Incruse^® 55 micrograms inhalation powder, pre-dispensed

Each single inhalation provides a delivered dose (the dose leaving the mouthpiece of the inhaler) of 55 micrograms umeclidinium (equivalent to 65 micrograms of umeclidinium bromide). This corresponds to a pre-dispensed dose of 62.5 micrograms umeclidinium equivalent to 74.2 micrograms umeclidinium bromide.

Excipient with known effect:

Each delivered dose contains approximately 12.5 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Inhalation powder, pre-dispensed (inhalation powder).

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

Incruse is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD).

Posology

Adults

The recommended dose is one inhalation of umeclidinium bromide once daily.

Incruse should be administered once daily at the same time of the day each day to maintain bronchodilation. The maximum dose is one inhalation of umeclidinium bromide once daily.

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 or moderate hepatic impairment. Incruse has not been studied in patients with severe hepatic impairment and should be used with caution (see section 5.2).

Paediatric population

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

Method of administration

Incruse is for inhalation use only.

Instructions for use:

The following instructions for the 30 dose inhaler also apply to the 7 dose inhaler.

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 eaten or inhaled.

The inhaler will be in the 'closed' position when it is first taken out of its sealed tray. It should not be opened until it is ready to be inhaled. The inhaler does not need to be stored in the foil laminate tray once it has been opened.

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.

a) Prepare a dose

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

Slide the cover down 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.

c) Close the inhaler

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

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

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1

Asthma

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

Paradoxical bronchospasm

Administration of umeclidinium bromide may produce paradoxical bronchospasm that may be life-threatening. Treatment should be discontinued immediately if paradoxical bronchospasm occurs and alternative therapy instituted if necessary.

Deterioration of disease

Umeclidinium bromide is intended for the maintenance treatment of COPD. It should not be used for the relief of acute symptoms, i.e. as rescue therapy for the treatment of acute episodes of bronchospasm. Acute symptoms should be treated with an inhaled short-acting bronchodilator. Increasing use of short-acting bronchodilators to relieve symptoms indicates deterioration of control. In the event of deterioration of COPD during treatment with umeclidinium bromide, a re-eva luation of the patient and of the COPD treatment regimen should be undertaken.

Cardiovascular effects

Cardiovascular effects, such as cardiac arrhythmias e.g. atrial fibrillation and tachycardia, may be seen after the administration of muscarinic receptor antagonists including umeclidinium bromide. In addition, patients with clinically significant uncontrolled cardiovascular disease were excluded from clinical studies. Therefore, umeclidinium bromide should be used with caution in patients with severe cardiovascular disorders, particularly cardiac arrhythmias.

Antimuscarinic activity

Consistent with its antimuscarinic activity, umeclidinium bromide should be used with caution in patients with urinary retention or with narrow-angle glaucoma.

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.

Clinically significant interactions mediated by umeclidinium bromide at clinical doses are considered unlikely due to the low plasma concentrations achieved after inhaled dosing.

Other antimuscarinics

Co-administration of umeclidinium bromide with other long-acting muscarinic antagonists or medicinal products containing this active substance has not been studied and is not recommended as it may potentiate known inhaled muscarinic antagonist adverse reactions.

Metabolic and transporter based interactions

Umeclidinium bromide is a substrate of cytochrome P450 2D6 (CYP2D6). The steady-state pharmacokinetics of umeclidinium bromide were assessed in healthy volunteers lacking CYP2D6 (poor metabolisers). No effect on umeclidinium AUC or C_max was observed at a dose 4-fold higher than the therapeutic dose. An approximately 1.3-fold increase in umeclidinium bromide AUC was observed at an 8-fold higher dose with no effect on umeclidinium bromide C_max. Based on the magnitude of these changes, no clinically relevant drug interaction is expected when umeclidinium is co-administered with CYP2D6 inhibitors or when administered to subjects genetically deficient in CYP2D6 activity (poor metabolisers).

Umeclidinium bromide is a substrate of P-glycoprotein (P-gp) transporter. The effect of the moderate P-gp inhibitor verapamil (240 mg once daily) on the steady-state pharmacokinetics of umeclidinium bromide was assessed in healthy volunteers. No effect of verapamil was observed on umeclidinium bromide Cmax. An approximately 1.4-fold increase in umeclidinium bromide AUC was observed. Based on the magnitude of these changes, no clinically relevant interaction is expected when umeclidinium bromide is co-administered with P-gp inhibitors.

Other medicinal products for COPD

Although no formal in vivo interaction studies have been performed, inhaled umeclidinium bromide has been used concomitantly with other COPD medicinal products including short and long acting sympathomimetic bronchodilators and inhaled corticosteroids without clinical evidence of interactions.

Pregnancy

There are no data from the use of umeclidinium bromide in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

Umeclidinium bromide should be used during pregnancy only if the expected benefit to the mother justifies the potential risk to the fetus.

Breast-feeding

It is unknown whether umeclidinium bromide is excreted in human milk. A risk to breastfed newborns/infants cannot be excluded.

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

Fertility

There are no data on the effects of umeclidinium bromide on human fertility. Animal studies indicate no effects of umeclidinium bromide on fertility.

Umeclidinium bromide has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most frequently reported adverse reactions with Incruse were nasopharyngitis and upper respiratory tract infection.

Tabulated summary of adverse reactions

The safety profile of umeclidinium bromide was eva luated from 1663 patients with COPD who received doses of 55 micrograms or greater for up to one year. This includes 576 patients who received the recommended dose of 55 micrograms once daily.

The frequencies assigned to the adverse reactions identified in the table below include crude incidence rates observed from four efficacy studies and the long-term safety study (which involved 1,412 patients who received umeclidinium bromide).

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).

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:

Ireland

IMB Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.imb.ie; e-mail: imbpharmacovigilance@imb.ie

United Kingdom

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

An overdose of umeclidinium bromide will likely produce signs and symptoms consistent with the known inhaled muscarinic antagonist adverse effects (e.g. dry mouth, visual accommodation disturbances and tachycardia).

If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary.

Pharmacotherapeutic group: Drugs for obstructive airway diseases, anticholinergics, ATC code: R03BB07

Mechanism of action

Umeclidinium bromide is a long acting muscarinic receptor antagonist (also referred to as an anticholinergic). It is a quinuclidine derivative that is a muscarinic receptor antagonist with activity across multiple muscarinic cholinergic receptor subtypes. Umeclidinium bromide exerts its bronchodilatory activity by competitively inhibiting the binding of acetylcholine with muscarinic cholinergic 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.

Pharmacodynamic effects

In a Phase III, 6-month study (DB2113373) Incruse provided a clinically meaningful improvement over placebo in lung function (as measured by forced expiratory volume in 1 second [FEV1]) over 24 hours following once daily administration, which was evident at 30 minutes following administration of the first dose (improvement over placebo by 102 mL, p<0.001*) The mean peak improvements in FEV1 within the first 6 hours following dosing relative to placebo were 130 ml (p<0.001*) at Week 24. There was no evidence for tachyphylaxis in the effect of Incruse over time.

Cardiac electrophysiology

The effect of umeclidinium 500 micrograms (pre-dispensed) on the QT interval was eva luated in a placebo- and moxifloxacin-controlled QT trial of 103 healthy volunteers. Following repeat doses of umeclidinium 500 micrograms once daily for 10 days, no clinically relevant effect on prolongation of QT interval (corrected using the Fridericia method) or effects on heart rate were observed.

Clinical efficacy

The clinical efficacy of Incruse administered once daily was eva luated in 904 adult patients who received umeclidinium bromide or placebo from two Phase III clinical studies with a clinical diagnosis of COPD; a 12-week study (AC4115408) and a 24-week study (DB2113373).

Effects on lung function

In both the 12-week and 24-week studies, Incruse demonstrated statistically significant and clinically meaningful improvements in lung function (as defined by change from baseline trough FEV₁ at Week 12 and Week 24 respectively, which was the primary efficacy endpoint in each study) compared with placebo (see Table 1). The bronchodilatory effects with Incruse compared with placebo were evident after the first day of treatment in both studies and were maintained over the 12-week and 24-week treatment periods.

There was no attenuation of the bronchodilator effect over time.

Table 1: Trough FEV₁ (ml) at Week 12 and Week 24 (primary endpoint)

mcg = micrograms

^1.least squares mean (95% confidence interval)

Incruse demonstrated a statistically significant greater improvement from baseline in weighted mean FEV₁ over 0-6 hours post-dose at Week 12 compared with placebo (166 ml, p<0.001) in the 12-week study. Incruse demonstrated a greater improvement from baseline in weighted mean FEV₁ over 0-6 hours post-dose at Week 24 compared with placebo (150 ml, p<0.001*) in the 24-week study.

Symptomatic outcomes

Breathlessness:

In the 12-week study, a statistically significant improvement compared with placebo in the TDI focal score at Week 12 was not demonstrated for Incruse (1.0 units, p=0.05). A statistically significant improvement compared with placebo in the TDI focal score at Week 24 was demonstrated for Incruse (1.0 units, p<0.001) in the 24-week study.

The proportion of patients who responded with at least the minimum clinically important difference (MCID) of 1 unit TDI focal score at Week 12 was greater for Incruse (38%) compared with placebo (15%) in the 12-week study. Similarly, a greater proportion of patients achieved ≥1 unit TDI focal score for Incruse (53%) compared with placebo (41%) at Week 24 in the 24-week study.

Health-related quality of life:

Incruse also demonstrated a statistically significant improvement in health-related quality of life measured using the St. George's Respiratory Questionnaire (SGRQ) as indicated by a reduction in SGRQ total score at Week 12 compared with placebo (-7.90 units, p<0.001) in the 12-week study. A greater improvement compared with placebo in the change from baseline in SGRQ total score at Week 24 was demonstrated for Incruse (-4.69 units, p<0.001) in the 24-week study.

The proportion of patients who responded with at least the MCID in SGRQ score (defined as a decrease of 4 units from baseline) at Week 12 was greater for Incruse 55 micrograms (44%) compared with placebo (26%) in the 12-week study. Similarly, a greater proportion of patients achieved at least the MCID for Incruse at Week 24 (44%) compared with placebo (34%) in the 24-week study.

COPD exacerbations

In the 24-week study, Incruse lowered the risk of a COPD exacerbation compared with placebo (analysis of time to first exacerbation; Hazard Ratio 0.6, p=0.035*). The probability of having an exacerbation in patients receiving Incruse at week 24 was 8.9% compared with 13.7% for placebo. These studies were not specifically designed to eva luate the effect of treatments on COPD exacerbations and patients were withdrawn from the study if an exacerbation occurred.

Use of rescue medicinal product

In the 12-week study, Incruse statistically significantly reduced the use of rescue medication with salbutamol compared with placebo (on average a reduction of 0.7 puffs per day over Weeks 1-12, p=0.025) and demonstrated a higher percentage of days when no rescue medication was needed (on average 46.3%) compared with placebo (on average 35.2%; no formal statistical analysis was performed on this endpoint). In the 24-week study treatment with Incruse, the mean (SD) change from baseline in the number of puffs of rescue salbutamol over the 24-week treatment period was -1.4 (0.20) for placebo and -1.7 (0.16) for Incruse (Difference = -0.3; 95% CI: -0.8, 0.2, p=0.276). Patients receiving Incruse had a higher percentage of days when no rescue medication was needed (on average 31.1%) compared with placebo (on average 21.7%). No formal statistical testing was performed on this endpoint.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Incruse in all subsets of the paediatric population in COPD (see section 4.2 for information on paediatric use).

*A step-down statistical testing procedure was used in this study and this comparison was below a comparison that did not achieve statistical significance. Therefore, statistical significance on this comparison cannot be inferred.

Absorption

Following inhaled administration of umeclidinium bromide in healthy volunteers, Cmax occurred at 5 to 15 minutes. The absolute bioavailability of inhaled umeclidinium bromide was on average 13% of the dose, with negligible contribution from oral absorption. Following repeat dosing of inhaled umeclidinium bromide, steady state was achieved within 7 to 10 days with 1.5 to 1.8-fold accumulation.

Distribution

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

Biotransformation

In vitro studies showed that umeclidinium bromide is principally metabolised by cytochrome P450 2D6 (CYP2D6) and is a substrate for the P-glycoprotein (P-gp) transporter. The primary metabolic routes for umeclidinium bromide 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.

Elimination

Plasma clearance following intravenous administration was 151 litres/hour. Following intravenous administration, approximately 58% of the administered radiolabelled dose (or 73% of the recovered radioactivity) was excreted in faeces by 192 hours post-dose. Urinary elimination accounted for 22% of the administered radiolabelled dose by 168 hours (27% of recovered radioactivity). The excretion of the drug-related material in the faeces following intravenous dosing indicated secretion into the bile. Following oral administration to healthy male subjects, total radioactivity was excreted primarily in faeces (92% of the administered radiolabelled dose or 99% of the recovered radioactivity) by 168 hours post-dose. Less than 1% of the orally administered dose (1% of recovered radioactivity) was excreted in urine, suggesting negligible absorption following oral administration. Umeclidinium bromide 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.

Characteristics in specific groups of healthy volunteers or patients

Elderly

A population pharmacokinetic analysis showed that pharmacokinetics of umeclidinium bromide are similar between COPD patients 65 years and older and those younger than 65 years of age.

Renal impairment

Subjects with severe renal impairment (creatinine clearance <30mL/min) showed no evidence of an increase in systemic exposure to umeclidinium bromide (C_max and AUC), and no evidence of altered protein binding between subjects with severe renal impairment and healthy volunteers.

Hepatic impairment

Subjects with moderate hepatic impairment (Child-Pugh Class B) showed no evidence of an increase in systemic exposure to umeclidinium bromide (C_max and AUC), and no evidence of altered protein binding between subjects with moderate hepatic impairment and healthy volunteers. Umeclidinium bromide has not been eva luated in subjects with severe hepatic impairment.

Other special populations

A population pharmacokinetic analysis showed that no dose adjustment is required for umeclidinium bromide based on the effect of age, race, gender, inhaled corticosteroid use or weight. A study in CYP2D6 poor metabolisers showed no evidence of a clinically significant effect of CYP2D6 genetic polymorphism on systemic exposure to umeclidinium bromide.

Non clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. In nonclinical studies with umeclidinium bromide, findings were those typically associated with the primary pharmacology of muscarinic receptor antagonists and/or local irritancy.

Reproductive toxicity

Umeclidinium bromide was not teratogenic in rats or rabbits. In a pre- and post-natal study,subcutaneous administration of umeclidinium bromide 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 80-times the human clinical exposure of umeclidinium 55 micrograms, based on AUC).

Lactose monohydrate,

Magnesium stearate.

Not applicable.

2 years

In-use shelf-life: 6 weeks

Do not store above 30°C. If stored in the refrigerator, allow the inhaler to return to room temperature for at least an hour before use.

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

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

The inhaler contains one aluminium foil laminate blister of 7 or 30 doses.

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

Pack sizes of 7 and 30 dose inhaler.

Multipack of 3 x 30 dose inhalers.

Not all pack sizes may be marketed.

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

For instructions for handling, see section 4.2.

Glaxo Group Limited

980 Great West Road

Brentford

Middlesex

TW8 9GS

United Kingdom

EU/1/14/922/001

EU/1/14/922/002

EU/1/14/922/003

Date of first authorisation: 28 April 2014

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