BREO™ ELLIPTA™ (fluticasone furoate and vilanterol inhalation powder)

WARNING: ASTHMA-RELATED DEATH
See full prescribing information for complete boxed warning.

1. Long-acting beta2-adrenergic agonists (LABA), such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death. A placebo-controlled trial with another LABA (salmeterol) showed an increase in asthma-related deaths in subjects receiving salmeterol. This finding with salmeterol is considered a class effect of all LABA, including vilanterol.
2. The safety and efficacy of BREO ELLIPTA in patients with asthma have not been established. BREO ELLIPTA is not indicated for the treatment of asthma.

Under standardized in vitro test conditions, BREO ELLIPTA delivers 92 mcg of fluticasone furoate and 22 mcg of vilanterol per blister when tested at a flow rate of 60 L/min for 4 seconds.

In adult subjects with obstructive lung disease and severely compromised lung function (COPD with FEV1/FVC less than 70% and FEV1 less than 30% predicted or FEV1 less than 50% predicted plus chronic respiratory failure), mean peak inspiratory flow through the ELLIPTA inhaler was 66.5 L/min (range: 43.5 to 81.0 L/min).

The actual amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow profile.

Fluticasone Furoate: Fluticasone furoate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. Fluticasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is approximately 29.9 times that of dexamethasone and 1.7 times that of fluticasone propionate. The clinical relevance of these in vitro findings is unknown. The precise mechanism through which fluticasone furoate affects COPD symptoms is not known. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. Specific effects of fluticasone furoate demonstrated in in vitro and in vivo models included activation of the glucocorticoid response element, inhibition of pro-inflammatory transcription factors such as NFkB, and inhibition of antigen-induced lung eosinophilia in sensitized rats.

Vilanterol: Vilanterol is a LABA. In vitro tests have shown the functional selectivity of vilanterol was similar to salmeterol. The clinical relevance of this in vitro finding is unknown.

Although beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the heart, there are also beta2-receptors in the human heart comprising 10% to 50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta2-agonists may have cardiac effects.

The pharmacologic effects of beta2-adrenoceptor agonist drugs, including vilanterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3’,5’-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

Important limitations: Not indicated for relief of acute bronchospasm or for treatment of asthma.

WARNINGS AND PRECAUTIONS

1. LABA increase the risk of asthma-related death.
2. Do not initiate in acutely deteriorating COPD or to treat acute symptoms.
3. Do not use in combination with an additional medicine containing LABA because of risk of overdose.
4. Candida albicans infection of the mouth and pharynx may occur. Monitor patients periodically. Advise the patient to rinse his/her mouth without swallowing after inhalation to help reduce the risk.
5. Increased risk of pneumonia in patients with COPD taking BREO ELLIPTA. Monitor patients for signs and symptoms of pneumonia.
6. Potential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infection; ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients.
7. Risk of impaired adrenal function when transferring from systemic corticosteroids. Taper patients slowly from systemic corticosteroids if transferring to BREO ELLIPTA.
8. Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue BREO ELLIPTA slowly.
9. If paradoxical bronchospasm occurs, discontinue BREO ELLIPTA and institute alternative therapy.
10. Use with caution in patients with cardiovascular disorders because of beta-adrenergic stimulation.
11. Assess for decrease in bone mineral density initially and periodically thereafter.
12. Close monitoring for glaucoma and cataracts is warranted.
13. Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis.
14. Be alert to hypokalemia and hyperglycemia.

ADVERSE REACTIONS
Most common adverse reactions (incidence ≥3%) are nasopharyngitis, upper respiratory tract infection, headache, and oral candidiasis.

To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

1. Strong cytochrome P450 3A4 inhibitors (e.g., ketoconazole): Use with caution. May cause systemic corticosteroid and cardiovascular effects.
2. Monoamine oxidase inhibitors and tricyclic antidepressants: Use with extreme caution. May potentiate effect of vilanterol on vascular system.
3. Beta-blockers: Use with caution. May block bronchodilatory effects of beta-agonists and produce severe bronchospasm.
4. Diuretics: Use with caution. Electrocardiographic changes and/or hypokalemia associated with non–potassium-sparing diuretics may worsen with concomitant beta-agonists.

USE IN SPECIFIC POPULATIONS
Hepatic impairment: Fluticasone furoate exposure may increase in patients with moderate or severe impairment. Monitor for systemic corticosteroid effects.

See PACKAGE INSERT for PATIENT COUNSELING INFORMATION and Medication Guide.

BREO ELLIPTA should be taken at the same time every day. Do not use BREO ELLIPTA more than 1 time every 24 hours.

No dosage adjustment is required for geriatric patients, patients with hepatic impairment, or renally impaired patients

Inhalation Powder. Inhaler containing 2 double-foil blister strips of powder formulation for oral inhalation. One strip contains fluticasone furoate 100 mcg per blister and the other contains vilanterol 25 mcg per blister.

©2013, GlaxoSmithKline. All rights reserved.
Revised: May 2013. Accessed: Jan 2014