Vilanterol

Brand name: Breo Ellipta (combination)
Drug class: Selective beta-2-Adrenergic Agonists
VA class: RE102
Chemical name: α,α-Diphenylbenzeneacetic acid compd. with (α1R)-α1-[[[6-[2-[(2,6-dichlorophenyl)methoxy]ethoxy]hexyl]amino]methyl]-4-hydroxy-1,3-benzenedimethanol (1:1)
Molecular formula: C₂₄H₃₃Cl₂NO₅•C₂₀H₁₆O₂
CAS number: 503070-58-4

Introduction

Bronchodilator; a relatively selective, long-acting β₂-adrenergic agonist.

Uses for Vilanterol

Bronchospasm in COPD

Vilanterol/fluticasone or vilanterol/umeclidinium fixed-combination therapy: Long-term maintenance treatment of airflow obstruction associated with COPD, including chronic bronchitis and emphysema.

Vilanterol/fluticasone fixed-combination therapy: Reduction of COPD exacerbations in patients with a history of exacerbations.

Vilanterol/fluticasone or vilanterol/umeclidinium fixed-combination therapy: Not indicated for treatment of acute bronchospasm (i.e., as rescue therapy for treatment of acute episodes of bronchospasm).

Other Uses

Vilanterol/umeclidinium fixed-combination therapy: Not indicated for treatment of asthma^{† [off-label]}; safety and efficacy in asthma not established.

Vilanterol Dosage and Administration

Administration

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

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

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

Oral Inhalation

Oral Inhalation Administration

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

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

Before inhaling dose, exhale completely; do not exhale into mouthpiece of inhaler. Place mouthpiece between lips and inhale deeply through inhaler with a steady, even breath; do not inhale through nose. Do not block air vent on inhaler during inhalation. 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. After dose is administered, close inhaler by sliding cover over mouthpiece as far as possible.

After inhalation of vilanterol/fluticasone in fixed combination, rinse mouth with water without swallowing.

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

Dosage

Available as vilanterol trifenatate; dosage expressed in terms of vilanterol.

Each foil-wrapped blister in the Breo Ellipta inhaler device contains 40 mcg of vilanterol trifenatate (equivalent to 25 mcg of vilanterol) or 100 mcg of fluticasone furoate (in separate blisters). In vitro, each pair of blisters from the inhaler delivered 22 mcg of vilanterol and 92 mcg of fluticasone furoate. Precise amount of drug delivered to lungs depends on factors (e.g., patient’s inspiratory flow).

Breo Ellipta inhaler delivers 30 doses (or 14 doses for the sample or institutional package).

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

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

Adults

COPD

Vilanterol/Fluticasone Fixed-combination Therapy

Oral Inhalation

25 mcg of vilanterol and 100 mcg of fluticasone furoate (1 inhalation) once daily.

Vilanterol/Umeclidinium Fixed-combination Therapy

Oral Inhalation

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

Prescribing Limits

Adults

COPD

Vilanterol/Fluticasone Fixed-combination Therapy

Oral Inhalation

Do not administer more than once every 24 hours.

Vilanterol/Umeclidinium Fixed-combination Therapy

Oral Inhalation

Do not administer more than once every 24 hours.

Special Populations

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

Hepatic Impairment

Vilanterol/fluticasone fixed-combination therapy: No dosage adjustment required. (See Absorption under Pharmacokinetics.)

Vilanterol/umeclidinium fixed-combination therapy: No dosage adjustment required in patients with moderate hepatic impairment; not studied in patients with severe hepatic impairment. (See Absorption under Pharmacokinetics.)

Renal Impairment

No dosage adjustment required.

Geriatric Patients

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

Cautions for Vilanterol

Contraindications

• Known hypersensitivity to vilanterol or any ingredient in the formulation.

• Known severe hypersensitivity to milk proteins.

Warnings/Precautions

Use of Fixed Combinations

When used in fixed combination with fluticasone or umeclidinium, consider the cautions, precautions, contraindications, and interactions associated with fluticasone or umeclidinium.

Serious Asthma-related Events

Increased risk of asthma-related death reported with long-acting β₂-adrenergic agonists (e.g., vilanterol) when used as monotherapy. Data from clinical trials also suggest that use of long-acting β₂-adrenergic agonists as monotherapy increases the risk of asthma-related hospitalization in children and adolescents.

Large safety study (Salmeterol Multicenter Asthma Research Trial [SMART]) showed an increase in asthma-related deaths in patients receiving salmeterol. Increased risk of asthma-related death with use of salmeterol as monotherapy considered class effect of long-acting β₂-adrenergic agonists, including vilanterol.

Based on review of 4 clinical trials (3 in adults and adolescents and 1 in children), FDA concluded that there is no clinically important increased risk of serious asthma-related events (i.e., asthma-related hospitalization, intubation, death) associated with the use of fixed-combination therapy with long-acting β₂-adrenergic agonists and inhaled corticosteroids compared with use of inhaled corticosteroids alone for the treatment of asthma. These studies also showed that fixed-combination therapy with long-acting β₂-adrenergic agonists and inhaled corticosteroids was more effective in reducing the incidence of asthma exacerbations compared with use of inhaled corticosteroids alone.

Not known whether death rate is increased in patients with COPD receiving long-acting β₂-adrenergic agonists, including vilanterol.

Deterioration of Disease and Acute Episodes

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

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 vilanterol in fixed combination with fluticasone or umeclidinium or to a supplemental short-acting, inhaled β₂-agonist may indicate worsening COPD. Immediately reevaluate the patient and treatment regimen. Do not use extra or increased dosages in such situations.

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

Possible fatalities and/or adverse cardiovascular effects reported in association with excessive use of inhaled sympathomimetic drugs.

Do not use vilanterol in fixed combination with fluticasone or umeclidinium more frequently or at dosages higher than recommended or concomitantly with other preparations containing long-acting β₂-adrenergic agonists, since overdosage may result.

Do not use vilanterol in fixed combination with fluticasone or umeclidinium with another preparation containing a long-acting β₂-agonist for any reason.

Paradoxical Bronchospasm

Possible acute, life-threatening paradoxical bronchospasm may occur. If paradoxical bronchospasm occurs, immediately treat patient with an inhaled, short-acting bronchodilator; discontinue therapy with vilanterol in fixed combination with fluticasone or umeclidinium; and institute alternative therapy.

Sensitivity Reactions

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

Postmarketing reports of hypersensitivity reactions including anaphylaxis, angioedema, rash, and urticaria when used in fixed combination with fluticasone.

Cardiovascular Effects

Possible clinically important increases in pulse rate, systolic or diastolic BP, and also reports of cardiac arrhythmias; may require discontinuance of drug.

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

Administration of large dosages of orally inhaled vilanterol (4 times the recommended dosage) in combination with fluticasone in healthy individuals resulted in clinically important prolongation of the QT_c interval.

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

No clinically important effects on heart rate, QT_c, or BP observed in patients with COPD receiving vilanterol alone or in combination with fluticasone in clinical trials.

No clinically important effects on cardiac rhythm observed in patients with COPD or on QT_c in healthy individuals receiving vilanterol in combination with umeclidinium bromide in clinical trials.

Metabolic and Electrolyte Effects

Use with caution in patients with thyrotoxicosis.

IV albuterol (IV preparation not commercially available in US) reported to aggravate preexisting diabetes mellitus and ketoacidosis. β₂-Adrenergic agonists may produce transient hyperglycemia in some patients.

Clinically important hypokalemia (usually transient and not requiring supplementation) may occur in some patients receiving β₂-adrenergic agonists; may result in adverse cardiovascular effects. (See Cardiovascular Effects under Cautions.)

Changes in serum glucose or potassium concentrations not observed in patients with COPD receiving vilanterol in fixed combination with fluticasone or umeclidinium in clinical trials of 6 or 12 months’ duration.

Nervous System Effects

Use with caution in patients with seizure disorders and in those unusually responsive to sympathomimetic amines.

Specific Populations

Pregnancy

Category C.

May interfere with uterine contractility. Carefully weigh benefit versus risk in labor.

Lactation

Not known whether distributed into milk; other β₂-adrenergic agonists distributed into human milk. Use caution.

Pediatric Use

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

Geriatric Use

No overall differences in safety and efficacy observed between geriatric and younger adults. No evidence of age-related differences from other clinical experience but increased sensitivity cannot be ruled out. (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Vilanterol exposure not substantially altered in patients with hepatic impairment.

Vilanterol/fluticasone in fixed combination: Use with caution in patients with moderate or severe hepatic impairment. Dosage adjustment not required in patients with hepatic impairment. (See Absorption under Pharmacokinetics.)

Vilanterol/umeclidinium in fixed combination: Dosage adjustment not required in patients with moderate hepatic impairment; not studied in patients with severe hepatic impairment. (See Absorption under Pharmacokinetics.)

Renal Impairment

Vilanterol exposure not substantially increased in patients with severe renal impairment (Cl_cr <30 mL/minute). Dosage adjustment not required.

Common Adverse Effects

Vilanterol/fluticasone in fixed combination: Nasopharyngitis, headache, upper respiratory tract infection, oropharyngeal candidiasis.

Vilanterol/umeclidinium in fixed combination: Pharyngitis, sinusitis, lower respiratory tract infection, constipation, diarrhea, extremity pain, muscle spasms, neck pain, chest pain.

Interactions for Vilanterol

Substrate of CYP3A4 and P-glycoprotein (P-gp).

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

Potent inhibitors of CYP3A4: Potential pharmacokinetic interaction (increased vilanterol concentrations). Use caution with long-term concomitant therapy.

Potent inhibitors of P-gp: Clinically important effects on pharmacokinetics unlikely.

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

Vilanterol Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral inhalation; absolute bioavailability of vilanterol in fixed combination with fluticasone is approximately 27%, principally due to absorption of drug delivered to the lungs.

Oral bioavailability of the swallowed portion of an inhaled dose is low (<2% for vilanterol in fixed combination with fluticasone) because of extensive first-pass metabolism.

Peak plasma concentrations reached within 5–15 minutes following oral inhalation.

Steady-state concentrations achieved after 6 days of once-daily dosing of vilanterol/fluticasone fixed-combination therapy and within 14 days of once-daily dosing of vilanterol/umeclidinium fixed-combination therapy.

Onset

Vilanterol/fluticasone in fixed combination: Median time to onset (defined as a 100-mL increase from baseline in FEV₁) 16 minutes.

Vilanterol/umeclidinium in fixed combination: Median time to onset 27 minutes.

Duration

Bronchodilation generally persists for 24 hours.

Special Populations

Vilanterol/fluticasone in fixed combination: No clinically important changes in peak concentrations or AUC of vilanterol, but increased exposure of fluticasone observed in patients with mild, moderate, or severe hepatic impairment. (See Hepatic Impairment under Cautions.)

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

Distribution

Extent

Not known whether distributed into human milk.

Plasma Protein Binding

Approximately 94%.

Elimination

Metabolism

Extensively metabolized, mainly by CYP3A4.

Elimination Route

Excreted mainly as metabolites in urine (70%) and feces (30%) following oral administration.

Half-life

Effective half-life for vilanterol in fixed combination with fluticasone: 21.3 hours following oral inhalation of multiple doses in patients with COPD.

Effective half-life of vilanterol in fixed combination with umeclidinium: 11–19 hours following oral inhalation of multiple doses in healthy individuals.

Special Populations

No clinically important differences in pharmacokinetics based on age, race, or gender.

Possible increased exposure in patients with severe renal impairment.

Stability

Storage

Oral Inhalation

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

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

Actions

• Synthetic sympathomimetic amine.

• Relatively selective, long-acting β₂-adrenergic agonist.

• Functional selectivity of vilanterol in vitro similar to that of salmeterol; clinical importance unknown.

• Increases concentrations of cyclic adenosine-3′,5′-monophosphate (cAMP), resulting in relaxation of bronchial smooth muscle.

• Appears to inhibit release of mediators of immediate hypersensitivity from cells, especially mast cells.

Advice to Patients

• When used in fixed combination with fluticasone or umeclidinium, importance of informing patients of important cautionary information about fluticasone or umeclidinium.

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

• Importance of informing patients that monotherapy with long-acting β₂-adrenergic agonists (including vilanterol) increases the risk of asthma-related death.

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

• Importance of not using vilanterol to relieve acute COPD symptoms; do not use extra doses for such symptoms.

• Importance of adherence to dosing schedules, including not altering the dose or frequency of use unless otherwise instructed by a clinician.

• 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 or taking more than one dose in a 24-hour period.

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

• Importance of discontinuing regular use of short-acting, inhaled β₂-agonists when initiating vilanterol-containing preparations and using short-acting, inhaled β₂-agonists to relieve acute symptoms.

• Importance of contacting a clinician immediately if symptoms worsen, the short-acting inhaled β₂-agonist becomes less effective or more inhalations than usual are required, or clinically important decrease in lung function occurs.

• Importance of advising patients receiving vilanterol-containing preparations not to use additional vilanterol or other long-acting, inhaled β₂-agonists for any reason.

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

• Importance of informing patients of adverse effects associated with β₂-agonists (e.g., palpitations, chest pain, rapid heart rate, tremor, nervousness).

• Importance of advising patients that hypersensitivity reactions (e.g., anaphylaxis, angioedema, rash, urticaria) may occur following administration of vilanterol in fixed combination with fluticasone and instructing patients to discontinue the drug if such reactions occur.

• Importance of advising patients with severe milk protein allergy to avoid use of vilanterol-containing preparations.

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

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., cardiac disease, hypertension, seizures, thyroid disease, diabetes mellitus, allergies to drugs or food).

• Importance of informing patients of other important precautionary information. (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.

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