Umeclidinium and Vilanterol (Oral Inhalation) (Monograph)

Brand name: Anoro Ellipta (combination)
Drug class: Antimuscarinics/Antispasmodics

Introduction

Fixed-combination preparation containing a long-acting muscarinic antagonist (umeclidinium) and a long-acting β₂-adrenergic agonist (vilanterol).

Uses for Umeclidinium and Vilanterol (Oral Inhalation)

COPD

Maintenance treatment of COPD.

Not indicated for relief of acute bronchospasm. A short-acting inhaled β₂-adrenergic agonist should be used to treat acute symptoms.

Inhaled bronchodilators such as long-acting β₂-adrenergic agonists (LABA) and long-acting muscarinic antagonists (LAMA) are central to symptom management in COPD. Both LABAs and LAMAs have been shown to improve lung function, dyspnea, health status, and exacerbation rates, but LAMAs have a greater effect on preventing exacerbations and reduce hospitalizations.

Combination therapy with an inhaled LAMA/LABA or an inhaled corticosteroid/LABA can be used in patients who are inadequately controlled on monotherapy.

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guideline states that combination therapy with a LABA and LAMA increases FEV₁ and reduces symptoms and exacerbations compared to monotherapy.

Umeclidinium and Vilanterol (Oral Inhalation) Dosage and Administration

General

Patient Monitoring

• Failure to respond to a previously effective dosage of umeclidinium/vilanterol or to a supplemental short-acting, inhaled β₂-agonist (e.g., increased need for additional short-acting, inhaled β₂-agonists) may indicate deterioration of COPD. In this setting, immediately reevaluate the patient and treatment regimen.

• Monitor patients for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination), especially those with prostatic hyperplasia or bladder-neck obstruction.

• Monitor patients for signs and symptoms of acute narrow angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema).

Administration

Oral Inhalation

Administer by oral inhalation once daily using a disposable inhaler that delivers powdered umeclidinium and vilanterol in fixed combination from foil-wrapped blisters.

Administer at the same time every day and do not use more than once every 24 hours. If a dose is missed, take it as soon as remembered. Take the next dose at the usual time. Do not take 2 doses at the same time.

Prior to use, store in the original foil tray at room temperature in a dry place away from direct heat and sunlight; remove from tray immediately before initial use.

Document the date the tray is opened and the discard date (6 weeks after opening) on the inhaler label.

The number of doses remaining in the inhaler is displayed on the counter.

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

Do not administer another dose even if delivery of dose not perceived.

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

Dosage

Dosage of umeclidinium bromide is expressed in terms of umeclidinium; dosage of vilanterol trifenatate Is expressed in terms of vilanterol.

Umeclidinium/vilanterol is supplied with a disposable plastic inhaler containing 2 foil strips, each with 30 blisters (or 7 blisters in the institutional package). One strip contains umeclidinium (62.5 mcg per blister), and the other strip contains vilanterol (25 mcg per blister).

A blister from each strip is used to create 1 dose.

Precise amount of drug delivered to the lungs depends on patient factors such as inspiratory flow.

Adults

COPD

Umeclidinium/Vilanterol Fixed-combination Therapy

Oral Inhalation

62.5 mcg of umeclidinium and 25 mcg of vilanterol (1 inhalation) once daily. Do not use more than 1 time every 24 hours.

Special Populations

Hepatic Impairment

No dosage adjustment required in patients with moderate hepatic impairment. Not studied in patients with severe hepatic impairment.

Renal Impairment

No dosage adjustment required.

Geriatric Patients

No dosage adjustment required.

Related/similar drugs

Breztri Aerosphere, prednisone, Symbicort, Ventolin HFA, Ventolin, Breo Ellipta, Spiriva

Cautions for Umeclidinium and Vilanterol (Oral Inhalation)

Contraindications

• Severe hypersensitivity to milk proteins or known hypersensitivity to umeclidinium, vilanterol, or any ingredients in the formulation.

• Use of long-acting β₂-adrenergic agonists (LABA), including vilanterol, without an inhaled corticosteroid is contraindicated in patients with asthma. Umeclidinium/vilanterol is not indicated for the treatment of asthma.

Warnings/Precautions

Serious Asthma-related Events

Safety and effectiveness in patients with asthma not established; not indicated for the treatment of asthma.

Increased risk of asthma-related death reported with long-acting β₂-adrenergic agonists (LABA) when used as monotherapy. However, when LABA used in fixed combination with inhaled corticosteroids, data from large clinical trials do not show a significant increase in risk of serious asthma-related events (hospitalizations, intubations, death) compared with use of inhaled corticosteroids alone.

Available data do not suggest an increased risk of death with use of LABA in patients with COPD.

Deterioration of Disease and Acute Episodes

Do not initiate in patients with rapidly deteriorating or potentially life-threatening episodes of COPD. Not studied in this setting.

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

When initiating therapy, discontinue regular use of short-acting oral or inhaled β₂-agonists and use only for relief of acute COPD symptoms.

Failure to respond to a previously effective dosage of umeclidinium/vilanterol or to a supplemental short-acting, inhaled β₂-agonist may indicate worsening COPD. Immediately reevaluate the patient and treatment regimen. Do not increase the daily dose of umeclidinium/vilanterol in this situation.

Excessive Use and Use With Other Long-acting β2-Adrenergic Agonists

Clinically important cardiovascular effects and fatalities reported with excessive use of inhaled sympathomimetic drugs.

Do not use more frequently or at dosages higher than recommended or concomitantly with other preparations containing LABA, since overdosage may result.

Drug Interactions with Strong Cytochrome P-450 3A4 Inhibitors

Use caution when considering concomitant administration of umeclidinium/vilanterol with ketoconazole and other strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole); increased adverse cardiovascular effects may occur.

Paradoxical Bronchospasm

As with other inhaled drugs, patients receiving umeclidinium/vilanterol may develop paradoxical bronchospasm, which may be life-threatening.

If paradoxical bronchospasm occurs, treat patient immediately with an inhaled, short-acting bronchodilator. Discontinue umeclidinium/vilanterol immediately and institute alternative therapy.

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., anaphylaxis, angioedema, rash, urticaria) may occur. Discontinue if such reactions occur.

Anaphylactic reactions reported in patients with severe milk protein allergy following oral inhalation of powder products containing lactose; contraindicated in patients with severe hypersensitivity to milk proteins.

Cardiovascular Effects

Possible increases in pulse rate, systolic or diastolic blood pressure, or cardiac arrhythmias (e.g., supraventricular tachycardia, extrasystoles) with β₂-agonists, including vilanterol. If such effects occur, discontinuance of umeclidinium/vilanterol therapy may be required.

ECG changes (e.g., flattening of T wave, prolongation of QT_c interval, ST-segment depression) reported with β₂-agonists; clinical importance unknown. Fatalities reported with excessive use of inhaled sympathomimetic drugs.

Use umeclidinium/vilanterol with caution in patients with cardiovascular disorders (e.g., coronary insufficiency, cardiac arrhythmias, hypertension).

Comorbid Conditions

Use with caution in patients with convulsive disorders or thyrotoxicosis, and those who are unusually responsive to sympathomimetic amines.

IV albuterol (IV preparation not commercially available in the US) reported to aggravate preexisting diabetes mellitus and ketoacidosis.

Worsening of Narrow-angle Glaucoma

Use caution in patients with narrow-angle glaucoma.

Monitor patients for signs and symptoms of acute narrow angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a healthcare provider immediately if any of these signs or symptoms develop.

Worsening of Urinary Retention

Use caution in patients with urinary retention.

Monitor patients for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination), especially in those with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to consult a healthcare provider immediately if any of these signs or symptoms develop.

Hypokalemia and Hyperglycemia

Increased blood glucose levels reported in patients receiving beta-adrenergic agonist therapies.

Clinically important hypokalemia, which may result in adverse cardiovascular effects, may occur in some patients receiving β₂-adrenergic agonists. Usually transient and does not require supplementation.

Changes in serum glucose or potassium concentrations not observed in patients with COPD receiving umeclidinium/vilanterol in clinical trials of 6 months’ duration.

Specific Populations

Pregnancy

Insufficient data in pregnant women. No adverse developmental effects observed in animal reproduction studies.

Use during late gestation and labor only if potential benefit justifies potential risks related to beta-agonists interfering with uterine contractility.

Lactation

Not known whether umeclidinium or vilanterol is distributed into milk or whether the drugs can affect milk production or the breast-fed child; presence in maternal milk is suggested by animal studies.

Consider the developmental and health benefits of breast-feeding along with the mother’s clinical need for umeclidinium/vilanterol and any potential adverse effects on the breast-fed child from the drugs or underlying maternal condition.

Pediatric Use

Safety and effectiveness not established in pediatric patients; not indicated in this patient population.

Geriatric Use

No overall differences in safety, efficacy, or response observed between patients ≥65 years of age and younger patients. Although dosage adjustment not necessary, greater sensitivity in some older individuals cannot be ruled out.

Hepatic Impairment

In patients with moderate hepatic impairment (Child-Pugh score 7–9), no relevant increases in peak plasma concentrations or AUC of umeclidinium or vilanterol observed. No evidence of altered protein binding in such patients.

Patients with severe hepatic impairment not evaluated.

Renal Impairment

Systemic exposure to either umeclidinium or vilanterol not increased in patients with severe renal impairment (Cl_cr <30 mL/minute). No dosage adjustment required in patients with renal impairment.

Common Adverse Effects

Common adverse reactions (≥1%): pharyngitis, sinusitis, lower respiratory tract infection, constipation, diarrhea, pain in extremity, muscle spasms, neck pain, chest pain.

Drug Interactions

Umeclidinium is metabolized primarily by CYP2D6. Vilanterol is a substrate of CYP3A4.

Vilanterol and umeclidinium are both substrates of P-glycoprotein (P-gp).

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Concomitant use of umeclidinium/vilanterol with strong inhibitors of CYP3A4 (e.g., clarithromycin, conivaptan, ketoconazole, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, troleandomycin, voriconazole) is expected to result in increased systemic exposure to vilanterol. Use concomitantly with caution.

Drugs that Prolong the QT Interval

Potential pharmacologic interaction (increased risk of ventricular arrhythmias and possible potentiation of vilanterol effects on cardiovascular system). Use extreme caution during concomitant therapy or within 2 weeks of discontinuance of such agents.

Specific Drugs

Umeclidinium and Vilanterol (Oral Inhalation) Pharmacokinetics

Absorption

Bioavailability

Umeclidinium: Exhibits linear pharmacokinetics over dose range of 62.5–500 mcg. Steady-state plasma concentrations achieved within 14 days, with 1.8-fold accumulation, following repeated once-daily inhalation. Peak plasma concentrations are reached within 5–15 minutes following oral inhalation.

Vilanterol: Exhibits linear pharmacokinetics over dose range of 25–100 mcg. Steady-state plasma concentrations achieved within 14 days of repeated once-daily inhalation; up to 1.7-fold accumulation observed. Peak plasma concentrations are reached within 5–15 minutes following oral inhalation.

Distribution

Plasma Protein Binding

Umeclidinium: Approximately 89%.

Vilanterol: Approximately 94%.

Elimination

Metabolism

Umeclidinium is metabolized primarily by CYP2D6. Principal routes of metabolism are oxidation via hydroxylation and O-dealkylation followed by conjugation (e.g., glucuronidation).

Vilanterol is extensively metabolized, principally by CYP3A4, to metabolites with substantially reduced β₁- and β₂-agonist activity compared with the parent drug.

Elimination Route

Umeclidinium undergoes biliary elimination (58 and 22% of a radiolabeled IV dose is recovered in feces and urine, respectively). Following oral administration, 92% and less than 1% of a radiolabeled dose of umeclidinium is excreted in feces and urine, respectively.

Following oral administration, approximately 70 and 30% of a radiolabeled dose of vilanterol is excreted in urine and feces, respectively, mostly as metabolites.

Half-life

Effective half-life following once daily oral dosing of umeclidinium is 11 hours.

Effective half-life following once daily inhalation dosing of vilanterol is 11 hours.

Special Populations

Pharmacogenomics: Following repeated administration of umeclidinium, no clinically important effect was observed on exposure in poor CYP2D6 metabolizers compared with ultrarapid, extensive, and intermediate metabolizers.

No effects of age, gender, weight, race, and use of inhaled corticosteroids on umeclidinium or vilanterol pharmacokinetics.

Stability

Storage

Oral Inhalation

20–25°C (excursions permitted to 15–30°C); store in a dry place away from direct heat or sunlight.

Keep inhaler in sealed tray until immediately before use. Discard 6 weeks after opening foil tray or when all blisters have been used, whichever comes first.

Actions

• Contains umeclidinium and vilanterol.

• Umeclidinium, a synthetic quaternary ammonium antimuscarinic agent, is a long-acting, orally inhaled bronchodilator. Nonselective competitive antagonist at muscarinic (M1–M5) receptors.

• Vilanterol, a synthetic sympathomimetic amine, is a relatively selective, long-acting β₂-adrenergic agonist.

Advice to Patients

• Umeclidinium/vilanterol is not indicated for use in the treatment of asthma. Inform patients that monotherapy with long-acting β₂-adrenergic agonists (LABA) increases the risk of asthma-related death.

• Inform patients that umeclidinium/vilanterol is not meant to relieve acute symptoms of COPD and extra doses should not be used for that purpose. Advise patients to treat acute symptoms with an inhaled, short-acting β₂-adrenergic agonist such as albuterol. Provide patients with such medication and instruct them in how it should be used.

• Instruct patients to seek medical attention immediately if they experience decreasing effectiveness of inhaled, short-acting β₂-adrenergic agonists, need for more inhalations than usual of inhaled, short-acting β₂-adrenergic agonists, or a significant decrease in lung function as outlined by the physician.

• Inform patients that they should not stop taking umeclidinium/vilanterol without physician/provider guidance since symptoms may recur after discontinuation.

• Instruct patients not to use other LABAs for COPD.

• As with other inhaled medicines, umeclidinium/vilanterol can cause paradoxical bronchospasm. If paradoxical bronchospasm occurs, instruct patients to discontinue umeclidinium/vilanterol and contact their healthcare provider right away.

• Inform patients of adverse effects associated with β₂-adrenergic agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.

• Instruct patients to be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately if any of these signs or symptoms develop.

• Instruct patients to be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination). Instruct patients to consult a physician immediately if any of these signs or symptoms develop.

• Advise women to inform their clinicians if they are or plan to become pregnant or plan to breast-feed.

• Advise patients to inform their clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Inform patients of other important precautionary information. (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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.

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