Aerosolized Agents - metered-dose inhalers: beta2 adrenergic drugs (short-acting) - Index

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

  • Revision history
    • April 28, 2023
    • April 23, 2021
    • March 2019
    • March 2017
    • May 2016
    • Feb. 2016
    • July 2014
    • Oct. 2012
    • Oct. 2010
    • Jan. 2008
    • March 2003
    • March 2002
    • March 2001
    • March 2000
    • May 1999
    • Feb. 1999
    • Feb. 1998
    • March 1997
    • Aug. 1995
  • Initially developed
    • Jan. 1995

1.1. Adults

Beta2-adrenergic drugs, used routinely in asthma management, can be identified as long-acting or short-acting agents. Both short- and long-acting compounds can be used to prevent bronchospasm. However, short-acting compounds are the drugs of choice for acute bronchospasm as these agents act within minutes to cause bronchodilation. Drugs in this category include albuterol and levalbuterol. For acute bronchospasm, treatment is initiated with a short-acting beta2-adrenergic agent either as a metered-dose inhaler or a nebulizer solution. Treatment of acute attacks is usually for a finite time period based on the intensity of the attack and/or the need for medical attention either through emergency department management or hospitalization. Usage is individualized based on patient characteristics..

Although not FDA-approved, beta2-selective adrenergic agents such as albuterol are effective in chronic obstructive pulmonary disease (COPD) maintenance therapy to improve lung function and mucociliary clearance. Albuterol has become one of the mainstays of therapy for acute exacerbations of chronic obstructive pulmonary disease COPD due to rapid onset of action as well as efficacy in producing bronchodilation.

For preventive/ maintenance therapy, albuterol is FDA-approved as preventive therapy for exercise-induced asthma. To manage exercise-induced bronchospasm (EIB) in adults, two 90 mcg albuterol inhalations are administered at least 15 to 30 minutes before exercise on an as-needed basis.

Ipratropium/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 bronchodilator.

Maximum recommended daily doses for available inhalational beta2-adrenergic agents as monotherapy and combination therapy are summarized in Tables 1 and 2. Prescribed dosages exceeding these criteria will be reviewed.

Table 1: Maximum Adult Daily Dose for Inhalational Beta2-Adrenergic Agents (Short-Acting) - Monotherapy1-7
Drug Name Treatment Indication Dosage Form/Strength Maximum Recommended Dosage
albuterol aerosol solution (Proventil HFA®, Ventolin HFA, generic) asthma, prevention of exercise-induced bronchospasm aerosol (90 mcg albuterol base/actuation) 12 actuations/day (total dose = 1080 mcg albuterol base)
albuterol inhalation powder (ProAir RespiClick®, ProAir Digihaler) asthma, prevention of exercise-induced bronchospasm (90 mcg albuterol base/actuation) 12 actuations/day (total dose = 1080 mcg albuterol base)
levalbuterol (Xopenex HFA, generic) asthma aerosol (45 mcg levalbuterol free base/actuation) 12 actuations/day (total dose = 540 mcg levalbuterol free base)
Table 2: Maximum Adult Daily Dose for Inhalational Beta2-Adrenergic Agents (Short-Acting) – Combination Therapy1,11
Drug Name Treatment Indication Dosage Form/Strength Maximum Recommended Dosage
ipratropium/ albuterol (Combivent Respimat®) chronic obstructive pulmonary disease inhalation spray (20 mcg ipratropium/ 100 mcg albuterol/ actuation) 6 actuations/day (total dose = 120 mcg ipratropium/ 600 mcg albuterol)

1.2. Pediatrics

Proventil HFA, Ventolin HFA, ProAir RespiClick, ProAir Digihaler, and generic albuterol HFA are FDA-approved for use in children 4 years of age and older for prevention/treatment of bronchospasm and prevention of exercise-induced bronchospasm1-6. Levalbuterol is FDA-approved for use in children 4 years of age and older for prevention/treatment of bronchospasm1, 7.;

To prevent EIB in pediatric patients 4 years of age and older, two albuterol 90 mcg inhalations are administered at least 15 to 30 minutes before exercise on an as-needed basis.

Combination therapy with ipratropium and albuterol is not FDA-approved for use in pediatric patients as safety and efficacy in this patient population have not been established.

Pediatric dosages for short-acting beta2-agonists used to manage acute asthma exacerbations are summarized in Table 3. Dosages exceeding these recommendations will be reviewed.

Table 3: Maximum Recommended Pediatric Daily Dose for Inhalational Beta2-Adrenergic Agents (Short-Acting) - Monotherapy1-7
Drug Name Treatment Indication Dosage Form/Strength Maximum Recommended Dosage
albuterol (Proventil HFA®, Ventolin HFA) Asthma, prevention of exercise-induced bronchospasm aerosol solution (90 mcg albuterol base/actuation)
  • Greater than or equal to 4 years of age:
    • 12 actuations/day (total dose = 1080 mcg albuterol base)
albuterol (ProAir RespiClick®, ProAir Digihaler®) Asthma, prevention of exercise-induced bronchospasm inhalation powder (90 mcg albuterol base/actuation)
  • Greater than or equal to 4 years of age:
    • 12 actuations/day (total dose = 1080 mcg albuterol base)
levalbuterol (Xopenex HFA®) Asthma aerosol (45 mcg levalbuterol free base/actuation)
  • Greater than or equal to 4 years of age:
    • 12 actuations/day (total dose = 540 mcg levalbuterol free base)

2. Duration of Therapy

Metered-dose inhalers are designed to deliver a set number of inhalations based on the canister size as well as the medication prescribed. Days’ supply for inhalational beta2-adrenergic agents is summarized in Table 4 and 5, based on the maximum recommended doses listed in Tables 1-3, and the number of actuations per canister or number of capsules per blister card listed in Tables 4 and 5. Excessive use may be identified based on refill frequency. Inappropriate supply of short-acting beta2-adrenergic agents will be monitored by reviewing excessive refills.

Table 4: Days’ Supply for Available Short-Acting Beta2-Adrenergic Agent Metered-Dose Inhalers (Adult and Pediatric Patients) - Monotherapy2-7
Drug # of Actuations Per Canister Days’ Supply (based on maximum dose per day) +
Albuterol (generic)
  • 8.5 g canister
 200 ~ 16 days
Albuterol (ProAir RespiClick®)
  • 0.65 g inhaler
 200 ~16 days
Albuterol (ProAir Digihaler®)
  • 0.65 g inhaler
 200 ~16 days
Albuterol (Proventil HFA®)
  • 6.7 g canister
 200 ~16 days
Albuterol (Ventolin HFA®) 
  • 8 g canister
  • 18 g canister
 60
200		 5 days
~16 days
Levalbuterol (Xopenex HFA®)
  • 15 g canister
 200 ~ 16 days

Legend:

  • + calculated based on canister size and maximum dose allowed per day (summarized in Tables 1 and 2)
Table 5: Days’ Supply for Available Short-Acting Beta2-Adrenergic Agent Metered-Dose Inhalers (Adult Patients) – Combination Therapy11
Drug # of Actuations Per Canister Days Supply (based on maximum dose per day) +
Ipratropium/albuterol (Combivent® Respimat®) (4 g cartridge) 120 20 days

3. Duplicative Therapy

The use of two or more metered-dose inhaler short-acting beta2-adrenergic compounds concurrently for prevention and control of asthma symptoms is not justified and will be reviewed. Nebulized short-acting beta2-adrenergic therapy is available for pediatric patients who are too ill or too young to obtain medication from an aerosolized metered-dose device.  However, adjunctive administration of a short-acting beta2-adrenergic agonist metered-dose inhaler with a short-acting beta2-agonist nebulized bronchodilator is also 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-agonist like salmeterol may be prescribed concomitantly. Patients may receive a long- and short-acting beta2-adrenergic drug concurrently for short time periods to manage acute attacks. Patient profiles containing excessive prescriptions for a short-acting beta2-adrenergic drug (i.e., frequent refill of short-acting beta2-adrenergic agonist within a 30-day time period) in conjunction with long-acting beta2-agonists 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 interactions considered clinically relevant for short-acting beta2-adrenergic bronchodilators are summarized in Table 6. 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 6: Inhaled Short-Acting Beta2-Adrenergic Agents Drug-Drug Interactions
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 2-major (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 3-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) 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 3-moderate (CP)
beta2-agonists QTc interval-prolonging medications (e.g., class I, III anti-arrhythmic, 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 2-major, 3-moderate (CP)
ipratropium/albuterol antimuscarinics co-administration may produce additive anticholinergic effects and potential for increased adverse effects cautiously administer ipratropium with other antimuscarinics; monitor for increased adverse effects 3-moderate (CP)

Legend:

  • +CP = Clinical Pharmacology
  • COPD = chronic obstructive pulmonary disease
  • ECG = electrocardiogram
  • MAOIs = monoamine oxidase inhibitors
  • TCAs = tricyclic antidepressants

5. References

  1. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2023. Available at: http://clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed February 23, 2023.
  2. Albuterol sulfate HFA aerosol, metered package insert. Preferred Pharmaceuticals Inc., 2022.
  3. Albuterol inhalation aerosol (Proventil® HFA) package insert. Sandoz, September 2022.
  4. Albuterol inhalation aerosol (Ventolin® HFA) package insert. GlaxoSmithKline, August 2021.
  5. Albuterol inhalation powder (ProAir RespiClick®) package insert. Teva Respiratory, September 2022.
  6. Albuterol inhalation powder (ProAir Digihaler®) package insert. Teva Respiratory, December 2022.
  7. Levalbuterol inhalation aerosol (Xopenex HFA®) package insert. Sunovion Pharmaceuticals Inc., June 2020.
  8. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2022. Available from: https://ginasthma.org/gina-reports/. Accessed February 23, 2023.
  9. Expert Panel Working Group of the National Heart, Lung, and Blood Institute (NHLBI) administered and coordinated National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC). 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol. 2020 Dec;146(6):1217-1270. 
  10. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease. 2023 report. Available at: https://goldcopd.org/2023-gold-report-2/. Accessed February 23, 2023.
  11. Ipratropium/albuterol (Combivent® Respimat® Inhalation Spray) package insert.  Boehringer Ingelheim Pharmaceuticals, Inc., December 2021.