1 INDICATIONS AND USAGE Fluticasone Furoate/Vilanterol ELLIPTA is a combination of fluticasone furoate, a corticosteroid, and vilanterol, a long‑acting beta 2 -adrenergic agonist (LABA), indicated for: • the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD).

( 1.1 ) • the maintenance treatment of asthma in patients aged 5 years and older.

( 1.2 ) Limitations of Use: Not indicated for relief of acute bronchospasm.

( 1.3 , 5.2 ) 1.1 Maintenance Treatment of Chronic Obstructive Pulmonary Disease Fluticasone Furoate/Vilanterol ELLIPTA is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD).

1.2 Maintenance Treatment of Asthma Fluticasone Furoate/Vilanterol ELLIPTA is indicated for the maintenance treatment of asthma in patients aged 5 years and older.

1.3 Limitations of Use Fluticasone Furoate/Vilanterol ELLIPTA is NOT indicated for the relief of acute bronchospasm.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: • Serious Asthma-Related Events – Hospitalizations, Intubations, Death [see Warnings and Precautions ( 5.1 )] • Oropharyngeal Candidiasis [see Warnings and Precautions ( 5.4 )] • Pneumonia [see Warnings and Precautions ( 5.5 )] • Immunosuppression and Risk of Infections [see Warnings and Precautions ( 5.6 )] • Hypercorticism and Adrenal Suppression [see Warnings and Precautions ( 5.8 )] • Paradoxical Bronchospasm [see Warnings and Precautions ( 5.10 )] • Cardiovascular Effects [see Warnings and Precautions ( 5.12 )] • Reduction in Bone Mineral Density [see Warnings and Precautions ( 5.13 )] • Growth Effects [see Warnings and Precautions ( 5.14 )] • Glaucoma and Cataracts [see Warnings and Precautions ( 5.15 )] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

• COPD: Most common adverse reactions (incidence ≥3%) are nasopharyngitis, upper respiratory tract infection, headache, oral candidiasis, back pain, pneumonia, bronchitis, sinusitis, cough, oropharyngeal pain, arthralgia, hypertension, influenza, pharyngitis, and pyrexia.

( 6.1 ) • Asthma: Most common adverse reactions (incidence ≥2%) are nasopharyngitis, oral candidiasis, headache, influenza, upper respiratory tract infection, bronchitis, sinusitis, oropharyngeal pain, dysphonia, and cough.

( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Prasco Laboratories at 1-866-525-0688 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience in Chronic Obstructive Pulmonary Disease The safety data described below are based on two 6-month and two 12-month trials and one long-term mortality trial.

In these studies, 5,356 patients with COPD received at least 1 dose of fluticasone furoate/vilanterol ELLIPTA 100/25 mcg.

Adverse reactions observed in other studies of fluticasone furoate/vilanterol ELLIPTA in COPD patients were similar to those observed in these 5 trials.

6-Month Trials The incidence of adverse reactions associated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg in Table 2 is based on 2 placebo-controlled, 6-month clinical trials (Trials 1 and 2; n = 1,224 and n = 1,030, respectively).

Of the 2,254 patients, 70% were male and 84% were White.

They had a mean age of 62 years and an average smoking history of 44 pack years, with 54% identified as current smokers.

At screening, the mean postbronchodilator percent predicted FEV 1 was 48% (range: 14% to 87%), the mean postbronchodilator FEV 1 /forced vital capacity (FVC) ratio was 47% (range: 17% to 88%), and the mean percent reversibility was 14% (range: -41% to 152%).

Patients received 1 inhalation once daily of the following: fluticasone furoate/vilanterol ELLIPTA 100/25 mcg, fluticasone furoate/vilanterol ELLIPTA 200/25 mcg, fluticasone furoate/vilanterol 50/25 mcg, fluticasone furoate 100 mcg, fluticasone furoate 200 mcg, vilanterol 25 mcg, or placebo.

Table 2.

Adverse Reactions with Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg with ≥3% Incidence and More Common than Placebo in Patients with Chronic Obstructive Pulmonary Disease a Includes oral candidiasis, oropharyngeal candidiasis, candidiasis, and fungal oropharyngitis.

Adverse Reaction Fluticasone Furoate/ Vilanterol ELLIPTA 100/25 mcg (n = 410) % Vilanterol 25 mcg (n = 408) % Fluticasone Furoate 100 mcg (n = 410) % Placebo (n = 412) % Infections and infestations Nasopharyngitis 9 10 8 8 Upper respiratory tract infection 7 5 4 3 Oropharyngeal candidiasis a 5 2 3 2 Nervous system disorders Headache 7 9 7 5 12-Month Trials Long-term safety data are based on two 12-month trials (Trials 3 and 4; n = 1,633 and n = 1,622, respectively).

Trials 3 and 4 included 3,255 patients, of which 57% were male and 85% were White.

They had a mean age of 64 years and an average smoking history of 46 pack years, with 44% identified as current smokers.

At screening, the mean postbronchodilator percent predicted FEV 1 was 45% (range: 12% to 91%), and the mean postbronchodilator FEV 1 /FVC ratio was 46% (range: 17% to 81%), indicating that the patient population had moderate to very severely impaired airflow obstruction.

Patients received 1 inhalation once daily of the following: fluticasone furoate/vilanterol ELLIPTA 100/25 mcg, fluticasone furoate/vilanterol ELLIPTA 200/25 mcg, fluticasone furoate/vilanterol 50/25 mcg, or vilanterol 25 mcg.

In addition to the reactions shown in Table 2 , adverse reactions occurring in ≥3% of the patients treated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg (n = 806) for 12 months included back pain, pneumonia [see Warnings and Precautions ( 5.5 )] , bronchitis, sinusitis, cough, oropharyngeal pain, arthralgia, influenza, pharyngitis, and pyrexia.

Mortality Trial Safety data are available from a mortality trial in patients with moderate COPD (moderate airflow limitation [≥50% and ≤70% predicted FEV 1 ]) who either had a history of, or were at risk of, cardiovascular disease and were treated for up to 4 years (median treatment duration of 1.5 years).

The trial included 16,568 patients, 4,140 of whom received fluticasone furoate/vilanterol ELLIPTA 100/25 mcg.

In addition to the events in COPD trials shown in Table 2 , adverse reactions occurring in ≥3% of the patients treated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg and more common than placebo included pneumonia, back pain, hypertension, and influenza.

6.2 Clinical Trials Experience in Asthma The safety data described below are based on trials that evaluated fluticasone furoate/vilanterol ELLIPTA 100/25 mcg in 1,757 patients and fluticasone furoate/vilanterol ELLIPTA 200/25 mcg in 745 patients.

While patients aged 12 to 17 years were included in these trials, fluticasone furoate/vilanterol ELLIPTA 200/25 mcg is not approved for use in this age group [see Dosage and Administration ( 2.2 )] .

One additional 24-week trial enrolled 902 pediatric patients with asthma.

In this trial, fluticasone furoate/vilanterol ELLIPTA 100/25 mcg was studied in 117 patients aged 12 to 17 years and fluticasone furoate/vilanterol ELLIPTA 50/25 mcg was studied in 337 patients aged 5 to 11 years.

Adult Patients The safety of fluticasone furoate/vilanterol ELLIPTA for the maintenance treatment of asthma in adult patients was based on the data from Trials 8, 9, 10, 11, and 12 [see Clinical Studies ( 14.2 )] .

Trial 8 was a 12-week trial that evaluated the efficacy of fluticasone furoate/vilanterol ELLIPTA 100/25 mcg in patients with asthma compared with fluticasone furoate 100 mcg and placebo.

The incidence of adverse reactions associated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg is shown in Table 3 .

Table 3.

Adverse Reactions with Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg with ≥2% Incidence and More Common than Placebo in Patients with Asthma (Trial 8) a Includes oral candidiasis and oropharyngeal candidiasis.

Adverse Reaction Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg (n = 201) % Fluticasone Furoate 100 mcg (n = 205) % Placebo (n = 203) % Infections and infestations Nasopharyngitis 10 7 7 Oral candidiasis a 2 2 0 Nervous system disorders Headache 5 4 4 Respiratory, thoracic, and mediastinal disorders Oropharyngeal pain 2 2 1 Dysphonia 2 1 0 Trial 9 was a 12-week trial that evaluated the efficacy of fluticasone furoate/vilanterol ELLIPTA 100/25 mcg, fluticasone furoate/vilanterol ELLIPTA 200/25 mcg, and fluticasone furoate 100 mcg in patients with asthma.

This trial did not have a placebo arm.

The incidence of adverse reactions associated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg and fluticasone furoate/vilanterol ELLIPTA 200/25 mcg is shown in Table 4 .

Table 4.

Adverse Reactions with Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg and Fluticasone Furoate/Vilanterol ELLIPTA 200/25 mcg with ≥2% Incidence in Patients with Asthma (Trial 9) Adverse Reaction Fluticasone Furoate/Vilanterol ELLIPTA 200/25 mcg (n = 346) % Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg (n = 346) % Fluticasone Furoate 100 mcg (n = 347) % Nervous system disorders Headache 8 8 9 Infections and infestations Nasopharyngitis 7 6 7 Influenza 3 3 1 Upper respiratory tract infection 2 2 3 Sinusitis 2 1 <1 Bronchitis 2 <1 2 Respiratory, thoracic, and mediastinal disorders Oropharyngeal pain 2 2 1 Cough 1 2 1 24-Week Trial Trial 10 was a 24-week trial that evaluated the efficacy of fluticasone furoate/vilanterol ELLIPTA 200/25 mcg once daily, fluticasone furoate 200 mcg once daily, and fluticasone propionate 500 mcg twice daily in patients with asthma.

This trial did not have a placebo arm.

In addition to the reactions shown in Tables 3 and 4, adverse reactions occurring in ≥2% of patients treated with fluticasone furoate/vilanterol ELLIPTA 200/25 mcg included viral respiratory tract infection, pharyngitis, pyrexia, and arthralgia.

12-Month Trial Long-term safety data are based on a 12-month trial that evaluated the safety of fluticasone furoate/vilanterol ELLIPTA 100/25 mcg once daily (n = 201), fluticasone furoate/vilanterol ELLIPTA 200/25 mcg once daily (n = 202), and fluticasone propionate 500 mcg twice daily (n = 100) in patients with asthma (Trial 11).

In addition to the reactions shown in Tables 3 and 4, adverse reactions occurring in ≥2% of the patients treated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg or fluticasone furoate/vilanterol ELLIPTA 200/25 mcg for 12 months included pyrexia, back pain, extrasystoles, upper abdominal pain, respiratory tract infection, allergic rhinitis, pharyngitis, rhinitis, arthralgia, supraventricular extrasystoles, ventricular extrasystoles, acute sinusitis, and pneumonia.

Adult and Pediatric Patients Aged 12 to 17 Years Exacerbation Trial Trial 12 included both adult and pediatric patients 12 years of age and older.

Although this trial did not support efficacy of fluticasone furoate/vilanterol ELLIPTA for maintenance treatment of asthma in pediatric patients 12 to 17 years of age, it was used to evaluate safety in both adult and pediatric patients 12 to 17 years of age.

Patients received fluticasone furoate/vilanterol ELLIPTA 100/25 mcg (n = 1,009) or fluticasone furoate 100 mcg (n = 1,010).

Patients participating in this trial had a history of 1 or more asthma exacerbations that required treatment with oral/systemic corticosteroids or emergency department visit or in-patient hospitalization for the treatment of asthma in the year prior to trial entry.

Asthma-related hospitalizations occurred in 10 patients (1%) treated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg compared with 7 patients (0.7%) treated with fluticasone furoate 100 mcg.

Among patients aged 12 to 17 years, asthma-related hospitalizations occurred in 4 patients (2.6%) treated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg (n = 151) compared with 0 patients treated with fluticasone furoate 100 mcg (n = 130).

There were no asthma-related deaths or asthma-related intubations observed in this trial.

Pediatric Patients Aged 5 to 17 Years The safety of fluticasone furoate/vilanterol ELLIPTA for the maintenance treatment of asthma in pediatric patients 5 years and older was based on the data from Trial 14, a 24-week clinical trial that enrolled 902 patients with asthma aged 5 to 17 years (aged 5 to 11 years [n = 673]; aged 12 to 17 years [n = 229]).

Pediatric patients aged 12 to 17 years were randomized to fluticasone furoate/vilanterol ELLIPTA 100/25 mcg (n = 117) or fluticasone furoate 100 mcg (n = 112).

Pediatric patients aged 5 to 11 years were randomized to fluticasone furoate/vilanterol ELLIPTA 50/25 mcg (n = 337) or fluticasone furoate 50 mcg (n = 336) [see Clinical Studies ( 14.2 )] .

Adverse reactions reported in ≥3% of pediatric patients treated with fluticasone furoate/vilanterol ELLIPTA is shown in Table 5 .

Table 5.

Adverse Reactions with Fluticasone Furoate/Vilanterol ELLIPTA with ≥3% Incidence in Pediatric Patients with Asthma (Trial 14) a The dose of fluticasone furoate/vilanterol ELLIPTA was 100/25 mcg once daily for pediatric patients aged 12 to 17 years and 50/25 mcg once daily for pediatric patients aged 5 to 11 years.

b The dose of fluticasone furoate was 100 mcg once daily for pediatric patients aged 12 to 17 years and 50 mcg once daily for pediatric patients aged 5 to 11 years.

Adverse Reaction Fluticasone Furoate/Vilanterol ELLIPTA a (n = 454) % Fluticasone Furoate b (n = 448) % Infections and infestations Nasopharyngitis 10 8 Upper respiratory tract infection 7 6 Rhinitis 3 1 Viral upper respiratory tract infection 3 <1 Respiratory, thoracic, and mediastinal disorders Rhinitis allergic 4 1 Nervous system disorders Headache 3 2 6.3 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during post approval use of fluticasone furoate/vilanterol ELLIPTA.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to fluticasone furoate/vilanterol ELLIPTA or a combination of these factors.

Cardiac Disorders Palpitations, tachycardia.

Immune System Disorders Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria.

Metabolism and Nutrition Disorders Hyperglycemia.

Musculoskeletal and Connective Tissue Disorders Muscle spasms.

Nervous System Disorders Tremor.

Psychiatric Disorders Nervousness.

Respiratory, Thoracic, and Mediastinal Disorders Paradoxical bronchospasm.