-very severe chronic obstructive pulmonary disease.
        Respir Res. 2017; 18: 8
        • Martinez F.J.
        • Rabe K.F.
        • Ferguson G.T.
        • et al.
        Efficacy and safety of glycopyrrolate/fomoterol metered dose inhaler formulated usingco-suspension delivery technology in patients with COPD.
        Chest. 2017; 151: 340-357
        • Hanaia N.A.
        • Tashkin D.P.
        • Kerwin E.M.
        • et al.
        Long-term safety and efficacy of glycopyrrolate/formoterol metered dose inhaler using novel Co-suspension Delivery Technology in patients with chroncic obstructive pulmonary disease.
        Respir Med. 2017; 126: 105-115
        • Saunders K.B.
        Misuse of inhaled bronchodilators.
        Br Med J. 1965; 1: 1037-1038
        • Melani A.S.
        • Bonavia M.
        • Cilenti V.
        • et al.
        Inhaler mishandling remains common in real life and is associated with reduced disease control.
        Respir Med. 2011; 105: 930-938
        • Sanchis J.
        • Gich I.
        • Pedersen S.
        Systematic review of errors in inhaler use: has patient technique improved over time?.
        Chest. 2016; 150: 394-406
        • Singh D.
        • Collarini S.
        • Poli G.
        • et al.
        Effect of AeroChamber Plus on the lung and systemic bioavailability of beclomethasone dipropionate/formoterol pMDI.
        Br J Clin Pharmacol. 2011; 72: 932-939
        • National Jewish Health
        Asthma inhalers.
        (Available at) (Accessed May 23, 2017)
        • Leach C.L.
        • Davidson P.J.
        • Hasselquist B.E.
        • Boudreau R.J.
        Influence of particle size and patient dosing technique on lung deposition of HFA-beclomethasone from a metered dose inhaler.
        J Aerosol Med. 2005; 18: 379-385
        • De Backer W.
        • Devolder A.
        • Poli G.
        • et al.
        Lung deposition of BDP/formoterol HFA pMDI in healthy volunteers, asthmatic, and COPD patients.
        J Aerosol Med Pulm Drug Deliv. 2010; 23: 137-147
        • Giraud V.
        • Roche N.
        Misuse of corticosteroid metered-dose inhaler is associated with decreased asthma stability.
        Eur Respir J. 2002; 19: 246-251
        • Self T.H.
        • Hoth L.M.
        • Bolin J.M.
        • Stewart C.
        Metered-dose inhaler technique per the Global Initiative for Asthma and Expert Panel Report 3: why do pharmaceutical companies have one critical difference.
        Ann Allergy Asthma Immunol. 2016; 117: 101-102
        • Rogliani P.
        • Calzetta L.
        • Coppola A.
        • et al.
        Optimizing drug delivery in COPD: the role of inhaler devices.
        Respir Med. 2017; 124: 6-14

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