Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Aerosol, Inhalation:
Bevespi Aerosphere: Glycopyrrolate 9 mcg and formoterol fumarate dihydrate 4.8 mcg per actuation (5.9 g, 10.7 g)
Pharmacology
Mechanism of Action
Glycopyrrolate: In COPD, competitively and reversibly inhibits the action of acetylcholine at muscarinic receptor subtypes 1-3 (greater affinity for subtypes 1 and 3) in bronchial smooth muscle thereby causing bronchodilation.
Formoterol: Relaxes bronchial smooth muscle by selective action on beta2 receptors with little effect on heart rate. Formoterol has a long-acting effect.
Use in Specific Populations
Special Populations: Renal Function Impairment
Formoterol systemic exposure (AUC0-12) in subjects with moderate renal impairment (CrCl 45 mL/minute) is expected to be approximately 45% higher.
Use: Labeled Indications
Chronic obstructive pulmonary disease: Maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema
Contraindications
Hypersensitivity to glycopyrrolate, formoterol, or any component of the formulation; monotherapy (without use of a concomitant inhaled corticosteroid) in the treatment of asthma.
Dosage and Administration
Dosing: Adult
COPD: Oral inhalation: Metered-dose inhaler: Two inhalations (glycopyrrolate 9 mcg/formoterol 4.8 mcg per inhalation) twice daily; (maximum: 2 inhalations twice daily)
Dosing: Geriatric
Refer to adult dosing.
Administration
Oral inhalation: Metered-dose inhaler: For oral inhalation using the Bevespi Aerosphere only. Prior to use, inhaler must be primed by releasing 4 test sprays into the air (away from face and eyes), shake well before each spray. Inhaler must be reprimed if not used >7 days by releasing 2 sprays into the air. Shake well before each use. Clean inhaler (remove canister out of actuator) one time each week by running warm water through the actuator and allow to air dry. Reprime the inhaler after each cleaning by releasing 2 sprays into the air.
Storage
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F); temperatures above 49°C (120°F) may cause bursting. Contents under pressure; do not puncture, incinerate, or store near heat or open flame. Discard inhaler after the labeled number of inhalations have been used (the dose indicator display window will read “0”) or 3 months after removal from the foil pouch, whichever comes first. Never immerse the canister into water to determine the amount remaining in the canister (“float test”).
Drug Interactions
Acetylcholinesterase Inhibitors: May diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Monitor therapy
Aclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination
Amantadine: May enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy
Anticholinergic Agents: May enhance the anticholinergic effect of Glycopyrrolate (Oral Inhalation). Avoid combination
AtoMOXetine: May enhance the tachycardic effect of Beta2-Agonists. Monitor therapy
AtoMOXetine: May enhance the hypertensive effect of Sympathomimetics. AtoMOXetine may enhance the tachycardic effect of Sympathomimetics. Monitor therapy
Atosiban: Beta2-Agonists may enhance the adverse/toxic effect of Atosiban. Specifically, there may be an increased risk for pulmonary edema and/or dyspnea. Monitor therapy
Beta2-Agonists (Long-Acting): May enhance the adverse/toxic effect of other Beta2-Agonists (Long-Acting). Avoid combination
Beta-Blockers (Beta1 Selective): May diminish the bronchodilatory effect of Beta2-Agonists. Of particular concern with nonselective beta-blockers or higher doses of the beta1 selective beta-blockers. Monitor therapy
Beta-Blockers (Nonselective): May diminish the bronchodilatory effect of Beta2-Agonists. Avoid combination
Betahistine: May diminish the therapeutic effect of Beta2-Agonists. Monitor therapy
Botulinum Toxin-Containing Products: May enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy
Caffeine and Caffeine Containing Products: May enhance the adverse/toxic effect of Formoterol. Caffeine and Caffeine Containing Products may enhance the hypokalemic effect of Formoterol. Monitor therapy
Cannabinoid-Containing Products: May enhance the tachycardic effect of Sympathomimetics. Exceptions: Cannabidiol. Monitor therapy
Cannabinoid-Containing Products: Anticholinergic Agents may enhance the tachycardic effect of Cannabinoid-Containing Products. Exceptions: Cannabidiol. Monitor therapy
Chloral Betaine: May enhance the adverse/toxic effect of Anticholinergic Agents. Monitor therapy
Cimetropium: Anticholinergic Agents may enhance the anticholinergic effect of Cimetropium. Avoid combination
Cocaine (Topical): May enhance the hypertensive effect of Sympathomimetics. Management: Consider alternatives to use of this combination when possible. Monitor closely for substantially increased blood pressure or heart rate and for any evidence of myocardial ischemia with concurrent use. Consider therapy modification
Doxofylline: Sympathomimetics may enhance the adverse/toxic effect of Doxofylline. Monitor therapy
Eluxadoline: Anticholinergic Agents may enhance the constipating effect of Eluxadoline. Avoid combination
Gastrointestinal Agents (Prokinetic): Anticholinergic Agents may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Monitor therapy
Glucagon: Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Monitor therapy
Glycopyrronium (Topical): May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination
Guanethidine: May enhance the arrhythmogenic effect of Sympathomimetics. Guanethidine may enhance the hypertensive effect of Sympathomimetics. Monitor therapy
Inhalational Anesthetics: May enhance the arrhythmogenic effect of Formoterol. Monitor therapy
Ipratropium (Oral Inhalation): May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination
Itopride: Anticholinergic Agents may diminish the therapeutic effect of Itopride. Monitor therapy
Levosulpiride: Anticholinergic Agents may diminish the therapeutic effect of Levosulpiride. Avoid combination
Linezolid: May enhance the hypertensive effect of Sympathomimetics. Management: Reduce initial doses of sympathomimetic agents, and closely monitor for enhanced pressor response, in patients receiving linezolid. Specific dose adjustment recommendations are not presently available. Consider therapy modification
Loop Diuretics: Beta2-Agonists may enhance the hypokalemic effect of Loop Diuretics. Monitor therapy
Loxapine: Agents to Treat Airway Disease may enhance the adverse/toxic effect of Loxapine. More specifically, the use of Agents to Treat Airway Disease is likely a marker of patients who are likely at a greater risk for experiencing significant bronchospasm from use of inhaled loxapine. Management: This is specific to the Adasuve brand of loxapine, which is an inhaled formulation. This does not apply to non-inhaled formulations of loxapine. Avoid combination
Methacholine: Beta2-Agonists (Long-Acting) may diminish the therapeutic effect of Methacholine. Management: Hold long-acting beta2 agonists for 36 hours before methacholine use. Consider therapy modification
Methacholine: Long-acting muscarinic antagonists (LAMAs) may diminish the therapeutic effect of Methacholine. Consider therapy modification
Mianserin: May enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy
Mirabegron: Anticholinergic Agents may enhance the adverse/toxic effect of Mirabegron. Monitor therapy
Monoamine Oxidase Inhibitors: May enhance the adverse/toxic effect of Beta2-Agonists. Monitor therapy
Nitroglycerin: Anticholinergic Agents may decrease the absorption of Nitroglycerin. Specifically, anticholinergic agents may decrease the dissolution of sublingual nitroglycerin tablets, possibly impairing or slowing nitroglycerin absorption. Monitor therapy
Opioid Agonists: Anticholinergic Agents may enhance the adverse/toxic effect of Opioid Agonists. Specifically, the risk for constipation and urinary retention may be increased with this combination. Monitor therapy
Oxatomide: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination
Potassium Chloride: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Chloride. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium chloride. Avoid combination
Potassium Citrate: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Citrate. Avoid combination
Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Consider therapy modification
QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy
Ramosetron: Anticholinergic Agents may enhance the constipating effect of Ramosetron. Monitor therapy
Revefenacin: Anticholinergic Agents may enhance the anticholinergic effect of Revefenacin. Avoid combination
Secretin: Anticholinergic Agents may diminish the therapeutic effect of Secretin. Management: Avoid concomitant use of anticholinergic agents and secretin. Discontinue anticholinergic agents at least 5 half-lives prior to administration of secretin. Consider therapy modification
Solriamfetol: Sympathomimetics may enhance the hypertensive effect of Solriamfetol. Monitor therapy
Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Monitor therapy
Tedizolid: May enhance the hypertensive effect of Sympathomimetics. Tedizolid may enhance the tachycardic effect of Sympathomimetics. Monitor therapy
Theophylline Derivatives: May enhance the adverse/toxic effect of Formoterol. Theophylline Derivatives may enhance the hypokalemic effect of Formoterol. Monitor therapy
Thiazide and Thiazide-Like Diuretics: Beta2-Agonists may enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy
Thiazide and Thiazide-Like Diuretics: Anticholinergic Agents may increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Monitor therapy
Tiotropium: Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium. Avoid combination
Topiramate: Anticholinergic Agents may enhance the adverse/toxic effect of Topiramate. Monitor therapy
Umeclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination
Adverse Reactions
See individual agents.
1% to 10%:
Cardiovascular: Chest pain (1% to <2%)
Central nervous system: Anxiety (1% to <2%), dizziness (1% to <2%), falling (1% to <2%), fatigue (1% to <2%), headache (1% to <2%)
Gastrointestinal: Vomiting (1% to <2%), xerostomia (1% to <2%)
Genitourinary: Urinary tract infection (3%)
Hematologic & oncologic: Bruise (1% to <2%)
Infection: Influenza (1% to <2%), tooth abscess (1% to <2%)
Neuromuscular & skeletal: Arthralgia (1% to <2%), limb pain (1% to <2%), muscle spasm (1% to <2%)
Respiratory: Cough (4%), acute sinusitis (1% to <2%), oropharyngeal pain (1% to <2%)
Frequency not defined: Respiratory: Paradoxical bronchospasm
<1%, postmarketing, and/or case reports: Hypersensitivity reaction, urinary retention
Warnings/Precautions
Concerns related to adverse effects:
- Asthma-related deaths: Monotherapy with a long-acting beta-2 agonist (LABA) is contraindicated in the treatment of asthma. In a large, randomized, placebo-controlled US clinical trial (SMART 2006), salmeterol was associated with an increase in asthma-related deaths (when added to usual asthma therapy); risk is considered a class effect among all LABAs. When LABAs are used in a fixed-dose combination with inhaled corticosteroids, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared to inhaled corticosteroids alone. Current guidelines recommend the use of an inhaled corticosteroid before adding an LABA (GINA 2018; NIH/NHLBI 2007). In a more recent multicenter, randomized, double-blinded trial, the use of salmeterol and an inhaled corticosteroid (ie, fluticasone) combined in a single inhaler in a large number of children, adolescent, and adult patients with persistent asthma (non-life-threatening and stable) did not increase the risk of serious asthma-related events compared with fluticasone alone; in addition, patients receiving fluticasone/salmeterol had fewer severe asthma exacerbations compared with patients receiving fluticasone alone (Peters 2016; Stempel 2016a; Stempel 2016b). Glycopyrrolate/formoterol is not indicated for the treatment of asthma. Available data do not suggest an increased risk of death with use of LABA in patients with chronic obstructive pulmonary disease (COPD).
- Bronchospasm: Paradoxical bronchospasm that may be life-threatening may occur with use of inhaled bronchodilating agents; this should be distinguished from inadequate response. If paradoxical bronchospasm occurs, discontinue use and institute alternative therapy.
- CNS effects: May cause drowsiness, dizziness, and/or blurred vision; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).
- Hypersensitivity: Immediate hypersensitivity reactions, including angioedema, rash, or urticaria may occur; discontinue immediately if signs/symptoms of a hypersensitivity reaction occur.
- Serious effects/fatalities: Do not exceed recommended dose or frequency or use with other medications containing LABAs; serious adverse events, including fatalities, have been associated with excessive use of inhaled sympathomimetics.
Disease-related concerns:
- Cardiovascular disease: Use with caution in patients with cardiovascular disease (eg, arrhythmia, coronary insufficiency, hypertension); beta agonists may cause elevation in blood pressure and heart rate. Beta-2 agonists may also produce changes in the ECG (eg, T-wave flattening, QTc prolongation, ST segment depression).
- Diabetes: Use with caution in patients with diabetes mellitus; beta-2 agonists may aggravate preexisting diabetes and ketoacidosis and increase serum glucose.
- Glaucoma: Use with caution in patients with narrow angle glaucoma; may increase intraocular pressure.
- Hepatic impairment: Use with caution; beta-2 agonists exposure may be increased with hepatic impairment; monitor closely.
- Hyperthyroidism: Use with caution in patients with hyperthyroidism; beta-2 agonists may stimulate thyroid activity.
- Hypokalemia: Use with caution in patients with hypokalemia; beta-2 agonists may decrease serum potassium (transient).
- Renal impairment: Use with caution in patients with severe renal impairment (CrCl ≤30 mL/minute/1.73 m2) or ESRD on dialysis.
- Seizures: Use with caution in patients with seizure disorders; beta-2 agonists may result in CNS stimulation/excitation.
- Urinary retention: Use with caution in patients with urinary retention. Monitor for signs and symptoms of urinary retention, especially in patients with prostatic hyperplasia or bladder-neck obstruction.
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Special populations:
- Pediatric: LABAs, when used as monotherapy, may increase the risk of asthma-related hospitalization in pediatric and adolescent patients. When LABAs are used in a fixed-dose combination with inhaled corticosteroids, data from large clinical trials in adolescents do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared to inhaled corticosteroids alone.
Other warnings/precautions:
- Appropriate use: Not indicated for the initial (rescue) treatment of acute episodes of bronchospasm or with acutely deteriorating or potentially life-threatening COPD; after initiation of therapy, patients should use short-acting bronchodilators only on an as needed basis for acute symptoms.
Monitoring Parameters
FEV1, peak flow, and/or other pulmonary function tests; serum potassium, serum glucose; blood pressure, heart rate; CNS stimulation; signs/symptoms of glaucoma; hypersensitivity reactions; urinary retention.
Pregnancy
Pregnancy Risk Factor
C
Pregnancy Considerations
Animal reproduction studies have not been conducted with this combination. Beta-agonists have the potential to affect uterine contractility if administered during labor. Refer to individual monographs.
Patient Education
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Have patient report immediately to prescriber signs of high blood sugar (confusion, fatigue, more thirst, hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit), signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), signs of a urinary tract infection (blood in the urine, burning or painful urination, passing a lot of urine, fever, lower abdominal pain, or pelvic pain), severe headache, severe dizziness, passing out, chest pain, fast heartbeat, abnormal heartbeat, tremors, severe anxiety, vision changes, eye pain, severe eye irritation, seeing halos or bright colors around lights, eye redness, difficult urination, painful urination, passing a lot of urine, change in amount of urine passed, difficulty breathing, wheezing, or cough (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
