TRELEGY ELLIPTA 92mcg / 55mcg / 22mcg single-dose inhalation powder medication leaflet

Trelegy Ellipta 92 micrograms/55 micrograms/22 micrograms inhalation powder, pre-dispensed

Each single inhalation provides a delivered dose (the dose leaving the mouthpiece) of 92 microgramsfluticasone furoate, 65 micrograms umeclidinium bromide equivalent to 55 micrograms umeclidinium and22 micrograms vilanterol (as trifenatate). This corresponds to a pre-dispensed dose of 100 microgramsfluticasone furoate, 74.2 micrograms umeclidinium bromide equivalent to 62.5 micrograms umeclidiniumand 25 micrograms vilanterol (as trifenatate).

Each delivered dose contains approximately 25 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

Inhalation powder, pre-dispensed (inhalation powder)

White powder in a light grey inhaler (Ellipta) with a beige mouthpiece cover and a dose counter.

Trelegy Ellipta is indicated as a maintenance treatment in adult patients with moderate to severe chronicobstructive pulmonary disease (COPD) who are not adequately treated by a combination of an inhaledcorticosteroid and a long-acting β2-agonist or a combination of a long-acting β2-agonist and a long-actingmuscarinic antagonist (for effects on symptom control and prevention of exacerbations see section 5.1).

The recommended and maximum dose is one inhalation once daily, each day at the same time.

If a dose is missed the next dose should be inhaled at the usual time the next day.

No dose adjustment is required in patients 65 years of age or older (see section 5.2).

No dose adjustment is required in patients with renal impairment (see section 5.2).

No dose adjustment is required in patients with mild, moderate or severe hepatic impairment. Trelegy Elliptashould be used with caution in patients with moderate to severe hepatic impairment (see sections 4.4 and5.2).

There is no relevant use of Trelegy Ellipta in the paediatric population (under 18 years of age) for theindication of COPD.

For inhalation use only.

The following instructions for the 30 dose (30 day supply) inhaler also apply to the 14 dose (14 day supply)inhaler.

a) Prepare a dose

Open the cover when ready to inhale a dose. The inhaler should not be shaken.

Slide the cover down fully until a “click” is heard. The medicinal product is now ready to be inhaled.

The dose counter counts down by 1 to confirm. If the dose counter does not count down as the “click” isheard, the inhaler will not deliver a dose and should be taken back to a pharmacist for advice.

b) How to inhale the medicinal product

The inhaler should be held away from the mouth breathing out as far as is comfortable, but not breathing outinto the inhaler.

The mouthpiece should be placed between the lips and the lips should then be closed firmly around it. Theair vents should not be blocked with fingers during use.

* Inhale with one long, steady, deep breath in. This breath should be held in for as long as possible (atleast 3-4 seconds).

* Remove the inhaler from the mouth.

* Breathe out slowly and gently.

The medicinal product may not be tasted or felt, even when using the inhaler correctly.

The mouthpiece of the inhaler may be cleaned using a dry tissue before closing the cover.

c) Close the inhaler and rinse your mouth

Slide the cover upwards as far as it will go, to cover the mouthpiece.

Rinse your mouth with water after you have used the inhaler, do not swallow.

This will make it less likely to develop a sore mouth or throat as side effects.

For further instructions on handling the device, see section 6.6.

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Asthma

This medicinal product should not be used in patients with asthma since it has not been studied in this patientpopulation.

There are no clinical data to support the use of Trelegy Ellipta for the treatment of acute episodes ofbronchospasm, or to treat an acute COPD exacerbation (i.e. as a rescue therapy).

Increasing use of short-acting bronchodilators to relieve symptoms may indicate deterioration of diseasecontrol. In the event of deterioration of COPD during treatment with Trelegy Ellipta, a re-evaluation of thepatient and of the COPD treatment regimen should be undertaken.

Patients should not stop therapy with Trelegy Ellipta without physician supervision since symptoms mayrecur after discontinuation.

Administration of fluticasone furoate/umeclidinium/vilanterol may produce paradoxical bronchospasm withan immediate wheezing and shortness of breath after dosing and may be life-threatening. If paradoxicalbronchospasm occurs, treatment should be discontinued immediately. The patient should be assessed andalternative therapy instituted if necessary.

Cardiovascular effects, such as cardiac arrhythmias, e.g. atrial fibrillation and tachycardia, may be seen afterthe administration of muscarinic receptor antagonists and sympathomimetics, including umeclidinium andvilanterol, respectively (see section 4.8). Therefore, Trelegy Ellipta should be used with caution in patientswith unstable or life-threatening cardiovascular disease.

Patients with moderate to severe hepatic impairment receiving Trelegy Ellipta should be monitored forsystemic corticosteroid-related adverse reactions (see section 5.2).

Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for longperiods. These effects are much less likely to occur than with oral corticosteroids.

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents withsymptoms such as blurred vision or other visual disturbances, the patient should be considered for referral toan ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseasessuch as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topicalcorticosteroids.

Coexisting conditions

Trelegy Ellipta should be used with caution in patients with convulsive disorders or thyrotoxicosis, and inpatients who are unusually responsive to beta2-adrenergic agonists.

Trelegy Ellipta should be administered with caution in patients with pulmonary tuberculosis or in patientswith chronic or untreated infections.

Trelegy Ellipta should be used with caution in patients with narrow-angle glaucoma. Patients should beinformed about the signs and symptoms of acute narrow-angle glaucoma and should be informed to stopusing Trelegy Ellipta and to contact their doctor immediately should any of these signs or symptomsdevelop.

Caution should be advised when prescribing Trelegy Ellipta in patients with urinary retention or risk factorsfor urinary retention, e.g. benign prostatic hypertrophy. Cases of acute urinary retention have been observedin the post-marketing setting (see section 4.8).

An increase in the incidence of pneumonia, including pneumonia requiring hospitalisation, has beenobserved in patients with COPD receiving inhaled corticosteroids. There is some evidence of an increasedrisk of pneumonia with increasing steroid dose but this has not been demonstrated conclusively across allstudies.

There is no conclusive clinical evidence for intra-class differences in the magnitude of the pneumonia riskamong inhaled corticosteroid products.

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as theclinical features of such infections overlap with the symptoms of COPD exacerbations.

Risk factors for pneumonia in patients with COPD include current smoking, older age, low body mass index(BMI) and severe COPD.

Beta2-adrenergic agonists may produce significant hypokalaemia in some patients, which has the potential toproduce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiringsupplementation.

No clinically relevant effects of hypokalaemia were observed in clinical studies with Trelegy Ellipta at therecommended therapeutic dose. Caution should be exercised when Trelegy Ellipta is used with othermedicinal products that also have the potential to cause hypokalaemia (see section 4.5).

Beta2-adrenergic agonists may produce transient hyperglycaemia in some patients. No clinically relevanteffects on plasma glucose were observed in clinical studies with fluticasone furoate/umeclidinium/vilanterolat the recommended therapeutic dose. There have been reports of increases in blood glucose levels indiabetic patients treated with fluticasone furoate/umeclidinium/vilanterol and this should be considered whenprescribing to patients with a history of diabetes mellitus (see section 4.8). Upon initiation of treatment with

Trelegy Ellipta, plasma glucose should be monitored more closely in diabetic patients.

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, totallactase deficiency or glucose-galactose malabsorption should not use this medicinal product.

Clinically significant drug interactions mediated by fluticasone furoate/umeclidinium/vilanterol at clinicaldoses are considered unlikely due to the low plasma concentrations achieved after inhaled dosing.

Interaction with beta-blockers

Beta2-adrenergic blockers may weaken or antagonise the effect of beta2-adrenergic agonists, such asvilanterol. If beta-blockers are required, cardioselective beta-blockers should be considered, however,caution should be exercised during concurrent use of both non-selective and selective beta-blockers.

Interaction with CYP3A4 inhibitor

Fluticasone furoate and vilanterol are rapidly cleared by extensive first pass metabolism mediated by enzyme

Caution is advised when co-administering with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir,cobicistat-containing products) as there is potential for increased systemic exposure to both fluticasonefuroate and vilanterol, which could lead to an increased potential for adverse reactions. Co-administrationshould be avoided unless the benefit outweighs the increased risk of systemic corticosteroid adversereactions, in which case patients should be monitored for systemic corticosteroid adverse reactions. A repeatdose study was performed in healthy subjects with the fluticasone furoate/vilanterol combination(184/22 micrograms) and ketoconazole (400 milligrams, a strong CYP3A4 inhibitor). Co-administrationincreased mean fluticasone furoate AUC(0-24) and Cmax by 36% and 33%, respectively. The increase influticasone furoate exposure was associated with a 27% reduction in 0-24 hours weighted mean serumcortisol. Co-administration increased mean vilanterol AUC(0-t) and Cmax by 65% and 22%, respectively. Theincrease in vilanterol exposure was not associated with an increase in beta2-agonist related systemic effectson heart rate or blood potassium.

Interaction with CYP2D6 inhibitors/CYP2D6 polymorphism

Umeclidinium is a substrate of cytochrome P450 2D6 (CYP2D6). The steady-state pharmacokinetics ofumeclidinium was assessed in healthy volunteers lacking CYP2D6 (poor metabolisers). No effect onumeclidinium AUC or Cmax was observed at a dose 8-fold higher than the therapeutic dose. Anapproximately 1.3-fold increase in umeclidinium AUC was observed at 16-fold higher dose with no effect onumeclidinium Cmax. Based on the magnitude of these changes, no clinically relevant drug interaction isexpected when fluticasone furoate/umeclidinium/vilanterol is co-administered with CYP2D6 inhibitors orwhen administered to patients who are genetically deficient in CYP2D6 activity (poor metabolisers).

Interaction with P-glycoprotein inhibitors

Fluticasone furoate, umeclidinium and vilanterol are substrates of the P-glycoprotein transporter (P-gp). Theeffect of the moderate P-gp inhibitor verapamil (240 mg once daily) on the steady-state pharmacokinetics ofumeclidinium and vilanterol was assessed in healthy volunteers. No effect of verapamil was observed onumeclidinium or vilanterol Cmax. An approximately 1.4-fold increase in umeclidinium AUC was observedwith no effect on vilanterol AUC. Based on the magnitude of these changes, no clinically relevant druginteraction is expected when fluticasone furoate/umeclidinium/vilanterol is co-administered with P-gpinhibitors. Clinical pharmacology studies with a specific P-gp inhibitor and fluticasone furoate have not beenconducted.

Other long acting antimuscarinics and long acting beta2- adrenergic agonists

Co-administration of Trelegy Ellipta with other long-acting muscarinic antagonists or long-acting beta2-adrenergic agonists has not been studied and is not recommended as it may potentiate the adverse reactions(see sections 4.8 and 4.9).

Concomitant hypokalaemic treatment with methylxanthine derivatives, steroids, or non-potassium-sparingdiuretics may potentiate the possible hypokalaemic effect of beta2-adrenergic agonists, therefore cautionshould be exercised (see section 4.4).

There are limited data from the use of fluticasone furoate/umeclidinium/vilanterol in pregnant women.

Studies in animals have shown reproductive toxicity at exposures which are not clinically relevant (seesection 5.3).

Administration of Trelegy Ellipta to pregnant women should only be considered if the expected benefit to themother justifies the potential risk to the foetus.

It is unknown whether fluticasone furoate, umeclidinium, vilanterol or their metabolites are excreted inhuman milk. However, other corticosteroids, muscarinic antagonists and beta2-adrenergic agonists aredetected in human milk. A risk to newborns/infants cannot be excluded. A decision must be made whether todiscontinue breast-feeding or to discontinue Trelegy Ellipta therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

There are no data on the effects of fluticasone furoate/umeclidinium/vilanterol on human fertility. Animalstudies indicate no effects of fluticasone furoate, umeclidinium or vilanterol on male or female fertility (seesection 5.3).

Fluticasone furoate/umeclidinium/vilanterol has no or negligible influence on the ability to drive and usemachines.

The most frequently reported adverse reactions are nasopharyngitis (7%), headache (5%) and upperrespiratory tract infection (2%).

The safety profile of Trelegy Ellipta is based on three phase III clinical studies and spontaneous reporting.

Where adverse reaction frequencies differed between studies, the higher frequency is reported below.

Adverse reactions are listed by MedDRA system organ class.

The frequency of adverse reactions is defined using the following convention: very common (≥1/10);common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare(<1/10 000) and not known (cannot be estimated from available data).

System Organ Class Adverse reactions Frequency

Infections and infestations Pneumonia Common

Upper respiratory tract infection

Bronchitis

Pharyngitis

Rhinitis

Sinusitis

Influenza

Nasopharyngitis

Candidiasis of mouth and throat

Viral respiratory tract infection Uncommon

Immune system disorders Hypersensitivity reactions, including Rareanaphylaxis, angioedema, urticaria, andrash

Metabolism and nutrition Hyperglycaemia Raredisorders

Psychiatric disorders Anxiety Rare

Nervous system disorders Headache Common

Dysgeusia Uncommon

Tremor Rare

Eye disorders Vision blurred (see section 4.4) Uncommon

Glaucoma

Eye pain

Intraocular pressure increased Rare

Cardiac disorders Supraventricular tachyarrhythmia Uncommon

Atrial fibrillation

Palpitations Rare

Respiratory, thoracic & Cough Commonmediastinal disorders Oropharyngeal pain

Dysphonia Uncommon

Gastrointestinal disorders Constipation Common

Dry mouth Uncommon

Musculoskeletal and Arthralgia Commonconnective tissue disorders Back pain

Fractures Uncommon

Muscle spasms Rare

Renal and urinary disorders Urinary retention Rare

Dysuria

In a total of 1 810 patients with advanced COPD (mean post-bronchodilator screening FEV1 45% ofpredicted, standard deviation (SD) 13%), 65% of whom had experienced a moderate/severe COPDexacerbation in the year prior to study entry (study CTT116853), there was a higher incidence of pneumoniaevents reported up to 24 weeks in patients receiving Trelegy Ellipta (20 patients, 2%) than in patientsreceiving budesonide/formoterol (7 patients, <1%). Pneumonia which required hospitalisation occurred in1% of patients receiving Trelegy Ellipta and <1% of patients receiving budesonide/formoterol up to 24weeks. One fatal case of pneumonia was reported in a patient who received Trelegy Ellipta. In the subset of430 patients treated for up to 52 weeks, the incidence of pneumonia events reported in both Trelegy Elliptaand budesonide/formoterol arms was equal at 2%. The incidence of pneumonia with Trelegy Ellipta iscomparable with that observed in the fluticasone furoate/vilanterol (FF/VI) 100/25 arm of FF/VI clinicalstudies in COPD.

In a 52-week study, with a total of 10 355 patients with COPD and a history of moderate or severeexacerbations within the prior 12 months (mean post-bronchodilator screening FEV1 46% of predicted, SD15%) (study CTT116855), the incidence of pneumonia was 8% (317 patients) for Trelegy Ellipta (n = 4 151),7% (292 subjects) for fluticasone furoate/vilanterol (n = 4 134), and 5% (97 subjects) forumeclidinium/vilanterol (n = 2 070). Fatal pneumonia occurred in 12 of 4 151 patients (3.5 per 1 000 patient-years) receiving Trelegy Ellipta, 5 of 4 134 patients (1.7 per 1 000 patient-years) receiving fluticasonefuroate/vilanterol, and 5 of 2 070 patients (2.9 per 1 000 patient-years) receiving umeclidinium/vilanterol.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are askedto report any suspected adverse reactions via the national reporting system listed in Appendix V.

An overdose will likely produce signs, symptoms or adverse reactions associated with the individualcomponents’ pharmacological actions (e.g. Cushing’s syndrome, Cushingoid features, adrenal suppression,decrease in bone mineral density, dry mouth, visual accommodation disturbances, tachycardia, arrhythmias,tremor, headache, palpitations, nausea, hyperglycaemia and hypokalaemia).

There is no specific treatment for an overdose with Trelegy Ellipta. If overdose occurs, the patient should betreated supportively with appropriate monitoring as necessary.

Cardioselective beta-blockade should only be considered for profound vilanterol overdose effects that areclinically concerning and unresponsive to supportive measures. Cardioselective beta-blocking medicinalproducts should be used with caution in patients with a history of bronchospasm.

Further management should be clinically indicated or as recommended by the national poisons centre, whereavailable.

Pharmacotherapeutic group: Drugs for obstructive airway diseases, adrenergics in combination withanticholinergics including triple combinations with corticosteroids, ATC code: R03AL08.

Fluticasone furoate/umeclidinium/vilanterol is a combination of inhaled synthetic corticosteroid, long-actingmuscarinic receptor antagonist and long-acting beta2-adrenergic agonist (ICS/LAMA/LABA). Following oralinhalation, umeclidinium and vilanterol act locally on airways to produce bronchodilation by separatemechanisms and fluticasone furoate reduces inflammation.

Fluticasone furoate

Fluticasone furoate is a corticosteroid with potent anti-inflammatory activity. The precise mechanismthrough which fluticasone furoate affects COPD symptoms is not known. Corticosteroids have been shownto have a wide range of actions on multiple cell types (e.g. eosinophils, macrophages, lymphocytes) andmediators (e.g. cytokines and chemokines) involved in inflammation.

Umeclidinium

Umeclidinium is a long-acting muscarinic receptor antagonist (also referred to as an anticholinergic).

Umeclidinium exerts its bronchodilatory activity by competitively inhibiting the binding of acetylcholinewith muscarinic receptors on airway smooth muscle. It demonstrates slow reversibility at the human M3muscarinic receptor subtype in vitro and a long duration of action in vivo when administered directly to thelungs in pre-clinical models.

Vilanterol

Vilanterol is a selective long-acting, beta2-adrenergic receptor agonist (LABA). The pharmacologic effects ofbeta2-adrenergic agonists, including vilanterol, are at least in part attributable to stimulation of intracellularadenylate cyclase, the enzyme that catalyses the conversion of adenosine triphosphate (ATP) to cyclic-3’,5’-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smoothmuscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mastcells.

The effect of fluticasone furoate/umeclidinium/vilanterol on the QT interval has not been evaluated in athorough QT (TQT) study. TQT studies for FF/VI and umeclidinium/vilanterol (UMEC/VI) did not showclinically relevant effects on QT interval at clinical doses of FF, UMEC and VI.

No clinically relevant effects on the QTc interval were observed on review of centrally read ECGs from 911subjects with COPD exposed to fluticasone furoate/umeclidinium/vilanterol for up to 24 weeks, or in thesubset of 210 subjects exposed for up to 52 weeks.

The efficacy of Trelegy Ellipta (92/55/22 micrograms), administered as a once-daily treatment, has beenevaluated in patients with a clinical diagnosis of COPD in two, active-controlled studies and in a single, non-inferiority study. All three studies were multicentre, randomised, double-blind studies that required patientsto be symptomatic with a COPD Assessment Test (CAT) score ≥10 and on daily maintenance treatment fortheir COPD for at least three months prior to study entry.

FULFIL (CTT116853) was a 24-week study (N=1 810), with an extension up to 52 weeks in a subset ofsubjects (n=430), that compared Trelegy Ellipta (92/55/22 micrograms) with budesonide/formoterol400/12 micrograms (BUD/FOR) administered twice-daily. At screening, the mean post-bronchodilatorpercent predicted FEV1 was 45% and 65% of patients reported a history of one or more moderate/severeexacerbation in the past year.

IMPACT (CTT116855) was a 52-week study (N=10 355) that compared Trelegy Ellipta(92/55/22 micrograms) with fluticasone furoate/vilanterol 92/22 micrograms (FF/VI) andumeclidinium/vilanterol 55/22 micrograms (UMEC/VI). At screening, the mean post-bronchodilator percentpredicted FEV1 was 46% and over 99% of patients reported a history of one or more moderate/severeexacerbation in the past year.

At study entry, the most common COPD medications reported in the FULFIL and IMPACT studies were

ICS +LABA+LAMA (28%, 34% respectively), ICS+LABA (29%, 26% respectively), LAMA+LABA (10%,8% respectively) and LAMA (9%, 7% respectively). These patients may have also been taking other COPDmedications (e.g. mucolytics or leukotriene receptor antagonists).

Study 200812 was a 24-week, non-inferiority study (N=1 055) that compared Trelegy Ellipta(92/55/22 micrograms) with FF/VI (92/22 micrograms) + UMEC (55 micrograms), co-administered oncedaily as a multi-inhaler therapy in patients with a history of moderate or severe exacerbations within the prior12 months.

In FULFIL, bronchodilatory effects with Trelegy Ellipta were evident on the first day of treatment and weremaintained over the 24-week treatment period (mean changes from baseline in FEV1 were 90-222 mL onday 1 and 160-339 mL at week 24). Trelegy Ellipta significantly improved (p<0.001) lung function (asdefined by mean change from baseline in trough FEV1 at week 24) (see Table 1) and the improvement wasmaintained in the subset of patients who continued treatment to week 52.

Table 1. Lung function endpoint in FULFIL

Trelegy BUD/FOR Treatment difference

Ellipta (95% CI)

Comparison with(N= 911) (N=899) BUD/FOR

Trough FEV1 (L) at week 24, LS mean change 0.142 -0.029 0.171from baseline (SE)a (0.0083) (0.0085) 0.148, 0.194

FEV1=forced expiratory volume in 1 second; L=litres; LS=least squares; SE= standard error, N=number in the intent-to-treat population; CI= confidence interval, a Statistically significant treatment difference for FF/UMEC/VI vs. BUD/FORalso observed at the other assessment timepoints (weeks 2, 4 and 12).

In IMPACT, Trelegy Ellipta significantly improved (p<0.001) lung function when compared with FF/VI and

UMEC/VI over a 52-week period (See Table 2).

Table 2 - Lung function endpoint in IMPACT

Treatment difference 95%

CI

Trelegy Comparison Comparison

Ellipta FF/VI UMEC/VI Trelegy vs. Trelegy vs.(N = 4 151) (N = 4 134) (N = 2 070) FF/VI UMEC/VI

Trough FEV1 (L) at week 52,

LS mean change from baseline 0.094 -0.003 0.040 0.097 0.054(SE) a (0.004) (0.004) (0.006) 0.085, 0.109 0.039, 0.069

FEV1= forced expiratory volume in 1 second; L= litres; LS=least squares; SE= standard error; N= number in the intent-to-treat population; CI= confidence interval; a Statistically significant treatment differences for FF/UMEC/VI vs. FF/VIand FF/UMEC/VI vs. UMEC/VI were also observed at the other assessment timepoints (weeks 4, 16, 28, and 40).

In Study 200812, Trelegy Ellipta was non-inferior compared with FF/VI+UMEC, co-administered in twoinhalers, in the improvement from baseline in trough FEV1 at week 24. The pre-specified non-inferioritymargin was 50 mL.

In IMPACT, over 52 weeks, Trelegy Ellipta significantly reduced (p<0.001) the annual rate ofmoderate/severe exacerbations by 15% (95% CI:10, 20) compared with FF/VI (rate; 0.91 vs 1.07 events perpatient year) and by 25% (95% CI: 19, 30) compared with UMEC/VI (rate; 0.91 vs 1.21 events per patientyear). In FULFIL, based upon data up to 24 weeks, Trelegy Ellipta significantly reduced (p=0.002) theannual rate of moderate/severe exacerbations by 35% (95% CI: 14, 51) compared with BUD/FOR.

In IMPACT, Trelegy Ellipta prolonged the time to first moderate/severe exacerbation and significantlydecreased (p<0.001) the risk of a moderate/severe exacerbation, as measured by time to first exacerbation,compared with both FF/VI (14.8%; 95% CI: 9.3, 19.9) and UMEC/VI (16.0%; 95% CI: 9.4, 22.1). In

FULFIL, Trelegy Ellipta significantly decreased the risk of a moderate/severe exacerbation compared with

BUD/FOR over 24 weeks (33%; 95% CI: 12, 48; p=0.004).

In IMPACT, treatment with Trelegy Ellipta reduced the annual rate of severe exacerbations (i.e., requiringhospitalisation or resulting in death) by 13% compared with FF/VI (95% CI: -1, 24; p=0.064). Treatmentwith Trelegy Ellipta significantly reduced the annual rate of severe exacerbations by 34% compared with

UMEC/VI (95% CI: 22, 44; p<0.001).

Trelegy Ellipta significantly improved (p<0.001) Health Related Quality of Life (as measured by the St

George’s Respiratory Questionnaire [SGRQ] total score) in both FULFIL (week 24) when compared with

BUD/FOR (-2.2 units; 95% CI: -3.5, -1.0) and IMPACT (week 52) when compared with FF/VI (-1.8 units;95% CI: -2.4, -1.1) and UMEC/VI (-1.8 units; 95% CI: -2.6, -1.0).

A higher percentage of patients receiving Trelegy Ellipta responded with a clinically meaningfulimprovement in SGRQ total score in FULFIL at week 24 compared with BUD/FOR (50% and 41%respectively), odds ratios of response vs. non-response (OR) (1.41; 95% CI: 1.16, 1.70) and in IMPACT atweek 52 compared with FF/VI and UMEC/VI (42%, 34% and 34% respectively), OR vs. FF/VI (1.41; 95%

CI:1.29, 1.55) and OR vs. UMEC/VI (1.41; 95% CI: 1.26, 1.57); all treatment comparisons were statisticallysignificant (p<0.001).

In FULFIL, the proportion of patients who were CAT responders (defined as 2 units below baseline orlower) at week 24, was significantly higher (p<0.001) for patients treated with Trelegy Ellipta comparedwith BUD/FOR (53% vs. 45%; OR 1.44; 95% CI: 1.19, 1.75). In IMPACT, the proportion of patientswho were CAT responders at week 52 was significantly higher (p<0.001) for patients treated with

Trelegy Ellipta (42%) compared with FF/VI (37%; OR 1.24; 95% CI: 1.14, 1.36) and UMEC/VI (36%;

OR 1.28; 95% CI: 1.15, 1.43).

Breathlessness was measured using the Transition Dyspnoea Index (TDI) focal score at week 24 in FULFILand week 52 in IMPACT (a subset of patients, n=5 058). In FULFIL the proportion of responders accordingto TDI (defined as at least 1 unit) was significantly higher (p<0.001) for Trelegy Ellipta compared with

BUD/FOR (61% vs 51%; OR 1.61; 95% CI: 1.33, 1.95). In IMPACT, the proportion of responders was alsosignificantly higher (p<0.001) for Trelegy Ellipta (36%) compared with FF/VI (29%; OR 1.36; 95% CI:1.19, 1.55) and UMEC/VI (30%; OR 1.33; 95% CI: 1.13, 1.57).

In FULFIL, Trelegy Ellipta improved daily symptoms of COPD as assessed by E-RS: COPD total score,compared with BUD/FOR (≥2 unit decrease from baseline). The proportion of responders during weeks21-24 was significantly higher (p<0.001) for patients treated with Trelegy Ellipta compared with BUD/FOR(47% and 37% respectively; OR 1.59; 95% CI: 1.30, 1.94).

In FULFIL, Trelegy Ellipta significantly reduced (p<0.001) the use of rescue medication between weeks1-24 compared with BUD/FOR (treatment difference: -0.2 occasions per day; 95% CI: -0.3, -0.1).

In IMPACT, Trelegy Ellipta significantly reduced (p<0.001) the use of rescue medication (occasions perday) at each 4-week time period compared with FF/VI and UMEC/VI. At weeks 49-52, the treatmentdifference was -0.28 (95% CI: -0.37, -0.19) when compared with FF/VI and -0.30 (95% CI: -0.41, -0.19)with UMEC/VI.

Nighttime awakenings

In IMPACT, Trelegy Ellipta statistically significantly reduced the mean number of nighttime awakeningsdue to COPD compared with FF/VI (-0.05; 95% CI: -0.08, -0.01; p=0.005) and with UMEC/VI (-0.10; 95%

CI: -0.14, -0.05; p<0.001) at weeks 49 to 52. Significant reductions were observed over all other timepointsfor UMEC/VI (p<0.001) and for the all but two of the of timepoints for FF/VI (p≤0.021).

The European Medicines Agency has waived the obligation to submit the results of studies with Trelegy

Ellipta in all subsets of the paediatric population in COPD (see section 4.2 for information on paediatric use).

When fluticasone furoate, umeclidinium and vilanterol were administered in combination by the inhaledroute from a single inhaler in healthy subjects, the pharmacokinetics of each component were similar to thoseobserved when each active substance was administered either as fluticasone furoate/vilanterol combinationor as an umeclidinium/vilanterol combination or umeclidinium monotherapy.

Population PK analyses for FF/UMEC/VI were conducted using a combined PK dataset from three phase IIIstudies in 821 COPD subjects. Systemic drug levels (steady state Cmax and AUC) of FF, UMEC and VIfollowing FF/UMEC/VI in one inhaler (triple combination) were within the range of those observedfollowing FF/VI + UMEC as two inhalers, dual combinations (FF/VI and UMEC/VI), as well as individualsingle inhalers (FF, UMEC and VI). Covariate analysis showed higher FF apparent clearance (42%) whencomparing FF/VI to FF/UMEC/VI; however, this is not considered clinically relevant.

Fluticasone furoate

Following inhaled administration of fluticasone furoate/umeclidinium/vilanterol in healthy subjects,fluticasone furoate Cmax occurred at 15 minutes. The absolute bioavailability of fluticasone furoate whenadministrated as fluticasone furoate/vilanterol by inhalation was 15.2%, primarily due to absorption of theinhaled portion of the dose delivered to the lung, with negligible contribution from oral absorption.

Following repeat dosing of inhaled fluticasone furoate/vilanterol, steady state was achieved within 6 dayswith up to 1.6-fold accumulation.

Umeclidinium

Following inhaled administration of fluticasone furoate/umeclidinium/vilanterol in healthy subjects,umeclidinium Cmax occurred at 5 minutes. The absolute bioavailability of inhaled umeclidinium was onaverage 13%, with negligible contribution from oral absorption. Following repeat dosing of inhaledumeclidinium, steady state was achieved within 7 to 10 days with 1.5 to 2-fold accumulation.

Vilanterol

Following inhaled administration of fluticasone furoate/umeclidinium/vilanterol in healthy subjects,vilanterol Cmax occurred at 7 minutes. The absolute bioavailability of inhaled vilanterol was 27%, withnegligible contribution from oral absorption. Following repeat dosing of inhaled umeclidinium/vilanterol,steady state was achieved within 6 days with up to 1.5-fold accumulation.

Fluticasone furoate

Following intravenous dosing of fluticasone furoate to healthy volunteers, the mean volume of distribution atsteady state of 661 litres. Fluticasone furoate has a low association with red blood cells. In vitro plasmaprotein binding in human plasma of fluticasone furoate was high, on average >99.6%.

Umeclidinium

Following intravenous administration of umeclidinium to healthy volunteers, the mean volume ofdistribution was 86 litres. In vitro plasma protein binding in human plasma was on average 89%.

Vilanterol

Following intravenous administration of vilanterol to healthy volunteers, the mean volume of distribution atsteady state was 165 litres. Vilanterol has a low association with red blood cells. In vitro plasma proteinbinding in human plasma was on average 94%.

Fluticasone furoate

In vitro studies showed that fluticasone furoate is primarily metabolised by cytochrome P450 3A4(CYP3A4) and is a substrate for the P-gp transporter. The primary metabolic route for fluticasone furoate ishydrolysis of the S-fluoromethyl carbothioate group to metabolites with significantly reduced corticosteroidactivity. Systemic exposure to the metabolites is low.

Umeclidinium

In vitro studies showed that umeclidinium is primarily metabolised by cytochrome P450 2D6 (CYP2D6) andis a substrate for the P-gp transporter. The primary metabolic routes for umeclidinium are oxidative(hydroxylation, O-dealkylation) followed by conjugation (glucuronidation, etc), resulting in a range ofmetabolites with either reduced pharmacological activity or for which the pharmacological activity has notbeen established. Systemic exposure to the metabolites is low.

Vilanterol

In vitro studies showed that vilanterol is primarily metabolised by cytochrome P450 3A4 (CYP3A4) and is asubstrate for the P-gp transporter. The primary metabolic routes for vilanterol are O-dealkylation to a rangeof metabolites with significantly reduced beta1- and beta2-adrenergic agonist activity. Plasma metabolicprofiles following oral administration of vilanterol in a human radiolabel study were consistent with highfirst-pass metabolism. Systemic exposure to the metabolites is low.

Fluticasone furoate

The apparent plasma elimination half-life of fluticasone furoate following inhaled administration offluticasone furoate/vilanterol was, on average, 24 hours. Following intravenous administration, theelimination phase half-life averaged 15.1 hours. Plasma clearance following intravenous administration was65.4 litres/hour. Urinary excretion accounted for approximately 2 % of the intravenously administered dose.

Following oral administration, fluticasone furoate was eliminated in humans mainly by metabolism withmetabolites being excreted almost exclusively in faeces, with <1% of the recovered radioactive doseeliminated in the urine.

Umeclidinium

Umeclidinium plasma elimination half-life following inhaled dosing for 10 days averaged 19 hours, with 3%to 4% active substance excreted unchanged in urine at steady-state. Plasma clearance following intravenousadministration was 151 litres/hour. Following intravenous administration, approximately 58% of theadministered radiolabelled dose was excreted in faeces and approximately 22% of the administeredradiolabelled dose was excreted in urine. The excretion of the drug-related material in the faeces followingintravenous dosing indicated secretion into the bile. Following oral administration, 92% of the administeredradiolabelled dose was excreted primarily in faeces. Less than 1% of the orally administered dose (1% ofrecovered radioactivity) was excreted in urine, suggesting negligible absorption following oraladministration.

Vilanterol

Vilanterol plasma elimination half-life following inhaled dosing for 10 days averaged 11 hours. Plasmaclearance of vilanterol following intravenous administration was 108 litres/hour. Following oraladministration of radiolabelled vilanterol, 70% of the radiolabel was excreted in urine and 30% in faeces.

Primary elimination of vilanterol was by metabolism followed by excretion of metabolites in urine andfaeces.

The effects of age on the pharmacokinetics of fluticasone furoate, umeclidinium and vilanterol wereevaluated in the population pharmacokinetic analysis. No clinically relevant effects requiring doseadjustment were observed.

The effect of fluticasone furoate/umeclidinium/vilanterol has not been evaluated in subjects with renalimpairment. However, studies have been conducted with fluticasone furoate/vilanterol andumeclidinium/vilanterol that showed no evidence of an increase in systemic exposure to fluticasone furoate,umeclidinium or vilanterol. In vitro protein binding studies between subjects with severe renal impairmentand healthy volunteers were conducted, and no clinically significant evidence of altered protein binding wasseen.

The effects of haemodialysis have not been studied.

The effect of fluticasone furoate/umeclidinium/vilanterol has not been evaluated in subjects with hepaticimpairment. However, studies have been conducted with fluticasone furoate/vilanterol andumeclidinium/vilanterol.

The fluticasone furoate/vilanterol component of Trelegy Ellipta was assessed in patients with all severities ofhepatic impairment (Child-Pugh A, B or C). For fluticasone furoate, patients with moderate hepaticimpairment showed up to three times higher systemic exposure (FF 184 micrograms); therefore, patientswith severe hepatic impairment received half the dose (FF 92 micrograms). At this dose, no effects onsystemic exposure were observed. Therefore, caution is advised in moderate to severe hepatic impairment,but no specific dose adjustment based on hepatic function is recommended. There was no significantincrease in systemic exposure to vilanterol.

Patients with moderate hepatic impairment showed no evidence of an increase in systemic exposure to eitherumeclidinium or vilanterol (Cmax and AUC). Umeclidinium has not been evaluated in patients with severehepatic impairment.

The effects of race, gender and weight on the pharmacokinetics of fluticasone furoate, umeclidinium andvilanterol were also evaluated in the population pharmacokinetic analysis.

In 113 East Asian subjects with COPD (Japanese and East Asian Heritage), who received FF/UMEC/VIfrom a single inhaler (27% subjects), fluticasone furoate AUC(ss) estimates were on average 30% highercompared with Caucasian subjects. However, these higher systemic exposures remain below the thresholdfor FF-induced reduction of serum and urine cortisol and are not considered clinically relevant.

There was no effect of race on pharmacokinetic parameters of umeclidinium or vilanterol in subjects with

COPD.

No clinically relevant differences requiring dose adjustment based on race, gender or weight were observedin fluticasone furoate, umeclidinium or vilanterol systemic exposure.

In terms of other patient characteristics, a study in CYP2D6 poor metabolisers showed no evidence of aclinically significant effect of CYP2D6 genetic polymorphism on systemic exposure to umeclidinium.

Pharmacological and toxicological effects seen with fluticasone furoate, umeclidinium or vilanterol innonclinical studies were those typically associated with glucocorticoids, muscarinic receptor antagonists, orbeta2-adrenergic receptor agonists. Administration of combined fluticasone furoate, umeclidinium andvilanterol to dogs did not result in any significant new toxicity or any major exacerbation of expectedfindings associated with fluticasone furoate, umeclidinium or vilanterol alone.

Fluticasone furoate

Fluticasone furoate was not genotoxic in a standard battery of studies and was not carcinogenic in lifetimeinhalation studies in rats or mice at exposures of 1.4- or 2.9-fold, respectively, those seen in humans at adaily dose of 92 micrograms fluticasone furoate, based on AUC.

Umeclidinium

Umeclidinium was not genotoxic in a standard battery of studies and was not carcinogenic in lifetimeinhalation studies in mice or rats at exposures ≥ 20- or ≥ 17- fold the human clinical exposure at a daily doseof 55 micrograms umeclidinium, based on AUC respectively.

Vilanterol

Vilanterol (as alpha-phenylcinnamate) and triphenylacetic acid were not genotoxic indicating that vilanterol(as trifenatate) does not represent a genotoxic hazard to humans. Consistent with findings for other beta2agonists, in lifetime inhalation studies vilanterol trifenatate caused proliferative effects in the female rat andmouse reproductive tract and rat pituitary gland. There was no increase in tumour incidence in rats or mice atexposures 0.9- or 22-fold, respectively, the human clinical exposure of vilanterol at a daily dose of22 micrograms based on AUC.

Toxicity to reproduction and development

Fluticasone furoate, umeclidinium and vilanterol did not have any adverse effects on male or female fertilityin rats.

Fluticasone furoate

Fluticasone furoate was not teratogenic in rats or rabbits, but delayed development in rats and causedabortion in rabbits at maternally toxic doses. There were no effects on development in rats at exposures 6.6-fold the human clinical exposure at a daily dose of 92 micrograms, based on AUC. Fluticasone furoate hadno adverse effect on pre- or post-natal development in rats.

Umeclidinium

Umeclidinium was not teratogenic in rats or rabbits. In a pre- and post-natal study, subcutaneousadministration of umeclidinium to rats resulted in lower maternal body weight gain and food consumptionand slightly decreased pre-weaning pup body weights in dams given 180 micrograms/kg/day dose(approximately 61-fold the human clinical exposure of umeclidinium at a daily dose of 55 micrograms,based on AUC).

Vilanterol

Vilanterol was not teratogenic in rats. In inhalation studies in rabbits, vilanterol caused effects similar tothose seen with other beta2-adrenergic agonists (cleft palate, open eyelids, sternebral fusion and limbflexure/malrotation). When given subcutaneously there were no effects at exposures 62-fold the humanclinical exposure at a daily dose of 22 micrograms, based on AUC. Vilanterol had no adverse effect on pre-or post-natal development in rats.

Lactose monohydrate

Magnesium stearate

Not applicable.

2 years

Shelf-life after opening the tray: 6 weeks

Do not store above 30 °C.

If stored in a refrigerator allow the inhaler to return to room temperature for at least an hour before use.

Keep the inhaler inside the sealed tray in order to protect from moisture and only remove immediately beforefirst use.

The Ellipta inhaler consists of a light grey body, beige mouthpiece cover and a dose counter, packed into afoil laminate tray containing a silica gel desiccant sachet. The tray is sealed with a peelable foil lid.

The inhaler is a multi-component device composed of polypropylene, high density polyethylene,polyoxymethylene, polybutylene terephthalate, acrylonitrile butadiene styrene, polycarbonate and stainlesssteel.

The inhaler contains two aluminium foil laminate blister strips that deliver a total of 14 or 30 doses (14 or 30day supply). Each blister in one strip contains fluticasone furoate, each blister in the other strip containsumeclidinium (as bromide) and vilanterol (as trifenatate).

Pack sizes of 1 inhaler with 14 or 30 doses.

Multipacks containing 90 (3 inhalers of 30) doses.

Not all pack sizes may be marketed.

After inhalation, patients should rinse their mouth with water without swallowing.

The inhaler is packaged in a tray containing a desiccant sachet, to reduce moisture. The desiccant sachetshould be thrown away and it should not be opened, eaten or inhaled. The patient should be advised to notopen the tray until they are ready to inhale a dose.

The inhaler will be in the ‘closed’ position when it is first taken out of its sealed tray. The “Discard by” dateshould be written on the inhaler label and carton in the space provided. The date should be added as soon asthe inhaler has been removed from the tray. The “Discard by” date is 6 weeks from the date of opening thetray. After this date the inhaler should no longer be used. The tray can be discarded after first opening.

If the inhaler cover is opened and closed without inhaling the medicinal product, the dose will be lost. Thelost 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 an extra dose or a double dose in one inhalation.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

GlaxoSmithKline Trading Services Limited12 Riverwalk

Citywest Business Campus

Dublin 24

Ireland

EU/1/17/1236/001

EU/1/17/1236/002

EU/1/17/1236/003

Date of first authorisation: 15 November 2017

Date of latest renewal: 15 July 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.