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Umeclidinium Bromide

Class: Antimuscarinics/Antispasmodics
VA Class: RE105
Chemical Name: 4-(Hydroxydiphenylmethyl)-1-[2-(phenylmethoxy)ethyl]-1-azoniabicyclo[2.2.2]octane bromide (1:1)
Molecular Formula: C29H34BrNO2
CAS Number: 869113-09-7
Brands: Anoro Ellipta, Incruse Ellipta

Introduction

Bronchodilator; synthetic quaternary ammonium antimuscarinic agent.1 2 3 4 5 6 7 8 10

Uses for Umeclidinium Bromide

Bronchospasm in COPD

Long-term maintenance treatment of reversible bronchospasm associated with COPD, including chronic bronchitis and/or emphysema.1 2 3 4 5 6 8 10

Not indicated for treatment of acute bronchospasm (i.e., as rescue therapy for treatment of acute episodes of bronchospasm).1 2

Other Uses

Not indicated for treatment of asthma; safety and efficacy in asthma not established.2

Umeclidinium Bromide Dosage and Administration

Administration

Administer umeclidinium by oral inhalation only using a specific oral inhalation device (Incruse Ellipta) that delivers powdered drug from foil-wrapped blisters.1

Administer umeclidinium in fixed combination with vilanterol by oral inhalation only using a specific preloaded inhaler (Anoro Ellipta) that delivers powdered umeclidinium in fixed combination with vilanterol from foil-wrapped blisters.2

Administer umeclidinium alone or in fixed combination with vilanterol once daily at the same time every day.1 2

Oral Inhalation

Oral Inhalation Administration

Before first use of either the Incruse Ellipta or Anoro Ellipta inhaler, remove device from foil tray; discard enclosed desiccant out of reach of children and pets.1 2 Write date the tray is opened and inhaler is to be discarded (6 weeks after opening) on label.1 2 Do not open inhaler cover until immediately before use; to avoid wasting doses, do not close cover again until dose is inhaled.1 2

Open cover fully to expose the mouthpiece and expect to hear a click.1 2 If dose counter does not advance when click is heard, inform clinician that dose is not properly prepared.1 2

Before inhaling dose, exhale completely; do not exhale into mouthpiece of inhaler.1 2 Place mouthpiece between lips and inhale deeply through inhaler with a steady, even breath; do not inhale through nose.1 2 Do not block air vent on inhaler during inhalation.1 2 Remove inhaler from mouth, hold the breath for about 3–4 seconds (or as long as comfortable), then exhale slowly and gently.1 2

Do not administer another dose even if delivery of dose not perceived.1 2 After dose is administered, close inhaler by sliding cover over mouthpiece as far as possible.1 2

Routine cleaning of inhaler is not necessary; may clean mouthpiece with dry tissue if desired.1 2

Dosage

Available as umeclidinium bromide; dosage expressed in terms of umeclidinium.1

Each foil-wrapped blister in the Incruse Ellipta inhaler device contains 74.2 mcg of umeclidinium bromide (equivalent to 62.5 mcg of umeclidinium).1 In vitro, each blister from the inhaler delivered 55 mcg of umeclidinium.1 Precise amount of drug delivered to lungs depends on patient-specific factors (e.g., inspiratory flow).1

Incruse Ellipta inhaler delivers 30 doses (or 7 doses for the sample or institutional package).1

Each foil-wrapped blister in the Anoro Ellipta inhaler device contains 74.2 mcg of umeclidinium bromide (equivalent to 62.5 mcg of umeclidinium) or 40 mcg of vilanterol trifenatate (equivalent to 25 mcg of vilanterol) (in separate blisters).2 In vitro, each pair of blisters from the inhaler delivered 55 mcg of umeclidinium and 22 mcg of vilanterol.2 Precise amount of drug delivered to lungs depends on patient-specific factors (e.g., inspiratory flow).2

Anora Ellipta inhaler delivers 30 doses (or 7 doses for the sample or institutional package).2

Adults

COPD
Umeclidinium
Oral Inhalation

62.5 mcg of umeclidinium (1 inhalation) once daily.1

Umeclidinium/Vilanterol Fixed-combination
Oral Inhalation

62.5 mcg of umeclidinium and 25 mcg of vilanterol (1 inhalation) once daily.2

Prescribing Limits

Adults

COPD
Umeclidinium
Oral Inhalation

Do not administer more than once every 24 hours.1

Umeclidinium/Vilanterol Fixed-combination
Oral Inhalation

Do not administer more than once every 24 hours.2

Special Populations

When umeclidinium is used in fixed combination with vilanterol, dosage requirements for vilanterol should be considered.2

Hepatic Impairment

No dosage adjustment required in patients with moderate hepatic impairment; not studied in patients with severe hepatic impairment.1 2 (See Absorption under Pharmacokinetics.)

Renal Impairment

No dosage adjustment required.1 2 11 12

Geriatric Patients

No dosage adjustment required.1 2 (See Geriatric Use under Cautions.)

Cautions for Umeclidinium Bromide

Contraindications

  • Known hypersensitivity to umeclidinium or any ingredient in the formulation.1 2

  • Known severe hypersensitivity to milk proteins.1 2

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity reactions may occur.1 2 Anaphylactic reactions reported following oral inhalation of other powder preparations containing lactose in patients with severe milk protein allergy.1 2 (See Contraindications under Cautions.)

Use of Fixed Combinations

When used in fixed combination with vilanterol, consider the cautions, precautions, contraindications, and interactions associated with vilanterol.2

Deterioration of Disease and Acute Episodes

Do not initiate umeclidinium alone or in fixed combination with vilanterol in patients with acutely deteriorating COPD, which may be life-threatening.1 2

Do not use for relief of acute symptoms.1 2 Not studied in patients with acute symptoms; do not use extra doses of the drug in such situations.1 2 Use a short-acting, inhaled β2-agonist as needed for acute symptoms.1 2

Failure to respond to a previously effective dosage of umeclidinium alone or in fixed combination with vilanterol or to a supplemental short-acting, inhaled β2-agonist may indicate worsening COPD.1 2 Immediately reevaluate the patient and treatment regimen.1 2 Do not use extra or increased dosages in such situations.1 2

Paradoxical Bronchospasm

Acute, life-threatening paradoxical bronchospasm may occur.1 2

If paradoxical bronchospasm occurs, immediately treat patient with an inhaled, short-acting bronchodilator; discontinue therapy with umeclidinium (alone or in fixed combination with vilanterol); institute alternative therapy.1 2

Ocular Effects

Use caution in patients with acute angle-closure glaucoma.1 2 Possible worsening of acute angle-closure glaucoma manifested by ocular pain or discomfort, blurred vision, visual halos, or colored images in association with red eyes from conjunctival congestion and corneal edema.1 2 (See Advice to Patients.)

GU Effects

Use caution in patients with urinary retention.1 2 May worsen symptoms and signs (e.g., urinary retention, dysuria) associated with prostatic hyperplasia or bladder neck obstruction.1 2 (See Advice to Patients.)

Cardiovascular Effects

Atrial fibrillation reported in <1% of patients; reported more frequently with umeclidinium than with placebo.1 5

Prolongation of QTc not observed in healthy individuals.1 2 9

Specific Populations

Pregnancy

Category C.1 2

Use during labor only if potential benefit outweighs potential risk.1 2

Lactation

May be distributed into milk in rats; not known whether distributed into human milk.1 2 Discontinue nursing or the drug, taking into account the importance of the drug to the woman.1 2

Pediatric Use

Not indicated for use in pediatric patients.1 2 Safety and efficacy not established.1 2

Geriatric Use

No overall differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1 2 (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Exposure not substantially altered in patients with moderate hepatic impairment (Child-Pugh score of 7–9).1 2 Not studied in patients with severe hepatic impairment.1 2 (See Absorption under Pharmacokinetics.)

Renal Impairment

Exposure not substantially altered in patients with severe renal impairment (Clcr <30 mL/minute).1 2 11

Common Adverse Effects

Umeclidinium: nasopharyngitis,1 upper respiratory tract infection,1 cough,1 arthralgia.1

Umeclidinium/vilanterol fixed combination: Pharyngitis,2 sinusitis,2 lower respiratory tract infection,2 constipation,2 diarrhea,2 extremity pain,2 muscle spasms,2 neck pain,2 chest pain.2

Interactions for Umeclidinium Bromide

Substrate of CYP2D6 and P-glycoprotein (P-gp).1 2

Drugs Affecting Hepatic Microsomal Enzymes and/or the P-glycoprotein Transport System

No clinically important effect on umeclidinium exposure in individuals who were poor-metabolizers of CYP2D6 substrates compared with ultrarapid, extensive, and intermediate metabolizers.1 2 (See Elimination: Special Populations under Pharmacokinetics.) Therefore, dosage adjustment is not required when used concomitantly with CYP2D6 inhibitors.1 2

Specific Drugs

Drug

Interaction

Comments

Anticholinergic agents

Additive anticholinergic effects1 2

Avoid concomitant use1 2

Verapamil

Increased umeclidinium AUC; no change in umeclidinium peak concentration1 2

Dosage adjustment of umeclidinium not required1 2

Umeclidinium Bromide Pharmacokinetics

Absorption

Bioavailability

Exhibits linear pharmacokinetics over dosage range of 62.5–500 mcg.1 2

Peak umeclidinium concentrations reached within 5–15 minutes following oral inhalation;1 2 plasma concentrations may not predict therapeutic effect.1 2

Mostly absorbed from the lung following oral inhalation; minimal contribution from oral absorption.1 2

Steady-state plasma concentrations achieved within 14 days; 1.8-fold accumulation following repeated once-daily inhalation.1 2

Special Populations

Umeclidinium/vilanterol fixed combination: No clinically important changes in peak concentrations or AUC of umeclidinium or vilanterol in patients with moderate hepatic impairment.1 2 (See Hepatic Impairment under Cautions.)

Distribution

Extent

Not known whether distributed into human milk.1 2

Plasma Protein Binding

Approximately 89%.1 2

Elimination

Metabolism

Metabolized mainly by CYP2D6; also a substrate for the P-gp transport system.1 2

Principal routes of metabolism involve oxidation via hydroxylation and O-dealkylation followed by conjugation (e.g., glucuronidation); low systemic exposure to metabolites.1 2

Elimination Route

Undergoes biliary elimination.1 2

58 and 22% of radiolabeled IV dose excreted in feces and urine, respectively.1 2

Negligible oral absorption; 92 and <1% of radiolabeled oral dose excreted in feces and urine, respectively.1 2

Half-life

Effective half-life following once daily dosing: 11 hours.1 2

Special Populations

No clinically important differences in pharmacokinetics based on age, gender, weight, race, or use of inhaled corticosteroids.1 2 12

Poor-metabolizers of CYP2D6 substrates: No clinically important effect on umeclidinium exposure observed following repeated administration of 500 mcg (8 times usual recommended dosage) compared with healthy ultrarapid, extensive, and intermediate metabolizers.1 2

Stability

Storage

Oral Inhalation

20–25°C (may be exposed to 15–30°C) in a dry place away from direct heat or sunlight.1 2

Keep inhaler in sealed tray until immediately before use.1 2 Discard inhaler after every blister used or 6 weeks after removal of inhaler from foil tray, whichever comes first.1 2

Actions

  • Synthetic quaternary ammonium antimuscarinic agent.1 2 3 4 5 6 7

  • Long-acting, orally inhaled bronchodilator.1 2 3 4 5 6 7 8 10

  • Nonselective competitive antagonist at muscarinic (M1–M5) receptors.1 2 6 7 8

  • Competitively and reversibly inhibits the actions of acetylcholine and other cholinergic stimuli at M3 receptors in respiratory tract smooth muscle leading to bronchodilation.1 2 6 7 8

Advice to Patients

  • When used in fixed combination with vilanterol, importance of informing patients of important cautionary information about vilanterol.2

  • Provide copy of the manufacturer’s patient information (medication guide) to all patients each time drug is dispensed.1 2 Importance of instructing patients to read the patient information prior to initiation of therapy and each time prescription is refilled.1 2

  • Importance of informing clinician of any history of hypersensitivity reactions to umeclidinium or severe allergy to milk proteins.1 2

  • Importance of adequate understanding of proper storage and inhalation techniques, including use of the inhalation delivery systems.1 2

  • Importance of advising patients that if a dose is missed, to take the dose as soon as it is remembered; importance of not doubling the dose and of not taking more than one dose in a 24-hour period.1 2

  • Importance of all patients being provided with and instructed in the use of a short-acting, inhaled β2-adrenergic agonist as supplemental therapy for acute symptoms.1 2

  • Importance of contacting a clinician immediately if symptoms worsen or if the short-acting β2-agonist becomes less effective or more inhalations than usual are required to relieve symptoms.1 2

  • Importance of patients not discontinuing therapy without medical supervision, since symptoms may recur after discontinuance.1 2

  • Importance of not using umeclidinium to relieve acute symptoms or exacerbations of COPD.1 2

  • Importance of discontinuing umeclidinium and informing a clinician if paradoxical bronchospasm occurs.1 2

  • Importance of informing a clinician immediately if eye pain or discomfort, blurred vision, visual halos, or colored images in association with red eyes from conjunctival congestion or corneal edema occur.1 2

  • Importance of informing a clinician immediately if urinary retention or dysuria occurs.1 2

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (e.g., eye drops) and herbal supplements, as well as any concomitant illnesses (e.g., urinary retention, enlarged prostate, angle-closure glaucoma).1 2

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 2

  • Importance of informing patients of other important precautionary information.1 2 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Umeclidinium Bromide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral Inhalation

Powder for inhalation

62.5 mcg (of umeclidinium) per inhalation

Incruse Ellipta

GlaxoSmithKline

Umeclidinium Bromide Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral Inhalation

Powder for inhalation

62.5 mcg (of umeclidinium) with Vilanterol Trifenatate 25 mcg (of vilanterol) per inhalation

Anoro Ellipta

GlaxoSmithKline

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

References

1. GlaxoSmithKline. Incruse Ellipta (umeclidinium inhalation powder) prescribing information. Research Triangle Park, NC; 2014 Jun.

2. GlaxoSmithKline. Anoro Ellipta (umeclidinium and vilanterol inhalation powder) prescribing information. Research Triangle Park, NC; 2014 May.

3. Trivedi R, Richard N, Mehta R et al. Umeclidinium in patients with COPD: a randomised, placebo-controlled study. Eur Respir J. 2014; 43:72-81. [PubMed 23949963]

4. Donohue JF, Maleki-Yazdi MR, Kilbride S et al. Efficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPD. Respir Med. 2013; 107:1538-46. [PubMed 23830094]

5. . Umeclidinium (Incruse Ellipta) for COPD. Med Lett Drugs Ther. 2015; 57:63-4. [PubMed 25897550]

6. Segreti A, Calzetta L, Rogliani P et al. Umeclidinium for the treatment of chronic obstructive pulmonary disease. Expert Rev Respir Med. 2014; 8:665-71. [PubMed 25312239]

7. Salmon M, Luttmann MA, Foley JJ et al. Pharmacological characterization of GSK573719 (umeclidinium): a novel, long-acting, inhaled antagonist of the muscarinic cholinergic receptors for treatment of pulmonary diseases. J Pharmacol Exp Ther. 2013; 345:260-70. [PubMed 23435542]

8. Scott LJ, Hair P. Umeclidinium/Vilanterol: first global approval. Drugs. 2014; 74:389-95. [PubMed 24532124]

9. Kelleher D, Tombs L, Preece A et al. A randomized, placebo- and moxifloxacin-controlled thorough QT study of umeclidinium monotherapy and umeclidinium/vilanterol combination in healthy subjects. Pulm Pharmacol Ther. 2014; 29:49-57. [PubMed 25020273]

10. . Anoro Ellipta: an inhaled umeclidinium/vilanterol combination for COPD. Med Lett Drugs Ther. 2014; 56:30-1. [PubMed 24736248]

11. Mehta R, Hardes K, Brealey N et al. Effect of severe renal impairment on umeclidinium and umeclidinium/vilanterol pharmacokinetics and safety: a single-blind, nonrandomized study. Int J Chron Obstruct Pulmon Dis. 2015; 10:15-23. [PubMed 25565796]

12. Goyal N, Beerahee M, Kalberg C et al. Population pharmacokinetics of inhaled umeclidinium and vilanterol in patients with chronic obstructive pulmonary disease. Clin Pharmacokinet. 2014; 53:637-48. [PubMed 24756395]

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