Breo Ellipta

BREO ELLIPTA is a combination of fluticasone furoate, a corticosteroid, and vilanterol, a long-acting beta₂-adrenergic agonist (LABA), indicated for:

• •the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). (
  1.1 Maintenance Treatment of Chronic Obstructive Pulmonary Disease

  BREO ELLIPTA is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD).
  )
• •the maintenance treatment of asthma in patients aged 5 years and older. (
  1.2 Maintenance Treatment of Asthma

  BREO ELLIPTA is indicated for the maintenance treatment of asthma in patients aged 5 years and older.
  )

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

• •For oral inhalation only. (
  2.3 Administration Information

  • •After inhalation, the patient should rinse his/her mouth with water without swallowing to help reduce the risk of oropharyngeal candidiasis
    [see Warnings and Precautions ]
    .
    Pediatric Patients Aged 5 to 11 Years

    The recommended dosage of BREO ELLIPTA 50/25 mcg (containing fluticasone furoate 50 mcg and vilanterol 25 mcg) is 1 actuation once daily by oral inhalation

    [see Warnings and Precautions ]
    .
  )
• •Maintenance treatment of asthma in pediatric patients aged 12 to 17 years: 1 actuation of BREO ELLIPTA 100/25 mcg once daily administered by oral inhalation. (
  2.2 Recommended Dosage for Maintenance Treatment of Asthma

  Adult Patients Aged 18 Years and Older

  The recommended dosage of BREO ELLIPTA 100/25 mcg (containing fluticasone furoate 100 mcg and vilanterol 25 mcg) is 1 actuation once daily by oral inhalation or BREO ELLIPTA 200/25 mcg (containing fluticasone furoate 200 mcg and vilanterol 25 mcg) is 1 actuation once daily by oral inhalation.

  • •When choosing the starting dosage strength of BREO ELLIPTA, consider the patients’ disease severity, their previous asthma therapy, including the inhaled corticosteroid (ICS) dosage, as well as the patients’ current control of asthma symptoms and risk of future exacerbation.
  • •The median time to onset, defined as a 100-mL increase from baseline in mean forced expiratory volume in 1 second (FEV1), was approximately 15 minutes after beginning treatment. Individual patients will experience a variable time to onset and degree of symptom relief.
  • •For patients who do not respond adequately to BREO ELLIPTA 100/25 mcg once daily, increasing the dose to BREO ELLIPTA 200/25 mcg once daily may provide additional improvement in asthma control. For patients who do not respond adequately to BREO ELLIPTA 200/25 mcg once daily, re-evaluate and consider other therapeutic regimens and additional therapeutic options.
  • •The maximum recommended dosage is 1 inhalation of BREO ELLIPTA 200/25 mcg once daily.
  • •If asthma symptoms arise in the period between doses, an inhaled, short-acting beta2-agonist (rescue medicine, e.g., albuterol) should be used for immediate relief.

  Pediatric Patients Aged 12 to 17 Years

  The recommended dosage of BREO ELLIPTA 100/25 mcg (containing fluticasone furoate 100 mcg and vilanterol 25 mcg) is 1 actuation once daily by oral inhalation

  [see Warnings and Precautions ]

  .

  Pediatric Patients Aged 5 to 11 Years

  The recommended dosage of BREO ELLIPTA 50/25 mcg (containing fluticasone furoate 50 mcg and vilanterol 25 mcg) is 1 actuation once daily by oral inhalation

  [see Warnings and Precautions ]

  .
  )
• •Maintenance treatment of asthma in pediatric patients aged 5 to 11 years: 1 actuation of BREO ELLIPTA 50/25 mcg once daily administered by oral inhalation. (
  2.2 Recommended Dosage for Maintenance Treatment of Asthma

  Adult Patients Aged 18 Years and Older

  The recommended dosage of BREO ELLIPTA 100/25 mcg (containing fluticasone furoate 100 mcg and vilanterol 25 mcg) is 1 actuation once daily by oral inhalation or BREO ELLIPTA 200/25 mcg (containing fluticasone furoate 200 mcg and vilanterol 25 mcg) is 1 actuation once daily by oral inhalation.

  • •When choosing the starting dosage strength of BREO ELLIPTA, consider the patients’ disease severity, their previous asthma therapy, including the inhaled corticosteroid (ICS) dosage, as well as the patients’ current control of asthma symptoms and risk of future exacerbation.
  • •The median time to onset, defined as a 100-mL increase from baseline in mean forced expiratory volume in 1 second (FEV1), was approximately 15 minutes after beginning treatment. Individual patients will experience a variable time to onset and degree of symptom relief.
  • •For patients who do not respond adequately to BREO ELLIPTA 100/25 mcg once daily, increasing the dose to BREO ELLIPTA 200/25 mcg once daily may provide additional improvement in asthma control. For patients who do not respond adequately to BREO ELLIPTA 200/25 mcg once daily, re-evaluate and consider other therapeutic regimens and additional therapeutic options.
  • •The maximum recommended dosage is 1 inhalation of BREO ELLIPTA 200/25 mcg once daily.
  • •If asthma symptoms arise in the period between doses, an inhaled, short-acting beta2-agonist (rescue medicine, e.g., albuterol) should be used for immediate relief.

  Pediatric Patients Aged 12 to 17 Years

  The recommended dosage of BREO ELLIPTA 100/25 mcg (containing fluticasone furoate 100 mcg and vilanterol 25 mcg) is 1 actuation once daily by oral inhalation

  [see Warnings and Precautions ]

  .

  Pediatric Patients Aged 5 to 11 Years

  The recommended dosage of BREO ELLIPTA 50/25 mcg (containing fluticasone furoate 50 mcg and vilanterol 25 mcg) is 1 actuation once daily by oral inhalation

  [see Warnings and Precautions ]

  .
  )

Inhalation powder:

• •50 mcg fluticasone furoate and 25 mcg vilanterol (50/25 mcg) per actuation
• •100 mcg fluticasone furoate and 25 mcg vilanterol (100/25 mcg) per actuation
• •200 mcg fluticasone furoate and 25 mcg vilanterol (200/25 mcg) per actuation

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

12.3 Pharmacokinetics

Linear pharmacokinetics was observed for fluticasone furoate (200 to 800 mcg) and vilanterol (25 to 100 mcg). On 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 administered 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 patients with COPD or asthma was 46% or 7% lower, respectively, 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 administered 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 (<2%) due to extensive first-pass metabolism. Systemic exposure (AUC) in patients with COPD was 24% higher than observed in healthy subjects. Systemic exposure (AUC) in patients with asthma was 21% lower 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%).

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 on average 94%.

Elimination

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 β₁- and β₂-agonist activity.

Excretion: 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 doses, 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%, respectively, of the recovered radioactive dose). The plasma elimination half-life of vilanterol, as determined from inhalation administration of multiple doses of vilanterol 25 mcg, is 21.3 hours in patients with COPD and 16.0 hours in patients with asthma.

Specific Populations

The effects of renal and hepatic impairment and other intrinsic factors on the pharmacokinetics of fluticasone furoate and vilanterol are shown in Figure 1.

Figure 1. Impact of Intrinsic Factors on the Pharmacokinetics (PK) of Fluticasone Furoate (FF) and Vilanterol (VI) Following Administration as Fluticasone Furoate/Vilanterol Combination

• ^aSevere renal impairment (CrCl <30 mL/min) compared with healthy subjects; mild (Child‑Pugh A), moderate (Child-Pugh B), and severe (Child-Pugh C) hepatic impairment compared with healthy subjects.
• ^bFor COPD and asthma, the following comparisons were made: age compared with ≤65 years, gender compared with female, and ethnicity compared with White.

Pediatric Patients: Fluticasone Furoate:

A population pharmacokinetics analysis to assess impact of age on fluticasone furoate systemic exposure was conducted using combined data from clinical trials in pediatric patients aged 5 to 11 years (n = 306). There was no relevant effect of age on the apparent clearance of fluticasone furoate. The dose-adjusted fluticasone furoate systemic exposure at steady state in children aged 5 to 11 years following 50 mcg were comparable to that observed in adult and pediatric patients 12 years and older following dosing with fluticasone furoate 100 mcg monotherapy.

Vilanterol:

A population pharmacokinetic analysis was conducted to characterize vilanterol pharmacokinetics using combined data from clinical trials in pediatric patients aged 5 to 11 years (n = 142). There was no relevant effect of age, weight, body mass index, sex, ethnicity, and race on vilanterol clearance. A cross-study comparison in pediatric patients with asthma showed that at steady-state, when combined with fluticasone furoate, vilanterol had similar AUC values but lower C_maxvalues compared to vilanterol administered alone. Vilanterol systemic exposure at steady state, in patients with asthma aged 5 to 11 years, was similar to those observed in adult and pediatric patients 12 years and older with asthma following repeat dosing of BREO ELLIPTA 100/25 mcg.

Racial or Ethnic Groups: Fluticasone Furoate:

Systemic exposure [AUC_(0-24)] to inhaled fluticasone furoate 200 mcg was 27% to 49% higher in healthy subjects of Japanese, Korean, and Chinese heritage compared with White subjects. Similar differences were observed for patients with COPD or asthma . However, there is no evidence that this higher exposure to fluticasone furoate results in clinically relevant effects on urinary cortisol excretion or on efficacy in these racial groups.

Vilanterol:

There was no effect of race on the pharmacokinetics of vilanterol in patients with COPD. In patients with asthma, vilanterol C_maxis estimated to be higher (3-fold) and AUC_(0-24)comparable for those patients from an Asian heritage compared with patients from a non-Asian heritage. However, the higher C_maxvalues are similar to those seen in healthy subjects.

Patients with Hepatic Impairment: Fluticasone Furoate:

Following repeat dosing of fluticasone furoate/vilanterol 200/25 mcg (100/12.5 mcg in the severe impairment group) for 7 days, there was an increase of 34%, 83%, and 75% in fluticasone furoate systemic exposure (AUC) in patients with mild, moderate, and severe hepatic impairment, respectively, compared with healthy subjects .

In patients with moderate hepatic impairment receiving fluticasone furoate/vilanterol 200/25 mcg, mean serum cortisol (0 to 24 hours) was reduced by 34% (90% CI: 11%, 51%) compared with healthy subjects. In patients with severe hepatic impairment receiving fluticasone furoate/vilanterol 100/12.5 mcg, mean serum cortisol (0 to 24 hours) was increased by 14% (90% CI: -16%, 55%) compared with healthy subjects. Patients with moderate to severe hepatic disease should be closely monitored.

Vilanterol:

Hepatic impairment had no effect on vilanterol systemic exposure [C_maxand AUC_(0-24)on Day 7] following repeat-dose administration of fluticasone furoate/vilanterol 200/25 mcg (100/12.5 mcg in the severe impairment group) for 7 days .

There were no additional clinically relevant effects of the fluticasone furoate/vilanterol combinations on heart rate or serum potassium in patients with mild or moderate hepatic impairment (vilanterol 25 mcg combination) or with severe hepatic impairment (vilanterol 12.5 mcg combination) compared with healthy subjects.

Patients with Renal Impairment:

Fluticasone furoate systemic exposure was not increased and vilanterol systemic exposure [AUC_(0-24)] was 56% higher in patients with severe renal impairment compared with healthy subjects . There was no evidence of greater corticosteroid or beta-agonist class-related systemic effects (assessed by serum cortisol, heart rate, and serum potassium) in patients with severe renal impairment compared with healthy subjects.

Drug Interaction Studies

There were no clinically relevant differences in the pharmacokinetics or pharmacodynamics of either fluticasone furoate or vilanterol when administered in combination compared with administration alone. The potential for fluticasone furoate and vilanterol to inhibit or induce metabolic enzymes and transporter systems is negligible at low inhalation doses.

Inhibitors of Cytochrome P450 3A4:

The exposure (AUC) of fluticasone furoate and vilanterol were 36% and 65% higher, respectively, when coadministered with ketoconazole 400 mg compared with placebo . The increase in fluticasone furoate exposure was associated with a 27% reduction in weighted mean serum cortisol (0 to 24 hours). The increase in vilanterol exposure was not associated with an increase in beta-agonist–related systemic effects on heart rate or blood potassium.

Figure 2. Impact of Coadministered Drugs^aon the Pharmacokinetics (PK) of Fluticasone Furoate (FF) and Vilanterol (VI) Following Administration as Fluticasone Furoate/Vilanterol Combination or Vilanterol Coadministered with a Long-Acting Muscarinic Antagonist

• ^aCompared with placebo group.

Inhibitors of P-glycoprotein:

Fluticasone furoate and vilanterol are both substrates of P-glycoprotein (P-gp). Coadministration of repeat-dose (240 mg once daily) verapamil (a moderate CYP3A4 inhibitor and a P-gp inhibitor) did not affect the vilanterol C_maxor AUC in healthy subjects . Drug interaction trials with a specific P-gp inhibitor and fluticasone furoate have not been conducted.

Figure 1. Impact of Intrinsic Factors on the Pharmacokinetics (PK) of Fluticasone Furoate (FF) and Vilanterol (VI) Following Administration as Fluticasone Furoate/Vilanterol Combination

Figure 2. Impact of Coadministered Drugsa on the Pharmacokinetics (PK) of Fluticasone Furoate (FF) and Vilanterol (VI) Following Administration as Fluticasone Furoate/Vilanterol Combination or Vilanterol Coadministered with a Long-Acting Muscarinic Antagonist

• •LABA monotherapy increases the risk of serious asthma-related events. (
  5.1 Serious Asthma-Related Events – Hospitalizations, Intubations, Death

  Use of Long-acting Beta₂-adrenergic Agonist (LABA) as monotherapy (without ICS) for asthma is associated with an increased risk of asthma-related death

  [see Salmeterol Multicenter Asthma Research Trial (SMART)]

  . Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric patients. These findings are considered a class effect of LABA monotherapy. When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma‑related events (hospitalizations, intubations, death) compared with ICS alone

  (see Serious Asthma-Related Events with Inhaled Corticosteroid/Long-Acting Beta₂-Adrenergic Agonists)

  .

  Serious Asthma-Related Events with Inhaled Corticosteroid/Long-Acting Beta₂-Adrenergic Agonists

  Four (4) large, 26-week, randomized, double-blind, active-controlled clinical safety trials were conducted to evaluate the risk of serious asthma-related events when LABA were used in fixed-dose combination with ICS compared with ICS alone in patients with asthma. Three (3) trials included adult and pediatric patients aged 12 years and older: 1 trial compared budesonide/formoterol with budesonide, 1 trial compared fluticasone propionate/salmeterol inhalation powder with fluticasone propionate inhalation powder, and 1 trial compared mometasone furoate/formoterol with mometasone furoate. The fourth trial included pediatric patients aged 4 to 11 years and compared fluticasone propionate/salmeterol inhalation powder with fluticasone propionate inhalation powder. The primary safety endpoint for all 4 trials was serious asthma-related events (hospitalizations, intubations, death). A blinded adjudication committee determined whether events were asthma related.

  The 3 adult and pediatric trials were designed to rule out a risk margin of 2.0, and the pediatric trial was designed to rule out a risk margin of 2.7. Each individual trial met its pre-specified objective and demonstrated non-inferiority of ICS/LABA to ICS alone. A meta-analysis of the 3 adult and pediatric trials did not show a significant increase in risk of a serious asthma-related event with ICS/LABA fixed-dose combination compared with ICS alone . These trials were not designed to rule out all risk for serious asthma-related events with ICS/LABA compared with ICS.

  Table 1. Meta-Analysis of Serious Asthma-Related Events in Patients with Asthma Aged 12 Years and Older

  ICS = Inhaled Corticosteroid, LABA = Long-acting Beta2-adrenergic Agonist.
  aRandomized patients who had taken at least 1 dose of study drug. Planned treatment used for analysis.
  bEstimated using a Cox proportional hazards model for time to first event with baseline hazards stratified by each of the 3 trials.
  cNumber of patients with event that occurred within 6 months after the first use of study drug or 7 days after the last date of study drug, whichever date was later. Patients can have one or more events, but only the first event was counted for analysis. A single, blinded, independent adjudication committee determined whether events were asthma related.
  	ICS/LABA (n = 17,537)a	ICS (n = 17,552)a	ICS/LABA vs. ICS Hazard Ratio (95% CI)b
  Serious asthma-related eventc	116	105	1.10 (0.85, 1.44)
  Asthma-related death	2	0
  Asthma-related intubation (endotracheal)	1	2
  Asthma-related hospitalization (≥24-hour stay)	115	105

  The pediatric safety trial included 6,208 pediatric patients aged 4 to 11 years who received ICS/LABA (fluticasone propionate/salmeterol inhalation powder) or ICS (fluticasone propionate inhalation powder). In this trial, 27/3,107 (0.9%) patients randomized to ICS/LABA and 21/3,101 (0.7%) patients randomized to ICS experienced a serious asthma-related event. There were no asthma-related deaths or intubations. ICS/LABA did not show a significantly increased risk of a serious asthma-related event compared with ICS based on the pre-specified risk margin (2.7), with an estimated hazard ratio of time to first event of 1.29 (95% CI: 0.73, 2.27).

  Salmeterol Multicenter Asthma Research Trial (SMART)

  A 28-week, placebo-controlled, U.S. trial that compared the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol (13/13,176 in patients treated with salmeterol vs. 3/13,179 in patients treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). Use of background ICS was not required in SMART. The increased risk of asthma-related death is considered a class effect of LABA monotherapy.
  )
• •Do not initiate in acutely deteriorating COPD or asthma. Do not use to treat acute symptoms. (
  5.2 Deterioration of Disease and Acute Episodes

  BREO ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD or asthma. BREO ELLIPTA has not been studied in patients with acutely deteriorating COPD or asthma. The initiation of BREO ELLIPTA in this setting is not appropriate.

  In COPD, if BREO ELLIPTA 100/25 mcg no longer controls symptoms of bronchoconstriction; the patient’s inhaled, short-acting, beta₂-agonist becomes less effective; or the patient needs more short-acting beta₂-agonist than usual, these may be markers of deterioration of disease. In this setting, re-evaluate the patient and the COPD treatment regimen at once. For COPD, the daily dose of BREO ELLIPTA 100/25 mcg should not be increased.

  Increasing use of inhaled, short-acting beta₂-agonists is a marker of deteriorating asthma. In this situation, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the need for additional therapeutic options. Patients should not use more than 1 inhalation once daily of BREO ELLIPTA.

  BREO ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. BREO ELLIPTA has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta₂-agonist.

  When beginning treatment with BREO ELLIPTA, patients who have been taking oral or inhaled, short-acting beta₂-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs and to use them only for symptomatic relief of acute respiratory symptoms. When prescribing BREO ELLIPTA, the healthcare provider should also prescribe an inhaled, short-acting beta₂-agonist and instruct the patient on how it should be used.
  )
• •Do not use in combination with additional therapy containing a LABA because of risk of overdose. (
  5.3 Risk Associated with Excessive Use of Long-Acting Beta₂-Agonists, including BREO ELLIPTA

  BREO ELLIPTA should not be used more often than recommended, at higher doses than recommended

  [see Dosage and Administration ]

  , or in conjunction with other therapies containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using BREO ELLIPTA should not use another therapy containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.
  )
• •
  Candida albicans
  infection of the mouth and pharynx may occur. Monitor patients periodically. Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk. (
  5.4 Oropharyngeal Candidiasis

  BREO ELLIPTA contains fluticasone furoate, an ICS. Localized infections of the mouth and pharynx with

  Candida albicans

  have occurred in patients treated with orally inhaled drug products containing fluticasone furoate. Monitor patients periodically. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with BREO ELLIPTA continues. In some cases, therapy with BREO ELLIPTA may need to be interrupted. Advise the patient to rinse his/her mouth with water without swallowing following administration of BREO ELLIPTA to help reduce the risk of oropharyngeal candidiasis.
  )
• •Increased risk of pneumonia in patients with COPD. Monitor patients for signs and symptoms of pneumonia. (
  5.5 Pneumonia

  An increase in the incidence of pneumonia has been observed in patients with COPD receiving BREO ELLIPTA 100/25 mcg in clinical trials. There was also an increased incidence of pneumonias resulting in hospitalization. In some incidences these pneumonia events were fatal. Healthcare providers should remain vigilant for the possible development of pneumonia in patients with COPD as clinical features of pneumonia and exacerbations frequently overlap.

  In replicate 12-month trials in 3,255 patients with moderate to severe COPD who had experienced a COPD exacerbation in the previous year, there was a higher incidence of pneumonia reported in patients receiving fluticasone furoate/vilanterol 50/25 mcg: 6% (48 of 820 patients); BREO ELLIPTA 100/25 mcg: 6% (51 of 806 patients); or BREO ELLIPTA 200/25 mcg: 7% (55 of 811 patients) than in patients receiving vilanterol 25 mcg: 3% (27 of 818 patients). There was no fatal pneumonia in patients receiving vilanterol or fluticasone furoate/vilanterol 50/25 mcg. There was fatal pneumonia in 1 patient receiving BREO ELLIPTA 100/25 mcg and in 7 patients receiving BREO ELLIPTA 200/25 mcg (<1% for each treatment group).

  In a mortality trial with a median treatment duration of 1.5 years in 16,568 patients with moderate COPD and cardiovascular disease, the annualized incidence rate of pneumonia was 3.4 per 100 patient-years for BREO ELLIPTA 100/25 mcg, 3.2 for placebo, 3.3 for fluticasone furoate 100 mcg, and 2.3 for vilanterol 25 mcg. Adjudicated, on-treatment deaths due to pneumonia occurred in 13 patients receiving BREO ELLIPTA 100/25 mcg, 9 patients receiving placebo, 10 patients receiving fluticasone furoate 100 mcg, and 6 patients receiving vilanterol 25 mcg (<0.2 per 100 patient-years for each treatment group).
  )
• •Potential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infections; 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. (
  5.6 Immunosuppression and Risk of Infections

  Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chickenpox and measles can have a more serious or even fatal course in susceptible patients using corticosteroids. In such patients who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective Prescribing Information for VZIG and IG) If chickenpox develops, treatment with antiviral agents may be considered.

  ICS should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.
  )
• •Risk of impaired adrenal function when transferring from systemic corticosteroids. Wean patients slowly from systemic corticosteroids if transferring to BREO ELLIPTA. (
  5.7 Transferring Patients from Systemic Corticosteroid Therapy

  Hypothalamic-Pituitary-Adrenal Suppression/Adrenal Insufficiency

  Particular care is needed for patients who have been transferred from systemically active corticosteroids to ICS because deaths due to adrenal insufficiency have occurred in patients during and after transfer from systemic corticosteroids to less systemically available ICS. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.

  Patients who have been previously maintained on 20 mg or more of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although BREO ELLIPTA may control COPD or asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.

  During periods of stress, a severe COPD exacerbation, or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their healthcare practitioner for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress, a severe COPD exacerbation, or a severe asthma attack.

  Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to BREO ELLIPTA. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with BREO ELLIPTA. Lung function (FEV₁or peak expiratory flow), beta-agonist use, and COPD or asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.

  Unmasking of Allergic Conditions Previously Suppressed by Systemic Corticosteroids

  Transfer of patients from systemic corticosteroid therapy to BREO ELLIPTA may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions).

  Corticosteroid Withdrawal Symptoms

  During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function.
  )
• •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. (
  5.8 Hypercorticism and Adrenal Suppression

  Inhaled fluticasone furoate is absorbed into the circulation and can be systemically active. Effects of fluticasone furoate on the HPA axis are not observed with the therapeutic doses of fluticasone furoate in BREO ELLIPTA. However, exceeding the recommended dosage or coadministration with a strong cytochrome P450 3A4 (CYP3A4) inhibitor may result in HPA dysfunction

  [see Warnings and Precautions , Drug Interactions ]

  .

  Because of the possibility of significant systemic absorption of ICS in sensitive patients, patients treated with BREO ELLIPTA should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.

  It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects. If such effects occur, reduce the dose of BREO ELLIPTA slowly, consistent with accepted procedures for reducing systemic corticosteroids, and consider other treatments for management of COPD or asthma symptoms.
  )
• •If paradoxical bronchospasm occurs, discontinue BREO ELLIPTA and institute alternative therapy. (
  5.10 Paradoxical Bronchospasm

  BREO ELLIPTA can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with BREO ELLIPTA, it should be treated immediately with an inhaled, short-acting bronchodilator; BREO ELLIPTA should be discontinued immediately; and alternative therapy should be instituted

  [see Adverse Reactions ]

  .
  )
• •Use with caution in patients with cardiovascular disorders because of beta-adrenergic stimulation. (
  5.12 Cardiovascular Effects

  BREO ELLIPTA, like other drugs containing beta₂-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and also cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles

  [see Adverse Reactions ]

  . If such effects occur, BREO ELLIPTA may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiographic changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression, although the clinical significance of these findings is unknown

  [see Clinical Pharmacology ]

  . Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

  In healthy subjects, large doses of inhaled fluticasone furoate/vilanterol (4 times the recommended dose of vilanterol, representing a 12- or 10-fold higher systemic exposure than seen in patients with COPD or asthma, respectively) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias. Therefore, BREO ELLIPTA, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

  In a mortality trial with a median treatment duration of 1.5 years in 16,568 patients with moderate COPD and cardiovascular disease, the annualized incidence rate of adjudicated cardiovascular events (composite of myocardial infarction, stroke, unstable angina, transient ischemic attack, or on-treatment death due to cardiovascular events) was 2.5 per 100 patient-years for BREO ELLIPTA 100/25 mcg, 2.7 for placebo, 2.4 for fluticasone furoate 100 mcg, and 2.6 for vilanterol 25 mcg. Adjudicated, on-treatment deaths due to cardiovascular events occurred in 82 patients receiving BREO ELLIPTA 100/25 mcg, 86 patients receiving placebo, 80 patients receiving fluticasone furoate 100 mcg, and 90 patients receiving vilanterol 25 mcg (annualized incidence rate ranged from 1.2 to 1.3 per 100 patient-years for the treatment groups).
  )
• •Assess for decrease in bone mineral density (BMD) initially and periodically thereafter. (
  5.13 Reduction in Bone Mineral Density

  Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing ICS. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating BREO ELLIPTA and periodically thereafter. If significant reductions in BMD are seen and BREO ELLIPTA is still considered medically important for that patient’s COPD therapy, use of therapy to treat or prevent osteoporosis should be strongly considered.

  In replicate 12-month trials in 3,255 patients with moderate to severe COPD, bone fractures were reported by 2% of patients receiving the fluticasone furoate/vilanterol combination (50/25 mcg: 2% [14 of 820 patients]; 100/25 mcg: 2% [19 of 806 patients]; or 200/25 mcg: 2% [14 of 811 patients]) compared with <1% of patients receiving vilanterol 25 mcg alone (8 of 818 patients).

  Similar findings were seen in a mortality trial with a median treatment duration of 1.5 years in 16,568 patients with moderate COPD and cardiovascular disease.
  )
• •Monitor growth of pediatric patients (
  5.14 Effect on Growth

  Orally inhaled corticosteroids, , including fluticasone furoate, a component in BREO ELLIPTA may cause a reduction in growth velocity when administered to pediatric patients. The safety and effectiveness of BREO ELLIPTA have not been established in pediatric patients less than 5 years of age. Monitor the growth of pediatric patients receiving BREO ELLIPTA routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including BREO ELLIPTA, titrate each patient’s dose to the lowest dosage that effectively controls his/her symptoms

  [see Dosage and Administration , Use in Specific Populations ]

  .
  )
• •Glaucoma and cataracts may occur with long-term use of Inhaled Corticosteroid (ICS). Consider referral to an ophthalmologist in patients who develop ocular symptoms or use BREO ELLIPTA long term. (
  5.15 Glaucoma and Cataracts

  Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD or asthma following the long-term administration of ICS, including fluticasone furoate, a component in BREO ELLIPTA. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use BREO ELLIPTA long term.
  )
• •Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. (
  5.16 Risk of Using Sympathomimetic Amines in Certain Coexisting Conditions

  BREO ELLIPTA, like all therapies containing sympathomimetic amines, should be used with caution in patients with convulsive disorders, thyrotoxicosis, or diabetes mellitus and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta₂-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.
  )
• •Increased blood glucose levels have been reported. Also, be alert to hypokalemia. (
  5.17 Hyperglycemia and Hypokalemia

  There have been reports of increases in blood glucose levels with BREO ELLIPTA. This should be considered in patients with a history of, or with risk factors for, diabetes mellitus

  [see Adverse Reactions ]

  .

  Beta-adrenergic agonist therapies may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. In clinical trials evaluating BREO ELLIPTA in patients with COPD or asthma, there was no evidence of a treatment effect on serum potassium.
  )