Aerosolized Agents - metered-dose inhalers: anti-cholinergic drugs
Aerosolized Agents - metered-dose inhalers: anti-cholinergic drugs - Index
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
- Revised April 23, 2021
- March 2019
- March 2017
- Nov. 2015
- March 2014
- Aug. 2012
- June 2012
- Oct. 2010
- Jan. 2008
- Jan. 2003
- Jan. 2002
- Jan. 2001
- March 2000
- Jan. 2000
- Feb. 1999
- Feb. 1998
- Feb. 1997
- Aug. 1995.
- Initially developed
- January 1995
1. Dosage
1.1. Adults
Ipratropium (Atrovent), a short-acting, inhalational anticholinergic agent, is FDA-approved to manage bronchospasm associated with chronic bronchitis and emphysema, collectively known as chronic obstructive pulmonary disease (COPD). Ipratropium is considered a second-line agent in the treatment of asthma as the bronchodilatory effects seen with ipratropium are less than those seen with beta-adrenergic drugs. 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 exacerbations, and the Global Initiative for Asthma (GINA) guidelines state that ipratropium may be considered an alternative bronchodilator in patients who experience adverse effects to short-acting beta2-agonists (e.g., nausea, tachycardia, arrhythmia, tremor). Additionally, ipratropium may be administered in conjunction with short-acting beta agonists, corticosteroids, or oxygen in patients with acute, life-threatening asthma exacerbations awaiting transfer to an acute care center. The “2020 Focused Updates to the Asthma Management Guidelines” do not address the use of short acting muscarinic antagonist agents. Ipratropium is available as a metered-dose, inhalation aerosol solution and is FDA-approved for use in adult COPD patients receiving an aerosol bronchodilator who continue to have bronchospasm and require a second bronchodilator.
Tiotropium (Spiriva) is a long-acting, inhalational anticholinergic agent FDA-approved for long-term use in managing bronchospasm associated with COPD and reducing COPD exacerbations, as well as maintenance therapy for asthma. GINA guidelines state that tiotropium is recommended as Step 4 and 5 add-on therapy in adults, adolescents, and children 6 years of age or older with asthma and a history of exacerbations. Tiotropium is available as a dry inhalation powder in capsule form or aerosol solution for oral inhalation. Due to the compound’s extended duration of action, tiotropium is approved for only once daily administration.
Aclidinium (Tudorza Pressair), is FDA-approved as long-term maintenance therapy for bronchospasm associated with COPD, is available as a breath-actuated dry powder inhaler and is dosed twice daily. Umeclidinium (Incruse Ellipta), another breath-actuated inhalation powder, is also approved for long-term COPD maintenance treatment.
Ipratropium is also available in combination with albuterol as Combivent Respimat, which is FDA- approved for use in adult COPD patients receiving an aerosol bronchodilator who continue to have bronchospasm and require a second bronchodilator. This propellant-free product provides a slow-moving mist to supply the active ingredients and has replaced the metered-dose inhaler which used chlorofluorocarbons to deliver medication (i.e., Combivent). Combivent Respimat requires only one actuation per dose compared to the older Combivent product, which required two actuations per dose.
Combination therapy including umeclidinium (inhaled anticholinergic) plus the long-acting beta-2 agonist (LABA), vilanterol, marketed as Anoro Ellipta, is FDA-approved for use in adults with COPD as maintenance therapy. This product is the first dual therapy bronchodilator available for once daily use. Three additional anticholinergic/LABA combination products, tiotropium/olodaterol (Stiolto Respimat), glycopyrrolate/formoterol (Bevespi Aerosphere), and aclidinium bromide/ formoterol (Duaklir Pressair) are also FDA approved for COPD maintenance therapy.
Triple therapy with fluticasone (inhaled corticosteroid), umeclidinium (inhaled anticholinergic), and vilanterol (inhaled LABA), marketed as Trelegy Ellipta, is the most recent inhaled anticholinergic combination therapy FDA-approved for use to manage COPD in adults who continue to have bronchospasm while treated with a bronchodilator and require a second bronchodilator. In September of 2020 it was approved for the maintenance treatment of asthma in patients 18 years of age and older.
Recommended doses for anticholinergic MDI monotherapy and combination products are summarized in Tables 1 and 2, respectively. Dosages exceeding the approved recommendations will be reviewed.
| Drug Name | Dosage Form/Strength | Treatment Indication | Maximum Recommended Dosage |
|---|---|---|---|
| aclidinium (Tudorza Pressair®) | dry powder inhaler (400 mcg/actuation) | chronic obstructive pulmonary disease (COPD) | 2 actuations/day (total dose = 800 mcg) |
| ipratropium bromide HFA (Atrovent HFA®) | aerosol (17 mcg/actuation) | COPD | 12 actuations/day in divided doses (total dose = 204 mcg) |
| tiotropium (Spiriva HandiHaler®) | inhalation capsule (18 mcg/capsule) | COPD | 2 inhalations of one capsule powder contents once daily (total dose = 18 mcg) |
| tiotropium (Spiriva Respimat®) | inhalation cartridge (1.25 mcg/ actuation) | Asthma | 2 inhalations of 1.25 mcg/actuation once daily (total dose = 2.5 mcg) |
| inhalation cartridge (2.5 mcg/ actuation) | COPD | 2 inhalations of 2.5 mcg/actuation once daily (total dose = 5 mcg) | |
| umeclidinium (Incruse Ellipta®) | dry powder inhaler (62.5 mcg/actuation) | COPD | 1 actuation/day (total dose = 62.5 mcg) |
| Drug Name | Dosage Form/Strength | Treatment Indication | Maximum Recommended Dosage |
|---|---|---|---|
| aclidinium bromide/ formoterol fumarate (Duaklir Pressair) | inhalation powder: 400 mcg/ 12 mcg/ inhalation | COPD | 2 actuations/day (1 actuation twice daily); total dose = 800 mcg/24 mcg/day |
| budesonide, glycopyrrolate, formoterol fumarate (Breztri Aerosphere) | inhalation powder: 100 mcg/ 62.5 mcg/ 25 mcg/ inhalation | Asthma | 1 inhalation/day (total dose = 100 mcg/62.5 mcg/ 25 mcg) |
| COPD | 1 inhalation/day (total dose = 100 mcg/62.5 mcg/ 25 mcg) | ||
| inhalation powder: 200 mcg/ 62.5 mcg/ 25 mcg/ inhalation | Asthma | 1 actuation/day; total dose = 200 mcg/62.5 mcg/ 25 mcg/day | |
| glycopyrrolate/ formoterol (Bevespi Aerosphere®) | aerosol (9 mcg/4.8 mcg/actuation) | COPD | 4 actuations/day in two divided doses (total dose = 36 mcg/19.2 mcg) |
| ipratropium/ albuterol (Combivent Respimat®) | aerosol solution (20 mcg ipratropium/100 mcg albuterol base/actuation) | COPD | 6 actuations/day in divided doses (no more than 6 inhalations/day) (total dose = 120 mcg ipratropium/600 mcg albuterol base) |
| tiotropium/ olodaterol (Stiolto Respimat®) | aerosol solution (2.5 mcg/2.5 mcg/ actuation) | COPD | 2 inhalations once daily (total dose = 5 mcg/5 mcg) |
| umeclidinium/ vilanterol (Anoro Ellipta®) | inhalation powder (62.5 mcg/25 mcg/actuation) | COPD | 1 actuation/day (total dose = 62.5 mcg/25 mcg) |
1.2. Pediatrics
Tiotropium is FDA-approved for asthma maintenance therapy in pediatric patients 6-17 years of age. Safety and efficacy of inhaled aclidinium, ipratropium, umeclidinium, and glycopyrrolate in children have not been established, as COPD does not usually develop in the pediatric population. Maximum recommended inhaled anticholinergic pediatric dosages are summarized in Table 3. Dosages exceeding these recommendations will be reviewed.
| Drug Name | Dosage Form/Strength | Treatment Indication | Patient Age/Maximum Recommended Dosage |
|---|---|---|---|
| tiotropium (Spiriva® Respimat®) | inhalation cartridge (1.25 mcg/ actuation) | Asthma | 6-17 years of age: 2 inhalations of 1.25 mcg/ actuation once daily (total dose = 2.5 mcg) |
2. Duration of Therapy
Inhalational anticholinergic agents are suitable for chronic administration as side effects are minimal and drug effectiveness is maintained over years of regular, continuous use. Since inhalation anticholinergics are indicated in the management of chronic, lifelong diseases, there is no basis for limiting the duration of therapy. However, days’ supply for each MDI anticholinergic canister is limited based on the number of inhalations per canister as well as the maximum recommended dose per day. Days’ supply for inhalational anticholinergic therapy is summarized in Tables 4 and 5, based on the maximum recommended dose and the number of actuations per canister or number of capsules per blister card listed in Tables 1-3. Excessive use may be identified based on refill frequency. Inappropriate supply of inhaled anticholinergic agents will be monitored by reviewing excessive refills.
| Drug | Number of Actuations Per Canister | Days’ Supply (based on maximum dose per day)+ |
|---|---|---|
| aclidinium 400 mcg/ actuation |
30 60 |
15 30 |
| ipratropium bromide HFA (12.9 g inhaler) | 200 | ~16-17 |
| tiotropium inhalation capsules (5 capsules, 30 capsules, 90 capsules) | 5 to 90 (based on capsule number prescribed) | 5 to 90 (based on number of capsules prescribed) |
| tiotropium inhalation spray 1.25 mg/actuation | 60 | 30 |
| tiotropium inhalation spray 2.5 mcg/actuation | 28 60 |
14 30 |
| umeclidinium inhalation powder box of 30 foil blister powder strips |
30 | 30 |
Legend:
- + calculated based on canister size/blister package size and maximum dose allowed per day
| Drug | Number of Actuations Per Canister | Days’ Supply (based on maximum dose per day)+ |
|---|---|---|
| aclidinium bromide/ formoterol fumarate inhalation 400 mcg/12 mcg/inhalation |
60 | 30 |
| budesonide/ glycopyrrolate/ formoterol fumarate 160 mcg/ 9 mcg/ 4.8 mcg/ actuation |
120 | 30 |
| fluticasone furoate/ umeclidinium/ vilanterol inhalation powder~ 100 mcg/62.5 mcg/25 mcg/actuation 28 blisters (one strip contains fluticasone, one strip contains umeclidinium and vilanterol) 60 blisters (one strip contains fluticasone, one strip contains umeclidinium and vilanterol) |
14 30 |
14 30 |
| fluticasone furoate/ umeclidinium/ vilanterol inhalation powder~ 200 mcg/62.5 mcg/25 mcg/actuation 28 blisters (one strip contains fluticasone, one strip contains umeclidinium and vilanterol) 60 blisters (one strip contains fluticasone, one strip contains umeclidinium and vilanterol) |
14 30 |
14 30 |
| glycopyrrolate/formoterol aerosol inhalation (10.7 g inhaler) |
28 120 |
7 30 |
| ipratropium/albuterol spray (4 g cartridge) | 120 | 20 |
| tiotropium/olodaterol spray (4 g cartridge) | 60 | 30 |
| umeclidinium/vilanterol inhalation powder~ 14 blisters (one strip contains umeclidinium, one strip contains vilanterol) 60 blisters (one strip contains umeclidinium, one strip contains vilanterol) |
70 30 |
70 30 |
Legend:
- + calculated based on canister size/blister package size and maximum dose allowed per day
- ~ not indicated for use in children
3. Duplicative Therapy
Concurrent administration of inhaled anticholinergics has not been evaluated in controlled studies and may not offer additional clinical benefit but may increase anticholinergic adverse effects. Combined administration of multiple inhaled anticholinergics is not recommended and will be reviewed.
Although inhaled anticholinergic systemic absorption is minimal, adjunctive administration with other anticholinergic medications has the potential to amplify anticholinergic pharmacologic and adverse effects. Combined therapy with inhaled anticholinergics and other anticholinergic dosage forms should be considered cautiously.
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 inhaled anticholinergics with beta agonists 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.
| Target Drug | Interacting Drug | Interaction | Recommendation | Clinical Significance Level |
|---|---|---|---|---|
| fluticasone/umeclidinium/vilanterol | strong CYP3A4 inhibitors (e.g., azole antifungals, erythromycin, clarithromycin, protease inhibitors) | potential for increased steroid concentrations with risk for excessive adrenal suppression and Cushing syndrome development | concurrent administration not advised; if combined administration necessary, give cautiously; monitor patients for signs/ symptoms of corticosteroid excess | major (CP) |
| ipratropium/albuterol, umeclidinium/vilanterol, glycopyrrolate/formoterol, tiotropium/olodaterol | MAOIs* (including linezolid) | concurrent administration of MAOIs with beta2-agonists may increase risk of development 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) |
| ipratropium/albuterol, umeclidinium/vilanterol, glycopyrrolate/formoterol, tiotropium/olodaterol | beta blockers | concurrent administration may decrease effectiveness of beta-adrenergic blocker or beta2- agonists like albuterol | combination not recommended in asthma/COPD patients; if adjunctive therapy necessary, utilize cardioselective beta blocker (e.g., atenolol, bisoprolol) | major (CP) |
| ipratropium/albuterol, umeclidinium/vilanterol, glycopyrrolate/formoterol, tiotropium/olodaterol | diuretics | potential for worsening of diuretic associated hypokalemia and/or ECG changes with beta-agonist concurrent administration, especially with high beta-agonist doses | administer combination cautiously; monitoring potassium levels may be necessary | moderate (CP) |
| steroids | quinolones | increased potential for serious tendonitis, tendon rupture with concurrent therapy | closely monitor patients requiring combination therapy; discontinue quinolone if tendon pain develops | moderate (CP) |
| systemic steroids | bupropion | potential increased seizure risk due to systemic steroid-induced lowering of seizure threshold | utilize only recommended bupropion dosages; initiate bupropion therapy with low doses and titrate slowly when combination therapy warranted; closely monitor patients for seizure development | moderate (CP) |
| umeclidinium/vilanterol | strong CYP3A4 inhibitors (e.g., fluconazole, ketoconazole, ritonavir, nefazodone) | adjunctive administration may result in elevated vilanterol serum levels and enhanced pharmacologic and adverse effects, including QT interval prolongation, as vilanterol is a CYP3A4 substrate | administer combination cautiously, and closely monitor patients for adverse cardiovascular/QT interval outcomes | moderate (CP) |
Legend:
- + CP = Clinical Pharmacology
- *MAOIs = monoamine oxidase inhibitors
- ^TCAs = tricyclic antidepressant
5. References
- IBM Micromedex® DRUGDEX® (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. Available at: https://www-micromedexsolutions-com.libproxy.uthscsa.edu/ (cited: February 17, 2023).
- Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2021. Available at: http://clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed February 17, 2023.
- Ipratropium bromide HFA inhalation aerosol (Atrovent® HFA) package insert. Boehringer Ingelheim Pharmaceuticals, Inc., January 2021.
- National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Full Report 2007. (NIH Publication No. 07-4051). Available at: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf. Accessed February 17, 2023.
- Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2022. Available from: https://ginasthma.org/gina-reports/. Accessed February 17, 2023.
- National Heart, Lung, and Blood Institute. 2020 focused updates to the asthma management guidelines: a report from the national asthma education and prevention program coordinating committee expert panel working group. National Institutes of Health. December 2020. Accessed February 17, 2023.
- 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 2023.
- Tiotropium inhalation powder (Spiriva® HandiHaler®) package insert. Boehringer Ingelheim Pharmaceuticals, Inc., January 2022.
- Tiotropium inhalation spray (Spiriva® Respimat®) package insert. Boehringer Ingelheim Pharmaceuticals, Inc., January 2022.
- Aclidinium inhalation powder (Tudorza® Pressair®) package insert. AstraZeneca, February 2021.
- Umeclidinium inhalation powder (Incruse® Ellipta®) package insert. GlaxoSmithKline, August 2020.
- Ipratropium/albuterol inhalation spray (Combivent® Respimat®) package insert. Boehringer Ingelheim Pharmaceuticals, Inc., January 2022.
- Umeclidinium/vilanterol inhalation powder (Anoro® Ellipta®) package insert. GlaxoSmithKline, October 2022.
- Aclidinium/ formoterol fumarate powder (Duaklir Pressair®) metered dose inhaler package insert. Circassia Pharmaceuticals, Inc., January 2022.
- Tiotropium/olodaterol inhalation spray (Stiolto® Respimat®) package insert. Boehringer Ingelheim Pharmaceuticals, Inc., January 2022.
- Glycopyrrolate/formoterol inhalation aerosol (Bevespi Aerosphere®) package insert. AstraZeneca, November 2020.
- Fluticasone/umeclidinium/vilanterol inhalation powder (Trelegy® Ellipta®) package insert. GlaxoSmithKline, December 2022.
- Budesonide/ glycopyrrolate, formoterol fumarate inhalation spray (Breztri Aerosphere®) package insert. AstraZeneca Pharmaceuticals, LP. January 2022.