Trelegy Ellipta (Fluticasone Furoate, Umeclidinium Bromide And Vilanterol Trifenatate)

TRELEGY ELLIPTA is a combination of fluticasone furoate, an inhaled corticosteroid (ICS); umeclidinium, an anticholinergic; 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

  TRELEGY ELLIPTA is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD).
  )
• •the maintenance treatment of asthma in patients aged 18 years and older. (
  1.2 Maintenance Treatment of Asthma

  TRELEGY ELLIPTA is indicated for the maintenance treatment of asthma in patients aged 18 years and older.
  )

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

• •For oral inhalation only. (
  2.1 Dosage and Administration Overview

  • •Administer 1 actuation of TRELEGY ELLIPTA once daily by oral inhalation.
  • •After inhalation, rinse the mouth with water without swallowing to help reduce the risk of oropharyngeal candidiasis.
  • •TRELEGY ELLIPTA should be used at the same time every day. Do not use TRELEGY ELLIPTA more than 1 time every 24 hours.
  • •No dosage adjustment is required for geriatric patients, patients with renal impairment, or patients with moderate hepatic impairment
    [see Clinical Pharmacology ]
    .
  )
• •Maintenance treatment of COPD: 1 actuation of TRELEGY ELLIPTA 100/62.5/25 mcg once daily administered by oral inhalation. (
  2.2 Recommended Dosage for Maintenance Treatment of Chronic Obstructive Pulmonary Disease

  The recommended dosage of TRELEGY ELLIPTA for maintenance treatment of COPD is fluticasone furoate 100 mcg, umeclidinium 62.5 mcg, and vilanterol 25 mcg (1 actuation of TRELEGY ELLIPTA 100/62.5/25 mcg) once daily by oral inhalation.

  • •TRELEGY ELLIPTA 100/62.5/25 mcg is the only strength indicated for the treatment of COPD.
  • •If shortness of breath occurs in the period between doses, an inhaled, short-acting beta₂-agonist (rescue medicine, e.g., albuterol) should be used for immediate relief.
  )
• •Maintenance treatment of asthma: 1 actuation of TRELEGY ELLIPTA 100/62.5/25 mcg or TRELEGY ELLIPTA 200/62.5/25 mcg once daily administered by oral inhalation. (
  2.3 Recommended Dosage for Maintenance Treatment of Asthma

  The recommended starting dosage of TRELEGY ELLIPTA for maintenance treatment of asthma is fluticasone furoate 100 mcg, umeclidinium 62.5 mcg, and vilanterol 25 mcg (1 actuation of TRELEGY ELLIPTA 100/62.5/25 mcg) or fluticasone furoate 200 mcg, umeclidinium 62.5 mcg, and vilanterol 25 mcg (1 actuation of TRELEGY ELLIPTA 200/62.5/25 mcg) once daily, by oral inhalation.

  • •When choosing the starting dosage strength of TRELEGY 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 maximum recommended dosage is 1 inhalation of TRELEGY ELLIPTA 200/62.5/25 mcg once daily.
  • •For patients who do not respond adequately to TRELEGY ELLIPTA 100/62.5/25 mcg once daily, increasing the dose to TRELEGY ELLIPTA 200/62.5/25 mcg once daily may provide additional improvement in asthma control. For patients who do not respond adequately to TRELEGY ELLIPTA 200/62.5/25 mcg once daily, re-evaluate and consider other therapeutic regimens and additional therapeutic options.
  • •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.
  )

Inhalation powder:

• •100 mcg fluticasone furoate, 62.5 mcg umeclidinium, and 25 mcg vilanterol (100/62.5/25 mcg) per actuation.
• •200 mcg fluticasone furoate, 62.5 mcg umeclidinium, and 25 mcg vilanterol (200/62.5/25 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), umeclidinium (62.5 to 500 mcg), and vilanterol (25 to 100 mcg). The pharmacokinetics of fluticasone furoate, umeclidinium, and vilanterol from TRELEGY ELLIPTA are comparable to the pharmacokinetics of fluticasone furoate, umeclidinium, and vilanterol when administered as fluticasone furoate/vilanterol or umeclidinium/vilanterol.

Systemic drug levels [steady-state C_maxand AUC_(0-24)] of fluticasone furoate, umeclidinium, and vilanterol following administration of TRELEGY ELLIPTA 100/62.5/25 mcg based on a combined pharmacokinetic dataset from 3 studies in subjects with COPD (N = 821) were within the range of those observed following administration of fluticasone furoate/vilanterol plus umeclidinium administered via 2 inhalers, fluticasone furoate/vilanterol and umeclidinium/vilanterol as the dual combinations, and after administration of fluticasone furoate, umeclidinium, and vilanterol as monotherapy.

Systemic drug levels [steady-state C_maxand AUC_(0-24)] of fluticasone furoate, umeclidinium, and vilanterol following administration of TRELEGY ELLIPTA (100/62.5/25 or 200/62.5/25 mcg) based on a population pharmacokinetic analysis from subjects with asthma (1,265 subjects for fluticasone furoate; 634 subjects for umeclidinium; 1,263 subjects for vilanterol) were within the range of those observed following administration of fluticasone furoate/vilanterol as the dual combination when compared with fluticasone furoate 100 and 200 mcg, respectively; the systemic exposure of umeclidinium 62.5 mcg following TRELEGY ELLIPTA (100/62.5/25 or 200/62.5/25 mcg) was within the range of those observed following administration of umeclidinium 62.5 mcg as monotherapy.

The pharmacokinetics of the individual components of TRELEGY ELLIPTA are presented as follows. Plasma levels of fluticasone furoate, umeclidinium, and vilanterol may not predict therapeutic effect.

Absorption

Fluticasone Furoate:

Following inhaled administration of fluticasone furoate, C_maxoccurred 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. Following repeat dosing of inhaled fluticasone furoate, steady state was achieved within 6 days with up to 2.6-fold accumulation.

Umeclidinium:

Following inhaled administration of umeclidinium in healthy subjects, C_maxoccurred at 5 to 15 minutes. Umeclidinium is mostly absorbed from the lung after inhaled doses with minimum contribution from oral absorption. Following repeat dosing of inhaled umeclidinium, steady state was achieved within 14 days with up to 1.8-fold accumulation.

Vilanterol:

Following inhaled administration of vilanterol in healthy subjects, C_maxoccurred at 5 to 15 minutes. Vilanterol is mostly absorbed from the lung after inhaled doses with negligible contribution from oral absorption. Following repeat dosing of inhaled vilanterol, steady state was achieved within 14 days with up to 1.7-fold accumulation.

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%).

Umeclidinium:

Following intravenous administration to healthy subjects, the mean volume of distribution was 86 L. In vitro plasma protein binding in human plasma was on average 89%.

Vilanterol:

Following intravenous administration to healthy subjects, the mean volume of distribution at steady state was 165 L. In vitro plasma protein binding in human plasma 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.

Umeclidinium:

In vitro data showed that umeclidinium is primarily metabolized by the enzyme cytochrome P450 2D6 (CYP2D6) and is a substrate for the P-glycoprotein (P-gp) transporter. The primary metabolic routes for umeclidinium are oxidative (hydroxylation, O-dealkylation) followed by conjugation (e.g., glucuronidation), resulting in a range of metabolites with either reduced pharmacological activity or for which the pharmacological activity has not been established. Systemic exposure to the metabolites is low.

Vilanterol:

In vitro data showed that vilanterol is metabolized principally by CYP3A4 and is a substrate for the P-gp transporter. Vilanterol is metabolized to a range of metabolites with significantly reduced β₁- and β₂-agonist activity.

Excretion: Fluticasone Furoate:

The plasma elimination half-life following repeat-dose inhaled administration averaged 24 hours. Following intravenous dosing with radiolabeled fluticasone furoate, mass balance showed 90% of the radiolabel in the feces and 2% in the urine. Following oral dosing, radiolabel recovered in feces was 101% of the total dose and that in urine was approximately 1% of the total dose.

Umeclidinium:

The effective half-life after once-daily oral dosing is 11 hours. Following intravenous dosing with radiolabeled umeclidinium, mass balance showed 58% of the radiolabel in the feces and 22% in the urine. The excretion of the drug-related material in the feces following intravenous dosing indicated elimination in the bile. Following oral dosing to healthy male subjects, radiolabel recovered in feces was 92% of the total dose and that in urine was <1% of the total dose, suggesting negligible oral absorption.

Vilanterol:

The effective half-life for vilanterol, as determined from inhalation administration of multiple doses, is 11 hours. Following oral administration of radiolabeled vilanterol, mass balance showed 70% of the radiolabel in the urine and 30% in the feces.

Specific Populations

The effects of intrinsic and extrinsic factors on the pharmacokinetics of fluticasone furoate, umeclidinium, and vilanterol are shown in Figures 1, 2, 3, and 4. Based on population pharmacokinetic analyses in COPD and asthma, none of the covariates assessed (i.e., age, race, gender) had a clinically relevant effect on fluticasone furoate, umeclidinium, or vilanterol pharmacokinetics when administered as TRELEGY ELLIPTA.

Figure 1. Impact of Intrinsic Factors on the Pharmacokinetics (PK) of Fluticasone Furoate (FF), Umeclidinium (UMEC), and Vilanterol (VI) following Coadministration in COPD

Figure 2. Impact of Intrinsic Factors on the Pharmacokinetics (PK) of Fluticasone Furoate (FF), Umeclidinium (UMEC), and Vilanterol (VI) following Coadministration in Asthma^a

^aAge, ethnicity, and gender comparison for TRELEGY ELLIPTA 200/62.5/25 mcg in subjects with asthma.

Figure 3. Impact of Intrinsic Factors^aand Coadministered Drugs^bon the Pharmacokinetics (PK) of Fluticasone Furoate (FF) and Vilanterol (VI) following Administration as Fluticasone Furoate/Vilanterol Combination or following Vilanterol Coadministered with Umeclidinium

^aRenal groups (fluticasone furoate/vilanterol 200/25 mcg) and hepatic groups (fluticasone furoate/vilanterol 200/25 mcg or fluticasone furoate/vilanterol 100/12.5 mcg).

^bCompared with placebo group.

Figure 4. Impact of Intrinsic Factors and Coadministered Drugs on the Systemic Exposure of Umeclidinium

Racial or Ethnic Groups: Fluticasone Furoate:

Systemic exposure [AUC_(0-24)] to inhaled fluticasone furoate was approximately 30% higher in subjects with COPD of East Asian heritage (n = 113) compared with White subjects (Figure 1). However, this higher exposure to fluticasone furoate is not expected to have clinically relevant effects on serum or urine cortisol or on efficacy in these racial groups. In East Asian subjects with asthma (Japanese, East Asian, and Southeast Asian heritage) (n = 92), there was no effect of race on pharmacokinetics of fluticasone furoate (Figure 2).

Umeclidinium:

There was no effect of race on the pharmacokinetics of umeclidinium in subjects with COPD or asthma (Figures 1 and 2).

Vilanterol:

There was no effect of race on the pharmacokinetics of vilanterol in subjects with COPD (Figure 1). In East Asian subjects with asthma (Japanese, East Asian, and Southeast Asian heritage) (n = 92), estimates of vilanterol C_maxat steady state were approximately 3-fold higher than non-East Asian subjects (Figure 2). However, the higher systemic exposure is not expected to have a clinically relevant effect on heart rate.

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 subjects with mild, moderate, and severe hepatic impairment, respectively, compared with healthy subjects (Figure 3).

In subjects 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 subjects 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.

Umeclidinium:

The impact of hepatic impairment on the pharmacokinetics of umeclidinium has been evaluated in subjects with moderate hepatic impairment (Child-Pugh score of 7-9). There was no evidence of an increase in systemic exposure to umeclidinium (C_maxand AUC) (Figure 4). There was no evidence of altered protein binding in subjects with moderate hepatic impairment compared with healthy subjects. TRELEGY ELLIPTA has not been evaluated in subjects with severe hepatic impairment.

Vilanterol:

Hepatic impairment had no effect on vilanterol systemic exposure (C_maxand AUC_sson 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 (Figure 3).

There were no additional clinically relevant effects of the fluticasone furoate/vilanterol combinations on heart rate or serum potassium in subjects 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 in subjects with severe renal impairment compared with healthy subjects (Figure 3). There was no evidence of greater corticosteroid class-related systemic effects (assessed by serum cortisol) in subjects with severe renal impairment compared with healthy subjects.

Umeclidinium:

The pharmacokinetics of umeclidinium has been evaluated in subjects with severe renal impairment (CrCl <30 mL/min). There was no evidence of an increase in systemic exposure to umeclidinium (C_maxand AUC) (Figure 4). There was no evidence of altered protein binding in subjects with severe renal impairment compared with healthy subjects.

Vilanterol:

Systemic exposure (AUC_ss) was 56% higher in subjects with severe renal impairment compared with healthy subjects (Figure 3). There was no evidence of greater beta‑agonist class-related systemic effects (assessed by heart rate and serum potassium) in subjects with severe renal impairment compared with healthy subjects.

Drug Interaction Studies

No drug-drug interaction studies have been conducted with TRELEGY ELLIPTA. The information below is from drug-drug interaction studies conducted with umeclidinium, fluticasone furoate/vilanterol, or umeclidinium/vilanterol. The potential for fluticasone furoate, umeclidinium, 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 (Figure 3). 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.

Cytochrome P450 2D6:

In vitro metabolism of umeclidinium is mediated primarily by CYP2D6. However, no clinically meaningful difference in systemic exposure to umeclidinium (500 mcg) (8 times the approved dose) was observed following repeat daily inhaled dosing to normal (ultra‑rapid, extensive, and intermediate metabolizers) and CYP2D6 poor metabolizer subjects.

Inhibitors of P-glycoprotein:

Fluticasone furoate, umeclidinium, and vilanterol are substrates of 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 (Figure 3). Drug interaction trials with a specific P-gp inhibitor and fluticasone furoate have not been conducted. The effect of the moderate P-gp transporter inhibitor verapamil (240 mg once daily) on the steady-state pharmacokinetics of umeclidinium was assessed in healthy subjects. No effect on umeclidinium C_maxwas observed; however, an approximately 1.4-fold increase in umeclidinium AUC was observed (Figure 4).

• •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 agonists (LABA) as monotherapy (without ICS) for asthma is associated with an increased risk of asthma-related death. Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent 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 subjects with asthma. Three (3) trials included adult and adolescent subjects 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 subjects 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 adolescent 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 adolescent 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 Subjects with Asthma Aged 12 Years and Older

  ICS = Inhaled Corticosteroid, LABA = Long-acting Beta2-adrenergic Agonist. a Randomized subjects who had taken at least 1 dose of study drug. Planned treatment used for analysis. b Estimated using a Cox proportional hazards model for time to first event with baseline hazards stratified by each of the 3 trials. c Number of subjects 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. Subjects can have 1 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 subjects 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%) subjects randomized to ICS/LABA and 21/3,101 (0.7%) subjects 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). TRELEGY ELLIPTA is not indicated for use in pediatric patients aged 17 years and younger.

  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 subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol vs. 3/13,179 in subjects 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

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

  If TRELEGY ELLIPTA 100/62.5/25 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 TRELEGY ELLIPTA 100/62.5/25 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 TRELEGY ELLIPTA.

  TRELEGY ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. TRELEGY 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 TRELEGY 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 TRELEGY 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 Avoid Excessive Use of TRELEGY ELLIPTA and Avoid Use with Other Long-acting Beta₂-agonists

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

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

  Candida albicans

  have occurred in subjects treated with orally inhaled drug products containing fluticasone furoate. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with TRELEGY ELLIPTA continues. In some cases, therapy with TRELEGY ELLIPTA may need to be interrupted. Advise the patient to rinse his/her mouth with water without swallowing following administration of TRELEGY 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

  Lower respiratory tract infections, including pneumonia, have been reported following the inhaled administration of corticosteroids.

  Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as clinical features of pneumonia and exacerbations frequently overlap.

  In two 12-week trials of subjects with COPD (N = 824), the incidence of pneumonia was <1% for both treatment arms: umeclidinium 62.5 mcg + fluticasone furoate/vilanterol 100/25 mcg or placebo + fluticasone furoate/vilanterol 100/25 mcg. Fatal pneumonia occurred in 1 subject receiving placebo + fluticasone furoate/vilanterol 100/25 mcg.

  In a 52-week trial of subjects with COPD (N = 10,355), the incidence of pneumonia was 8% for TRELEGY ELLIPTA 100/62.5/25 mcg (n = 4,151), 7% for fluticasone furoate/vilanterol 100/25 mcg (n = 4,134), and 5% for umeclidinium/vilanterol 62.5/25 mcg (n = 2,070). Fatal pneumonia occurred in 12 of 4,151 patients (0.35 per 100 patient-years) receiving TRELEGY ELLIPTA 100/62.5/25 mcg; 5 of 4,134 patients (0.17 per 100 patient-years) receiving fluticasone furoate/vilanterol 100/25 mcg; and 5 of 2,070 patients (0.29 per 100 patient-years) receiving umeclidinium/vilanterol 62.5/25 mcg.

  In a mortality trial with fluticasone furoate/vilanterol 100/25 mcg with a median treatment duration of 1.5 years in 16,568 subjects with moderate COPD and cardiovascular disease, the annualized incidence rate of pneumonia was 3.4 per 100 patient-years for fluticasone furoate/vilanterol 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 subjects receiving fluticasone furoate/vilanterol 100/25 mcg, 9 subjects receiving placebo, 10 subjects receiving fluticasone furoate 100 mcg, and 6 subjects 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

  Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults 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 safety and effectiveness of TRELEGY have not been established in pediatric patients and TRELEGY is not indicated for use in this population. 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 TRELEGY ELLIPTA. (
  5.7 Transferring Patients from Systemic Corticosteroid Therapy

  HPA 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 TRELEGY 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 health care 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 TRELEGY ELLIPTA. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with TRELEGY ELLIPTA. Lung function (FEV₁), 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 TRELEGY 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 TRELEGY 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 TRELEGY 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 TRELEGY 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 TRELEGY 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 TRELEGY ELLIPTA and institute alternative therapy. (
  5.10 Paradoxical Bronchospasm

  As with other inhaled therapies, TRELEGY ELLIPTA can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with TRELEGY ELLIPTA, it should be treated immediately with an inhaled, short-acting bronchodilator; TRELEGY ELLIPTA should be discontinued immediately; and alternative therapy should be instituted.
  )
• •Use with caution in patients with cardiovascular disorders because of beta-adrenergic stimulation. (
  5.12 Cardiovascular Effects

  Vilanterol, like other 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. If such effects occur, TRELEGY 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.

  TRELEGY ELLIPTA, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

  In a 52-week trial of subjects with COPD, the exposure-adjusted rates for any on-treatment major adverse cardiac event, including non-fatal central nervous system hemorrhages and cerebrovascular conditions, non-fatal myocardial infarction (MI), non-fatal acute MI, and adjudicated on-treatment death due to cardiovascular events, was 2.2 per 100 patient-years for TRELEGY ELLIPTA (n = 4,151), 1.9 per 100 patient-years for fluticasone furoate/vilanterol 100/25 mcg (n = 4,134), and 2.2 per 100 patient-years for umeclidinium/vilanterol 62.5/25 mcg (n = 2,070). Adjudicated on-treatment deaths due to cardiovascular events occurred in 20 of 4,151 patients (0.54 per 100 patient-years) receiving TRELEGY ELLIPTA; 27 of 4,134 patients (0.78 per 100 patient-years) receiving fluticasone furoate/vilanterol; and 16 of 2,070 patients (0.94 per 100 patient-years) receiving umeclidinium/vilanterol.

  In a mortality trial with fluticasone furoate/vilanterol with a median treatment duration of 1.5 years in 16,568 subjects 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 fluticasone furoate/vilanterol 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 subjects receiving fluticasone furoate/vilanterol 100/25 mcg, 86 subjects receiving placebo, 80 subjects receiving fluticasone furoate 100 mcg, and 90 subjects 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 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 TRELEGY ELLIPTA and periodically thereafter. If significant reductions in BMD are seen and TRELEGY ELLIPTA is still considered medically important for that patient’s COPD therapy, use of therapy to treat or prevent osteoporosis should be strongly considered.
  )
• •Glaucoma and cataracts may occur with long-term use of ICS. Worsening of narrow-angle glaucoma may occur. Use with caution in patients with narrow-angle glaucoma and instruct patients to contact a healthcare provider immediately if symptoms occur. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use TRELEGY ELLIPTA long term. (
  5.14 Glaucoma and Cataracts, Worsening of Narrow-Angle Glaucoma

  Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD or asthma following the long-term administration of ICS or with use of inhaled anticholinergics. TRELEGY ELLIPTA should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should also be alert for signs and symptoms of acute narrow‑angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a healthcare provider immediately if any of these signs or symptoms develop. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use TRELEGY ELLIPTA long term.
  )
• •Worsening of urinary retention may occur. Use with caution in patients with prostatic hyperplasia or bladder-neck obstruction and instruct patients to contact a healthcare provider immediately if symptoms occur. (
  5.15 Worsening of Urinary Retention

  TRELEGY ELLIPTA, like all therapies containing an anticholinergic, should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to consult a healthcare provider immediately if any of these signs or symptoms develop.
  )
• •Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. (
  5.16 Coexisting Conditions

  TRELEGY ELLIPTA, like all therapies containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis 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.
  )
• •Be alert to hypokalemia and hyperglycemia. (
  5.17 Hypokalemia and Hyperglycemia

  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. Beta-agonist therapies may produce transient hyperglycemia in some patients.
  )