Nebulized Bronchodilators

Medications listed in the tables and non-FDA approved indications included in these retrospective criteria are not indicative of Texas Vendor Drug Program formulary coverage.

  • Revision history
    • April 2022; March 2020; March 2018; Feb. 2016; June 2014; Nov. 2012; Sept. 2012; Oct. 2010. 
  • Initially developed
    • Feb. 2008

1.1. Adults

Short-acting, nebulized beta2-adrenergic bronchodilators are FDA-approved for use in the relief of acute, potentially recurrent bronchospasm in patients with reversible obstructive airway disease1-6. Long-acting, nebulized beta2-adrenergic agents are FDA-approved for use as maintenance therapy in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema1,2,7,8. Revefenacin (Yupelri®) is FDA-approved as a maintenance therapy for COPD1,2,9. A nebulized formulation of the long acting antimuscarinic anticholinergic agent glycopyrrolate (Lonhala Magnair®) was approved by the FDA in 2017 for the long-term maintenance treatment of airflow obstruction in patients with COPD1,2,10. The anticholinergic, ipratropium, is FDA-approved to manage bronchospasm associated with exacerbations of COPD, including bronchitis and emphysema, either as monotherapy or in combination with beta adrenergic agents1,2,11. While not FDA-approved, the Expert Panel 3 guidelines from the National Heart Lung and Blood Institute document benefit when multiple ipratropium doses are administered adjunctively with beta2-agonists in the emergency department to manage more severe acute asthma exacerbations12. Additionally, the Global Initiative for Asthma (GINA) guidelines state that ipratropium may be considered a potential alternative bronchodilator for routine relief of asthma symptoms, and it may be used in combination with a short-acting beta2-adrenergic agonist in the emergency treatment of moderate to severe exacerbations.13 Ipratropium/racemic albuterol combination therapy is FDA-approved for use as second-line therapy in adult COPD patients who continue to experience bronchospasm with an aerosol bronchodilator and require a second bronchodilator1,2,14. Recommended adult dosages are summarized in Tables 1-5. Patient profiles with dosages exceeding these recommendations will be reviewed.

Table 1. Maximum Recommended Nebulized Bronchodilator Dosages in Adults: Monotherapy: Short-Acting Sympathomimetics1-6
Treatment Indication Drug Name Dosage Strength Maximum Recommended Dosage
Bronchospasm in reversible obstructive airway disease (e.g., asthma) Racemic albuterol (various generics) 2.5 mg/3 mL; (0.083%); 2.5 mg/0.5 mL (0.5%) 2.5 mg four times daily by nebulization* (maximum dose per day: 10 mg)
Bronchospasm in reversible obstructive airway disease (e.g., asthma) Levalbuterol (Xopenex®, generics) 0.31 mg/3 ml; 0.63 mg/3 ml; 1.25 mg/3 ml; 1.25 mg/0.5 ml 1.25 mg three times daily by nebulization^

Legend:

  • *Manufacturers of racemic albuterol state that more frequent administration or higher doses not recommended; however, in severe asthma exacerbations, the National Asthma Education and Prevention Program Expert Panel (NAEPPEP) recommends racemic albuterol doses of 2.5-5 mg every 20 minutes for 3 doses, then 2.5-10 mg every 1-4 hours as needed, or 10-15 mg/hour by continuous nebulization12
  • ^For acute asthma exacerbations, NAEPPEP recommends levalbuterol doses of 1.25-2.5 mg every 20 minutes for 3 doses, then 1.25-5 mg every 1-4 hours as needed12
Table 2. Maximum Recommended Nebulized Bronchodilator Dosages in Adults: Monotherapy: Short-Acting Anticholinergics1,2,11
Treatment Indication Drug Name Dosage Strength Maximum Recommended Dosage
Chronic obstructive pulmonary disease (COPD) Ipratropium (various generics) 500 mcg/2.5 ml (0.02%) 500 mcg four times daily, with doses 6 hours apart
Table 3. Maximum Recommended Nebulized Bronchodilator Dosages in Adults: Monotherapy: Long-Acting Sympathomimetics1,2,7,8
Treatment Indication Drug Name Dosage Strength Maximum Recommended Dosage 
Chronic obstructive pulmonary disease (COPD) Arformoterol (Brovana®, generic) 15 mcg/2 ml 15 mcg twice daily by nebulization
COPD Formoterol (Perforomist®, generic) 20 mcg/2 ml 20 mcg twice daily by nebulization
Table 4. Maximum Recommended Nebulized Bronchodilator Dosages in Adults: Monotherapy: Long-Acting Anticholinergics1,2,9,10
Treatment Indication Drug Name Dosage Strength Maximum Recommended Dosage
Chronic obstructive pulmonary disease (COPD) – maintenance therapy Glycopyrrolate (Lonhala® Magnair®) 25 mcg/ mL 25 mcg twice daily by nebulization!
COPD – maintenance therapy Revefenacin (Yupelri®) 175 mcg/3 ml 175 mcg once daily

Legend:

  • ! Lonhala® Magnair® is approved for use with the Magnair® nebulization system10
Table 5. Maximum Recommended Nebulized Bronchodilator Dosages in Adults: Combination Therapy1,2,14
Treatment Indication Drug Name Dosage Strength Maximum Recommended Dosage 
Bronchospasm associated with chronic obstructive pulmonary disease (COPD) for patients requiring a second bronchodilator Ipratropium/ racemic albuterol (generic) 0.5 mg/3 mg# per 3 ml 3 ml 6 times per day^

Legend:

  • # 2.5 mg racemic albuterol base
  • ^ For moderate asthma exacerbations, NAEPPEP recommends ipratropium/albuterol doses of 3 mL (ipratropium bromide 0.5mg/ albuterol base 2.5 mg) every 4-6 hours in the emergency setting. For severe asthma exacerbations, NAEPPEP recommends ipratropium/albuterol doses of 3 mL (ipratropium bromide 0.5mg/ albuterol base 2.5 mg) every 20 minutes for 3 doses, then as needed for up to 3 hours in the emergency setting12

1.2. Pediatrics

Short-acting beta2-adrenergic bronchodilators are FDA-approved to manage bronchospasm episodes in pediatric patients with reversible obstructive airway disease1-6. Racemic albuterol nebulized solution is FDA-approved to provide bronchospasm relief in children 2 years of age and older with reversible obstructive airway disease1-5. Levalbuterol nebulized solutions are FDA-approved for use in the management and prevention of acute asthma exacerbations in children 6 years of age and older1,2,6. Ipratropium is FDA-approved for use in children 12 years of age and older for management of bronchospasm associated with COPD1,2,11. Recommended dosages are summarized in Tables 6 and 7. Patient profiles with dosages exceeding these recommendations will be reviewed.

Table 6. Maximum Recommended Nebulized Bronchodilator Pediatric Dosages: Short-Acting Sympathomimetics1-6
Drug Name Dosage Strength Maximum Recommended Dosage 
Racemic albuterol (generics) 0.63 mg/3 ml (0.021%) or 1.25 mg/3 ml (0.042%) 2-12 years of age: 1.25 mg 4 times daily (5 mg/day) + 
Racemic albuterol (generics) 2.5 mg/3 ml (0.083%); 2.5 mg/ 0.5 ml (0.5%) 2-12 years of age: 2.5 mg 4 times daily (10 mg/day) *+
  2.5 mg/ 0.5 ml (0.5%) Greater than 12 years of age: 2.5 mg 4 times daily (10 mg/day)+
Levalbuterol (Xopenex®, generics) 0.31 mg/3 ml; 0.63 mg/3 ml; 1.25 mg/3 ml; 1.25 mg/0.5 ml
  • 6 years to 11 years of age: #  
    • 0.63 mg three times daily (every 6-8 hours)
  • 12 years of age and older: ^ 
    • 1.25 mg three times daily (every 6-8 hours)

Legend:

  • * Children weighing less than15 kg who require less than 2.5 mg/dose should use the 0.5% albuterol inhalation solution instead of the 0.083% albuterol inhalation solution3
  • + Manufacturers state that more frequent administration or higher doses not recommended; however, in patients 12 years or younger with severe asthma exacerbations, the National Asthma Education and Prevention Program Expert Panel (NAEPPEP) recommends racemic albuterol doses of 0.15 mg/kg (minimum dose 2.5 mg) for 3 doses then 0.15-0.3 mg/kg (up to 10 mg) every 1-4 hours as needed, or 0.5 mg/kg/hour by continuous nebulization. In patients greater than 12 years of age the NAEPPEP recommends 2.5-5 mg every 20 minutes for 3 doses, then 2.5-10 mg every 1-4 hours as needed, or 10-15 mg/hour by continuous nebulization12
  • # For acute asthma exacerbations in children 12 years and younger, NAEPPEP recommends levalbuterol doses of 0.075 mg/kg (1.25 mg minimum) every 20 minutes x 3 doses, then 0.075—0.15 mg/kg (5 mg max) every 1—4 hours as needed12
  • ^ For acute asthma exacerbations in children greater than 12 years, NAEPPEP recommends levalbuterol doses of 1.25-2.5 mg every 20 minutes for 3 doses, then 1.25-5 mg every 1-4 hours as needed12
Table 7. Maximum Recommended Nebulized Bronchodilator Pediatric Dosages: Short-Acting Anticholinergics1,2,11
Drug Name Dosage Strength Maximum Recommended Dosage
Ipratropium (various generics) 500 mcg/2.5 ml (0.02%) Greater than or equalt to 12 years of age:
500 mcg 4 times daily, every 6 hours apart

Nebulized long-acting beta2-adrenergic bronchodilators and long-acting anticholinergics as well as combination therapy with ipratropium and racemic albuterol are not indicated for use in pediatric patients as safety and efficacy of these agents in this patient population have not been established1,2,7-10,14.

2. Duration of Therapy

Administration of short-acting, nebulized beta2-adrenergic bronchodilators may be repeated indefinitely for acute asthma exacerbations, as asthma is a chronic, lifelong disease1-5. However, administering short-acting, nebulized beta2-adrenergic agents for longer than 48 hours with each exacerbation is indicative of worsening asthma control12,15. Utilization of large quantities of short-acting beta2-adrenergic nebulizer solutions within a 90-day time period is not recommended and will be reviewed.

Ipratropium, long-acting, nebulized beta2-adrenergic bronchodilators, and combination therapy with ipratropium/racemic albuterol are indicated for the management of COPD, a chronic, lifelong disease, and may be continued indefinitely under accepted guidelines16.

3. Duplicative Therapy

Adjunctive administration of multiple short-acting or long-acting, nebulized beta2-adrenergic bronchodilators does not provide additional clinical benefit and may result in additive adverse effects1-8. Combined administration of multiple nebulized short-acting or long-acting beta2-adrenergic bronchodilators is not recommended and will be reviewed.

Acute asthma exacerbations require treatment with short-acting, beta2-adrenergic agents even though maintenance therapy with a long-acting, beta2-adrenergic agent may be prescribed concomitantly1-8. Patients may receive a long- and short-acting beta2-adrenergic drug concurrently for short time periods to manage acute attacks. Nebulized formoterol or arformoterol used in conjunction with excessive administration of a short-acting beta2-adrenergic drug (i.e., frequent refill of short-acting beta2-adrenergic agonist within a 30-day time period) is not recommended and will be reviewed.

Concurrent administration of ipratropium nebulized solution monotherapy with ipratropium/racemic albuterol combination therapy does not provide additional clinical benefit and may result in additive adverse effects1,2,14. Combined administration of ipratropium and ipratropium combination therapy is not recommended and will be reviewed.

4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically relevant for nebulized bronchodilators are summarized in Table 3. Only those drug-drug interactions classified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed:

Table 3. Nebulized Bronchodilator Drug-Drug Interactions1-11,14
Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level
beta2-agonists MAOIs+ (including linezolid) concurrent administration of MAOIs with beta2-agonists may increase risk of  tachycardia, hypomania, or agitation due to potentiation of effects on vascular system administer combination cautiously or within 2 weeks of MAOI discontinuation; observe patients for adverse effects major (DrugReax) 1-severe (CP)
beta2-agonists TCAs^ concurrent administration of TCAs with beta2-agonists may potentiate effects on cardiovascular system and increase risk of adverse events cautiously administer TCAs and beta2-agonists together, including within 2 weeks of TCA discontinuation;  monitor patients and  observe for changes in blood pressure, heart rate and ECG# moderate (DrugReax) moderate (CP)
beta2-agonists beta blockers concurrent administration may decrease effectiveness of beta-adrenergic blocker or beta-2 agonists combination not recommended in asthma/COPD patients; if adjunctive therapy necessary, utilize cardioselective beta blocker (e.g., atenolol, bisoprolol) major (DrugReax) 2-major (CP)
beta2-agonists diuretics potential for worsening of diuretic- associated  hypokalemia and/or ECG changes with beta2-agonist concurrent administration, especially with high beta2-agonist doses administer combination cautiously; monitor potassium levels as necessary 3-moderate (CP)
beta2-agonists atomoxetine concurrent administration may increase risk of cardiovascular adverse effects (e.g., tachycardia, hypertension); interaction may be less likely with inhaled beta2-agonists monitor patients for increased cardiovascular adverse effects major (DrugReax) 3-moderate (CP)
beta2-agonists QTc interval-prolonging medications (e.g., class I, III anti-arrhythmics, tricyclic antidepressants, dolasetron) concurrent administration may increase risk of cardiotoxicity (e.g., life-threatening arrhythmias, cardiac arrest) as arformoterol and formoterol may cause QTc interval prolongation and, rarely, torsades de pointes administer combination cautiously 1-severe, 2-major, 3-moderate (CP)
glycopyrrolate anticholinergics concurrent administration may produce additive anticholinergic effects and potential for increased adverse effects cautiously administer glycopyrrolate with other anticholinergics; monitor for increased adverse effects Major (Micromedex)
ipratropium, ipratropium/racemic albuterol antimuscarinics concurrent administration may produce additive anticholinergic effects and potential for increased adverse effects cautiously administer ipratropium with other antimuscarinics; monitor for increased adverse effects minor (DrugReax) 3-moderate (CP)

 

5. References

  1. DRUGDEX® System (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com.libproxy.uthscsa.edu/. Accessed March 23, 2022.
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2020. Available at: http://www.clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed March 23, 2022.
  3. Albuterol sulfate inhalation solution 0.083% package insert. Nephron Pharmaceuticals Corp., August 2018.
  4. Albuterol sulfate inhalation solution 0.5% package insert. Nephron Pharmaceuticals Corporation, February 2007.
  5. Albuterol sulfate solution 0.63 mg/3 ml, 1.25 mg/3 ml package insert. Mylan Pharmaceuticals, Inc., October 2021.
  6. Levalbuterol inhalation solution (Xopenex®) package insert. Akorn, Inc., February 2022.
  7. Arformoterol inhalation solution (Brovana®) package insert. Sunovion Pharmaceuticals Inc., May 2021.
  8. Formoterol inhalation solution (Perforomist®) package insert. Mylan Specialty, May 2019.
  9. Revefenacin inhalation solution (Yupelri®) package insert. Mylan Specialty LP, November 2021.
  10. Glycopyrrolate inhalation solution (Lonhala Magnair®) package insert. Sunovian Pharmaceuticals Inc., August 2020.
  11. Ipratropium bromide inhalation solution 0.02% package insert. Actavis Pharmaceuticals, Inc., April 2017.
  12. U.S. Department of Health and Human Services. National Institutes of Health. National Heart, Lung and Blood Institute. National Asthma Education and Prevention Program. Expert Panel 3: guidelines for the diagnosis and management of asthma. Full report 2007. NIH Publication No. 08-4051. Available at: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.  Accessed March 23, 2022.
  13. Global Initiative for Asthma. Global strategy for asthma management and prevention, 2021 update. Available at: https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdf. Accessed March 23, 2022.
  14. Ipratropium bromide and albuterol sulfate inhalation solution package insert. Aurobindo Pharma Limited, June 2020.
  15. U.S. Department of Health and Human Services. National Institutes of Health. National Heart, Lung and Blood Institute. National Asthma Education and Prevention Program. 2020 focused updates to the asthma management guidelines: a report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. Accessed March 23, 2022.
  16. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease. 2022 Report. Available at:  https://goldcopd.org/2022-gold-reports-2/. Accessed March 23, 2022.