Fluticasone Furoate Inhalation Powder

The active component of ARNUITY ELLIPTA is fluticasone furoate, a synthetic trifluorinated corticosteroid having the chemical name (6α,11β,16α,17α)-6,9-difluoro-17-{[(fluoro-methyl)thio]carbonyl}-11-hydroxy-16-methyl-3-oxoandrosta-1,4-dien-17-yl 2-furancarboxylate and the following chemical structure:

Fluticasone furoate is a white powder with a molecular weight of 538.6, and the empirical formula is C27H29F3O6S. It is practically insoluble in water.

ARNUITY ELLIPTA is a light grey and orange plastic inhaler containing a foil blister strip. Each blister on the strip contains a white powder mix of micronized fluticasone furoate (100 or 200 mcg) and lactose monohydrate (12.4 or 12.3 mg) for a total powder mix of 12.5 mg per blister. The lactose monohydrate contains milk proteins. After the inhaler is activated, the powder within the blister is exposed and ready for dispersion into the airstream created by the patient inhaling through the mouthpiece.

Under standardized in vitro test conditions, ARNUITY ELLIPTA 100 mcg and ARNUITY ELLIPTA 200 mcg deliver 90 and 182 mcg, respectively, of fluticasone furoate per blister when tested at a flow rate of 60 L/min for 4 seconds.

In adult subjects with asthma and a mean FEV1 of 2.55 L/sec (range: 1.63 to 3.97 L/sec), mean peak inspiratory flow through the ELLIPTA inhaler was 103.2 L/min (range: 71.2 to 133.1 L/min).

The actual amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow profile.

Mechanism Of Action

Fluticasone furoate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. Fluticasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is approximately 29.9 times that of dexamethasone and 1.7 times that of fluticasone propionate. The clinical relevance of these findings is unknown.

The precise mechanism of corticosteroid action on asthma is not known. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma.

Though effective for the treatment of asthma, corticosteroids may not affect symptoms immediately. Individual patients will experience a variable time to onset and degree of symptom relief. Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment. When corticosteroids are discontinued, asthma stability may persist for several days or longer.

Trials in subjects with asthma have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects with recommended doses of orally inhaled fluticasone furoate. This is explained by a combination of a relatively high local anti-inflammatory effect, negligible oral systemic bioavailability (approximately 1.3%), and the minimal pharmacological activity of the metabolites detected in man.

Pharmacodynamics

The pharmacodynamics of fluticasone furoate were characterized in trials of fluticasone furoate given as a single component and also in trials of fluticasone furoate given in combination with vilanterol.

Healthy Subjects: Inhaled fluticasone furoate at repeat doses up to 400 mcg was not associated with statistically significant decreases in serum or urinary cortisol in healthy subjects. Decreases in serum and urine cortisol levels were observed at fluticasone furoate exposures several-fold higher than exposures observed at the therapeutic dose.

Subjects with Asthma: A randomized, double-blind, parallel-group trial in 185 subjects with asthma showed no difference between once-daily treatment with fluticasone furoate/vilanterol 100 mcg/25 mcg or fluticasone furoate/vilanterol 200 mcg/25 mcg compared with placebo on serum cortisol weighted mean (0 to 24 hours), serum cortisol AUC(0-24), and 24-hour urinary cortisol after 6 weeks of treatment, whereas prednisolone 10 mg given once daily for 7 days resulted in significant cortisol suppression.

A QT/QTc trial did not demonstrate an effect of fluticasone furoate administration on the QTc interval. The effect of a single dose of 4,000 mcg of orally inhaled fluticasone furoate on the QTc interval was evaluated over 24 hours in 40 healthy male and female subjects in a placebo- and positive-controlled (a single dose of 400 mg oral moxifloxacin) cross-over trial. The QTcF maximal mean change from baseline following fluticasone furoate was similar to that observed with placebo with a treatment difference of 0.788 msec (90% CI: -1.802, 3.378). In contrast, moxifloxacin given as a 400-mg tablet resulted in prolongation of the QTcF maximal mean change from baseline compared with placebo with a treatment difference of 9.929 msec (90% CI: 7.339, 12.520).

Pharmacokinetics

The pharmacokinetics of fluticasone furoate were characterized in trials of fluticasone furoate given as a single component and also in trials of fluticasone furoate given in combination with vilanterol. Linear pharmacokinetics were observed for fluticasone furoate (200 to 800 mcg). On repeated once-daily inhalation administration, steady state of fluticasone furoate plasma concentration was achieved after 6 days, and the accumulation was up to 2.6-fold as compared with single dose.

Fluticasone furoate plasma levels may not predict therapeutic effect. Peak plasma concentrations are reached within 0.5 to 1 hour. Absolute bioavailability of fluticasone furoate when administrated by inhalation was 13.9%, primarily due to absorption of the inhaled portion of the dose delivered to the lung. Oral bioavailability from the swallowed portion of the dose is low (approximately 1.3%) due to extensive first-pass metabolism. Systemic exposure (AUC) in subjects with asthma was 26% lower than observed in healthy subjects.

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

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.

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.

Special Populations

The effect of renal and hepatic impairment and other intrinsic factors on the pharmacokinetics of fluticasone furoate is shown in Figure 1.

Figure 1: Impact of Intrinsic Factors on the Pharmacokinetics (PK) of Fluticasone Furoate (FF)

a Age, gender, and ethnicity comparison for ARNUITY ELLIPTA in subjects with asthma.

b Renal groups (fluticasone furoate/vilanterol 200 mcg/25 mcg) and hepatic groups (fluticasone furoate/vilanterol 200 mcg/25 mcg or fluticasone furoate/vilanterol 100 mcg/12.5 mcg) compared with healthy control group.

Race: 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 Caucasian subjects. Similar differences were observed for subjects with asthma (Figure 1). 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.

Hepatic Impairment: Following repeat dosing of fluticasone furoate/vilanterol 200 mcg/25 mcg (100 mcg/12.5 mcg in the severe impairment group) for 7 days, fluticasone furoate systemic exposure (AUC) increased 34%, 83%, and 75% in subjects with mild, moderate, and severe hepatic impairment, respectively, compared with healthy subjects (see Figure 1).

In subjects with moderate hepatic impairment receiving fluticasone furoate/vilanterol 200 mcg/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 mcg/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.

Renal Impairment: Fluticasone furoate systemic exposure was not increased in subjects with severe renal impairment compared with healthy subjects (see Figure 1). 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.

Drug Interactions

The potential for fluticasone furoate 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 was 36% higher after single and repeated doses when coadministered with ketoconazole 400 mg compared with placebo (see Figure 2). The increase in fluticasone furoate exposure was associated with a 27% reduction in weighted mean serum cortisol (0 to 24 hours).

Figure 2: Impact of Coadministered Ketoconazolea on the Pharmacokinetics (PK) of Fluticasone Furoate

a Compared with placebo group.

Clinical Studies

The safety and efficacy of ARNUITY ELLIPTA were evaluated in 3,611 subjects with asthma. The development program included 4 confirmatory trials of 3 and 6 months' duration and 3 dose-ranging trials of 8 weeks' duration. The efficacy of ARNUITY ELLIPTA is based primarily on the dose-ranging trials and the confirmatory trials described below.

Dose-Ranging Trials

Eight doses of fluticasone furoate ranging from 25 to 800 mcg once daily were evaluated in 3 randomized, double-blind, placebo-controlled, 8-week trials in subjects with asthma. Across the 3 trials, subjects were uncontrolled at baseline on treatments of short-acting beta2-agonist and/or non-corticosteroid controller medications (Trial 687), low-dose inhaled corticosteroid (Trial 685), or medium doses of inhaled corticosteroid (Trial 684). The trials in Figure 3 were dose-ranging trials of ARNUITY ELLIPTA not designed to provide comparative effectiveness data and should not be interpreted as evidence of superiority/inferiority to fluticasone propionate. A dose-related increase in trough FEV1 at Week 8 was seen for doses from 25 to 200 mcg with no consistent additional benefit for doses above 200 mcg as seen in Figure 3. To evaluate dosing frequency, a separate trial compared fluticasone furoate 200 mcg once daily, fluticasone furoate 100 mcg twice daily, fluticasone propionate 100 mcg twice daily, and fluticasone propionate 200 mcg once daily. The results supported the selection of the once-daily dosing frequency.

Figure 3: Dose-Ranging Trials

FF = Fluticasone furoate.
FP = Fluticasone propionate.
OD = Once daily.
BD = Twice daily.

Confirmatory Trials

The clinical development program for ARNUITY ELLIPTA included 4 confirmatory trials in adolescent and adult subjects aged 12 years and older with asthma. The trials were designed to evaluate the safety and efficacy of ARNUITY ELLIPTA given once daily in the evening on lung function in subjects who were not controlled on their current treatments of inhaled corticosteroids, or combination therapy consisting of an inhaled corticosteroid plus a LABA. Study treatments were delivered as inhalation powders. The primary endpoint in all trials was change from baseline in evening trough FEV1 measured approximately 24 hours after the final dose of study medication. Trough FEV1 (assessed at approximately 24 hours after the previous dose) was also assessed at clinic visits throughout the trials. Trials 2 and 4 had a co-primary endpoint of change from baseline in weighted mean serial FEV1 measured after the final dose of study medication at 5, 15, and 30 minutes and 1, 2, 3, 4, 5, 12, 16, 20, 23, and 24 hours post-dose.

Trial 1 was a 24-week trial that evaluated the efficacy of ARNUITY ELLIPTA 100 mcg compared with placebo on lung function in subjects with asthma. Inhaled fluticasone propionate 250 mcg twice daily was included as an active control. Of the 343 subjects, 59% were female and 79% were Caucasian. The mean age was 41 years. The trial included a 4-week run-in period during which the subjects were symptomatic while taking their usual low- to mid-dose inhaled corticosteroid therapy (i.e., fluticasone propionate 100 to 500 mcg daily or equivalent). Mean baseline percent predicted FEV1 was approximately 73% overall and was similar across the 3 treatment groups. Thirty-five percent of subjects on placebo and 19% of subjects on ARNUITY ELLIPTA 100 mcg failed to complete the 24-week trial.

The change in trough FEV1 from baseline to Week 24, or the last available on-treatment visit prior to Week 24, was assessed to evaluate the efficacy of ARNUITY ELLIPTA 100 mcg. The mean change from baseline in trough FEV1 was greater among subjects receiving ARNUITY ELLIPTA 100 mcg than among those receiving placebo (mean treatment difference from placebo 146 mL; 95% CI: 36, 257) as shown in Table 3.

Table 3: Change from Baseline in Trough FEV1 (mL) at Week 24 – Trial 1

Trial 2 was a 12-week trial that evaluated the efficacy of ARNUITY ELLIPTA 100 mcg on lung function in subjects with asthma compared with placebo. The combination of fluticasone furoate 100 mcg and vilanterol 25 mcg was also included as a treatment arm. Of the 609 subjects, 58% were female and 84% were Caucasian. The mean age was 40 years. The trial included a 4-week run-in period during which the subjects were symptomatic while taking their usual low- to mid-dose inhaled corticosteroid (fluticasone propionate 200 to 500 mcg/day or equivalent). If LABA were used prior to screening, their use was discontinued during the run-in. Mean baseline percent predicted FEV1 was approximately 70% in both treatment groups. Twenty-six percent of subjects on placebo and 10% of subjects on ARNUITY ELLIPTA 100 mcg failed to complete the 12-week trial.

The co-primary efficacy endpoints in Trial 2 were change from baseline in trough FEV1 at Week 12 and weighted mean FEV1 (0-24 hours) at the end of the 12-week treatment period. Trough FEV1 was assessed at clinic visits throughout the trial. Weighted mean FEV1 (0-24 hours) was recorded at baseline and after the final study dose with serial measurements taken at frequent intervals (at 5, 15, and 30 minutes and 1, 2, 3, 4, 5, 12, 16, 20, 23, and 24 hours post-dose) in a subset of subjects (n = 201).

ARNUITY ELLIPTA 100 mcg once daily had greater mean changes from baseline in trough FEV1 than placebo throughout the trial. At Week 12 or the last available on-treatment visit prior to Week 12, the mean change from baseline in trough FEV1 was greater among subjects receiving ARNUITY ELLIPTA 100 mcg once daily than among those receiving placebo (mean treatment difference 136 mL; 95% CI: 51, 222).

Lung function improvements were sustained over the 24-hour period following the final dose of ARNUITY ELLIPTA 100 mcg (see Figure 4). Compared with placebo, at Week 12 the change from baseline in weighted mean FEV1 was significantly greater for ARNUITY ELLIPTA 100 mcg (mean treatment difference 186 mL; 95% CI: 62, 310).

Figure 4: Mean Change from Baseline in Individual Serial FEV1 (mL) Assessments after 12 Weeks of Treatment – Trial 2

Subjects in both Trials 1 and 2 receiving ARNUITY ELLIPTA 100 mcg once daily had a greater improvement from baseline in percentage of 24-hour periods without need of beta2-agonist rescue medication use than subjects receiving placebo.

Trial 3 was a 24-week trial that evaluated the relative efficacy of ARNUITY ELLIPTA 100 mcg and ARNUITY ELLIPTA 200 mcg on lung function in subjects with asthma. Of the 219 subjects, 68% were female and 87% were Caucasian. The mean age was 46 years. The trial included a 4-week run-in period during which the subjects were symptomatic while taking their usual mid- to high-dose inhaled corticosteroid therapy (i.e., fluticasone propionate greater than 250 to 1,000 mcg/day or equivalent). If LABA were used prior to screening, their use was discontinued during the run-in. Mean baseline percent predicted FEV1 was approximately 68% overall and similar in the 2 treatment groups. Sixteen percent of subjects on ARNUITY ELLIPTA 100 mcg and 13% of subjects on ARNUITY ELLIPTA 200 mcg failed to complete the 24-week trial.

The primary efficacy endpoint was mean change from baseline in trough FEV1 at Week 24. There were trends toward greater mean changes from baseline in the group receiving ARNUITY ELLIPTA 200 mcg than the group receiving ARNUITY ELLIPTA 100 mcg throughout the trial (see Figure 5). At Week 24 or the last available on-treatment visit prior to Week 24, the mean change from baseline in trough FEV1 was 208 mL for ARNUITY ELLIPTA 100 mcg, as compared to 284 mL for ARNUITY ELLIPTA 200 mcg (difference of 77 mL; 95% CI: -39, 192) as seen in Figure 5.

Figure 5: Mean Change from Baseline in Trough FEV1 (mL) over Time – Trial 3

Trial 4 was a 24-week trial that evaluated the efficacy of ARNUITY ELLIPTA 200 mcg once daily and fluticasone propionate 500 mcg twice daily on lung function in subjects with asthma. The combination of fluticasone furoate 200 mcg and vilanterol 25 mcg was also included as a treatment arm (data not shown). Of the 586 subjects, 59% were female and 84% were Caucasian. The mean age was 46 years. The trial included a 4-week run-in period during which the subjects were symptomatic while taking their usual mid- to high-dose inhaled corticosteroid (fluticasone propionate 500 to 1,000 mcg/day or equivalent). If LABA were used prior to screening, their use was discontinued during the run-in. Mean baseline percent predicted FEV1 was approximately 67% in both treatment groups.

Both ARNUITY ELLIPTA 200 mcg once daily and fluticasone propionate 500 mcg twice daily produced improvement from baseline in lung function. At Week 24 the mean change from baseline in trough FEV1 was 201 mL for ARNUITY ELLIPTA 200 mcg once daily and 183 mL for fluticasone propionate 500 mcg twice daily (treatment difference of 18 mL, 95% CI: -66, 102).

Lung function improvements were sustained over the 24-hour period following the final dose of ARNUITY ELLIPTA 200 mcg (see Figure 6). At Week 24, the change from baseline in weighted mean FEV1 was 328 mL for ARNUITY ELLIPTA 200 mcg once daily and 258 mL for fluticasone propionate 500 twice daily (difference of 70 mL; 95% CI: -67, 208).

Figure 6: Mean Change from Baseline in Individual Serial FEV1 (mL) Assessments after 24 Weeks of Treatment – Trial 4

Dosage Forms And Strengths

Inhalation powder: Disposable light grey and beige plastic inhaler containing 2 foil blister strips of powder intended for oral inhalation only. One strip contains fluticasone furoate (100 mcg per blister) and the other strip contains a blend of umeclidinium and vilanterol (62.5 mcg and 25 mcg per blister, respectively).

Storage And Handling

TRELEGY ELLIPTA is supplied as a disposable light grey and beige plastic inhaler containing 2 foil strips, each with 30 blisters (or 14 blisters for the institutional pack). One strip contains fluticasone furoate (100 mcg per blister), and the other strip contains a blend of umeclidinium and vilanterol (62.5 mcg and 25 mcg per blister, respectively). A blister from each strip is used to create 1 dose. The inhaler is packaged within a moisture-protective foil tray with a desiccant and a peelable lid in the following packs:

NDC 0173-0887-10 TRELEGY ELLIPTA 30 inhalations (60 blisters)
NDC 0173-0887-14 TRELEGY ELLIPTA 14 inhalations (28 blisters), institutional pack

Store at room temperature between 68°F and 77°F (20°C and 25°C); excursions permitted from 59°F to 86°F (15°C to 30°C) [See USP Controlled Room Temperature]. Store in a dry place away from direct heat or sunlight. Keep out of reach of children.

TRELEGY ELLIPTA should be stored inside the unopened moisture-protective foil tray and only removed from the tray immediately before initial use. Discard TRELEGY ELLIPTA 6 weeks after opening the foil tray or when the counter reads “0” (after all blisters have been used), whichever comes first. The inhaler is not reusable. Do not attempt to take the inhaler apart.

GlaxoSmithKline, Research Triangle Park, NC 27709. Revised: Sep 2017

TRELEGY ELLIPTA
(TREL-e-gee e-LIP-ta)
(fluticasone furoate, umeclidinium, and vilanterol) Inhalation Powder

What is the most important information I should know about TRELEGY ELLIPTA?

TRELEGY ELLIPTA is approved only for use in chronic obstructive pulmonary disease (COPD).

TRELEGY ELLIPTA is not approved for the treatment of asthma.

TRELEGY ELLIPTA can cause serious side effects, including:

• People with asthma who take long-acting beta2-adrenergic agonist (LABA) medicines, such as vilanterol (one of the medicines in TRELEGY ELLIPTA), have an increased risk of death from asthma problems. It is not known whether fluticasone furoate, one of the medicines in TRELEGY ELLIPTA, reduces the risk of death from asthma problems seen with LABA medicines.
• It is not known if LABA medicines, such as vilanterol, increase the risk of death in people with COPD.
• Call your healthcare provider if breathing problems worsen over time while using TRELEGY ELLIPTA. You may need different treatment.
• Get emergency medical care if:
  • your breathing problems worsen quickly.
  • you use your rescue inhaler, but it does not relieve your breathing problems.

What is TRELEGY ELLIPTA?

• TRELEGY ELLIPTA combines 3 medicines in one inhaler, an inhaled corticosteroid (ICS) medicine, fluticasone furoate; an anticholinergic medicine, umeclidinium; and a LABA medicine, vilanterol.
• ICS medicines such as fluticasone furoate help to decrease inflammation in the lungs. Inflammation in the lungs can lead to breathing problems.
• Anticholinergic medicines such as umeclidinium and LABA medicines such as vilanterol help the muscles around the airways in your lungs stay relaxed to prevent symptoms such as wheezing, cough, chest tightness, and shortness of breath. These symptoms can happen when the muscles around the airways tighten. This makes it hard to breathe.
• TRELEGY ELLIPTA is a prescription medicine used to treat COPD. COPD is a chronic lung disease that includes chronic bronchitis, emphysema, or both. TRELEGY ELLIPTA is used long term as 1 inhalation 1 time each day to improve symptoms of COPD for better breathing and to reduce the number of flare-ups (the worsening of your COPD symptoms for several days).
• TRELEGY ELLIPTA is not used to relieve sudden breathing problems and will not replace a rescue inhaler. Always have a rescue inhaler (an inhaled, short-acting bronchodilator) with you to treat sudden breathing problems. If you do not have a rescue inhaler, contact your healthcare provider to have one prescribed for you.
• TRELEGY ELLIPTA should not be used in children. It is not known if TRELEGY ELLIPTA is safe and effective in children.

Do not use TRELEGY ELLIPTA if you:

• have a severe allergy to milk proteins. Ask your healthcare provider if you are not sure.
• are allergic to fluticasone furoate, umeclidinium, vilanterol, or any of the ingredients in TRELEGY ELLIPTA. See the end of this Medication Guide for a complete list of ingredients in TRELEGY ELLIPTA.

Before using TRELEGY ELLIPTA, tell your healthcare provider about all of your medical conditions, including if you:

• have heart problems.
• have high blood pressure.
• have seizures.
• have thyroid problems.
• have diabetes.
• have liver problems.
• have weak bones (osteoporosis).
• have an immune system problem.
• have eye problems such as glaucoma or cataracts. TRELEGY ELLIPTA may make your glaucoma worse.
• are allergic to milk proteins.
• have prostate or bladder problems, or problems passing urine. TRELEGY ELLIPTA may make these problems worse.
• have any type of viral, bacterial, parasitic, or fungal infection.
• are exposed to chickenpox or measles.
• are pregnant or plan to become pregnant. It is not known if TRELEGY ELLIPTA may harm your unborn baby.
• are breastfeeding. It is not known if the medicines in TRELEGY ELLIPTA pass into your milk and if they can harm your baby.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. TRELEGY ELLIPTA and certain other medicines may interact with each other. This may cause serious side effects.

Especially tell your healthcare provider if you take:

• anticholinergics (including tiotropium, ipratropium, aclidinium)
• atropine
• other LABA (including salmeterol, formoterol, arformoterol, olodaterol, and indacaterol)
• antifungal or anti-HIV medicines.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

How should I use TRELEGY ELLIPTA?

Read the step-by-step instructions for using TRELEGY ELLIPTA at the end of this Medication Guide.

• Do not use TRELEGY ELLIPTA unless your healthcare provider has taught you how to use the inhaler and you understand how to use it correctly.
• Use TRELEGY ELLIPTA exactly as your healthcare provider tells you to use it. Do not use TRELEGY ELLIPTA more often than prescribed.
• Use 1 inhalation of TRELEGY ELLIPTA 1 time each day. Use TRELEGY ELLIPTA at the same time each day.
• If you miss a dose of TRELEGY ELLIPTA, take it as soon as you remember. Do not take more than 1 inhalation per day. Take your next dose at your usual time. Do not take 2 doses at 1 time.
• If you take too much TRELEGY ELLIPTA, call your healthcare provider or go to the nearest hospital emergency room right away if you have any unusual symptoms, such as worsening shortness of breath, chest pain, increased heart rate, or shakiness.
• Do not use other medicines that contain a LABA or an anticholinergic for any reason. Ask your healthcare provider or pharmacist if any of your other medicines are LABA or anticholinergic medicines.
• Do not stop using TRELEGY ELLIPTA unless told to do so by your healthcare provider because your symptoms might get worse. Your healthcare provider will change your medicines as needed.
• TRELEGY ELLIPTA does not relieve sudden symptoms of COPD and you should not take extra doses of TRELEGY ELLIPTA to relieve these sudden symptoms. Always have a rescue inhaler with you to treat sudden symptoms. If you do not have a rescue inhaler, call your healthcare provider to have one prescribed for you.
• Call your healthcare provider or get medical care right away if:
  • your breathing problems get worse.
  • you need to use your rescue inhaler more often than usual.
  • your rescue inhaler does not work as well to relieve your symptoms.

What are the possible side effects of TRELEGY ELLIPTA?

TRELEGY ELLIPTA can cause serious side effects, including:

• See “What is the most important information I should know about TRELEGY ELLIPTA?”
• fungal infection in your mouth or throat (thrush). Rinse your mouth with water without swallowing after using TRELEGY ELLIPTA to help reduce your chance of getting thrush.
• pneumonia. People with COPD have a higher chance of getting pneumonia. TRELEGY ELLIPTA may increase the chance of getting pneumonia. Call your healthcare provider if you notice any of the following symptoms:
  • increase in mucus (sputum) production
  • chills
  • change in mucus color
  • increased cough
  • fever
  • increased breathing problems
• weakened immune system and increased chance of getting infections (immunosuppression).
• reduced adrenal function (adrenal insufficiency). Adrenal insufficiency is a condition where the adrenal glands do not make enough steroid hormones. This can happen when you stop taking oral corticosteroid medicines (such as prednisone) and start taking a medicine containing an ICS (such as TRELEGY ELLIPTA). During this transition period, when your body is under stress from fever, trauma (such as a car accident), infection, surgery, or worse COPD symptoms, adrenal insufficiency can get worse and may cause death.
  Symptoms of adrenal insufficiency include:
  • feeling tired
  • nausea and vomiting
  • lack of energy
  • low blood pressure
  • weakness
• sudden breathing problems immediately after inhaling your medicine. If you have sudden breathing problems immediately after inhaling your medicine, stop taking TRELEGY ELLIPTA and call your healthcare provider right away.
• serious allergic reactions. Call your healthcare provider or get emergency medical care if you get any of the following symptoms of a serious allergic reaction:
  • rash
  • swelling of your face, mouth, and tongue
  • hives
  • breathing problems
• effects on heart.
  • increased blood pressure
  • chest pain
  • a fast or irregular heartbeat, awareness of heartbeat
• effects on nervous system.
  • tremor
  • nervousness
• bone thinning or weakness (osteoporosis).
• new or worsening eye problems including glaucoma, narrow angle glaucoma, and cataracts. You should have regular eye exams while using TRELEGY ELLIPTA. Acute narrow-angle glaucoma can cause permanent loss of vision if not treated. Symptoms of acute narrow-angle glaucoma may include:
  • eye pain or discomfort
  • seeing halos or bright colors around lights
  • nausea or vomiting
  • red eyes
  • blurred vision
    If you have these symptoms, call your healthcare provider right away before taking another dose.
• urinary retention. People who take TRELEGY ELLIPTA may develop new or worse urinary retention. Symptoms of urinary retention may include:
  • difficulty urinating
  • urinating frequently
  • painful urination
  • urination in a weak stream or drips
    If you have these symptoms of urinary retention, stop taking TRELEGY ELLIPTA, and call your healthcare provider right away before taking another dose.
• changes in laboratory blood values, including high levels of blood sugar (hyperglycemia) and low levels of potassium (hypokalemia).

Common side effects of TRELEGY ELLIPTA include:

• headache
• nausea, vomiting, and diarrhea
• back pain
• cough
• taste disturbance
• mouth and/or throat pain

These are not all the possible side effects of TRELEGY ELLIPTA.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store TRELEGY ELLIPTA?

• Store TRELEGY ELLIPTA at room temperature between 68°F and 77°F (20°C and 25°C). Keep in a dry place away from heat and sunlight.
• Store TRELEGY ELLIPTA in the unopened tray and only open when ready for use.
• Safely throw away TRELEGY ELLIPTA in the trash 6 weeks after you open the tray or when the counter reads “0”, whichever comes first. Write the date you open the tray on the label on the inhaler.

Keep TRELEGY ELLIPTA and all medicines out of the reach of children.

General information about the safe and effective use of TRELEGY ELLIPTA.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use TRELEGY ELLIPTA for a condition for which it was not prescribed. Do not give TRELEGY ELLIPTA to other people, even if they have the same symptoms that you have. It may harm them.

You can ask your healthcare provider or pharmacist for information about TRELEGY ELLIPTA that is written for health professionals.

What are the ingredients in TRELEGY ELLIPTA?

Active ingredients: fluticasone furoate, umeclidinium, vilanterol

Inactive ingredients: lactose monohydrate (contains milk proteins), magnesium stearate

INSTRUCTIONS FOR USE

TRELEGY ELLIPTA
(TREL-e-gee e-LIP-ta)
(fluticasone furoate, umeclidinium, and vilanterol inhalation powder) for oral inhalation

Read this before you start:

• If you open and close the cover without inhaling the medicine, you will lose the dose.
• The lost dose will be securely held inside the inhaler, but it will no longer be available to be inhaled.
• It is not possible to accidentally take a double dose or an extra dose in 1 inhalation.

Your TRELEGY ELLIPTA inhaler

How to use your inhaler

• TRELEGY ELLIPTA comes in a tray.
• Peel back the lid to open the tray. See Figure A.
• The tray contains a desiccant to reduce moisture. Do not eat or inhale. Throw it away in the household trash out of reach of children and pets. See Figure B.

Figure A and Figure B

Important Notes:

• Your inhaler contains 30 doses (14 doses if you have a sample or institutional pack).
• Each time you fully open the cover of the inhaler (you will hear a clicking sound), a dose is ready to be inhaled. This is shown by a decrease in the number on the counter.
• If you open and close the cover without inhaling the medicine, you will lose the dose. The lost dose will be held in the inhaler, but it will no longer be available to be inhaled. It is not possible to accidentally take a double dose or an extra dose in 1 inhalation.
• Do not open the cover of the inhaler until you are ready to use it. To avoid wasting doses after the inhaler is ready, do not close the cover until after you have inhaled the medicine.
• Write the “Tray opened” and “Discard” dates on the inhaler label. The “Discard” date is 6 weeks from the date you open the tray.

Check the counter. See Figure C.

• Before the inhaler is used for the first time, the counter should show the number 30 (14 if you have a sample or institutional pack). This is the number of doses in the inhaler.
• Each time you open the cover, you prepare 1 dose of medicine.
• The counter counts down by 1 each time you open the cover.

Figure C

Prepare your dose:

Wait to open the cover until you are ready to take your dose.

Step 1. Open the cover of the inhaler. See Figure D.

• Slide the cover down to expose the mouthpiece. You should hear a “click.” The counter will count down by 1 number. You do not need to shake this kind of inhaler. Your inhaler is now ready to use.
• If the counter does not count down as you hear the click, the inhaler will not deliver the medicine. Call your healthcare provider or pharmacist if this happens.

Figure D

Step 2. Breathe out. See Figure E.

• While holding the inhaler away from your mouth, breathe out (exhale) fully. Do not breathe out into the mouthpiece.

Figure E

Step 3. Inhale your medicine. See Figure F.

• Put the mouthpiece between your lips, and close your lips firmly around it. Your lips should fit over the curved shape of the mouthpiece.
• Take one long, steady, deep breath in through your mouth. Do not breathe in through your nose.

Figure F

• Do not block the air vent with your fingers. See Figure G.

Figure G

• Remove the inhaler from your mouth and hold your breath for about 3 to 4 seconds (or as long as comfortable for you). See Figure H.

Figure H

Step 4. Breathe out slowly and gently. See Figure I.

• You may not taste or feel the medicine, even when you are using the inhaler correctly.
• Do not take another dose from the inhaler even if you do not feel or taste the medicine.

Figure I

Step 5. Close the inhaler. See Figure J.

• You can clean the mouthpiece if needed, using a dry tissue, before you close the cover. Routine cleaning is not required.
• Slide the cover up and over the mouthpiece as far as it will go.

Figure J

Step 6. Rinse your mouth. See Figure K.

• Rinse your mouth with water after you have used the inhaler and spit the water out. Do not swallow the water.

Figure K

Important Note: When should you get a refill?

• When you have fewer than 10 doses remaining in your inhaler, the left half of the counter shows red as a reminder to get a refill. See Figure L.
• After you have inhaled the last dose, the counter will show “0” and will be empty.
• Throw the empty inhaler away in your household trash out of reach of children and pets.

Figure L

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Systemic and local corticosteroid use may result in the following:

• Candida albicans infection [see WARNINGS AND PRECAUTIONS]
• Immunosuppression [see WARNINGS AND PRECAUTIONS]
• Hypercorticism and adrenal suppression [see WARNINGS AND PRECAUTIONS]
• Reduction in BMD [see WARNINGS AND PRECAUTIONS]
• Growth effects in pediatrics [see WARNINGS AND PRECAUTIONS]
• Glaucoma and cataracts [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

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.

The safety of ARNUITY ELLIPTA was evaluated in 10 double-blind, parallel-group, controlled trials (7 with placebo) of 8 to 76 weeks' duration, which enrolled 6,219 subjects with asthma. Doses of fluticasone furoate studied ranged from 25 to 800 mcg.

ARNUITY ELLIPTA 100 mcg was studied in 1,663 subjects, and ARNUITY ELLIPTA 200 mcg was studied in 608 subjects. Subject ages ranged from 12 to 84 years, 65% were female, and 75% were Caucasian.

In these trials, the proportion of subjects who discontinued study treatment early due to adverse reactions was 2% for subjects treated with both ARNUITY ELLIPTA 100 mcg and ARNUITY ELLIPTA 200 mcg and less than or equal to 1% for placebo-treated subjects. Serious adverse events, whether considered drug-related or not by the investigators, that occurred in more than 1 subject and in a greater percentage of subjects treated with ARNUITY ELLIPTA than placebo included hypertension, abscess, breast cancer, traumatic limb amputation, subarachnoid hemorrhage, and intervertebral disc protrusion; all events occurred at rates less than or equal to 1%.

The incidence of adverse reactions associated with ARNUITY ELLIPTA 100 mcg is shown in Table 1 and is based on one 24-week trial (Trial 1) in adolescent and adult subjects with asthma.

Table 1: Adverse Reactions with ARNUITY ELLIPTA 100 mcg with Greater than or Equal to 3% Incidence and More Common than Placebo (Trial 1, Intent-to-Treat Population)

The incidence of adverse reactions associated with ARNUITY ELLIPTA 200 mcg is shown in Table 2 and is based on one 24-week trial (Trial 3) in adolescent and adult subjects with asthma. This trial did not have a placebo arm.8

Table 2: Adverse Reactions with ARNUITY ELLIPTA 200 mcg with Greater than or Equal to 3% Incidence (Trial 3, Safety Population)

Adverse reactions observed in the other trials were consistent with those described in Tables 1 and 2.

Long-term safety data are based on 2 trials in adolescent and adult subjects with asthma. In one 52-week trial, subjects received fluticasone furoate 100 mcg (n = 201) or fluticasone furoate 200 mcg (n = 202) in combination with a LABA. Subjects had a mean age of 39 years (adolescents made up 16% of the population), 63% were female, and 67% were Caucasian. In addition to the events shown in Table 1 and Table 2, adverse events occurring in greater than or equal to 3% of the subjects treated with fluticasone furoate 100 mcg or fluticasone furoate 200 mcg, in combination with a LABA, included pyrexia, extrasystoles, upper abdominal pain, respiratory tract infection, diarrhea, and allergic rhinitis.

In a second 24- to 76-week trial, subjects received fluticasone furoate 100 mcg (n = 1,010). Subjects participating in this trial had a history of one or more asthma exacerbations that required treatment with oral/systemic corticosteroids or emergency department visit or in-patient hospitalization for the treatment of asthma within the previous 12 months. Subjects had a mean age of 42 years (adolescents made up 14% of the population), 67% were female, and 73% were Caucasian. In addition to the events shown in Table 1 and Table 2, adverse events occurring in greater than or equal to 3% of subjects treated with fluticasone furoate 100 mcg for up to 76 weeks included allergic rhinitis, nasal congestion, and arthralgia.

Read the entire FDA prescribing information for Arnuity Ellipta (Fluticasone Furoate Inhalation Powder)