This information is intended for use by health professionals

 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

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

2. Qualitative and quantitative composition

Each single inhalation provides a delivered dose (the dose leaving the mouthpiece) of 92 micrograms fluticasone furoate, 65 micrograms umeclidinium bromide equivalent to 55 micrograms umeclidinium and 22 micrograms vilanterol (as trifenatate). This corresponds to a pre-dispensed dose of 100 micrograms fluticasone furoate, 74.2 micrograms umeclidinium bromide equivalent to 62.5 micrograms umeclidinium and 25 micrograms vilanterol (as trifenatate).

Excipient with known effect

Each delivered dose contains approximately 25 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Inhalation powder, pre-dispensed (inhalation powder).

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

4. Clinical particulars
4.1 Therapeutic indications

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

4.2 Posology and method of administration

Posology

Adults

The recommended and maximum dose is one inhalation of Trelegy Ellipta 92/55/22 micrograms once daily, at the same time each day.

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

Special populations

Elderly patients

No dosage adjustment is required in patients over 65 years (see section 5.2).

Renal impairment

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

Hepatic impairment

No dosage adjustment is required in patients with mild, moderate or severe hepatic impairment. Trelegy Ellipta should be used with caution in patients with moderate to severe hepatic impairment (see sections 4.4 and 5.2).

Paediatric population

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

Method of administration

Trelegy Ellipta is for inhalation use only.

Instructions for use:

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

a) Prepare a dose

Open the cover when ready to take 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” is heard, 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 out into the inhaler.

The mouthpiece should be placed between the lips and the lips should then be closed firmly around it. The air 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 (at least 3-4 seconds).

• Remove the inhaler from the mouth.

• Breathe out slowly and gently.

The medicine 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.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Asthma

Trelegy Ellipta should not be used in patients with asthma since it has not been studied in this patient population.

Not for acute use

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

Deterioration of disease

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

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

Paradoxical bronchospasm

Administration of fluticasone furoate/umeclidinium/vilanterol may produce paradoxical bronchospasm with an immediate wheezing and shortness of breath after dosing and may be life-threatening. Treatment with Trelegy Ellipta should be discontinued immediately if paradoxical bronchospasm occurs. The patient should be assessed and alternative therapy instituted if necessary.

Cardiovascular effects

Cardiovascular effects, such as cardiac arrhythmias, e.g. atrial fibrillation and tachycardia, may be seen after the administration of muscarinic receptor antagonists and sympathomimetics, including umeclidinium and vilanterol, respectively. Therefore, Trelegy Ellipta should be used with caution in patients with unstable or life-threatening cardiovascular disease.

Patients with hepatic impairment

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

Systemic corticosteroid effects

Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods. 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 with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Coexisting conditions

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

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

Anticholinergic activity

Trelegy Ellipta should be used with caution in patients with narrow-angle glaucoma or urinary retention. Patients should be informed about the signs and symptoms of acute narrow-angle glaucoma and should be informed to stop using Trelegy Ellipta and to contact their doctor immediately should any of these signs or symptoms develop.

Pneumonia in patients with COPD

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

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

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical 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.

Hypokalaemia

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

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

Hyperglycaemia

Beta2-adrenergic agonists may produce transient hyperglycaemia in some patients. No clinically relevant effects on plasma glucose were observed in clinical studies with fluticasone furoate/umeclidinium/vilanterol at the recommended therapeutic dose. There have been reports of increases in blood glucose levels in diabetic patients treated with fluticasone furoate/umeclidinium/vilanterol and this should be considered when prescribing to patients with a history of diabetes mellitus. Upon initiation of treatment with Trelegy Ellipta, plasma glucose should be monitored more closely in diabetic patients.

Excipients

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5 Interaction with other medicinal products and other forms of interaction

Clinically significant drug interactions mediated by fluticasone furoate/umeclidinium/vilanterol at clinical doses 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 as vilanterol. 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 CYP3A4.

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 fluticasone furoate and vilanterol, which could lead to an increased potential for adverse reactions. Co-administration should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid adverse reactions, in which case patients should be monitored for systemic corticosteroid adverse reactions. A repeat dose study was performed in healthy subjects with the fluticasone furoate/vilanterol combination (184/22 micrograms) and ketoconazole (400 milligrams, a strong CYP3A4 inhibitor). Co-administration increased mean fluticasone furoate AUC(0-24) and Cmax by 36% and 33%, respectively. The increase in fluticasone furoate exposure was associated with a 27% reduction in 0-24 hours weighted mean serum cortisol. Co-administration increased mean vilanterol AUC(0-t) and Cmax by 65% and 22%, respectively. The increase in vilanterol exposure was not associated with an increase in beta2-agonist related systemic effects on heart rate or blood potassium.

Interaction with CYP2D6 inhibitors/CYP2D6 polymorphism

Umeclidinium is a substrate of cytochrome P450 2D6 (CYP2D6). The steady-state pharmacokinetics of umeclidinium was assessed in healthy volunteers lacking CYP2D6 (poor metabolisers). No effect on umeclidinium AUC or Cmax was observed at a dose 8-fold higher than the therapeutic dose. An approximately 1.3-fold increase in umeclidinium AUC was observed at 16-fold higher dose with no effect on umeclidinium Cmax. Based on the magnitude of these changes, no clinically relevant drug interaction is expected when fluticasone furoate/umeclidinium/vilanterol is co-administered with CYP2D6 inhibitors or when 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). The effect of the moderate P-gp inhibitor verapamil (240 mg once daily) on the steady-state pharmacokinetics of umeclidinium and vilanterol was assessed in healthy volunteers. No effect of verapamil was observed on umeclidinium or vilanterol Cmax. An approximately 1.4-fold increase in umeclidinium AUC was observed with no effect on vilanterol AUC. Based on the magnitude of these changes, no clinically relevant drug interaction is expected when fluticasone furoate/umeclidinium/vilanterol is co-administered with P-gp inhibitors. Clinical pharmacology studies with a specific P-gp inhibitor and fluticasone furoate have not been conducted.

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 section 4.8 and section 4.9).

Hypokalaemia

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

4.6 Fertility, pregnancy and lactation

Pregnancy

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 (see section 5.3).

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

Breast-feeding

It is unknown whether fluticasone furoate, umeclidinium, vilanterol or their metabolites are excreted in human milk. However, other corticosteroids, muscarinic antagonists and beta2-adrenergic agonists are detected in human milk. A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue 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.

Fertility

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

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

The most frequently reported adverse reactions with Trelegy Ellipta were nasopharyngitis (7%), headache (5%) and upper respiratory tract infection (2%).

Tabulated summary of adverse reactions

The safety profile of Trelegy Ellipta is based on safety data from 911 patients with COPD who received fluticasone furoate/umeclidinium/vilanterol 92/55/22 micrograms, once daily, for up to 24 weeks, of whom 210 patients received fluticasone furoate/umeclidinium/vilanterol 92/55/22 micrograms once daily for up to 52 weeks, during a phase III clinical study with an active comparator (study CTT116853). Adverse reactions detected during this clinical trial 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

Upper Respiratory Tract Infection

Pharyngitis

Rhinitis

Influenza

Nasopharyngitis

Common

Candidiasis of mouth and throat

Viral Respiratory Tract Infection

Uncommon

Nervous system disorders

Headache

Common

Eye disorders

Vision blurred (see section 4.4)

Not known

Cardiac disorders

Supraventricular tachyarrhythmia

Tachycardia

Atrial fibrillation

Uncommon

Respiratory, thoracic & mediastinal disorders

Cough

Common

Oropharyngeal pain

Uncommon

Musculoskeletal and connective tissue disorders

Arthralgia

Back pain

Common

Fractures

Uncommon

Description of selected adverse reactions

Pneumonia

In a total of 1810 patients with advanced COPD (mean post bronchodilatory screening FEV1 45% of predicted, standard deviation (SD) 13%), 65% of which had experienced a moderate/severe COPD exacerbation in the year prior to study entry, there was a higher incidence of pneumonia events reported up to 24 weeks in patients receiving Trelegy Ellipta (20 patients, 2%) than in patients receiving budesonide/formoterol (7 patients, <1%). Pneumonia which required hospitalisation occurred in 1% of patients receiving Trelegy Ellipta and <1% of patients receiving budesonide/formoterol up to 24 weeks. One fatal case of pneumonia was reported in a patient who received Trelegy Ellipta. In the subset of 430 subjects treated for up to 52 weeks, the incidence of pneumonia events reported in both Trelegy Ellipta and budesonide/formoterol arms was equal at 2%. The incidence of pneumonia with Trelegy Ellipta is comparable with that observed in the fluticasone furoate/vilanterol (FF/VI) 100/25 arm of FF/VI clinical studies in COPD.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

United Kingdom

the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

Ireland

HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie

4.9 Overdose

An overdose will likely produce signs, symptoms or adverse effects associated with the individual components' 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 be treated supportively with appropriate monitoring as necessary.

Cardioselective beta-blockade should only be considered for profound vilanterol overdose effects that are clinically concerning and unresponsive to supportive measures. Cardioselective beta-blocking medicinal products 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, where available.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs for obstructive airway diseases, ATC code: not yet assigned.

Mechanism of action

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

Fluticasone furoate

Fluticasone furoate is a corticosteroid with potent anti-inflammatory activity. The precise mechanism through which fluticasone furoate affects COPD symptoms is not known. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g. eosinophils, macrophages, lymphocytes) and mediators (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 acetylcholine with muscarinic receptors on airway smooth muscle. It demonstrates slow reversibility at the human M3 muscarinic receptor subtype in vitro and a long duration of action in vivo when administered directly to the lungs in pre-clinical models.

Vilanterol

Vilanterol is a selective long-acting, beta2-adrenergic receptor agonist (LABA). The pharmacologic effects of beta2-adrenergic agonists, including vilanterol, are at least in part attributable to stimulation of intracellular adenylate 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 smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

Pharmacodynamic effects

Cardiac electrophysiology

The effect of fluticasone furoate/umeclidinium/vilanterol on the QT interval has not been evaluated in a thorough QT (TQT) study. TQT studies for FF/VI and umeclidinium/vilanterol (UMEC/VI) did not show clinically 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 911 subjects with COPD exposed to fluticasone furoate/umeclidinium/vilanterol for up to 24 weeks, or in the subset of 210 subjects exposed for up to 52 weeks.

Clinical efficacy

The efficacy of Trelegy Ellipta (92/55/22 micrograms) administered as a once daily treatment in patients with a clinical diagnosis of COPD has been evaluated in one 24-week active-controlled study with an extension up to 52 weeks in a subset of subjects (CTT116853). Patients were required to be symptomatic with a CAT score ≥10 and on COPD maintenance therapy for at least three months prior to study entry. The mean age was 63.9 years, with 50% of patients aged 65 or over. At screening, the mean post bronchodilator FEV1 was 45% of predicted and 65% of patients reported a history of moderate/severe exacerbation in the past year. At study entry, the most common COPD medication combinations reported were ICS +LABA+LAMA (28%), ICS+LABA (29%), LAMA+LABA (10%) and LAMA (9%). These patients may have also been taking other COPD medications (e.g. mucolytics or leukotriene receptor antagonists).

Trelegy Ellipta (92/55/22 micrograms) administered once daily demonstrated a statistically significant improvement in lung function (as defined by change from baseline trough FEV1 at Week 24; co-primary endpoint) compared with budesonide/formoterol (BUD/FOR) 400 /12 micrograms administered twice-daily (see Table 1). Bronchodilatory effects with Trelegy Ellipta were evident on the first day of treatment and were maintained over the 24 week treatment period (changes from baseline in FEV1 were 90-222 mL on Day 1 and 160-339 mL at Week 24).

Trelegy Ellipta demonstrated a statistically significant improvement compared to BUD/FOR at Week 24 for Health Related Quality of Life (HRQoL) measured by the St George's Respiratory Questionnaire (SGRQ) total score (co-primary endpoint), SGRQ responder analysis, COPD Assessment Test (CAT) score, CAT responder analysis, respiratory symptoms measured using the Evaluating Respiratory Symptoms in COPD (E-RS:COPD) and sub-scale scores over Weeks 21-24, breathlessness measured using the Transitional Dyspnoea Index (TDI) focal score at Week 24, and rescue medication use measured by mean number of occasions of rescue medication use per day over Weeks 1-24 (see Table 1).

Trelegy Ellipta demonstrated a statistically significant reduction in the annual rate of moderate/severe exacerbations (i.e. requiring treatment with antibiotics or corticosteroids or hospitalisation; extrapolated from data up to Week 24) compared with BUD/FOR. A reduction in the risk of a moderate/severe exacerbation (i.e. requiring treatment with antibiotics or corticosteroids or hospitalisation) was observed with Trelegy Ellipta compared with BUD/FOR (based on analysis of the time to first exacerbation) (see Table 1).

Table 1. Lung function, HRQoL and Symptoms up to Week 24 (Study CTT116853, intent to treat population)

Study CTT116853

Trelegy Ellipta

FF/UMEC/VI

100/62.5/25

mcg OD

(n= 911)

BUD/FOR

400/12

mcg BID

(n=899)

Comparison with BUD/FOR

Treatment Difference

(95% CI)

p-value

Treatment Ratio

(95% CI)

p-value

Trough FEV1 (L) at Week 24, LS mean change from baseline (SE) (Co-primary) d

0.142 (0.0083)

-0.029 (0.0085)

0.171

(0.148, 0.194)

p<0.001

-

SGRQ Total Score at Week 24, LS mean change from baseline (SE) (Co-primary) e

-6.6 (0.45)

-4.3 (0.46)

-2.2

(-3.5, -1.0)

p<0.001

-

Responders according to SGRQ Total Score (≥4 unit decrease from baseline) at Week 24, % e

50%

41%

-

1.41 a

(1.16, 1.70)

p<0.001

Annual rate of on-treatment moderate/severe COPD exacerbation (based on data up to Week 24)

0.22

0.34

-

0.65 b

(0.49, 0.86)

p=0.002

Incidence of moderate/severe COPD exacerbation up to Week 24, %

10%

14%

-

0.67 c

(0.52, 0.88)

p=0.004

E-RS: COPD Total Score during Weeks 21-24, LS mean change from baseline (SE) f

-2.31 (0.157)

-0.96 (0.160)

-1.35

(-1.79, -0.91)

p<0.001

Responders according to E-RS: COPD Total Score (≥2 unit decrease from baseline) during Weeks 21-24, % f

47%

37%

-

1.59 a

(1.30, 1.94)

p<0.001

TDI focal score at Week 24, LS mean (SE) e

2.29 (0.096)

1.72 (0.099)

0.57

(0.30, 0.84)

p< 0.001

-

Responders according to TDI focal score at Week 24, % (≥1 unit score) e

61%

51%

-

1.61 a

(1.33, 1.95)

p<0.001

Daily activity percentage of days with score of 2 (able to perform more activities than usual) over Weeks 1-24, LS mean change from baseline (SE)

0.0 (0.38)

-0.1 (0.39)

0.1

(-0.9, 1.1)

p=0.817

-

Mean number of occasions of rescue medication use per day over Weeks 1-24, LS mean change from baseline (SE)

-0.1 (0.04)

0.1 (0.04)

-0.2

(-0.3, -0.1)

p<0.001

-

CAT Score at Week 24, LS mean change from baseline (SE) e

-2.5 (0.18)

-1.6 (0.19)

-0.9

(-1.4, -0.4)

p<0.001

-

Responders according to CAT Score (≥2 unit decrease from baseline) at Week 24, %

53%

45%

-

1.44 a

(1.19, 1.75)

p<0.001

a Odds ratio. b Rate ratio. c Hazard ratio based on analysis of time to first event

d Statistically significant treatment difference for FF/UMEC/VI vs. BUD/FOR also observed at Weeks 2, 4 and 12

e Statistically significant treatment difference for FF/UMEC/VI vs. BUD/FOR also observed at Week 4

f Statistically significant treatment difference for FF/UMEC/VI vs. BUD/FOR also observed over each 4-weekly period during the study duration

Abbreviations: BID=twice daily; CI= confidence interval; L= litres; LS= least squares; mcg= micrograms; OD= once daily; SE= standard error.

The lung function, HRQoL and symptoms outcomes up to 52 weeks in a subset of patients (n=430 double blind double dummy extension population) were consistent with the results up to 24 weeks.

12-week studies with umeclidinium and fluticasone furoate/vilanterol

In two 12-week, placebo controlled studies (200109 and 200110), the addition of umeclidinium to fluticasone furoate/vilanterol (FF/VI) (92/22 micrograms) once daily in adult patients aged 40 years or over with a clinical diagnosis of COPD (mean post bronchodilatory screening FEV1 45 and 47% of predicted, respectively; modified medical research council dyspnea score ≥2), resulted in statistically significant and clinically meaningful improvements in the primary endpoint of trough FEV1 at Day 85 compared to placebo plus FF/VI (124 mL [95% CI: 93, 154, p<0.001] in study 200109 and 122 mL [95% CI: 91, 152, p<0.001] in study 200110).

52-week COPD exacerbation studies with fluticasone furoate/vilanterol

The beneficial effect of fluticasone furoate/vilanterol on exacerbation rate was demonstrated in two 52 week randomised, double-blind, parallel-group, studies (HZC102970 and HZC102871) comparing the effect of fluticasone furoate/vilanterol with vilanterol administered once daily, on the rate of moderate/severe exacerbations in subjects with COPD. The primary endpoint was the rate of moderate and severe exacerbations.

The results of both studies showed that treatment with fluticasone furoate/vilanterol 92/22 micrograms once daily resulted in a lower rate of moderate/severe COPD exacerbations compared with vilanterol (Table 2).

Table 2: Analysis of Exacerbation Rates following 12 months of treatment

Endpoint

HZC102970

HZC102871

HZC102970 and HZC102871 integrated

Vilanterol

(n=409)

fluticasone furoate/ vilanterol

92/22

(n=403)

Vilanterol

(n=409)

fluticasone furoate/ vilanterol

92/22

(n=403)

Vilanterol

(n=818)

fluticasone furoate/ vilanterol

92/22

(n=806)

Moderate and severe exacerbations

Adjusted mean annual rate

1.14

0.90

1.05

0.70

1.11

0.81

Ratio vs VI

95% CI

p-value

% reduction

(95% CI)

0.79

(0.64,0.97)

0.024

21

(3, 36)

0.66

(0.54, 0.81)

<0.001

34

(19, 46)

0.73

(0.63, 0.84)

<0.001

27

(16, 37)

Absolute difference in number per year vs VI

(95% CI)

0.24

(0.03, 0.41)

0.36

(0.20, 0.48)

0.30

(0.18, 0.41)

Time to first exacerbation:

Hazard ratio

(95% CI)

% risk reduction

p-value

0.80

(0.66, 0.99)

20

0.036

0.72

(0.59, 0.89)

28

0.002

0.76

(0.66, 0.88)

24

p<0.001

Paediatric population

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).

5.2 Pharmacokinetic properties

When fluticasone furoate, umeclidinium and vilanterol were administered in combination by the inhaled route from a single inhaler in healthy subjects, the pharmacokinetics of each component were similar to those observed when each active substance was administered either as fluticasone furoate/vilanterol combination or umeclidinium/vilanterol combination.

Population PK analyses for FF/UMEC/VI were conducted in a subset of 74 COPD subjects from the phase III study. Systemic drug levels (steady state Cmax and AUC) of FF, UMEC and VI following FF/UMEC/VI in one inhaler (triple combination) were within the range of those observed following dual combinations (FF/VI and UMEC/VI) as well as individual single inhalers (FF, UMEC and VI).

Absorption

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 when administrated as fluticasone furoate/vilanterol by inhalation was 15.2%, primarily due to absorption of the inhaled 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 days with 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 on average 13%, with negligible contribution from oral absorption. Following repeat dosing of inhaled umeclidinium, 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%, with negligible 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.

Distribution

Fluticasone furoate

Following intravenous dosing of fluticasone furoate to healthy volunteers, the mean volume of distribution at steady state of 661 litres. Fluticasone furoate has a low association with red blood cells. In vitro plasma protein 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 of distribution 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 at steady state was 165 litres. Vilanterol has a low association with red blood cells. In vitro plasma protein binding in human plasma was on average 94%.

Biotransformation

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 is hydrolysis of the S-fluoromethyl carbothioate group to metabolites with significantly reduced corticosteroid activity. Systemic exposure to the metabolites is low.

Umeclidinium

In vitro studies showed that umeclidinium is primarily metabolised by cytochrome P450 2D6 (CYP2D6) and is 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 of metabolites with either reduced pharmacological activity or for which the pharmacological activity has not been established. Systemic exposure to the metabolites is low.

Vilanterol

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

Elimination

Fluticasone furoate

The apparent plasma elimination half-life of fluticasone furoate following inhaled administration of fluticasone furoate/vilanterol was, on average, 24 hours. Following intravenous administration, the elimination phase half-life averaged 15.1 hours. Plasma clearance following intravenous administration was 65.4 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 with metabolites being excreted almost exclusively in faeces, with <1% of the recovered radioactive dose eliminated 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 intravenous administration was 151 litres/hour. Following intravenous administration, approximately 58% of the administered radiolabelled dose was excreted in faeces and approximately 22% of the administered radiolabelled dose was excreted in urine. The excretion of the drug-related material in the faeces following intravenous dosing indicated secretion into the bile. Following oral administration, 92% of the administered radiolabelled dose was excreted primarily in faeces. Less than 1% of the orally administered dose (1% of recovered radioactivity) was excreted in urine, suggesting negligible absorption following oral administration.

Vilanterol

Vilanterol plasma elimination half-life following inhaled dosing for 10 days averaged 11 hours. Plasma clearance of vilanterol following intravenous administration was 108 litres/hour. Following oral administration 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 and faeces.

Special populations

Elderly

The effects of age on the pharmacokinetics of fluticasone furoate/umeclidinium/vilanterol have not been evaluated from the phase III study in COPD. Population PK analyses of fluticasone furoate/vilanterol and umeclidinium/vilanterol assessed effect of age on pharmacokinetics of fluticasone furoate, vilanterol and umeclidinium, vilanterol respectively. No clinically relevant effects requiring dose adjustment were observed.

Renal impairment

The effect of fluticasone furoate/umeclidinium/vilanterol has not been evaluated in subjects with renal impairment. However, studies have been conducted with fluticasone furoate/vilanterol and umeclidinium/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 impairment and healthy volunteers were conducted, and no clinically significant evidence of altered protein binding was seen.

The effects of haemodialysis have not been studied.

Hepatic impairment

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

The fluticasone furoate/vilanterol component of Trelegy Ellipta was assessed in patients with all severities of hepatic impairment (Child-Pugh A, B or C). For fluticasone furoate, patients with moderate hepatic impairment showed up to three times higher systemic exposure (FF 184 micrograms); therefore, patients with severe hepatic impairment received half the dose (FF 92 micrograms). At this dose, no effects on systemic 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 significant increase in systemic exposure to vilanterol.

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

Other special populations

In subjects with COPD estimates of fluticasone furoate AUC(0-24) for East Asian, Japanese and South East Asian subjects (13-14% subjects) were on average 23% to 30% higher compared with Caucasian subjects. However, there was no evidence for the higher systemic exposure in this population to be associated with greater effect on 24 hour urinary cortisol excretion. There was no effect of race on pharmacokinetic parameter estimates of vilanterol in subjects with COPD.

Population pharmacokinetic analyses in COPD subjects treated with fluticasone furoate/vilanterol and umeclidinium/vilanterol showed that no dose adjustment is required for fluticasone furoate, umeclidinium or vilanterol based on the effect of gender or weight. In terms of other patient characteristics, a study in CYP2D6 poor metabolisers showed no evidence of a clinically significant effect of CYP2D6 genetic polymorphism on systemic exposure to umeclidinium.

5.3 Preclinical safety data

Pharmacological and toxicological effects seen with fluticasone furoate, umeclidinium or vilanterol in nonclinical studies were those typically associated with glucocorticoids, muscarinic receptor antagonists, or beta2-adrenergic receptor agonists. Administration of combined fluticasone furoate, umeclidinium and vilanterol to dogs did not result in any significant new toxicity or any major exacerbation of expected findings associated with fluticasone furoate, umeclidinium or vilanterol alone.

Genotoxicity and carcinogenicity

Fluticasone furoate

Fluticasone furoate was not genotoxic in a standard battery of studies and was not carcinogenic in lifetime inhalation studies in rats or mice at exposures similar to those seen in humans at a daily 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 lifetime inhalation studies in mice or rats at exposures ≥ 24 or ≥ 20-fold the human clinical exposure at a daily dose of 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 beta2 agonists, in lifetime inhalation studies vilanterol trifenatate caused proliferative effects in the female rat and mouse reproductive tract and rat pituitary gland. There was no increase in tumour incidence in rats or mice at exposures 0.5- or 12-fold, respectively, the human clinical exposure of vilanterol at a daily dose of 22 micrograms based on AUC.

Reproductive toxicity

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

Fluticasone furoate

Fluticasone furoate was not teratogenic in rats or rabbits, but delayed development in rats and caused abortion in rabbits at maternally toxic doses. There were no effects on development in rats at exposures approximately 8-fold the human clinical exposure at a daily dose of 92 micrograms, based on AUC. Fluticasone furoate had no 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, subcutaneous administration of umeclidinium to rats resulted in lower maternal body weight gain and food consumption and slightly decreased pre-weaning pup body weights in dams given 180 micrograms/kg/day dose (approximately 73-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 to those seen with other beta2-adrenergic agonists (cleft palate, open eyelids, sternebral fusion and limb flexure/malrotation). When given subcutaneously there were no effects at exposures 34-fold the human clinical exposure at a daily dose of 22 micrograms, based on AUC. Vilanterol had no adverse effect on pre- or post-natal development in rats.

6. Pharmaceutical particulars
6.1 List of excipients

Lactose monohydrate

Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

Shelf-life after opening the tray: 6 weeks

6.4 Special precautions for storage

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 to protect from moisture and only remove immediately before first use.

Write the date that the inhaler should be discarded on the label and carton in the space provided. The date should be added as soon as the inhaler has been removed from the tray.

6.5 Nature and contents of container

The Ellipta inhaler consists of a light grey body, beige mouthpiece cover and a dose counter, packed into a foil laminate tray containing a 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 stainless steel.

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

Pack sizes of 14 or 30 dose inhalers.

Multipack of 90 (3 packs of 30) dose inhalers.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

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

The Ellipta inhaler contains pre-dispensed doses and is ready to use.

The inhaler is packaged in a tray containing a desiccant sachet, to reduce moisture. The desiccant sachet should be thrown away and it should not be opened, eaten or inhaled. The patient should be advised to not open 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” date should be written on the inhaler label and carton in the space provided. The date should be added as soon as the inhaler has been removed from the tray. The “Discard by” date is 6 weeks from the date of opening the tray. 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. 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 extra medicine or a double dose in one inhalation.

For further instructions for use and handling, see section 4.2.

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

7. Marketing authorisation holder

GSK Trading Services Ltd.

Currabinny

Co. Cork

Ireland

8. Marketing authorisation number(s)

EU/1/17/1236/01

EU/1/17/1236/02

EU/1/17/1236/03

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 15th November 2017

10. Date of revision of the text

15th November 2017

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.