By Clinical Content Hub

Chronic obstructive pulmonary disease (COPD) is a disorder of airway obstruction linked to preventable causes, including tobacco use, particulates, and other harmful fumes.1 In the United States, COPD affects 15 million people and might soon be the third leading cause of death in adults.1-4 The aggregate economic burden of COPD is estimated to be $49 billion annually, but prevalence is a regional phenomenon, with Puerto Rico and Hawaii having the fewest cases (3.7% of all US cases) and West Virginia the most (12%)3-4 (Figure 1).3

The Rationale for Nebulized Therapy

Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend long-acting bronchodilators as the foundation for maintenance pharmacotherapy for COPD, with either long-acting β2 agonists (LABA) or long-acting muscarinic antagonists (LAMA) for improving lung function, relieving dyspnea, and reducing the frequency of  exacerbations.5 For patients with more severe COPD, GOLD recommends combinations of LABA plus LAMA, along with inhaled corticosteroids.5
The following LABAs are delivered via a hand-held inhaler.1,5

  • Arformoterol
  • Formoterol
  • Indacaterol
  • Olodaterol
  • Salmeterol

Arformoterol and formoterol are also offered as inhalation solutions.

Of the following LAMAs, only glycopyrrolate and revefenacin offer nebulized solutions.1,5

  • Aclidinium
  • Glycopyrrolate
  • Revefenacin
  • Tiotropium
  • Umeclidinium

For select patients with COPD, nebulized drugs might offer an alternative to a breath-actuated, hand-held inhaler.5 Adherence to inhaled medication in patients with COPD is low, with the nonadherence rate ranging from 50% to 80%.6 Among the causes of nonadherence is the inability to use an inhaler as directed.6 Inhalers can be nearly impossible to use for patients who have a low inspiratory flow rate, minimal manual dexterity, and cognitive impairment.7 An estimated 19% to 78% of patients with COPD have a suboptimal peak inspiratory flow rate (sPIFR; <60 L/min); many of them might therefore be unable to use a hand-held inhaler properly.8
When patients cannot adhere to inhaler instructions — whether because of cognitive or physical limitations — a nebulized LAMA might offer another method to safely deliver medication. To that end, GOLD guidelines for COPD recommend tailoring treatment based on risk of exacerbation and symptom severity as well as on patient preference, including cost, availability, and the user’s ability to actuate a hand-held inhaler.5 Nebulized therapy might offer a sensible alternative: 80% of 400 COPD patients and 400 caregivers surveyed reported satisfaction with nebulizer therapy compared with inhaler-only therapy.9
A nebulizer can be helpful for patients who have poor inhalation technique because the device delivers medication through tidal breathing and can be more forgiving than a breath-actuated, hand-held inhaler, which is often prescribed for reasons of cost and convenience.2 Although nebulizers can be expensive, are less portable than an inhaler, and require maintenance, they can deliver larger doses of medication than an inhaler.2 However, guidelines do not state that nebulized devices are superior to hand-held devices.5
Regardless of the treatment modality, clinicians need to ensure that patients are using their device properly to receive the prescribed medication dosage.5

Glycopyrrolate: First Nebulized LAMA

In 2017, the US Food and Drug Administration approved the first nebulized anticholinergic agent with a proprietary nebulizer, the LAMA glycopyrrolate.10 The next year, the Food and Drug Administration approved a second nebulized LAMA, revefenacin, which can be used with a standard jet nebulizer.11 Although no head-to-head trials of the 2 agents have been conducted, evidence is solid for each compared with therapy delivered by hand-held inhaler.12,13
Twice-daily glycopyrrolate was studied in 2 replicate trials (GOLDEN 3; N=653 [ Identifier: NCT02347761]; GOLDEN 4; N=641 [ Identifier: NCT02347774]) in patients with moderate to very severe COPD who were randomly assigned to receive either placebo, glycopyrrolate 25 μg, or glycopyrrolate 50 μg, all twice daily for 12 weeks.14 Some patients in both studies continued to use a combination of a LABA and inhaled corticosteroids. The primary endpoint was the week 12 change from baseline in trough forced expiratory volume in 1 second (FEV1) compared with placebo. Secondary end points were change from baseline in forced vital capacity (FVC) at 12 weeks, change from baseline health status according to the St. George’s Respiratory Questionnaire (SGRQ), rescue medication use, and change in FEV1 area under the curve for 12 hours.14
In both studies, glycopyrrolate showed statistically significant changes in trough FEV1 at week 12 compared with placebo (GOLDEN 3: 0.105 L [25 μg] and 0.126 L [50 μg], P ≤.0001; GOLDEN 4: 0.084 L [25 μg] and 0.082 [50 μg], P ≤.0001]). The study drug also improved FVC from baseline, brought improvement in the SGRQ score, and did not spur a change in the use of rescue medications.14 Adverse effects (AEs) were similar in both studies; patients in the placebo group (52.3%) in the GOLDEN 3 study had more AEs than those taking either dose of glycopyrrolate (25 μg, 39.6%; 50 μg, 48.2%).14 In GOLDEN 3, major adverse cardiovascular events (MACE) occurred in 3 patients, all of whom received glycopyrrolate 50 μg. Two patients in the GOLDEN 4 placebo group experienced nonfatal myocardial infarction.
The phase 3, randomized, active-controlled, open-label GOLDEN 5 trial examined the tolerability and safety of nebulized glycopyrrolate 50 μg delivered twice daily compared with once-daily tiotropium 18 μg.12 In the 48-week study, 1086 patients received at least 1 dose of the study drug. Primary end points were treatment-emergent AEs, serious AEs, and discontinuation because of AEs. Secondary end points included MACE and change from baseline trough FEV1.
Although serious AEs were comparable for glycopyrrolate (12.3%) and tiotropium (10.5%), the discontinuation rate was higher in the glycopyrrolate group (10.0%) than in the tiotropium group (2.8%). Patients in the glycopyrrolate group also reported improved health outcomes, had fewer MACE, and showed improvement in trough FEV1 during the 48-week study.12

Glycopyrrolate adverse effects
Adverse effects commonly reported with glycopyrrolate include dyspnea and urinary tract infection.

Revefenacin: Once-daily LAMA Delivered by Standard Jet Nebulizer

Two replicate phase 3 efficacy and safety studies of once-daily revefenacin showed clinically significant improvement in patients with moderate to very severe COPD.15 The end point for these studies was 24-hour trough FEV1 on day 85 of the 12-week trials. Secondary end points were overall treatment effect on FEV1 and peak FEV1.
Study 0126 (N=619; Identifier: NCT02459080) and Study 0127 (N=611; Identifier: NCT02512510) both recruited patients with COPD who were at least 40 years old, had a smoking history of at least 10 pack-years, and had a post-ipratropium FEV1/FVC of less than 80% of predicted normal (but ≥700 mL at visit 1), which constituted moderate to very severe COPD.15 Results were comparable for the replicate studies.

  • Study 0126. Compared with placebo, a mean increase in trough FEV1 of 79.2 mL was reported for revefenacin 88 μg (P =.0003) and of 146.3 mL for revefenacin 175 μg (P <.0001).
  • Study 0127. Compared with placebo, revefenacin was associated with a mean increase in trough FEV1 of 160.5 mL for the 88-μg dose and of 147.0 mL for the 175-μg dose (both P <.0001).
  • Both studies. Revefenacin increased the overall treatment effect of trough FEV1 by ≥100 mL compared with placebo. Within the first 2 hours of treatment, the drug significantly increased FEV1.15

Treatment-emergent AEs were similar for the 88-μg and 175-μg revefenacin doses. The most common AEs were exacerbations of COPD (≤12.2%), headache (≤6.8%), respiratory infection (≤6.6%), dyspnea (≤5.7%), and cough (≤5.1%).15 During the 3-month studies, 5 major events occurred, most of which were cardiovascular related; none were caused by the study drug.15
A longer phase 3 study of 52 weeks ( Identifier: NCT02518139) in 1055 participants with moderate to very severe COPD examined the safety and tolerability of once-daily revefenacin 88 μg and 175 μg. Treatment-emergent AEs were comparable among all treatment groups, including the comparator tiotropium.13 Paradoxically, fewer COPD exacerbations (21.8%) occurred in the group receiving revefenacin 175 μg compared with 29.4% in those receiving revefenacin 88 μg and 28.1% in the comparator group. Study participants receiving revefenacin 175 μg also had fewer serious AEs (12.8%) than those receiving revefenacin 88 μg (15.9%) and the comparator agent (16.3%).13
Even among the most severe COPD cases, revefenacin demonstrated significant improvement in lung function in a post-hoc subgroup analysis.16 An 85-day trial that compared revefenacin to placebo showed that more patients in the active treatment group experienced a change from baseline in trough FEV1, in SGRQ scores, and in the Transition Dyspnea Index at the end of the 12-week study.16 Patient subgroups included those with severe airflow limitation (percent predicted FEV1, 30% to <50% and <30%); 2011 GOLD category D; reversibility (≥12% and ≥200-mL increase in FEV1) with short-acting bronchodilators; concurrent use of LABA or inhaled corticosteroids, or both; older age (>65 years); and risk factors for comorbidity (Figure 2). 16

Revefenacin adverse effects
Adverse effects commonly reported with revefenacin include cough, nasopharyngitis, headache, upper respiratory tract infection, and back pain.

Delivery Methods Need Further Study

Whether nebulized bronchodilators are superior to a dry-powder inhaler remains unknown.8 Efficacy of the once-daily LAMA bronchodilator revefenacin was studied with dry-powder inhaler-delivered tiotropium in a 28-day randomized, double-blind group trial of 206 patients with COPD and sPIFR. Although nebulized revefenacin improved trough FEV1 on day 29 from baseline compared with tiotropium, the difference between the drugs was not significant (17.0 mL [P =.4461]). However, among patients with FEV1 less than 50% predicted, revefenacin produced a mean difference of 49.1 mL in trough FEV1 (95% CI, 6.3-91.9) and 103.5 mL in FVC (95% CI, 7.7-199.3) compared with tiotropium. In the same patient population, revefenacin also produced a greater than 100-mL increase in FEV1 in 41.6% of patients compared with 34.4% of patients taking tiotropium.
Fewer AEs were reported in the revefenacin group than in the tiotropium group (with dyspnea and cough among the more common AEs), and there were fewer antimuscarinic effects (eg, dry mouth, constipation).8 More robust studies that compare bronchodilator delivery methods are needed, especially in patients with COPD with sPIFR.


1. Lal C, Khan A. Emerging treatments for COPD: evidence to date on revefenacin. COPD. 2020;17(1):112-119. doi:10.1080/15412555.2019.1702010

2. Terry PD, Dhand R. Maintenance therapy with nebulizers in patients with stable COPD: need for reevaluation. Pulm Ther. 2020;6(2):177-192. doi:10.1007/s41030-020-00120-x

3. US Centers for Disease Control and Prevention. Data and statistics. COPD prevalence in the United States. Accessed August 7, 2021.

4. Sullivan J, Pravosud V, Mannino DM, Siegel K, Choate R, Sullivan T. National and state estimates of COPD morbidity and mortality – United States, 2014-2015. Chronic Obstr Pulm Dis. 2018;5(4):324-333. doi:10.15326/jcopdf.5.4.2018.0157

5. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2020 report. GOLD website. Accessed August 7, 2021.

6. Donohue JF, Mahler DA, Sethi S. Revefenacin: a once-daily, long-acting bronchodilator for nebulized treatment of COPD. Int J Chron Obstruct Pulmon Dis. 2019;14:2947-2958. doi:10.2147/COPD.S157654

7. Tashkin DP. A review of nebulized drug delivery in COPD. Int J Chron Obstruct Pulmon Dis. 2016;11:2585-2596. doi:10.2147/COPD.S114034

8. Mahler DA, Ohar JA, Barnes CN, Moran EJ, Pendyala S, Crater GD. Nebulized versus dry powder long-acting muscarinic antagonist bronchodilators in patients with COPD and suboptimal peak inspiratory flow rate. Chronic Obstr Pulm Dis. 2019;6(4):321-331. doi:10.15326/jcopdf.6.4.2019.0137

9. Sharafkhaneh A, Wolf RA, Goodnight S, Hanania NA, Make BJ, Tashkin DP. Perceptions and attitudes toward the use of nebulized therapy for COPD: patient and caregiver perspectives. COPD. 2013;10(4):482-492. doi:10.3109/15412555.2013.773302

10. Lonhala Magnair. Prescribing information. Sunovion Pharmaceuticals Inc.; Updated August 2020. Accessed August 7, 2021

11. Yupelri. Prescribing information. Mylan Specialty LP; Updated May 2019. Accessed August 5, 2021.

12. Ferguson GT, Goodin T, Tosiello R, Wheeler A, Kerwin E. Long-term safety of glycopyrrolate/eFlow® CS in moderate-to-very-severe COPD: results from the Glycopyrrolate for Obstructive Lung Disease via Electronic Nebulizer (GOLDEN) 5 randomized study. Respir Med. 2017;132:251-260. doi:10.1016/j.rmed.2017.08.020

13. Donohue JF, Kerwin E, Sethi S, et al. Revefenacin, a once-daily, lung-selective, long-acting muscarinic antagonist for nebulized therapy: safety and tolerability results of a 52-week phase 3 trial in moderate to very severe chronic obstructive pulmonary disease. Respir Med. 2019;153:38-43. doi:10.1016/j.rmed.2019.05.010

14. Kerwin E, Donohue JF, Goodin T, Tosiello R, Wheeler A, Ferguson GT. Efficacy and safety of glycopyrrolate/eFlow® CS (nebulized glycopyrrolate) in moderate-to-very-severe COPD: results from the glycopyrrolate for obstructive lung disease via electronic nebulizer (GOLDEN) 3 and 4 randomized controlled trials. Respir Med. 2017;132:238-250. doi:10.1016/j.rmed.2017.07.011

15. Ferguson GT, Feldman G, Pudi KK, et al. Improvements in lung function with nebulized revefenacin in the treatment of patients with moderate to very severe COPD: Results from two replicate phase III clinical trials. Chronic Obstr Pulm Dis. 2019;6(2):154-165. doi:10.15326/jcopdf.6.2.2018.0152

16. Donohue JF, Kerwin E, Barnes CN, Moran EJ, Haumann B, Crater GD. Efficacy of revefenacin, a long-acting muscarinic antagonist for nebulized therapy, in patients with markers of more severe COPD: a post hoc subgroup analysis. BMC Pulm Med. 2020;20(1):134. doi:10.1186/s12890-020-1156-4

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Pulmonology Advisor had no role in this content’s preparation.

Reviewed August 2021