ENERZAIR BREEZHALER 114mcg / 46mcg / 136mcg capsules inhalation powder medication leaflet

Enerzair Breezhaler 114 micrograms/46 micrograms/136 micrograms inhalation powder, hardcapsules

Each capsule contains 150 mcg of indacaterol (as acetate), 63 mcg of glycopyrronium bromideequivalent to 50 mcg of glycopyrronium and 160 mcg of mometasone furoate.

Each delivered dose (the dose that leaves the mouthpiece of the inhaler) contains 114 mcg ofindacaterol (as acetate), 58 mcg of glycopyrronium bromide equivalent to 46 mcg of glycopyrroniumand 136 mcg of mometasone furoate.

Each capsule contains 25 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

Inhalation powder, hard capsule (inhalation powder).

Capsules with green transparent cap and uncoloured transparent body containing a white powder, withthe product code “IGM150-50-160” printed in black above two black bars on the body and with theproduct logo printed in black and surrounded by a black bar on the cap.

Enerzair Breezhaler is indicated as a maintenance treatment of asthma in adult patients not adequatelycontrolled with a maintenance combination of a long-acting beta2-agonist and a high dose of aninhaled corticosteroid who experienced one or more asthma exacerbations in the previous year.

The recommended dose is one capsule to be inhaled once daily.

The maximum recommended dose is 114 mcg/46 mcg/136 mcg once daily.

Treatment should be administered at the same time of the day each day. It can be administeredirrespective of the time of the day. If a dose is missed, it should be taken as soon as possible. Patientsshould be instructed not to take more than one dose in a day.

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

No dose adjustment is required in patients with mild to moderate renal impairment. Caution should beobserved in patients with severe renal impairment or end-stage renal disease requiring dialysis (seesections 4.4 and 5.2).

No dose adjustment is required in patients with mild or moderate hepatic impairment. No data areavailable for the use of the medicinal product in patients with severe hepatic impairment, therefore itshould be used in these patients only if the expected benefit outweighs the potential risk (seesection 5.2).

The safety and efficacy of Enerzair Breezhaler in paediatric patients below 18 years of age have notbeen established. No data are available.

For inhalation use only. The capsules must not be swallowed.

The capsules must be administered only using the inhaler provided (see section 6.6) with each newprescription.

Patients should be instructed on how to administer the medicinal product correctly. Patients who donot experience improvement in breathing should be asked if they are swallowing the medicinalproduct rather than inhaling it.

The capsules must only be removed from the blister immediately before use.

After inhalation, patients should rinse their mouth with water without swallowing (see sections 4.4 and6.6).

For instructions on use of the medicinal product before administration, see section 6.6.

Information for patients using a sensor for Enerzair Breezhaler

The pack may contain an electronic sensor to be attached to the base of the inhaler.

The sensor and App are not required for administration of the medicinal product to the patient. Thesensor and App do not control or interfere with delivery of the medicinal product using the inhaler.

The prescribing physician may discuss with the patient whether the use of the sensor and App isappropriate.

For detailed instructions on how to use the sensor and the App, see the Instructions for Use providedin the sensor pack and the App.

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

This medicinal product should not be used to treat acute asthma symptoms, including acute episodesof bronchospasm, for which a short-acting bronchodilator is required. Increasing use of short-actingbronchodilators to relieve symptoms indicates deterioration of control and patients should be reviewedby a physician.

Patients should not stop treatment without physician supervision since symptoms may recur afterdiscontinuation.

It is recommended that treatment with this medicinal product should not be stopped abruptly. Ifpatients find the treatment ineffective, they should continue treatment but must seek medical attention.

Increasing use of reliever bronchodilators indicates a worsening of the underlying condition andwarrants a reassessment of the therapy. Sudden and progressive deterioration in the symptoms ofasthma is potentially life-threatening and the patient should undergo urgent medical assessment.

Immediate hypersensitivity reactions have been observed after administration of this medicinalproduct. If signs suggesting allergic reactions occur, in particular angioedema (including difficulties inbreathing or swallowing, swelling of the tongue, lips and face), urticaria or skin rash, treatment shouldbe discontinued immediately and alternative therapy instituted.

As with other inhalation therapy, administration of this medicinal product may result in paradoxicalbronchospasm, which can be life-threatening. If this occurs, treatment should be discontinuedimmediately and alternative therapy instituted.

Like other medicinal products containing beta2-adrenergic agonists, this medicinal product mayproduce a clinically significant cardiovascular effect in some patients as measured by increases inpulse rate, blood pressure, and/or symptoms. If such effects occur, treatment may need to bediscontinued.

This medicinal product should be used with caution in patients with cardiovascular disorders(coronary artery disease, acute myocardial infarction, cardiac arrhythmias, hypertension), convulsivedisorders or thyrotoxicosis, and in patients who are unusually responsive to beta2-adrenergic agonists.

Patients with unstable ischaemic heart disease, a history of myocardial infarction in last 12 months,

New York Heart Association (NYHA) class III/IV left ventricular failure, arrhythmia, uncontrolledhypertension, cerebrovascular disease, history of long QT syndrome and patients being treated withmedicinal products known to prolong QTc were excluded from studies in theindacaterol/glycopyrronium/mometasone furoate clinical development programme. Thus safetyoutcomes in these populations are considered unknown.

While beta2-adrenergic agonists have been reported to produce electrocardiographic (ECG) changes,such as flattening of the T wave, prolongation of QT interval and ST segment depression, the clinicalsignificance of these findings is unknown.

Long-acting beta2-adrenergic agonists (LABA) or LABA-containing combination products such as

Enerzair Breezhaler should therefore be used with caution in patients with known or suspectedprolongation of the QT interval or who are being treated with medicinal products affecting the QTinterval.

Hypokalaemia with beta agonists

Beta2-adrenergic agonists may produce significant hypokalaemia in some patients, which has thepotential to produce adverse cardiovascular effects. The decrease in serum potassium is usuallytransient, not requiring supplementation. In patients with severe asthma, hypokalaemia may bepotentiated by hypoxia and concomitant treatment, which may increase the susceptibility to cardiacarrhythmias (see section 4.5).

Clinically relevant hypokalaemia has not been observed in clinical studies ofindacaterol/glycopyrronium/mometasone furoate at the recommended therapeutic dose.

Inhalation of high doses of beta2-adrenergic agonists and corticosteroids may produce increases inplasma glucose. Upon initiation of treatment, plasma glucose should be monitored more closely indiabetic patients.

This medicinal product has not been investigated in patients with Type I diabetes mellitus oruncontrolled Type II diabetes mellitus.

Anticholinergic effect related to glycopyrronium

Like other anticholinergic medicinal products, this medicinal product should be used with caution inpatients with narrow-angle glaucoma or urinary retention.

Patients should be advised about signs and symptoms of acute narrow-angle glaucoma and should beinstructed to stop treatment and to contact their doctor immediately should any of these signs orsymptoms develop.

Patients with severe renal impairment

For patients with severe renal impairment (estimated glomerular filtration rate below30 ml/min/1.73 m2), including those with end-stage renal disease requiring dialysis, caution should beobserved (see sections 4.2 and 5.2).

Prevention of oropharyngeal infections

In order to reduce the risk of oropharyngeal candida infection, patients should be advised to rinse theirmouth or gargle with water without swallowing it or brush their teeth after inhaling the prescribeddose.

Systemic effects of corticosteroids

Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed forprolonged periods. These effects are much less likely to occur than with oral corticosteroids and mayvary in individual patients and between different corticosteroid preparations.

Possible systemic effects may include Cushing’s syndrome, Cushingoid features, adrenal suppression,growth retardation in children and adolescents, decrease in bone mineral density, cataracts, glaucoma,and, more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity,sleep disorders, anxiety, depression or aggression (particularly in children). It is therefore importantthat the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control of asthmais maintained.

Visual disturbance may be reported with systemic and topical (including intranasal, inhaled andintraocular) corticosteroid use. Patients presenting with symptoms such as blurred vision or othervisual disturbances should be considered for referral to an ophthalmologist for evaluation of possiblecauses of visual disturbances, which may include cataract, glaucoma or rare diseases such as centralserous chorioretinopathy (CSCR) which have been reported after use of systemic and topicalcorticosteroids.

This medicinal product should be administered with caution in patients with pulmonary tuberculosis orin patients with chronic or untreated infections.

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

No specific interaction studies were conducted with indacaterol/glycopyrronium/mometasone furoate.

Information on the potential for interactions is based on the potential for each of the monotherapycomponents.

Medicinal products known to prolong the QTc interval

Like other medicinal products containing a beta2-adrenergic agonist, this medicinal product should beadministered with caution to patients being treated with monoamine oxidase inhibitors, tricyclicantidepressants, or medicinal products known to prolong the QT interval, as any effect of these on the

QT interval may be potentiated. Medicinal products known to prolong the QT interval may increasethe risk of ventricular arrhythmia (see sections 4.4 and 5.1).

Hypokalaemic treatment

Concomitant hypokalaemic treatment with methylxanthine derivatives, steroids, ornon-potassium-sparing diuretics may potentiate the possible hypokalaemic effect of beta2-adrenergicagonists (see section 4.4).

Beta-adrenergic blockers

Beta-adrenergic blockers may weaken or antagonise the effect of beta2-adrenergic agonists. Therefore,this medicinal product should not be given together with beta-adrenergic blockers unless there arecompelling reasons for their use. Where required, cardioselective beta-adrenergic blockers should bepreferred, although they should be administered with caution.

Interaction with CYP3A4 and P-glycoprotein inhibitors

Inhibition of CYP3A4 and P-glycoprotein (P-gp) has no impact on the safety of therapeutic doses of

Enerzair Breezhaler.

Inhibition of the key contributors of indacaterol clearance (CYP3A4 and P-gp) or mometasone furoateclearance (CYP3A4) raises the systemic exposure of indacaterol or mometasone furoate up totwo-fold.

Due to the very low plasma concentration achieved after inhaled dosing, clinically significantinteractions with mometasone furoate are unlikely. However, there may be a potential for increasedsystemic exposure to mometasone furoate when strong CYP3A4 inhibitors (e.g. ketoconazole,itraconazole, nelfinavir, ritonavir, cobicistat) are co-administered.

Cimetidine or other inhibitors of organic cation transport

In a clinical study in healthy volunteers, cimetidine, an inhibitor of organic cation transport which isthought to contribute to the renal excretion of glycopyrronium, increased total exposure (AUC) toglycopyrronium by 22% and decreased renal clearance by 23%. Based on the magnitude of thesechanges, no clinically relevant drug interaction is expected when glycopyrronium is co-administeredwith cimetidine or other inhibitors of the organic cation transport.

Other long-acting antimuscarinics and long-acting beta2-adrenergic agonists

The co-administration of this medicinal product with other medicinal products containing long-actingmuscarinic antagonists or long-acting beta2-adrenergic agonists has not been studied and is notrecommended as it may potentiate adverse reactions (see sections 4.8 and 4.9).

There are insufficient data from the use of Enerzair Breezhaler or its individual components(indacaterol, glycopyrronium and mometasone furoate) in pregnant women to determine whether thereis a risk.

Indacaterol and glycopyrronium were not teratogenic in rats and rabbits following subcutaneous orinhalation administration, respectively (see section 5.3). In animal reproduction studies with pregnantmice, rats and rabbits, mometasone furoate caused increased foetal malformations and decreased foetalsurvival and growth.

Like other medicinal products containing beta2-adrenergic agonists, indacaterol may inhibit labour dueto a relaxant effect on uterine smooth muscle.

This medicinal product should only be used during pregnancy if the expected benefit to the patientjustifies the potential risk to the foetus.

There is no information available on the presence of indacaterol, glycopyrronium or mometasonefuroate in human milk, on the effects on a breast-fed infant, or on the effects on milk production.

Other inhaled corticosteroids similar to mometasone furoate are transferred into human milk.

Indacaterol, glycopyrronium and mometasone furoate have been detected in the milk of lactating rats.

Glycopyrronium reached up to 10-fold higher concentrations in the milk of lactating rats than in theblood of the dam after intravenous administration.

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

Reproduction studies and other data in animals did not indicate a concern regarding fertility in eithermales or females.

This medicinal product has no or negligible influence on the ability to drive and use machines.

The most common adverse reactions over 52 weeks were asthma (exacerbation) (41.8%),nasopharyngitis (10.9%), upper respiratory tract infection (5.6%) and headache (4.2%).

Adverse drug reactions (ADRs) are listed by MedDRA system organ class (Table 1). The frequency ofthe ADRs is based on the IRIDIUM study. Within each system organ class, the adverse drug reactionsare ranked by frequency, with the most frequent reactions first. Within each frequency grouping,adverse drug reactions are presented in order of decreasing seriousness. In addition, the correspondingfrequency category for each adverse drug reaction is based on the following convention (CIOMS III):

very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000to <1/1,000); very rare (<1/10,000).

Table 1 Adverse reactions

System organ class Adverse reactions Frequencycategory

Nasopharyngitis Very common

Upper respiratory tract Common

Infections and infestations infection

Candidiasis*1 Common

Urinary tract infection*2 Common

Immune system disorders Hypersensitivity*3 Common

Metabolism and nutrition disorders Hyperglycaemia*4 Uncommon

Nervous system disorders Headache*5 Common

Eye disorders Cataract Uncommon

Cardiac disorders Tachycardia*6 Common

Asthma (exacerbation) Very common

Oropharyngeal pain*7 Common

Cough Common

Dysphonia Common

Gastroenteritis*8 Common

Dry mouth*9 Uncommon

Rash*10 Uncommon

Pruritus*11 Uncommon

Musculoskeletal pain*12 Common

Muscle spasms Common

Renal and urinary disorders Dysuria Uncommon

General disorders and administration site Pyrexia Commonconditions

* Indicates grouping of preferred terms (PTs):

1 Oral candidiasis, oropharyngeal candidiasis.

2 Asymptomatic bacteriuria, bacteriuria, cystitis, urethritis, urinary tract infection, urinary tract infection viral.

3 Drug eruption, drug hypersensitivity, hypersensitivity, rash, rash pruritic, urticaria.

4 Blood glucose increased, hyperglycaemia.

5 Headache, tension headache.

6 Sinus tachycardia, supraventricular tachycardia, tachycardia.

7 Odynophagia, oropharyngeal discomfort, oropharyngeal pain, throat irritation.

8 Chronic gastritis, enteritis, gastritis, gastroenteritis, gastrointestinal inflammation.

9 Dry mouth, dry throat.

10 Drug eruption, rash, rash papular, rash pruritic.

11 Eye pruritus, pruritus, pruritus genital.

12 Back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain.

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.

General supportive measures and symptomatic treatment should be initiated in cases of suspectedoverdose.

An overdose will likely produce signs, symptoms or adverse effects associated with thepharmacological actions of the individual components (e.g. tachycardia, tremor, palpitations,headache, nausea, vomiting, drowsiness, ventricular arrhythmias, metabolic acidosis, hypokalaemia,hyperglycaemia, increased intraocular pressure [causing pain, vision disturbances or reddening of theeye], constipation or difficulties in voiding, suppression of hypothalamic pituitary adrenal axisfunction).

Use of cardioselective beta blockers may be considered for treating beta2-adrenergic effects, but onlyunder the supervision of a physician and with extreme caution, since the use of beta2-adrenergicblockers may provoke bronchospasm. In serious cases, patients should be hospitalised.

Pharmacotherapeutic group: Drugs for obstructive airway diseases, adrenergics in combination withanticholinergics incl. triple combinations with corticosteroids. ATC code: R03AL12

This medicinal product is a combination of indacaterol, a long-acting beta2-adrenergic agonist(LABA), glycopyrronium, a long-acting muscarinic receptor antagonist (LAMA) and mometasonefuroate, an inhaled synthetic corticosteroid (ICS).

Indacaterol

The pharmacological effects of beta2-adrenoceptor agonists, including indacaterol, are at least in partattributable to increased cyclic-3’, 5’-adenosine monophosphate (cyclic AMP) levels, which causerelaxation of bronchial smooth muscle.

When inhaled, indacaterol acts locally in the lung as a bronchodilator. Indacaterol is a partial agonistat the human beta2-adrenergic receptor with nanomolar potency. In isolated human bronchus,indacaterol has a rapid onset of action and a long duration of action.

Although beta2-adrenergic receptors are the predominant adrenergic receptors in bronchial smoothmuscle and beta1-receptors are the predominant receptors in the human heart, there are alsobeta2-adrenergic receptors in the human heart comprising 10% to 50% of the total adrenergicreceptors.

Glycopyrronium works by blocking the bronchoconstrictor action of acetylcholine on airway smoothmuscle cells, thereby dilating the airways. Glycopyrronium bromide is a high-affinity muscarinicreceptor antagonist. It demonstrated 4- to 5-fold selectivity for the human M3 and M1 receptors overthe human M2 receptor in competition binding studies. It has a rapid onset of action, as evidenced byobserved receptor association/dissociation kinetic parameters and by the onset of action afterinhalation in clinical studies. The long duration of action can be partly attributed to sustained drugconcentrations in the lungs, as reflected by the prolonged terminal elimination half-life ofglycopyrronium after inhalation via the inhaler in contrast to the half-life after intravenousadministration (see section 5.2).

Mometasone furoate

Mometasone furoate is a synthetic corticosteroid with high affinity for glucocorticoid receptors andlocal anti-inflammatory properties. In vitro, mometasone furoate inhibits the release of leukotrienesfrom leukocytes of allergic patients. In cell culture, mometasone furoate demonstrated high potency ininhibition of synthesis and release of IL-1, IL-5, IL-6 and TNF-alpha. It is also a potent inhibitor ofleukotriene production and of the production of the Th2 cytokines IL-4 and IL-5 from human CD4+

T-cells.

The pharmacodynamic response profile of this medicinal product is characterised by rapid onset ofaction within 5 minutes after dosing and sustained effect over the whole 24-hour dosing interval.

The pharmacodynamic response profile is further characterised by increased mean peak forcedexpiratory volume in the first second (FEV1) of 172 ml followingindacaterol/glycopyrronium/mometasone furoate 114 mcg/46 mcg/136 mcg once daily compared tosalmeterol/fluticasone 50 mcg/500 mcg twice daily.

No tachyphylaxis to the lung function benefits of Enerzair Breezhaler was observed over time.

QTc interval

The effect of this medicinal product on the QTc interval has not been evaluated in a thorough QT(TQT) study. For mometasone furoate, no QTc prolonging properties are known.

Comparison of Enerzair Breezhaler to fixed combinations of LABA/ICS

The safety and efficacy of Enerzair Breezhaler in adult patients with persistent asthma was evaluatedin the phase III randomised, double-blind study (IRIDIUM). The IRIDIUM study was a 52-week studyevaluating Enerzair Breezhaler 114 mcg/46 mcg/68 mcg once daily (N=620) and114 mcg/46 mcg/136 mcg once daily (N=619) compared to indacaterol/mometasone furoate125 mcg/127.5 mcg once daily (N=617) and 125 mcg/260 mcg once daily (N=618), respectively. Athird active control arm included subjects treated with salmeterol/fluticasone propionate50 mcg/500 mcg twice daily (N=618). All subjects were required to have symptomatic asthma(ACQ-7 score ≥1.5) and were on asthma maintenance therapy using a medium or high dose inhaledsynthetic corticosteroid (ICS) and LABA combination therapy for at least 3 months prior to studyentry. The mean age was 52.2 years. At screening, 99.9% of patients reported a history of exacerbationin the past year. At study entry, the most common asthma medications reported were medium dose of

ICS in combination with a LABA (62.6%) and high dose of ICS in combination with a LABA(36.7%).

The primary objective of the study was to demonstrate superiority of either Enerzair Breezhaler114 mcg/46 mcg/68 mcg once daily over indacaterol/mometasone furoate 125 mcg/127.5 mcg oncedaily or Enerzair Breezhaler 114 mcg/46 mcg/136 mcg once daily over indacaterol/mometasonefuroate 125 mcg/260 mcg once daily in terms of trough FEV1 at week 26.

Enerzair Breezhaler 114 mcg/46 mcg/136 mcg once daily demonstrated statistically significantimprovements in trough FEV1 at week 26 compared to indacaterol/mometasone furoate atcorresponding dose. Clinically meaningful improvements in lung function (change from baselinetrough FEV1 at week 26, morning and evening peak expiratory flow) were also observed compared tosalmeterol/fluticasone propionate 50 mcg/500 mcg twice daily. Findings at week 52 were consistentwith week 26 (see Table 2).

All treatment groups showed clinically relevant improvements from baseline in ACQ-7 at week 26,however no statistically significant differences between groups were observed. The mean change frombaseline in ACQ-7 at week 26 (key secondary endpoint) and week 52 was around -1 for all treatmentgroups. The ACQ-7 responder rates (defined as a change decrease in score of ≥0.5) at different timepoints are described in Table 2.

Exacerbations were a secondary endpoint (not part of confirmatory testing strategy). Enerzair

Breezhaler 114 mcg/46 mcg/136 mcg once daily demonstrated a reduction in the annual rate ofexacerbations compared to salmeterol/fluticasone propionate 50 mcg/500 mcg twice daily andindacaterol/mometasone furoate 125 mcg/260 mcg once daily (see Table 2).

Results for the most clinically relevant endpoints are described in Table 2.

Table 2 Results of primary and secondary endpoints in IRIDIUM study at weeks 26 and 52

Endpoint Time point/ Enerzair Breezhaler1 vs Enerzair Breezhaler1 vs

Duration IND/MF2 SAL/FP3

Trough FEV 4

Week 26 65 ml 119 ml

Treatment (Primary <0.001 <0.001difference endpoint) (31, 99) (85, 154)

P value 86 ml 145 ml(95% CI) Week 52 <0.001 <0.001(51, 120) (111, 180)

Mean morning peak expiratory flow (PEF)

Treatment18.7 l/min 34.8 l/mindifference Week 52*(13.4, 24.1) (29.5, 40.1)(95% CI)

Mean evening peak expiratory flow (PEF)

Treatment17.5 l/min 29.5 l/mindifference Week 52*(12.3, 22.8) (24.2, 34.7)(95% CI)

ACQ responders (percentage of patients achieving minimal clinical important difference (MCID) frombaseline with ACQ ≥0.5)

Percentage Week 4 66% vs 63% 66% vs 53%

Odds ratio 1.21 1.72(95% CI) (0.94, 1.54) (1.35, 2.20)

Percentage Week 12 68% vs 67% 68% vs 61%

Odds ratio 1.11 1.35(95% CI) (0.86, 1.42) (1.05, 1.73)

Percentage Week 26 71% vs 74% 71% vs 67%

Odds ratio 0.92 1.21(95% CI) (0.70, 1.20) (0.93, 1.57)

Percentage Week 52 79% vs 78% 79% vs 73%

Odds ratio 1.10 1.41(95% CI) (0.83, 1.47) (1.06, 1.86)

Annualised rate of asthma exacerbations

AR Week 52 0.46 vs 0.54 0.46 vs 0.72

RR** Week 52 0.85 0.64(95% CI) (0.68, 1.04) (0.52, 0.78)

Severe exacerbations

AR Week 52 0.26 vs 0.33 0.26 vs 0.45

RR** Week 52 0.78 0.58(95% CI) (0.61, 1.00) (0.45, 0.73)

* Mean value for the treatment duration.

** RR <1.00 favours indacaterol/glycopyrronium/mometasone furoate.1 Enerzair Breezhaler 114 mcg/46 mcg/136 mcg od.2 IND/MF: indacaterol/mometasone furoate high dose: 125 mcg/260 mcg od.

Mometasone furoate 136 mcg in Enerzair Breezhaler is comparable to mometasone furoate 260 mcg inindacaterol/mometasone furoate.3 SAL/FP: salmeterol/fluticasone propionate high dose: 50 mcg/500 mcg bid (content dose).4 Trough FEV1: the mean of the two FEV1 values measured at 23 hours 15 min and 23 hours 45 minafter the evening dose.

Primary endpoint (trough FEV1 at week 26) and key secondary endpoint (ACQ-7 score at week 26) were partof confirmatory testing strategy and thus controlled for multiplicity. All other endpoints were not part ofconfirmatory testing strategy.

RR = rate ratio, AR = annualised rateod = once daily, bid = twice daily

Comparison of Enerzair Breezhaler to the concurrent open-label administration ofsalmeterol/fluticasone + tiotropium

A randomised, partially-blinded, active-treatment-controlled, non-inferiority study (ARGON)comparing Enerzair Breezhaler 114 mcg/46 mcg/136 mcg once daily (N=476) and114 mcg/46 mcg/68 mcg once daily (N=474) to the concurrent administration ofsalmeterol/fluticasone propionate 50 mcg/500 mcg twice daily + tiotropium 5 mcg once daily (N=475)over 24 weeks of treatment was conducted.

Enerzair Breezhaler demonstrated non-inferiority to salmeterol/fluticasone + tiotropium for theprimary endpoint (change from baseline for Asthma Quality of Life Questionnaire [AQLQ-S]), inpreviously symptomatic patients on ICS and LABA therapy with a difference of 0.073 (one-sidedlower 97.5% confidence limit [CL]: -0.027).

The European Medicines Agency has deferred the obligation to submit the results of studies withindacaterol/glycopyrronium/mometasone furoate in one or more subsets of the paediatric population inasthma (see section 4.2 for information on paediatric use).

Following inhalation of Enerzair Breezhaler, the median time to reach peak plasma concentrations ofindacaterol, glycopyrronium and mometasone furoate was approximately 15 minutes, 5 minutes and1 hour, respectively.

Based on the in vitro performance data, the dose of each of the monotherapy components delivered tothe lung is expected to be similar for the indacaterol/glycopyrronium/mometasone furoate combinationand the monotherapy products. Steady-state plasma exposure to indacaterol, glycopyrronium andmometasone furoate after inhalation of the combination was similar to the systemic exposure afterinhalation of indacaterol maleate, glycopyrronium or mometasone furoate as monotherapy products.

Following inhalation of the combination, the absolute bioavailability was estimated to be about 45%for indacaterol, 40% for glycopyrronium and less than 10% for mometasone furoate.

Indacaterol

Indacaterol concentrations increased with repeated once-daily administration. Steady-state wasachieved within 12 to 14 days. The mean accumulation ratio of indacaterol, i.e. AUC over the 24-hdosing interval on day 14 compared to day 1, was in the range of 2.9 to 3.8 for once-daily inhaleddoses between 60 and 480 mcg (delivered dose). Systemic exposure results from a composite ofpulmonary and gastrointestinal absorption; about 75% of systemic exposure was from pulmonaryabsorption and about 25% from gastrointestinal absorption.

About 90% of systemic exposure following inhalation is due to lung absorption and 10% is due togastrointestinal absorption. The absolute bioavailability of orally administered glycopyrronium wasestimated to be about 5%.

Mometasone furoate

Mometasone furoate concentrations increased with repeated once-daily administration via the

Breezhaler inhaler. Steady state was achieved after 12 days. The mean accumulation ratio ofmometasone furoate, i.e. AUC over the 24-h dosing interval on day 14 compared to day 1, was in therange of 1.28 to 1.40 for once-daily inhaled doses between 68 and 136 mcg as part of theindacaterol/glycopyrronium/mometasone furoate combination.

Following oral administration of mometasone furoate, the absolute oral systemic bioavailability ofmometasone furoate was estimated to be very low (<2%).

Indacaterol

After intravenous infusion the volume of distribution (Vz) of indacaterol was 2361 to 2557 litres,indicating an extensive distribution. The in vitro human serum and plasma protein binding were 94.1to 95.3% and 95.1 to 96.2%, respectively.

After intravenous dosing, the steady-state volume of distribution (Vss) of glycopyrronium was 83 litresand the volume of distribution in the terminal phase (Vz) was 376 litres. The apparent volume ofdistribution in the terminal phase following inhalation (Vz/F) was 7,310 litres, which reflects the muchslower elimination after inhalation. The in vitro human plasma protein binding of glycopyrronium was38% to 41% at concentrations of 1 to 10 ng/ml. These concentrations were at least 6-fold higher thanthe steady-state mean peak levels achieved in plasma for a 44 mcg once-daily dosing regimen.

Mometasone furoate

After intravenous bolus administration, the Vd is 332 litres. The in vitro protein binding formometasone furoate is high, 98% to 99% in concentration range of 5 to 500 ng/ml.

Indacaterol

After oral administration of radiolabelled indacaterol in a human ADME (absorption, distribution,metabolism, excretion) study, unchanged indacaterol was the main component in serum, accountingfor about one third of total drug-related AUC over 24 hours. A hydroxylated derivative was the mostprominent metabolite in serum. Phenolic O-glucuronides of indacaterol and hydroxylated indacaterolwere further prominent metabolites. A diastereomer of the hydroxylated derivative, an N-glucuronideof indacaterol, and C- and N-dealkylated products were further metabolites identified.

In vitro investigations indicated that UGT1A1 was the only UGT isoform that metabolised indacaterolto the phenolic O-glucuronide. The oxidative metabolites were found in incubations with recombinant

CYP1A1, CYP2D6 and CYP3A4. CYP3A4 is concluded to be the predominant isoenzyme responsiblefor hydroxylation of indacaterol. In vitro investigations further indicated that indacaterol is alow-affinity substrate for the efflux pump P-gp.

In vitro the UGT1A1 isoform is a major contributor to the metabolic clearance of indacaterol.

However, as shown in a clinical study in populations with different UGT1A1 genotypes, systemicexposure to indacaterol is not significantly affected by the UGT1A1-genotype.

In vitro metabolism studies showed consistent metabolic pathways for glycopyrronium bromidebetween animals and humans. No human-specific metabolites were found. Hydroxylation resulting ina variety of mono- and bis-hydroxylated metabolites and direct hydrolysis resulting in the formation ofa carboxylic acid derivative (M9) were seen.

In vitro investigations showed that multiple CYP isoenzymes contribute to the oxidativebiotransformation of glycopyrronium. The hydrolysis to M9 is likely to be catalysed by members ofthe cholinesterase family.

After inhalation, systemic exposure to M9 was on average in the same order of magnitude as theexposure to the parent drug. Since in vitro studies did not show lung metabolism and M9 was of minorimportance in the circulation (about 4% of parent drug Cmax and AUC) after intravenousadministration, it is assumed that M9 is formed from the swallowed dose fraction of orally inhaledglycopyrronium bromide by pre-systemic hydrolysis and/or via first-pass metabolism. After inhalationas well as after intravenous administration, only minimal amounts of M9 were found in the urine (i.e.

≤0.5% of dose). Glucuronide and/or sulfate conjugates of glycopyrronium were found in urine ofhumans after repeated inhalation, accounting for about 3% of the dose.

In vitro inhibition studies demonstrated that glycopyrronium bromide has no relevant capacity toinhibit CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4/5, theefflux transporters MDR1, MRP2 or MXR, and the uptake transporters OATP1B1, OATP1B3, OAT1,

OAT3, OCT1 or OCT2. In vitro enzyme induction studies did not indicate a clinically relevantinduction by glycopyrronium bromide for any of the cytochrome P450 isoenzymes tested as well asfor UGT1A1 and the transporters MDR1 and MRP2.

Mometasone furoate

The portion of an inhaled mometasone furoate dose that is swallowed and absorbed in thegastrointestinal tract undergoes extensive metabolism to multiple metabolites. There are no majormetabolites detectable in plasma. In human liver microsomes, mometasone furoate is metabolised by

Indacaterol

In clinical studies which included urine collection, the amount of indacaterol excreted unchanged viaurine was generally lower than 2% of the dose. Renal clearance of indacaterol was, on average,between 0.46 and 1.20 litres/hour. Compared with the serum clearance of indacaterol of 18.8 to23.3 litres/hour, it is evident that renal clearance plays a minor role (about 2 to 6% of systemicclearance) in the elimination of systemically available indacaterol.

In a human ADME study in which indacaterol was given orally, the faecal route of excretion wasdominant over the urinary route. Indacaterol was excreted into human faeces primarily as unchangedparent substance (54% of the dose) and, to a lesser extent, hydroxylated indacaterol metabolites (23%of the dose). Mass balance was complete, with ≥90% of the dose recovered in the excreta.

Indacaterol serum concentrations declined in a multi-phasic manner with an average terminal half-liferanging from 45.5 to 126 hours. The effective half-life, calculated from the accumulation ofindacaterol after repeated dosing, ranged from 40 to 52 hours, which is consistent with the observedtime to steady state of approximately 12 to 14 days.

After intravenous administration of [3H]-labelled glycopyrronium bromide to humans, the meanurinary excretion of radioactivity in 48 hours amounted to 85% of the dose. A further 5% of the dosewas found in the bile. Thus, mass balance was almost complete.

Renal elimination of parent drug accounts for about 60 to 70% of total clearance of systemicallyavailable glycopyrronium whereas non-renal clearance processes account for about 30 to 40%. Biliaryclearance contributes to the non-renal clearance, but the majority of non-renal clearance is thought tobe due to metabolism.

Mean renal clearance of glycopyrronium was in the range of 17.4 and 24.4 litres/hour. Active tubularsecretion contributes to the renal elimination of glycopyrronium. Up to 20% of the dose was found inurine as parent drug.

Glycopyrronium plasma concentrations declined in a multi-phasic manner. The mean terminalelimination half-life was much longer after inhalation (33 to 57 hours) than after intravenous(6.2 hours) and oral (2.8 hours) administration. The elimination pattern suggests a sustained lungabsorption and/or transfer of glycopyrronium into the systemic circulation at and beyond 24 h afterinhalation.

Mometasone furoate

After intravenous bolus administration, mometasone furoate has a terminal elimination T½ ofapproximately 4.5 hours. A radiolabelled, orally inhaled dose is excreted mainly in the faeces (74%)and to a lesser extent in the urine (8%).

Concomitant administration of orally inhaled indacaterol, glycopyrronium and mometasone furoateunder steady-state conditions did not affect the pharmacokinetics of any of the active substances.

A population pharmacokinetic analysis in patients with asthma after inhalation of Enerzair Breezhalerindicated no significant effect of age, gender, body weight, smoking status, baseline estimatedglomerular filtration rate (eGFR) and FEV1 at baseline on the systemic exposure to indacaterol,glycopyrronium or mometasone furoate.

The effect of renal impairment on the pharmacokinetics of indacaterol, glycopyrronium andmometasone furoate has not been evaluated in dedicated studies with Enerzair Breezhaler. In apopulation pharmacokinetic analysis, estimated glomerular filtration rate (eGFR) was not astatistically significant covariate for systemic exposure of indacaterol, glycopyrronium andmometasone furoate following administration of Enerzair Breezhaler in patients with asthma.

Due to the very low contribution of the urinary pathway to the total body elimination of indacateroland mometasone furoate, the effects of renal impairment on their systemic exposure have not beeninvestigated (see sections 4.2 and 4.4).

Renal impairment has an impact on the systemic exposure to glycopyrronium administered as amonotherapy. A moderate mean increase in total systemic exposure (AUClast) of up to 1.4-fold wasseen in subjects with mild and moderate renal impairment and up to 2.2-fold in subjects with severerenal impairment and end-stage renal disease. Based on a population pharmacokinetic analysis ofglycopyrronium in asthma patients following Enerzair Breezhaler administration, AUC0-24h increasedby 27% or decreased by 19% for patients with an absolute GFR of 58 or 143 ml/min, respectively,compared to a patient with an absolute GFR of 93 ml/min. Based on a population pharmacokineticanalysis of glycopyrronium in chronic obstructive pulmonary disease patients with mild and moderaterenal impairment (eGFR ≥30 ml/min/1.73 m2), glycopyrronium can be used at the recommended dose.

The effect of hepatic impairment on the pharmacokinetics of indacaterol, glycopyrronium andmometasone furoate has not been evaluated in subjects with hepatic impairment followingadministration of Enerzair Breezhaler. However, studies have been conducted with the monotherapycomponents indacaterol and mometasone furoate (see section 4.2).

Indacaterol

Patients with mild and moderate hepatic impairment showed no relevant changes in Cmax or AUC ofindacaterol, nor did protein binding differ between mild and moderate hepatic impaired subjects andtheir healthy controls. Studies in subjects with severe hepatic impairment were not performed.

Clinical studies in patients with hepatic impairment have not been conducted. Glycopyrronium iscleared predominantly from the systemic circulation by renal excretion. Impairment of the hepaticmetabolism of glycopyrronium is not thought to result in a clinically relevant increase in systemicexposure.

Mometasone furoate

A study evaluating the administration of a single inhaled dose of 400 mcg mometasone furoate by drypowder inhaler to subjects with mild (n=4), moderate (n=4), and severe (n=4) hepatic impairmentresulted in only 1 or 2 subjects in each group having detectable peak plasma concentrations ofmometasone furoate (ranging from 50 to 105 pcg/ml). The observed peak plasma concentrationsappear to increase with severity of hepatic impairment; however, the numbers of detectable levels(assay lower limit of quantification was 50 pcg/ml) were few.

There were no major differences in total systemic exposure (AUC) for indacaterol, glycopyrronium ormometasone furoate between Japanese and Caucasian subjects. Insufficient pharmacokinetic data areavailable for other ethnicities or races. Total systemic exposure (AUC) for glycopyrronium may be upto 1.8-fold higher in asthma patients with low body weight (35 kg) and up to 2.5-fold higher in asthmapatients with low body weight (35 kg) and low absolute GFR (45 ml/min).

No animal studies were performed with the combination of indacaterol, glycopyrronium andmometasone furoate. The non-clinical assessments of each monotherapy and ofindacaterol/mometasone and indacaterol/glycopyrronium combination products are presented below:

Indacaterol

Effects on the cardiovascular system attributable to the beta2-agonistic properties of indacaterolincluded tachycardia, arrhythmias and myocardial lesions in dogs. Mild irritation of the nasal cavityand larynx was seen in rodents.

Genotoxicity studies did not reveal any mutagenic or clastogenic potential.

Carcinogenicity was assessed in a two-year rat study and a six-month transgenic mouse study.

Increased incidences of benign ovarian leiomyoma and focal hyperplasia of ovarian smooth muscle inrats were consistent with similar findings reported for other beta2-adrenergic agonists. No evidence ofcarcinogenicity was seen in mice.

All these findings occurred at exposures sufficiently in excess of those anticipated in humans.

Following subcutaneous administration in a rabbit study, adverse effects of indacaterol with respect topregnancy and embryonal/foetal development could only be demonstrated at doses more than 500-foldthose achieved following daily inhalation of 150 mcg in humans (based on AUC0-24 h).

Although indacaterol did not affect general reproductive performance in a rat fertility study, a decreasein the number of pregnant F1 offspring was observed in the peri- and post-natal developmental ratstudy at an exposure 14-fold higher than in humans treated with indacaterol. Indacaterol was notembryotoxic or teratogenic in rats or rabbits.

Effects attributable to the muscarinic receptor antagonist properties of glycopyrronium included mildto moderate increases in heart rate in dogs, lens opacities in rats and reversible changes associatedwith reduced glandular secretions in rats and dogs. Mild irritancy or adaptive changes in therespiratory tract were seen in rats. All these findings occurred at exposures sufficiently in excess ofthose anticipated in humans.

Genotoxicity studies did not reveal any mutagenic or clastogenic potential for glycopyrronium.

Carcinogenicity studies in transgenic mice using oral administration and in rats using inhalationadministration revealed no evidence of carcinogenicity.

Glycopyrronium was not teratogenic in rats or rabbits following inhalation administration.

Glycopyrronium and its metabolites did not significantly cross the placental barrier of pregnant mice,rabbits and dogs. Published data for glycopyrronium in animals do not indicate any reproductivetoxicity issues. Fertility and pre- and post-natal development were not affected in rats.

Mometasone furoate

All observed effects are typical of the glucocorticoid class of compounds and are related toexaggerated pharmacological effects of glucocorticoids.

Mometasone furoate showed no genotoxic activity in a standard battery of in vitro and in vivo tests.

In carcinogenicity studies in mice and rats, inhaled mometasone furoate demonstrated no statisticallysignificant increase in the incidence of tumours.

Like other glucocorticoids, mometasone furoate is a teratogen in rodents and rabbits. Effects notedwere umbilical hernia in rats, cleft palate in mice and gallbladder agenesis, umbilical hernia and flexedfront paws in rabbits. There were also reductions in maternal body weight gains, effects on foetalgrowth (lower foetal body weight and/or delayed ossification) in rats, rabbits and mice, and reducedoffspring survival in mice. In studies of reproductive function, subcutaneous mometasone furoate at15 mcg/kg prolonged gestation and difficult labour occurred, with a reduction in offspring survivaland body weight.

Indacaterol and glycopyrronium combination

Findings during the nonclinical safety studies of indacaterol/glycopyrronium were consistent with theknown pharmacological effects of the indacaterol or glycopyrronium monotherapy components.

The effect on heart rate for indacaterol/glycopyrronium was increased in magnitude and durationcompared with the changes observed for each monotherapy component alone.

Shortening of electrocardiograph intervals and decreased systolic and diastolic blood pressure werealso apparent. Indacaterol administered to dogs alone or in the indacaterol/glycopyrroniumcombination was associated with a similar incidence of myocardial lesions.

Indacaterol and mometasone furoate combination

The findings during the 13-week inhalation toxicity studies were predominantly attributable to themometasone furoate and were typical pharmacological effects of glucocorticoids. Increased heart ratesassociated with indacaterol were apparent in dogs after administration of indacaterol/mometasonefuroate or indacaterol alone.

Lactose monohydrate

Magnesium stearate

Hypromellose

Not applicable.

30 months.

Do not store above 30°C.

Store in the original package in order to protect from light and moisture.

Inhaler body and cap are made from acrylonitrile butadiene styrene, push buttons are made frommethyl metacrylate acrylonitrile butadiene styrene. Needles and springs are made from stainless steel.

PA/Alu/PVC - Alu perforated unit-dose blister. Each blister contains 10 hard capsules.

Single pack containing 10 x 1, 30 x 1 or 90 x 1 hard capsules, together with 1 inhaler.

Pack containing 30 x 1 hard capsules, together with 1 inhaler and 1 sensor.

Multipacks containing 150 (15 packs of 10 x 1) hard capsules and 15 inhalers.

Not all pack sizes may be marketed.

The inhaler provided with each new prescription should be used. The inhaler in each pack should bedisposed of after all capsules in that pack have been used.

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

Instructions for handling and use

Please read the full Instructions for Use before using the Enerzair Breezhaler.

Insert Pierce and release Inhale deeply Check capsule is empty1 23 Check

Step 1a: Step 2a: Step 3a: Check capsule is empty

Pull off cap Pierce capsule once Breathe out fully Open the inhaler to see if

Hold the inhaler upright. Do not blow into the any powder is left in the

Pierce capsule by firmly inhaler. capsule.

pressing both sidebuttons at the same time. If there is powder left inthe capsule:

- Close the inhaler.

- Repeat steps 3a to 3d.

You should hear a noiseas the capsule is pierced.

Only pierce the capsule Powder Emptyonce. remaining

Step 1b: Step 3b:

Open inhaler Inhale medicine deeply

Hold the inhaler asshown in the picture.

Place the mouthpiece inyour mouth and closeyour lips firmly aroundit.

Step 2b: Do not press the side

Release side buttons buttons.

Breathe in quickly and asdeeply as you can.

During inhalation youwill hear a whirringnoise.

You may taste themedicine as you inhale.

Step 1c: Remove empty capsule

Remove capsule Put the empty capsule in

Separate one of the your household waste.

blisters from the blister Close the inhaler andcard. replace the cap.

Peel open the blister andremove the capsule.

Do not push the capsule

Step 3c:

through the foil.

Hold breath

Do not swallow the

Hold your breath for upcapsule.to 5 seconds.

Step 3d:

Rinse mouth

Rinse your mouth withwater after each dose andspit it out.

Important Information

- Enerzair Breezhalercapsules must always bestored in the blister cardand only removedimmediately before use.

Step 1d:

Insert capsule - Do not push the capsule

Never place a capsule through the foil todirectly into the remove it from themouthpiece. blister.

- Do not swallow thecapsule.

- Do not use the Enerzair

Breezhaler capsules withany other inhaler.

- Do not use the Enerzair

Breezhaler inhaler totake any other capsule

Step 1e: medicine.

Close inhaler - Never place the capsuleinto your mouth or themouthpiece of theinhaler.

- Do not press the sidebuttons more than once.

- Do not blow into themouthpiece.

- Do not press the sidebuttons while inhalingthrough the mouthpiece.

- Do not handle capsuleswith wet hands.

- Never wash your inhalerwith water.

Your Enerzair Breezhaler Inhaler pack contains: Frequently Asked Cleaning the inhaler

- One Enerzair Breezhaler inhaler Questions Wipe the mouthpiece

- One or more blister cards, each containing inside and outside with a10 Enerzair Breezhaler capsules to be used in Why didn’t the inhaler clean, dry, lint-free cloth tothe inhaler make a noise when I remove any powderinhaled? residue. Keep the inhaler

Capsule Mouthpiece The capsule may be stuck dry. Never wash yourchamber in the capsule chamber. If inhaler with water.

Capthis happens, carefully

Screen

Side loosen the capsule bybuttons tapping the base of the

Base Blisterinhaler. Inhale the

Inhaler Inhaler base Blister card medicine again byrepeating steps 3a to 3d.

Disposing of the inhaler

What should I do if there after useis powder left inside the Each inhaler should becapsule? disposed of after all

You have not received capsules have been used.

enough of your medicine. Ask your pharmacist how

Close the inhaler and to dispose of medicinesrepeat steps 3a to 3d. and inhalers that are nolonger required.

I coughed after inhaling- does this matter?

This may happen. As longas the capsule is emptyyou have received enoughof your medicine.

I felt small pieces of thecapsule on my tongue -does this matter?

This can happen. It is notharmful. The chances ofthe capsule breaking intosmall pieces will beincreased if the capsule ispierced more than once.

For detailed instructions on use of the sensor and the App, see the Instructions for Use provided in thesensor pack and the App.

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

EU/1/20/1438/001-005

03 July 2020

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

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