ATECTURA BREEZHALER 125mcg / 62.5mcg capsules inhalation powder medication leaflet

Atectura Breezhaler 125 micrograms/62.5 micrograms inhalation powder, hard capsules

Atectura Breezhaler 125 micrograms/127.5 micrograms inhalation powder, hard capsules

Atectura Breezhaler 125 micrograms/260 micrograms inhalation powder, hard capsules

Atectura Breezhaler 125 micrograms/62.5 micrograms inhalation powder, hard capsules

Each capsule contains 150 mcg indacaterol (as acetate) and 80 mcg mometasone furoate.

Each delivered dose (the dose that leaves the mouthpiece of the inhaler) contains 125 mcg indacaterol(as acetate) and 62.5 mcg mometasone furoate.

Atectura Breezhaler 125 micrograms/127.5 micrograms inhalation powder, hard capsules

Each capsule contains 150 mcg indacaterol (as acetate) and 160 mcg mometasone furoate.

Each delivered dose (the dose that leaves the mouthpiece of the inhaler) contains 125 mcg indacaterol(as acetate) and 127.5 mcg mometasone furoate.

Atectura Breezhaler 125 micrograms/260 micrograms inhalation powder, hard capsules

Each capsule contains 150 mcg indacaterol (as acetate) and 320 mcg mometasone furoate.

Each delivered dose (the dose that leaves the mouthpiece of the inhaler) contains 125 mcg indacaterol(as acetate) and 260 mcg mometasone furoate.

Each capsule contains approximately 24 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Inhalation powder, hard capsule (inhalation powder)

Atectura Breezhaler 125 micrograms/62.5 micrograms inhalation powder, hard capsules

Transparent capsule containing a white powder, with the product code “IM150-80” printed in blueabove one blue bar on the body and with the product logo printed in blue and surrounded by two bluebars on the cap.

Atectura Breezhaler 125 micrograms/127.5 micrograms inhalation powder, hard capsules

Transparent capsule containing a white powder, with the product code “IM150-160” printed in grey onthe body and with the product logo printed in grey on the cap.

Atectura Breezhaler 125 micrograms/260 micrograms inhalation powder, hard capsules

Transparent capsule containing a white powder, with the product code “IM150-320” printed in blackabove two black bars on the body and with the product logo printed in black and surrounded by twoblack bars on the cap.

Atectura Breezhaler is indicated as a maintenance treatment of asthma in adults and adolescents12 years of age and older not adequately controlled with inhaled corticosteroids and inhaled short-acting beta2-agonists.

Adults and adolescents aged 12 years and over

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

Patients should be given the strength containing the appropriate mometasone furoate dose for theseverity of their disease and should be regularly reassessed by a healthcare professional.

The maximum recommended dose is 125 mcg/260 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 renal impairment (see section 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 posology in patients 12 years of age and older is the same posology as in adults.

The safety and efficacy in paediatric patients below 12 years of age have not been established. No dataare 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 Atectura Breezhaler

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

The sensor for Atectura Breezhaler is for adult use only.

The sensor for Atectura Breezhaler should not be used for adolescent patients as the App does nothave patient consent verification or caregiver account functionality.

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.

Cardiovascular effects of beta agonists

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 or history of long QT syndrome and patients being treated withmedicinal products known to prolong QTc were excluded from studies in the indacaterol/mometasonefuroate clinical development programme. Thus safety outcomes in these populations are consideredunknown.

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 observations is unknown.

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

Atectura 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 of indacaterol/mometasonefuroate 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.

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/mometasone furoate. Information onthe potential for interactions is based on the potential for each of the monotherapy components.

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 or non-potassium-sparing diuretics may potentiate the possible hypokalaemic effect of beta2-adrenergic agonists (seesection 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

Atectura 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 to two-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.

Other long-acting beta2-adrenergic agonists

The co-administration of this medicinal product with other medicinal products containing long-actingbeta2-adrenergic agonists has not been studied and is not recommended as it may potentiate adversereactions (see sections 4.8 and 4.9).

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

Indacaterol was not teratogenic in rats and rabbits following subcutaneous administration (seesection 5.3). In animal reproduction studies with pregnant mice, rats and rabbits, mometasone furoatecaused increased foetal malformations and decreased foetal survival 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 or mometasone furoate in humanmilk, on the effects on a breast-fed infant, or on the effects on milk production. Other inhaledcorticosteroids similar to mometasone furoate are transferred into human milk. Indacaterol (includingits metabolites) and mometasone furoate have been detected in the milk of lactating rats.

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) (26.9%),nasopharyngitis (12.9%), upper respiratory tract infection (5.9%) and headache (5.8%).

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

Table 1 Adverse reactions

System organ class Adverse reactions Frequencycategory

Nasopharyngitis Very common

Upper respiratory tract Common

Infections and infestationsinfection

Candidiasis*1 Uncommon

Hypersensitivity*2 Common

Angioedema*3 Uncommon

Metabolism and nutrition disorders Hyperglycaemia*4 Uncommon

Nervous system disorders Headache*5 Common

Vision blurred Uncommon

Cataract*6 Uncommon

Cardiac disorders Tachycardia*7 Uncommon

Asthma (exacerbation) Very common

Respiratory, thoracic and mediastinal disorders Oropharyngeal pain*8 Common

Dysphonia Common

Rash*9 Uncommon

Pruritus*10 Uncommon

Musculoskeletal pain*11 Common

Muscle spasms Uncommon

* Indicates grouping of preferred terms (PTs):

1 Oral candidiasis, oropharyngeal candidiasis.

2 Drug eruption, drug hypersensitivity, hypersensitivity, rash, rash erythematous, rash pruritic, urticaria.

3 Allergic oedema, angioedema, periorbital swelling, swelling of eyelid.

4 Blood glucose increased, hyperglycaemia.

5 Headache, tension headache.

6 Cataract, cataract cortical.

7 Heart rate increased, tachycardia, sinus tachycardia, supraventricular tachycardia.

8 Oral pain, oropharyngeal discomfort, oropharyngeal pain, throat irritation, odynophagia.

9 Drug eruption, rash, rash erythematous, rash pruritic.

10 Anal pruritus, eye pruritus, nasal pruritus, pruritus, pruritus genital.

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

The safety profile of the medicinal product was assessed in the phase III study in adolescents (12 yearsand older) and adults. Frequency, type and severity of adverse reactions in adolescents are similar toadults.

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, suppression of hypothalamic pituitary adrenal axis function).

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 withcorticosteroids or other drugs, excl. anticholinergics, ATC code: R03AK14

This medicinal product is a combination of indacaterol, a long-acting beta2-adrenergic agonist(LABA), and mometasone furoate, 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 also beta2-adrenergic receptors in the human heart comprising 10% to 50% of the total adrenergic receptors.

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 24-hour dosing interval, asevidenced by improvements in trough forced expiratory volume in the first second (FEV1)improvements versus comparators 24 hours after dosing.

No tachyphylaxis to the lung function benefits of this medicinal product 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.

Two phase III randomised, double-blind studies (PALLADIUM and QUARTZ) of different durationsevaluated the safety and efficacy of Atectura Breezhaler in adult and adolescent patients withpersistent asthma.

The PALLADIUM study was a 52-week pivotal study evaluating Atectura Breezhaler125 mcg/127.5 mcg once daily (N=439) and 125 mcg/260 mcg once daily (N=445) compared tomometasone furoate 400 mcg once daily (N=444) and 800 mcg per day (given as 400 mcg twice daily)(N=442), respectively. A third active control arm included subjects treated with salmeterol/fluticasonepropionate 50 mcg/500 mcg twice daily (N=446). All subjects were required to have symptomaticasthma (ACQ-7 score ≥1.5) and were on asthma maintenance therapy using an inhaled syntheticcorticosteroid (ICS) with or without LABA for at least 3 months prior to study entry. At screening,31% of patients had history of exacerbation in the previous year. At study entry, the most commonasthma medications reported were medium dose of ICS (20%), high dose of ICS (7%) or low dose of

ICS in combination with a LABA (69%).

The primary objective of the study was to demonstrate superiority of either Atectura Breezhaler125 mcg/127.5 mcg once daily over mometasone furoate 400 mcg once daily or Atectura Breezhaler125 mcg/260 mcg once daily over mometasone furoate 400 mcg twice daily in terms of trough FEV1at week 26.

At week 26, Atectura Breezhaler 125 mcg/127.5 mcg and 125 mcg/260 mcg once daily bothdemonstrated statistically significant improvements in trough FEV1 and Asthma Control Questionnaire(ACQ-7) score compared to mometasone furoate 400 mcg once or twice daily, respectively (see

Table 2). Findings at week 52 were consistent with week 26.

Atectura Breezhaler 125 mcg/127.5 mcg and 125 mcg/260 mcg once daily both demonstrated aclinically meaningful reduction in the annual rate of moderate or severe exacerbations (secondaryendpoint), compared to mometasone furoate 400 mcg once and twice daily (see Table 2).

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

Lung function, symptoms and exacerbations

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

Endpoint Time point/ Atectura Breezhaler1 Atectura Breezhaler1

Duration vs MF2 vs SAL/FP3

Medium dose vs High dose vs High dose vsmedium dose high dose high dose

Trough FEV 4

Week 26 211 ml 132 ml 36 ml(primary endpoint) <0.001 <0.001 0.101

Treatment difference(167, 255) (88, 176) (-7, 80)

P value

Week 52 209 ml 136 ml 48 ml(95% CI)<0.001 <0.001 0.040(163, 255) (90, 183) (2, 94)

Mean morning peak expiratory flow (PEF)*

Treatment difference Week 52 30.2 l/min 28.7 l/min 13.8 l/min(95% CI) (24.2, 36.3) (22.7, 34.8) (7.7, 19.8)

Mean evening peak expiratory flow (PEF)*

Treatment difference Week 52 29.1 l/min 23.7 l/min 9.1 l/min(95% CI) (23.3, 34.8) (18.0, 29.5) (3.3, 14.9)

ACQ-7

Week 26 -0.248 -0.171 -0.054

Treatment difference (key secondary <0.001 <0.001 0.214

P value endpoint) (-0.334, -0.162) (-0.257, -0.086) (-0.140, 0.031)(95% CI) Week 52 -0.266 -0.141 0.010(-0.354, -0.177) (-0.229, -0.053) (-0.078, 0.098)

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

Percentage Week 26 76% vs 67% 76% vs 72% 76% vs 76%

Odds ratio Week 26 1.73 1.31 1.06(95% CI) (1.26, 2.37) (0.95, 1.81) (0.76, 1.46)

Percentage Week 52 82% vs 69% 78% vs 74% 78% vs 77%

Odds ratio Week 52 2.24 1.34 1.05(95% CI) (1.58, 3.17) (0.96, 1.87) (0.75, 1.49)

Percentage of rescue medication free days*

Treatment difference Week 52 8.6 9.6 4.3(95% CI) (4.7, 12.6) (5.7, 13.6) (0.3, 8.3)

Percentage of days with no symptoms*

Treatment difference Week 52 9.1 5.8 3.4(95% CI) (4.6, 13.6) (1.3, 10.2) (-1.1, 7.9)

Annualised rate of asthma exacerbations**

AR Week 52 0.27 vs 0.56 0.25 vs 0.39 0.25 vs 0.27

RR Week 52 0.47 0.65 0.93(95% CI) (0.35, 0.64) (0.48, 0.89) (0.67, 1.29)

Severe exacerbations

AR Week 52 0.13 vs 0.29 0.13 vs 0.18 0.13 vs 0.14

RR Week 52 0.46 0.71 0.89(95% CI) (0.31, 0.67) (0.47, 1.08) (0.58, 1.37)

* Mean value for the treatment duration

** RR <1.00 favours indacaterol/mometasone furoate.1 Atectura Breezhaler medium dose: 125 mcg/127.5 mcg od; high dose: 125 mcg/260 mcg od.2 MF: mometasone furoate medium dose: 400 mcg od; high dose: 400 mcg bid (content doses).

Mometasone furoate 127.5 mcg od and 260 mcg od in Atectura Breezhaler are comparable tomometasone furoate 400 mcg od and 800 mcg per day (given as 400 mcg bid).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

Pre-specified pooled analysis

Atectura Breezhaler 125 mcg/260 mcg once daily was also studied as an active comparator in anotherphase III study (IRIDIUM) in which all subjects had a history of asthma exacerbation requiringsystemic corticosteroids in the past year. A pre-specified pooled analysis across the IRIDIUM and

PALLADIUM studies was conducted to compare Atectura Breezhaler 125 mcg/260 mcg once daily tosalmeterol/fluticasone 50 mcg/500 mcg twice daily for the endpoints of trough FEV1 and ACQ-7 atweek 26 and annualised rate of exacerbations. The pooled analysis demonstrated that Atectura

Breezhaler improved trough FEV1 by 43 ml (95% CI: 17, 69) and ACQ-7 score by -0.091 (95% CI:

- 0.153, -0.030) at week 26 and reduced the annualised rate of moderate or severe asthma exacerbationsby 22% (RR: 0.78; 95% CI: 0.66, 0.93) and of severe exacerbations by 26% (RR: 0.74; 95% CI: 0.61,0.91) versus salmeterol/fluticasone.

The QUARTZ study was a 12-week study evaluating Atectura Breezhaler 125 mcg/62.5 mcg oncedaily (N=398) compared to mometasone furoate 200 mcg once daily (N=404). All subjects wererequired to be symptomatic and on asthma maintenance therapy using a low-dose ICS (with or without

LABA) for at least 1 month prior to study entry. At study entry, the most common asthma medicationsreported were low-dose ICS (43%) and LABA/low-dose ICS (56%). The primary endpoint of thestudy was to demonstrate superiority of Atectura Breezhaler 125 mcg/62.5 mcg once daily overmometasone furoate 200 mcg once daily in terms of trough FEV1 at week 12.

Atectura Breezhaler 125 mcg/62.5 mcg once daily demonstrated a statistically significantimprovement in baseline trough FEV1 at week 12 and Asthma Control Questionnaire (ACQ-7) scorecompared to mometasone furoate 200 mcg once daily.

Results for the most clinically relevant endpoints are described in Table 3.

Table 3 Results of primary and secondary endpoints in QUARTZ study at week 12

Endpoints Atectura Breezhaler low dose* vs

MF low dose**

Trough FEV1 (primary endpoint)***

Treatment difference 182 ml

P value <0.001(95% CI) (148, 217)

Mean morning peak expiratory flow (PEF)

Treatment difference 27.2 l/min(95% CI) (22.1, 32.4)

Evening peak expiratory flow (PEF)

Treatment difference 26.1 l/min(95% CI) (21.0, 31.2)

ACQ-7 (key secondary endpoint)

Treatment difference -0.218

P value <0.001(95% CI) (-0.293, -0.143)

Percentage of patients achieving MCID from baseline with ACQ ≥0.5

Percentage 75% vs 65%

Odds ratio 1.69(95% CI) (1.23, 2.33)

Percentage of rescue medication free days

Treatment difference 8.1(95% CI) (4.3, 11.8)

Percentage of days with no symptoms

Treatment difference 2.7(95% CI) (-1.0, 6.4)

* Atectura Breezhaler low dose: 125/62.5 mcg od.

** MF: mometasone furoate low dose: 200 mcg od (content dose).

Mometasone furoate 62.5 mcg in Atectura Breezhaler od is comparable to mometasone furoate200 mcg od (content dose).

*** Trough FEV1: the mean of the two FEV1 values measured at 23 hours 15 min and 23 hours45 min after the evening dose.

od = once daily, bid = twice daily

In the PALLADIUM study, which included 106 adolescents (12-17 years old), the improvements intrough FEV1 at week 26 were 0.173 litres (95% CI: -0.021, 0.368) for Atectura Breezhaler125 mcg/260 mcg once daily vs mometasone furoate 800 mcg (i.e. high doses) and 0.397 litres (95%

CI: 0.195, 0.599) for Atectura Breezhaler 125 mcg/127.5 mcg once daily vs mometasone furoate400 mcg once daily (i.e. medium doses).

In the QUARTZ study, which included 63 adolescents (12-17 years old), the Least Square meanstreatment difference for trough FEV1 at day 85 (week 12) was 0.251 litres (95% CI: 0.130, 0.371).

For the adolescent subgroups, improvements in lung function, symptoms and exacerbation reductionswere consistent with the overall population.

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

Following inhalation of Atectura Breezhaler, the median time to reach peak plasma concentrations ofindacaterol and mometasone furoate was approximately 15 minutes and 1 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/mometasone furoate combination and themonotherapy products. Steady-state plasma exposure to indacaterol and mometasone furoate afterinhalation of the combination was similar to the systemic exposure after inhalation of indacaterolmaleate or mometasone furoate as monotherapy products.

Following inhalation of the combination, the absolute bioavailability was estimated to be about 45%for indacaterol 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.

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 1.61 to 1.71 for once-daily inhaled doses between 62.5 and 260 mcg as part of theindacaterol/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 2 361 to 2 557 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.

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 a low-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.

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.

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 and mometasone furoate under steady-stateconditions did not affect the pharmacokinetics of either active substance.

Systemic exposure of mometasone furoate increased in a dose proportional manner following singleand multiple doses of Atectura Breezhaler 125 mcg/62.5 mcg and 125 mcg/260 mcg in healthysubjects. A less than proportional increase in steady-state systemic exposure was noted in patients withasthma over the dose range of 125 mcg/62.5 mcg to 125 mcg/260 mcg. Dose proportionalityassessments were not performed for indacaterol as only one dose was used across all dose strengths.

Atectura Breezhaler may be used in adolescent patients (12 years of age and older) at the sameposology as in adults.

A population pharmacokinetic analysis in patients with asthma after inhalation ofindacaterol/mometasone furoate indicated no significant effect of age, gender, body weight, smokingstatus, baseline estimated glomerular filtration rate (eGFR) and FEV1 at baseline on the systemicexposure to indacaterol and mometasone furoate.

Due to the very low contribution of the urinary pathway to total body elimination of indacaterol andmometasone furoate, the effects of renal impairment on their systemic exposure have not beeninvestigated (see section 4.2).

The effect of indacaterol/mometasone furoate has not been evaluated in subjects with hepaticimpairment. However, studies have been conducted with the monotherapy components (seesection 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. No data are available for subjects with severe hepatic impairment.

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 both compounds between

Japanese and Caucasian subjects. Insufficient pharmacokinetic data are available for other ethnicitiesor races.

Indacaterol and mometasone furoate combination

The findings during the 13-week inhalation toxicity studies were predominantly attributable to themometasone furoate component and were typical pharmacological effects of glucocorticoids.

Increased heart rates associated with indacaterol were apparent in dogs after administration ofindacaterol/mometasone furoate or indacaterol alone.

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.

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 genotoxicactivity 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.

Environmental risk assessment studies have shown that mometasone may pose a risk to surface water(see section 6.6).

Lactose monohydrate

Gelatin

Atectura Breezhaler 125 micrograms/62.5 micrograms inhalation powder, hard capsules

Shellac

Brilliant blue FCF (E133)

Propylene glycol (E1520)

Titanium dioxide (E171)

Black iron oxide (E172)

Atectura Breezhaler 125 micrograms/127.5 micrograms inhalation powder, hard capsules

Shellac

Titanium dioxide (E171)

Black iron oxide (E172)

Propylene glycol (E1520)

Yellow iron oxide (E172)

Ammonia hydroxide (E527)

Atectura Breezhaler 125 micrograms/260 micrograms inhalation powder, hard capsules

Shellac

Black iron oxide (E172)

Propylene glycol (E1520)

Ammonia hydroxide (E527)

Not applicable.

3 years.

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.

Atectura Breezhaler 125 micrograms/62.5 micrograms inhalation powder, hard capsules

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

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

Multipacks containing 90 (3 packs of 30 x 1) hard capsules and 3 inhalers.

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

Atectura Breezhaler 125 micrograms/127.5 micrograms inhalation powder, hard capsules

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

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

Multipacks containing 90 (3 packs of 30 x 1) hard capsules and 3 inhalers.

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

Atectura Breezhaler 125 micrograms/260 micrograms inhalation powder, hard capsules

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

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

Multipacks containing 90 (3 packs of 30 x 1) hard capsules and 3 inhalers.

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.

This medicinal product may pose a risk to the environment (see section 5.3).

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 Atectura Breezhaler.

Insert Pierce and release Inhale deeply Check capsule is empty1 2 3 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. Step 3c:

Do not push the capsule

Hold breaththrough the foil.

Hold your breath for up

Do not swallow theto 5 seconds.capsule.

Step 3d:

Rinse mouth

Rinse your mouth withwater after each dose andspit it out.

Important Information

* Atectura Breezhalercapsules must always bestored in the blister cardand only removedimmediately before use.

Step 1d: * Do not push the capsule

Insert capsule through the foil to

Never place a capsule remove it from thedirectly into the blister.mouthpiece. * Do not swallow thecapsule.

* Do not use the Atectura

Breezhaler capsules withany other inhaler.

* Do not use the Atectura

Breezhaler inhaler totake any other capsulemedicine.

* Never place the capsule

Step 1e: into your mouth or the

Close inhaler mouthpiece 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 Atectura Breezhaler Inhaler pack contains: Frequently Asked Cleaning the inhaler

* One Atectura Breezhaler inhaler Questions Wipe the mouthpiece

* One or more blister cards, each containing inside and outside with a10 Atectura 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 powder

Capsule Mouthpiece inhaled? residue. Keep the inhalerchamber The capsule may be stuck dry. Never wash your

Capin the capsule chamber. If inhaler with water.

Screenthis happens, carefully

Sidebuttons loosen the capsule by

Base Blister tapping the base of theinhaler. 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

Atectura Breezhaler 125 micrograms/62.5 micrograms inhalation powder, hard capsules

EU/1/20/1439/001-004

EU/1/20/1439/013

Atectura Breezhaler 125 micrograms/127.5 micrograms inhalation powder, hard capsules

EU/1/20/1439/005-008

EU/1/20/1439/014

Atectura Breezhaler 125 micrograms/260 micrograms inhalation powder, hard capsules

EU/1/20/1439/009-012

EU/1/20/1439/015

Date of first authorisation: 30 May 2020

Date of latest renewal:

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

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