TRELEGY ELLIPTA Inhalation powder, pre-dispensed Ref.[115954] Active ingredients: Fluticasone furoate Umeclidinium Vilanterol

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.

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 C_max 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 C_max 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 C_max 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 C_max. 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 C_max. 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).

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 beta₂adrenergic 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).

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

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).

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 the national reporting system listed in Appendix V.

Not applicable.