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Glycopyrrolate and Formoterol

Pronunciation

(glye koe PYE roe late & for MOH te rol)

Index Terms

  • Bevespi Aerosphere
  • Formoterol and Glycopyrrolate
  • Glycopyrrolate and Formoterol Fumarate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Aerosol, Inhalation:

Bevespi: Glycopyrrolate 90 mcg and formoterol fumarate dihydrate 4.8 mcg per actuation (10.7 g)

Brand Names: U.S.

  • Bevespi

Pharmacologic Category

  • Anticholinergic Agent
  • Anticholinergic Agent, Long-Acting
  • Beta2 Agonist
  • Beta2-Adrenergic Agonist, Long-Acting

Pharmacology

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.

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 compared to subjects with normal renal function (CrCl 94 mL/minute).

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

Limitations of use: Not indicated for the relief of acute bronchospasm or for the treatment of asthma

Contraindications

Hypersensitivity to glycopyrrolate, formoterol, or any component of the formulation; monotherapy in patients with asthma (ie, without use of a long-term asthma control medication).

Dosing: Adult

COPD (maintenance): Oral inhalation: Two inhalations (glycopyrrolate 9 mcg/formoterol 4.8 mcg per inhalation) twice daily; (maximum: 2 inhalations twice daily).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl >30 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

CrCl ≤30 mL/minute/1.73 m2 or end-stage renal disease (ESRD) on dialysis: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); use with caution.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); formoterol exposure may be increased with hepatic impairment; use with caution and monitor closely.

Administration

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. When dose is ready to be administered, breathe in slowly through the mouth and press the dose-release button; continue to breathe in slowly as long as possible, then hold breath for 10 seconds or for as long as comfortable; repeat for second inhalation. 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

AbobotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic effect of AbobotulinumtoxinA. Monitor therapy

Acetylcholinesterase Inhibitors: Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Acetylcholinesterase Inhibitors may diminish the therapeutic effect of Anticholinergic Agents. Monitor therapy

Aclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Analgesics (Opioid): Anticholinergic Agents may enhance the adverse/toxic effect of Analgesics (Opioid). Specifically, the risk for constipation and urinary retention may be increased with this combination. 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

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

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: 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. Avoid combination

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Inhalational Anesthetics: May enhance the arrhythmogenic effect of Formoterol. Monitor therapy

Iobenguane I 123: Sympathomimetics may diminish the therapeutic effect of Iobenguane I 123. Avoid combination

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

Long-Acting Beta2-Agonists: May enhance the adverse/toxic effect of other Long-Acting Beta2-Agonists. Avoid combination

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

MAO Inhibitors: May enhance the adverse/toxic effect of Beta2-Agonists. Monitor therapy

Mianserin: May enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Mirabegron: Anticholinergic Agents may enhance the adverse/toxic effect of Mirabegron. Monitor therapy

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. 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. Avoid combination

OnabotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic effect of OnabotulinumtoxinA. 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

Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Consider therapy modification

Ramosetron: Anticholinergic Agents may enhance the constipating effect of Ramosetron. Monitor therapy

RimabotulinumtoxinB: Anticholinergic Agents may enhance the anticholinergic effect of RimabotulinumtoxinB. Monitor therapy

Secretin: Anticholinergic Agents may diminish the therapeutic effect of Secretin. Management: Avoid using drugs with substantial anticholinergic effects in patients receiving secretin whenever possible. If such agents must be used in combination, monitor closely for a diminished response to secretin. Consider therapy modification

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%:

Genitourinary: Urinary tract infection (3%)

Respiratory: Cough (4%)

Frequency not defined:

Cardiovascular: Depression of ST segment on ECG, ECG changes (prolongation of the QTc interval), flattened T wave on ECG

Dermatologic: Skin rash, urticaria

Endocrine & metabolic: Exacerbation of diabetes mellitus, hypokalemia, ketoacidosis (exacerbation)

Genitourinary: Urinary retention (exacerbation)

Hypersensitivity: Angioedema, immediate hypersensitivity

Ophthalmic: Exacerbation of angle-closure glaucoma (narrow angle)

Respiratory: Paradoxical bronchospasm

ALERT: U.S. Boxed Warning

Asthma-related death:

Long-acting beta2-adrenergic agonists (LABAs) increase the risk of asthma-related death. Data from a large placebo-controlled US trial that compared the safety of another LABA (salmeterol) with placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is considered a class effect of LABAs, including formoterol.

The safety and efficacy of glycopyrrolate/formoterol in patients with asthma have not been established. Glycopyrrolate/formoterol is not indicated for the treatment of asthma.

Warnings/Precautions

Concerns related to adverse effects:

• Asthma-related deaths: [US Boxed Warning]: Long-acting beta2-agonists (LABAs) increase the risk of asthma-related death. The safety and efficacy of glycopyrrolate/formoterol in patients with asthma have not been established. Glycopyrrolate/formoterol is not indicated for 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. Data are not available to determine if the addition of an inhaled corticosteroid lessens this increased risk of death associated with LABA use; however, current guidelines recommend the use of an inhaled corticosteroid before adding a LABA (GINA 2015; 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 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 (Stempel 2016). Data are not available to determine if LABA use increases the risk of death in patients with COPD.

• Bronchospasm: Rarely, paradoxical, life-threatening bronchospasm may occur with use of inhaled beta2-agonists; distinguish from inadequate response and discontinue medication immediately if paradoxical bronchospasm occurs.

• CNS depression: 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 have been reported; if signs suggesting allergic reactions occur, in particular, angioedema (including difficulties in breathing or swallowing, swelling of the tongue, lips, and face), urticaria, or skin rash, discontinue therapy immediately.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with cardiovascular disease (arrhythmia, coronary insufficiency, hypertension, or heart failure); beta-agonists may cause elevation in blood pressure and heart rate. Beta2-agonists may also produce changes in the electrocardiogram (ECG) (eg, T-wave flattening, QTc prolongation, ST segment depression).

• Diabetes: Use with caution in patients with diabetes mellitus; beta2-agonists may aggravate preexisting diabetes and ketoacidosis and increase serum glucose.

• Hepatic impairment: Use with caution; formoterol exposure may be increased with hepatic impairment; monitor closely.

• Hyperthyroidism: Use with caution in patients with hyperthyroidism; may stimulate thyroid activity.

• Hypokalemia: Use with caution in patients with hypokalemia; beta2-agonists may decrease serum potassium.

• Narrow angle glaucoma: Use with caution in patients with narrow angle glaucoma; monitor of signs/symptoms of glaucoma.

• Renal impairment: Use with caution in patients with severe renal impairment (creatinine clearance [CrCl] ≤30 mL/minute/1.73 m2) or end-stage renal disease (ESRD) on dialysis.

• Seizure disorders: Use with caution in patients with seizure disorders; beta2-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.

Other warnings/precautions:

• Appropriate use: Do not use for acute episodes of COPD or for acute bronchospasm; always prescribe with an inhaled short-acting beta2-agonist (eg, albuterol) and educate patient on appropriate use. Upon initiation of the combination inhaler, use of short-acting beta2-agonists should be limited to treat acute symptoms. Do not initiate in patients with significantly worsening, potentially life-threatening or acutely deteriorating COPD. Do not increase the dose or frequency beyond what is recommended.

Monitoring Parameters

FEV1, FVC, and/or other pulmonary function tests; serum potassium, serum glucose; blood pressure, heart rate; CNS stimulation; signs/symptoms of glaucoma. Monitor for increased use of short-acting beta2-agonist inhalers; may be marker of a deteriorating condition. Monitor for changes in risk factors (eg, environmental exposure, smoking status).

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal reproduction studies have not been conducted with this combination. 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, polyuria, flushing, fast breathing, or breath that smells like fruit), signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), severe headache, severe dizziness, passing out, angina, tachycardia, tremors, severe anxiety, difficulty swallowing, vision changes, eye pain, severe eye irritation, visual halos or bright colors around lights, eye redness, difficult urination, painful urination, polyuria, 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.

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