INCRUSE 55mcg dose inhalation powder medication leaflet

Incruse Ellipta 55 micrograms inhalation powder, pre-dispensed

Each single inhalation provides a delivered dose (the dose leaving the mouthpiece of the inhaler) of55 micrograms umeclidinium (equivalent to 65 micrograms of umeclidinium bromide) Thiscorresponds to a pre-dispensed dose of 62.5 micrograms umeclidinium equivalent to 74.2 microgramsumeclidinium bromide.

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

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

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

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

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

No dose adjustment is required in patients with mild or moderate hepatic impairment. Incruse Elliptahas not been studied in patients with severe hepatic impairment and should be used with caution (seesection 5.2).

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

Incruse Ellipta is for inhalation use only.

The following instructions for the 30 dose inhaler (30 day supply) also apply to the 7 dose inhaler (7day supply).

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 desiccantsachet 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 “Discardby” date should be written on the inhaler label in the space provided. The “Discard by” date is 6 weeksfrom the date of opening the tray. After this date the inhaler should no longer be used. The tray can bediscarded 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 medicinal product 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 notbreathing 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 aspossible (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

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

Hypersensitivity to the active substance 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 thispatient population.

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

Umeclidinium bromide is intended for the maintenance treatment of COPD. It should not be used forthe relief of acute symptoms, i.e. as rescue therapy for the treatment of acute episodes ofbronchospasm. 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-evaluation ofthe patient and of the COPD treatment regimen should be undertaken.

Cardiovascular effects, such as cardiac arrhythmias e.g. atrial fibrillation and tachycardia, may be seenafter the administration of muscarinic receptor antagonists including umeclidinium bromide. Inaddition, patients with clinically significant uncontrolled cardiovascular disease were excluded fromclinical studies. Therefore, umeclidinium bromide should be used with caution in patients with severecardiovascular disorders, particularly cardiac arrhythmias.

Antimuscarinic activity

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

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

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

Other antimuscarinics

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

Metabolic and transporter based interactions

Umeclidinium bromide is a substrate of cytochrome P450 2D6 (CYP2D6). The steady-statepharmacokinetics of umeclidinium bromide were assessed in healthy volunteers lacking CYP2D6(poor metabolisers). No effect on umeclidinium AUC or Cmax was observed at a dose 4-fold higherthan the therapeutic dose. An approximately 1.3-fold increase in umeclidinium bromide AUC wasobserved at an 8-fold higher dose with no effect on umeclidinium bromide Cmax. Based on themagnitude of these changes, no clinically relevant drug interaction is expected when umeclidinium isco-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 umeclidiniumbromide was assessed in healthy volunteers. No effect of verapamil was observed on umeclidiniumbromide 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 whenumeclidinium 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 bromidehas been used concomitantly with other COPD medicinal products including short and long actingsympathomimetic bronchodilators and inhaled corticosteroids without clinical evidence ofinteractions.

There are no data from the use of umeclidinium bromide in pregnant women. Animal studies do notindicate 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 motherjustifies the potential risk to the foetus.

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

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

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

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

The most frequently reported adverse reactions with Incruse Ellipta were nasopharyngitis and upperrespiratory tract infection.

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

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

System Organ Class Adverse reactions Frequency

Infections and infestations Nasopharyngitis Common

Upper respiratory tract infection Common

Urinary tract infection Common

Sinusitis Common

Pharyngitis Uncommon

Immune system disorders Hypersensitivity reactions including:

Rash, urticaria and pruritus Uncommon

Nervous system disorders Headache Common

Dysgeusia Uncommon

Dizziness Not Known

Eye disorders Glaucoma Not known

Vision blurred Not known

Eye pain Rare

Intraocular pressure increased Not known

Cardiac disorders Atrial fibrillation Uncommon

Rhythm idioventricular Uncommon

Supraventricular tachycardia Uncommon

Supraventricular extrasystoles Uncommon

Tachycardia Common

Respiratory, thoracic and Cough Commonmediastinal disorders

Gastrointestinal disorders Constipation common

Dry mouth Uncommon

Skin and subcutaneous tissue Rash Uncommondisorders

Renal and urinary disorders Urinary retention Not known

Dysuria Not known

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

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

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

R03BB07

Umeclidinium bromide is a long acting muscarinic receptor antagonist (also referred to as ananticholinergic). It is a quinuclidine derivative that is a muscarinic receptor antagonist with activityacross multiple muscarinic cholinergic receptor subtypes. Umeclidinium bromide exerts itsbronchodilatory activity by competitively inhibiting the binding of acetylcholine with muscariniccholinergic receptors on airway smooth muscle. It demonstrates slow reversibility at the human M3muscarinic receptor subtype in vitro and a long duration of action in vivo when administered directlyto the lungs in pre-clinical models.

In a Phase III, 6-month study (DB2113373) Incruse Ellipta provided a clinically meaningfulimprovement 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 followingadministration of the first dose (improvement over placebo by 102 mL, p<0.001*). The mean peakimprovements 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 Ellipta overtime.

The effect of umeclidinium 500 micrograms (pre-dispensed) on the QT interval was evaluated in aplacebo- and moxifloxacin-controlled QT trial of 103 healthy volunteers. Following repeat doses ofumeclidinium 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.

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

Pivotal Efficacy Studies:

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

There was no attenuation of the bronchodilator effect over time.

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

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

Treatment with Incruse 12-Week Study 24-Week Study

Ellipta 55 mcg Treatment difference1 Treatment difference195% Confidence interval 95% Confidence intervalp-value p-value

Versus 127 115

Placebo (52, 202) (76, 155)<0.001 <0.001mcg = micrograms1.least squares mean (95% confidence interval)

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

Symptomatic outcomes

Breathlessness:

In the 12-week study, a statistically significant improvement compared with placebo in the TDI focalscore at Week 12 was not demonstrated for Incruse Ellipta (1.0 units, p=0.05). A statisticallysignificant improvement compared with placebo in the TDI focal score at Week 24 was demonstratedfor Incruse Ellipta (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 Ellipta (38%) compared withplacebo (15%) in the 12-week study. Similarly, a greater proportion of patients achieved 1 unit TDIfocal score for Incruse Ellipta (53%) compared with placebo (41%) at Week 24 in the 24-week study.

Incruse Ellipta also demonstrated a statistically significant improvement in health-related quality oflife 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. Agreater improvement compared with placebo in the change from baseline in SGRQ total score at Week24 was demonstrated for Incruse Ellipta (-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 adecrease of 4 units from baseline) at Week 12 was greater for Incruse Ellipta 55 micrograms (44%)compared with placebo (26%) in the 12-week study. Similarly, a greater proportion of patientsachieved at least the MCID for Incruse Ellipta at Week 24 (44%) compared with placebo (34%) in the24-week study.

COPD exacerbations

In the 24-week placebo-controlled study in patients with symptomatic COPD, Incruse Ellipta reducedthe risk of a moderate/severe COPD exacerbation by 40% compared with placebo (analysis of time tofirst exacerbation; Hazard Ratio 0.6; 95% CI: 0.4, 1.0, p=0.035*). The probability of having anexacerbation in patients receiving Incruse Ellipta at week 24 was 8.9% compared with 13.7% forplacebo. These studies were not specifically designed to evaluate the effect of treatments on COPDexacerbations and patients were withdrawn from the study if an exacerbation occurred.

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

Use of rescue medicinal product

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

Supporting efficacy studies

In a randomised, double-blind, 52-week study (CTT116855, IMPACT) of 10,355 adult patients withsymptomatic COPD and a history of 1 or more moderate or severe exacerbations within the prior 12months, treatment with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI99/55/22 micrograms) once daily as a single inhaler was compared with fluticasone furoate/vilanterol(FF/VI 99/22 micrograms) once daily as a single inhaler. The primary endpoint was annual rate of on-treatment moderate and severe exacerbations in subjects treated with FF/UMC/VI compared with

FF/VI. The mean annual rate of exacerbations was 0.91 and 1.07 for FF/UMEC/VI and FF/VIrespectively (Rate Ratio: 0.85; 95% CI: 0.80, 0.90; p<0.001).

At Week 52, a statistically significant improvement in the least-squares (LS) mean change frombaseline in trough FEV1 was observed for FF/UMEC/VI compared with FF/VI (mean change: +94 mLvs. -3 mL; treatment difference: 97 mL; 95% CI: 85, 109; p<0.001).

In two 12-week, placebo controlled studies (200109 and 200110), the addition of Incruse Ellipta tofluticasone furoate/vilanterol (FF/VI) (92/22 micrograms) once daily in adult patients with a clinicaldiagnosis of COPD, resulted in statistically significant and clinically meaningful improvements in theprimary endpoint of trough FEV1 at Day 85 compared to placebo plus FF/VI (124 mL 95% CI: 93,154; p<0.001and 122 mL 95% CI: 91, 152; p<0.001).

Improvements in lung function were supported with reductions in use of salbutamol over Weeks 1-12(-0.4 puffs per day (95% CI: -0.7, -0.2; p<0.001) and -0.3 puffs per day (95% CI: -0.5, -0.1; p=0.003))compared to placebo plus FF/VI but improvements in SGRQ at week 12 were not statisticallysignificant (200109) or clinically relevant (200109 and 200110). The short duration of these twostudies and limited number of exacerbation events, preclude any conclusion regarding additional effectof Incruse Ellipta on COPD exacerbation rate.

No new adverse drug reactions were identified with the addition of Incruse Ellipta to FF/VI in thesestudies.

The European Medicines Agency has waived the obligation to submit the results of studies with

Incruse Ellipta in all subsets of the paediatric population in COPD (see section 4.2 for information onpaediatric use).

Following inhaled administration of umeclidinium bromide in healthy volunteers, Cmax occurred at 5 to15 minutes. The absolute bioavailability of inhaled umeclidinium bromide was on average 13% of thedose, with negligible contribution from oral absorption. Following repeat dosing of inhaledumeclidinium bromide, steady state was achieved within 7 to 10 days with 1.5 to 1.8-foldaccumulation.

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

In vitro studies showed that umeclidinium bromide is principally metabolised by cytochrome P4502D6 (CYP2D6) and is a substrate for the P-glycoprotein (P-gp) transporter. The primary metabolicroutes for umeclidinium bromide are oxidative (hydroxylation, O-dealkylation) followed byconjugation (glucuronidation, etc), resulting in a range of metabolites with either reducedpharmacological activity or for which the pharmacological activity has not been established. Systemicexposure to the metabolites is low.

Plasma clearance following intravenous administration was 151 litres/hour. Following intravenousadministration, approximately 58% of the administered radiolabelled dose (or 73% of the recoveredradioactivity) 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 ofthe 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 infaeces (92% of the administered radiolabelled dose or 99% of the recovered radioactivity) by 168hours post-dose. Less than 1% of the orally administered dose (1% of recovered radioactivity) wasexcreted in urine, suggesting negligible absorption following oral administration. Umeclidiniumbromide 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 subjects or patients

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

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

Subjects with moderate hepatic impairment (Child-Pugh Class B) showed no evidence of an increasein systemic exposure to umeclidinium bromide (Cmax and AUC), and no evidence of altered proteinbinding between subjects with moderate hepatic impairment and healthy volunteers. Umeclidiniumbromide has not been evaluated in subjects with severe hepatic impairment.

A population pharmacokinetic analysis showed that no dose adjustment is required for umeclidiniumbromide 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 geneticpolymorphism on systemic exposure to umeclidinium bromide.

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

Toxicity to reproduction

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 weightgain and food consumption and slightly decreased pre-weaning pup body weights in dams given180 micrograms/kg/day dose (approximately 80-times the human clinical exposure of umeclidinium55 micrograms, based on AUC).

Lactose monohydrate

Magnesium stearate

Not applicable.

2 years

In-use shelf-life after opening the tray: 6 weeks.

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

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

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

The Ellipta inhaler consists of a grey body, light green mouthpiece cover and a dose counter, packedinto a foil laminate tray containing a silica gel desiccant sachet. The tray is sealed with a peelable foillid.

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

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

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 localrequirements.

GlaxoSmithKline (Ireland) Limited12 Riverwalk

Citywest Business Campus

Dublin 24

Ireland

EU/1/14/922/001

EU/1/14/922/002

EU/1/14/922/003

Date of first authorisation: 28 April 2014

Date of latest renewal: 11 January 2019

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.