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 or a combination of a long-acting β2-agonist and a long-acting muscarinic antagonist (for effects on symptom control and prevention of exacerbations see section 5.1).

4.2. Posology and method of administration

Posology

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.

Special populations

Elderly

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

Renal impairment

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

Hepatic impairment

No dose 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

For inhalation use only.

Instructions for use:

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” 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 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.

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

This medicinal product 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. If paradoxical bronchospasm occurs, treatment should be discontinued immediately. 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 (see section 4.8). 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. 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.

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

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 (see section 4.8). 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, total lactase deficiency or glucose-galactose malabsorption should not use 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 sections 4.8 and 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 are nasopharyngitis (7%), headache (5%) and upper respiratory tract infection (2%).

Tabulated list of adverse reactions

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

Upper respiratory tract infection

Bronchitis

Pharyngitis

Rhinitis

Sinusitis

Influenza

Nasopharyngitis

Candidiasis of mouth and throat

Urinary tract infection

Common

Viral respiratory tract infection

Uncommon

Immune system disorders

Hypersensitivity reactions, including anaphylaxis, angioedema, urticaria, and rash

Rare

Metabolism and nutrition disorders

Hyperglycaemia

Rare

Psychiatric disorders

Anxiety

Rare

Nervous system disorders

Headache

Common

Dysgeusia

Uncommon

Tremor

Rare

Eye disorders

Vision blurred (see section 4.4)

Glaucoma

Eye pain

Uncommon

Intraocular pressure increased

Rare

Cardiac disorders

Supraventricular tachyarrhythmia

Tachycardia

Atrial fibrillation

Uncommon

Palpitations

Rare

Respiratory, thoracic & mediastinal disorders

Cough

Oropharyngeal pain

Common

Dysphonia

Uncommon

Gastrointestinal disorders

Constipation

Common

Dry mouth

Uncommon

Musculoskeletal and connective tissue disorders

Arthralgia

Back pain

Common

Fractures

Uncommon

Muscle spasms

Rare

Renal and urinary disorders

Urinary retention

Dysuria

Rare

Description of selected adverse reactions

Pneumonia

In a total of 1 810 patients with advanced COPD (mean post-bronchodilator screening FEV1 45% of predicted, standard deviation (SD) 13%), 65% of whom had experienced a moderate/severe COPD exacerbation in the year prior to study entry (study CTT116853), 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 patients 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.

In a 52-week study, with a total of 10 355 patients with COPD and a history of moderate or severe exacerbations within the prior 12 months (mean post-bronchodilator screening FEV1 46% of predicted, SD 15%) (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) for umeclidinium/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 fluticasone furoate/vilanterol, and 5 of 2 070 patients (2.9 per 1 000 patient-years) receiving umeclidinium/vilanterol.

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 Yellow Card Scheme website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

An overdose will likely produce signs, symptoms or adverse reactions 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).

Management

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.