RELVAR ELLIPTA Inhalation powder, pre-dispensed Ref.[50872] Active ingredients: Fluticasone furoate Vilanterol Vilanterol and Fluticasone furoate

Deterioration of disease

Fluticasone furoate/vilanterol should not be used to treat acute asthma symptoms or an acute exacerbation in COPD, for which a short-acting bronchodilator is required. Increasing use of short-acting bronchodilators to relieve symptoms indicates deterioration of control and patients should be reviewed by a physician.

Patients should not stop therapy with fluticasone furoate/vilanterol in asthma or COPD, without physician supervision since symptoms may recur after discontinuation.

Asthma-related adverse events and exacerbations may occur during treatment with fluticasone furoate/vilanterol. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation of treatment with Relvar Ellipta.

Paradoxical bronchospasm

Paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. This should be treated immediately with a short-acting inhaled bronchodilator. Relvar Ellipta should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

Cardiovascular effects

Cardiovascular effects, such as cardiac arrhythmias e.g. supraventricular tachycardia and extrasystoles may be seen with sympathomimetic medicinal products including Relvar Ellipta. In a placebocontrolled study in subjects with moderate COPD and a history of, or an increased risk of cardiovascular disease, there was no increase in the risk of cardiovascular events in patients receiving fluticasone furoate/vilanterol compared with placebo (see section 5.1). However, fluticasone furoate/vilanterol should be used with caution in patients with severe cardiovascular disease or heart rhythm abnormalities, thyrotoxicosis, uncorrected hypokalaemia or patients predisposed to low levels of serum potassium.

Patients with hepatic impairment

For patients with moderate to severe hepatic impairment, the 92/22 micrograms dose should be used and patients 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. Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, decrease in bone mineral density, growth retardation in children and adolescents, cataract and glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children).

Fluticasone furoate/vilanterol should be administered with caution in patients with pulmonary tuberculosis or in patients with chronic or untreated infections.

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.

Hyperglycaemia

There have been reports of increases in blood glucose levels in diabetic patients and this should be considered when prescribing to patients with a history of diabetes mellitus.

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.

Pneumonia in patients with asthma

The incidence of pneumonia in patients with asthma was common at the higher dose. The incidence of pneumonia in patients with asthma taking fluticasone furoate/vilanterol 184/22 micrograms was numerically higher compared with those receiving fluticasone furoate/vilanterol 92/22 micrograms or placebo (see section 4.8). No risk factors were identified.

Excipients

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

Clinically significant drug interactions mediated by fluticasone furoate/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. Concurrent use of both non-selective and selective beta₂-adrenergic blockers should be avoided unless there are compelling reasons for their use.

Interaction with CYP3A4 inhibitors

Fluticasone furoate and vilanterol are both rapidly cleared by extensive first pass metabolism mediated by the liver enzyme CYP3A4.

Caution is advised when co-administering with strong CYP 3A4 inhibitors (e.g. ketoconazole, ritonavir, cobicistat-containing products) as there is potential for increased systemic exposure to both fluticasone furoate and vilanterol. Co-administration should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid undesirable effects, in which case patients should be monitored for systemic corticosteroid undesirable effects. A repeat dose CYP3A4 drug interaction study was performed in healthy subjects with the fluticasone furoate/vilanterol combination (184/22 micrograms) and the strong CYP3A4 inhibitor ketoconazole (400mg). 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 65% and 22%, respectively. The increase in vilanterol exposure was not associated with an increase in beta₂-agonist related systemic effects on heart rate, blood potassium or QTcF interval.

Interaction with P-glycoprotein inhibitors

Fluticasone furoate and vilanterol are both substrates of P-glycoprotein (P-gp). A clinical pharmacology study in healthy subjects with co-administered vilanterol and the potent P-gp and moderate CYP3A4 inhibitor verapamil did not show any significant effect on the pharmacokinetics of vilanterol. Clinical pharmacology studies with a specific P-gp inhibitor and fluticasone furoate have not been conducted.

Sympathomimetic medicinal products

Concomitant administration of other sympathomimetic medicinal products (alone or as part of combination therapy) may potentiate the adverse reactions of fluticasone furoate/vilanterol. Relvar Ellipta should not be used in conjunction with other long-acting beta₂-adrenergic agonists or medicinal products containing long-acting beta₂-adrenergic agonists.

Paediatric population

Interaction studies have only been performed in adults.

Pregnancy

Studies in animals have shown reproductive toxicity at exposures which are not clinically relevant (see section 5.3). There are no or limited data from the use of fluticasone furoate and vilanterol trifenatate in pregnant women.

Administration of fluticasone furoate/vilanterol to pregnant women should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus.

Breast-feeding

There is insufficient information on the excretion of fluticasone furoate or vilanterol trifenatate and/or metabolites in human milk. However, other corticosteroids and beta₂-agonists are detected in human milk (see section 5.3). A risk to breastfed newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue fluticasone furoate/vilanterol therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no fertility data in humans. Animal studies showed no effect of fluticasone furoate/vilanterol trifenatate on fertility (see section 5.3).

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

Summary of the safety profile

Data from large asthma and COPD clinical trials were used to determine the frequency of adverse reactions associated with fluticasone furoate/vilanterol. In the asthma clinical development programme a total of 7,034 patients were included in an integrated assessment of adverse reactions. In the COPD clinical development programme a total of 6,237 subjects were included in an integrated assessment of adverse reactions.

The most commonly reported adverse reactions with fluticasone furoate and vilanterol were headache and nasopharyngitis. With the exception of pneumonia and fractures, the safety profile was similar in patients with asthma and COPD. During clinical studies, pneumonia and fractures were more frequently observed in patients with COPD.

Tabulated list of adverse reactions

Adverse reactions are listed by system organ class and frequency. The following convention has been used for the classification of frequencies: 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).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

^*,** See below 'Description of selected adverse reactions'

Description of selected adverse reactions

^*Pneumonia (see section 4.4)

In an integrated analysis of the two replicate one year studies in moderate to severe COPD (mean predicted post-bronchodilator screening FEV1 of 45%, standard deviation (SD) 13%) with an exacerbation in the preceding year (n=3255), the number of pneumonia events per 1000 patient years was 97.9 with FF/VI 184/22 micrograms, 85.7 in the FF/VI 92/22 micrograms and 42.3 in the VI 22 micrograms group. For severe pneumonia the corresponding number of events per 1000 patient years were 33.6, 35.5, and 7.6 respectively, while for serious pneumonia the corresponding events per 1000 patient years were 35.1 for FF/VI 184/22 micrograms, 42.9 with FF/VI 92/22 micrograms, 12.1 with VI 22 micrograms. Finally, the exposure-adjusted cases of fatal pneumonia were 8.8 for FF/VI 184/22 micrograms versus 1.5 for FF/VI 92/22 micrograms and 0 for VI 22 micrograms.

In a placebo-controlled study (SUMMIT) in subjects with moderate COPD (mean percent postbronchodilator screening FEV1 of 60%, SD 6%), and a history of, or an increased risk of cardiovascular disease, the incidence of pneumonia with FF/VI, FF, VI and placebo was: adverse events (6%, 5%, 4%, 5%); serious adverse events (3%, 4%, 3%, 3%); adjudicated on treatment deaths due to pneumonia (0.3%, 0.2%, 0.1%, 0.2%); the exposure adjusted rates (per 1000 treatment years) were: adverse events (39.5, 42.4, 27.7, 38.4); serious adverse events (22.4, 25.1, 16.4, 22.2); adjudicated on-treatment deaths due to pneumonia (1.8, 1.5, 0.9, 1.4) respectively.

In an integrated analysis of 11 studies in asthma (7,034 patients), the incidence of pneumonia per 1000 patient years was 18.4 for FF/VI 184/22 micrograms versus 9.6 for FF/VI 92/22 micrograms and 8.0 in the placebo group.

^**Fractures

In two replicate 12 month studies in a total of 3,255 patients with COPD the incidence of bone fractures overall was low in all treatment groups, with a higher incidence in all Relvar Ellipta groups (2%) compared with the vilanterol 22 micrograms group (<1%). Although there were more fractures in the Relvar Ellipta groups compared with the vilanterol 22 micrograms group, fractures typically associated with corticosteroid use (e.g., spinal compression/thoracolumbar vertebral fractures, hip and acetabular fractures) occurred in <1% of the Relvar Ellipta and vilanterol treatment arms.

For the SUMMIT study, the incidence of all events of fracture with FF/VI, FF, VI and placebo were 2% in each arm; fractures commonly associated with ICS use were less than 1% in each arm. The exposure-adjusted rates (per 1000 treatment years) for all fracture events were 13.6, 12.8, 13.2, 11.5 respectively; fractures commonly associated with ICS use were 3.4, 3.9, 2.4, 2.1 respectively. In an integrated analysis of 11 studies in asthma (7,034 patients), the incidence of fractures was <1%, and usually associated with trauma.

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.