DRUG INTERACTIIONS

• Strong cytochrome P450 3A4 inhibitors (e.g., ketoconazole): Use with caution. May cause systemic corticosteroid and cardiovascular effects. 

 • Monoamine oxidase inhibitors and tricyclic antidepressants: Use with extreme caution. May potentiate effect of vilanterol on vascular system.

 • Beta-blockers: Use with caution. May block bronchodilatory effects of beta-agonists and produce severe bronchospasm.                                                                                                                                                                                                                                • Diuretics: Use with caution.       

• Electrocardiographic changes and/or hypokalemia associated with non–potassium-sparing diuretics may worsen with concomitant beta-agonists.

These highlights do not include all the information needed to use                                      BREO ELLIPTA safely and effectively. See full prescribing information for BREO ELLIPTA.

BREO ELLIPTA (fluticasone furoate and vilanterol inhalation powder) FOR ORAL INHALATION USE

Initial U.S. Approval: 2013

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

• 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.     

 • 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.

INDICATIONS AND USAGE

BREO ELLIPTA is a combination of fluticasone furoate, an inhaled corticosteroid (ICS), and vilanterol, a long-acting beta2-adrenergic agonist (LABA), indicated for long-term, once-daily, maintenance treatment of airflow obstruction and for reducing exacerbations in patients with chronic obstructive pulmonary disease (COPD).

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

DOSAGE AND ADMINISTRATION   

 • For oral inhalation only.                                                                                                     • Maintenance treatment of COPD:                                                                                       inhalation of BREO ELLIPTA 100 mcg/25 mcg once daily.

DOSAGE FORMS AND STRENGTHS- 

 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.

ADVERSE REACTIONS

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

CONTRAINDICATIONS-                                                                                                       Severe hypersensitivity to milk proteins or any ingredients.

WARNINGS AND PRECAUTIONS

• LABA increase the risk of asthma-related death.     

 • Do not initiate in acutely deteriorating COPD or to treat acute symptoms.     

• Do not use in combination with an additional medicine containing LABA because of         risk of overdose.   

• 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. 

 • Increased risk of pneumonia in patients with COPD taking BREO ELLIPTA. Monitor         patients for signs and symptoms of pneumonia.                                                             

 • 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.         

  • Risk of impaired adrenal function when transferring from systemic corticosteroids.            Taper patients slowly from systemic corticosteroids if transferring to BREO ELLIPTA.

 • Hypercorticism and adrenal suppression may occur with very high dosages or at the      regular dosage n susceptible individuals. If such changes occur, discontinue BREO         ELLIPTA slowly.       

 • If paradoxical bronchospasm occurs, discontinue BREO ELLIPTA and institute                alternative therapy.   

  • Use with caution in patients with cardiovascular disorders because of beta-adrenergic stimulation.

• Assess for decrease in bone mineral density initially and periodically thereafter.

• Close monitoring for glaucoma and cataracts is warranted.

• Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus,  and ketoacidosis.                                                                                                                                                                                                                                              • Be alert to hypokalemia and hyperglycemia.    

PATIENT INFORMATION AND MEDICATION GUIDE

 Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

1. Asthma-Related Death-                                                                                                  Patients should be informed that LABA, such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death. BREO ELLIPTA is not indicated for the treatment of asthma.

2. Not for Acute Symptoms-                                                                                                                             BREO ELLIPTA is not meant to relieve acute symptoms of COPD and extra doses should not be used for that purpose. Acute symptoms should be treated with a rescue inhaler such as albuterol. The physician should provide the patient with such medicine and instruct the patient in how it should be used.

Patients should be instructed to notify their physicians immediately if they experience any of the following:                                                                                                              • Symptoms get worse                                                                                                        • Need for more inhalations than usual of their rescue inhaler                                             • Significant decrease in lung function as outlined by the physician Patients should not stop therapy with BREO ELLIPTA without physician/provider guidance since symptoms may recur after discontinuation.

3. Do Not Use Additional Long-Acting Beta2-Agonists When patients are prescribed BREO ELLIPTA, other medicines containing a LABA should not be used.

4. Risks Associated With Corticosteroid Therapy Local Effects:                                  Patients should be advised that localized infections with Candida albicans occurred in the mouth and pharynx in some patients.

If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing therapy with BREO ELLIPTA, but at times therapy with BREO ELLIPTA may need to be temporarily interrupted under close medical supervision.                                                                                       Rinsing the mouth without swallowing after inhalation is advised to help reduce the risk of thrush.

 Pneumonia:                                                                                                                        Patients with COPD who have received BREO ELLIPTA have a higher risk of pneumonia and should be instructed to contact their healthcare providers if they develop symptoms of pneumonia (e.g., fever, chills, change in sputum color, increase in breathing problems).

Immunosuppression:                                                                                                         Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physicians without delay. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex.

 Hypercorticism and Adrenal Suppression:                                                                                              Patients should be advised that BREO ELLIPTA may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, patients should be instructed that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids.

 Reduction in Bone Mineral Density:                                                                                 Patients who are at an increased risk for decreased BMD should be advised that the use of corticosteroids may pose an additional risk.    

Ocular Effects:                                                                                                                      Long-term use of inhaled corticosteroids may increase the risk of some eye problems (cataracts or glaucoma); regular eye examinations should be considered.

5. Risks Associated With Beta-Agonist Therapy-                                                           Patients should be informed of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.

6. Hypersensitivity Reactions, Including Anaphylaxis-                                                  Advise patients that hypersensitivity reactions (e.g., anaphylaxis, angioedema, rash, urticaria) may occur after administration of BREO ELLIPTA.                                                                                                                                                                                     Instruct patients to discontinue BREO ELLIPTA if such reactions occur.                                                                                                                                                                There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder medications containing lactose; therefore, patients with severe milk protein allergy should not use BREO ELLIPTA.

BREO and ELLIPTA are registered trademarks of the GSK group of companies.      BREO ELLIPTA was developed in collaboration with .                                                  GlaxoSmithKline Research Triangle Park, NC 27709                                                                                  

CLINICAL PHARMACOLOGY

 1. Mechanism of Action-                                                                                                    BREO ELLIPTA: Since BREO ELLIPTA contains both fluticasone furoate and vilanterol, the mechanisms of action described below for the individual components apply to BREO ELLIPTA.

 These drugs represent 2 different classes of medications (a synthetic corticosteroid and a LABA) that have different effects on clinical and physiological indices.

 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.

Repeated once-daily inhalation administration, steady state of fluticasone furoate and vilanterol plasma concentrations was achieved after 6 days, and the accumulation was up to 2.6-fold for fluticasone furoate and 2.4-fold for vilanterol as compared with single dose.

Absorption:                                                                                                                        Fluticasone Furoate: Fluticasone furoate plasma levels may not predict therapeutic effect. Peak plasma concentrations are reached within 0.5 to 1 hour.

Absolute bioavailability of fluticasone furoate when administrated by inhalation was 15.2%, primarily due to absorption of the inhaled portion of the dose delivered to the lung.

Oral bioavailability from the swallowed portion of the dose is low (approximately 1.3%) due to extensive first-pass metabolism. Systemic exposure (AUC) in subjects with COPD was 46% lower than observed in healthy subjects.

Vilanterol: Vilanterol plasma levels may not predict therapeutic effect. Peak plasma concentrations are reached within 10 minutes following inhalation. Absolute bioavailability of vilanterol when administrated by inhalation was 27.3%, primarily due to absorption of the inhaled portion of the dose delivered to the lung.                                    

Oral bioavailability from the swallowed portion of the dose of vilanterol is low (less than 2%) due to extensive first-pass metabolism. Systemic exposure in subjects with COPD was 24% higher than observed in healthy subjects.

Distribution:                                                                                                                         Fluticasone Furoate: Following intravenous administration to healthy  subjects, the mean volume of distribution at steady state was 661 L. Binding of fluticasone furoate to human plasma proteins was high (99.6%).

 Vilanterol: Following intravenous administration to healthy subjects, the mean volume of distribution at steady state was 165 L. Binding of vilanterol to human plasma proteins was 93.9%.

 Metabolism:                                                                                                                        Fluticasone Furoate: Fluticasone furoate is cleared from systemic circulation principally by hepatic metabolism via CYP3A4 to metabolites with significantly reduced corticosteroid activity. There was no in vivo evidence for cleavage of the furoate moiety resulting in the formation of fluticasone.

Vilanterol: Vilanterol is mainly metabolized, principally via CYP3A4, to a range of metabolites with significantly reduced ß1-and ß2-agonist activity.

Elimination:                                                                                                     Fluticasone Furoate: Fluticasone furoate and its metabolites are eliminated primarily in the feces, accounting for approximately 101% and 90% of the orally and intravenously administered dose, respectively.                                                                                                                                                      Urinary excretion accounted for approximately 1% and 2% of the orally and intravenously administered doses, respectively. Following repeat dose inhaled administration, the plasma elimination phase half-life averaged 24 hours.

Vilanterol: Following oral administration, vilanterol was eliminated mainly by metabolism followed by excretion of metabolites in urine and feces (approximately 70% and 30% of the recovered radioactive dose, respectively). The effective half-life for accumulation of vilanterol, as determined from inhalation administration of multiple doses of vilanterol 25 mcg, is 21.3 hours in subjects with COPD.

USE IN SPECIFIC POPULATIONS

 1 Pregnancy Teratogenic Effects:                                                                                     Pregnancy Category C. -There are no adequate and well-controlled trials with BREO ELLIPTA in pregnant women. Corticosteroids and beta2-agonists have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels.

Because animal studies are not always predictive of human response, BREO ELLIPTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Women should be advised to contact their physicians if they become pregnant while taking BREO ELLIPTA.

2 Labor and Delivery -                                                                                                        There are no adequate and well-controlled human trials that have investigated the effects of BREO ELLIPTA during labor and delivery.  

Because beta-agonists may potentially interfere with uterine contractility, BREO ELLIPTA should be used during labor only if the potential benefit justifies the potential risk.

3. Nursing Mothers-                                                                                                            It is not known whether fluticasone furoate or vilanterol are excreted in human breast milk. However, other corticosteroids and beta2-agonists have been detected in human milk. Since there are no data from controlled trials on the use of BREO ELLIPTA by nursing mothers, caution should be exercised when it is administered to a nursing woman.

 4. Pediatric Use-                                                                                                                 BREO ELLIPTA is not indicated for use in children. The safety and efficacy in pediatric patients have not been established.

5. Geriatric Use-                                                                                                                   Based on available data, no adjustment of the dosage of BREO ELLIPTA in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out.                                                                                                                            Clinical trials of BREO ELLIPTA for COPD included 2,508 subjects aged 65 and older and 564 subjects aged 75 and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects.

6. Hepatic Impairment -                                                                                                       Fluticasone furoate systemic exposure increased by up to 3-fold in subjects with hepatic impairment compared with healthy subjects.

Hepatic impairment had no effect on vilanterol systemic exposure. Use BREO ELLIPTA with caution in patients with moderate or severe hepatic impairment. Monitor patients for corticosteroid-related side effects

7. Renal Impairment -                                                                                                         There were no significant increases in either fluticasone furoate or vilanterol exposure in subjects with severe renal impairment (CrCl<30 mL/min) compared with healthy subjects. No dosage adjustment is required in patients with renal impairment

OVERDOSAGE-                                                                                                                  No human overdosage data has been reported for BREO ELLIPTA. BREO ELLIPTA contains both fluticasone furoate and vilanterol; therefore, the risks associated with overdosage for the individual components described below apply to BREO ELLIPTA.

1. Fluticasone Furoate -Because of low systemic bioavailability (15.2%) and an absence of acute drug-related systemic findings in clinical trials, overdosage of fluticasone furoate is unlikely to require any treatment other than observation.                                   If used at excessive doses for prolonged periods, systemic effects such as hypercorticism may occur