Trelegy Ellipta

TRELEGY ELLIPTA- fluticasone furoate, umeclidinium bromide and vilanterol trifenatate powder
GlaxoSmithKline LLC

1 INDICATIONS AND USAGE

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).

1.2 Maintenance Treatment of Asthma

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

1.3 Limitations of Use

TRELEGY ELLIPTA is NOT indicated for the relief of acute bronchospasm.

2 DOSAGE AND ADMINISTRATION

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 (12.3)].

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.

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.

3 DOSAGE FORMS AND STRENGTHS

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.

4 CONTRAINDICATIONS

TRELEGY ELLIPTA is contraindicated in the following conditions:

•

Primary treatment of status asthmaticus or other acute episodes of COPD or asthma where intensive measures are required [see Warnings and Precautions (5.2)].

•

Severe hypersensitivity to milk proteins or demonstrated hypersensitivity to fluticasone furoate, umeclidinium, vilanterol, or any of the excipients [see Warnings and Precautions (5.11), Description (11)].

5 WARNINGS AND PRECAUTIONS

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 (Table 1). 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.