ULTIBRO BREEZHALER 85mcg / 43mcg inhalation powder capsules medication leaflet

Ultibro Breezhaler 85 micrograms/43 micrograms inhalation powder hard capsules

Each capsule contains 143 micrograms of indacaterol maleate equivalent to 110 micrograms ofindacaterol and 63 micrograms of glycopyrronium bromide equivalent to 50 micrograms ofglycopyrronium.

Each delivered dose (the dose that leaves the mouthpiece of the inhaler) contains 110 micrograms ofindacaterol maleate equivalent to 85 micrograms of indacaterol and 54 micrograms of glycopyrroniumbromide equivalent to 43 micrograms of glycopyrronium.

Each capsule contains 23.5 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Inhalation powder, hard capsule (inhalation powder).

Capsules with transparent yellow cap and natural transparent body containing a white to almost whitepowder, with the product code “IGP110.50” printed in blue under two blue bars on the body and thecompany logo ( ) printed in black on the cap.

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

The recommended dose is the inhalation of the content of one capsule once daily using the Ultibro

Breezhaler inhaler.

Ultibro Breezhaler is recommended to be administered at the same time of the day each day. If a doseis missed, it should be taken as soon as possible on the same day. Patients should be instructed not totake more than one dose in a day.

Ultibro Breezhaler can be used at the recommended dose in elderly patients (75 years of age andolder).

Ultibro Breezhaler can be used at the recommended dose in patients with mild to moderate renalimpairment. In patients with severe renal impairment or end-stage renal disease requiring dialysis itshould be used only if the expected benefit outweighs the potential risk (see sections 4.4 and 5.2).

Ultibro Breezhaler can be used at the recommended dose in patients with mild and moderate hepaticimpairment. There are no data available for the use of Ultibro Breezhaler in patients with severehepatic impairment, therefore caution should be observed in these patients (see section 5.2).

There is no relevant use of Ultibro Breezhaler in the paediatric population (under 18 years) in theindication COPD. The safety and efficacy of Ultibro Breezhaler in children have not been established.

No data are available.

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

The capsules must be administered only using the Ultibro Breezhaler inhaler (see section 6.6). Theinhaler provided with each new prescription should be used.

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.

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

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

Ultibro Breezhaler should not be administered concomitantly with medicinal products containing otherlong-acting beta-adrenergic agonists or long-acting muscarinic antagonists, the pharmacotherapeuticgroups to which the components of Ultibro Breezhaler belong (see section 4.5).

Asthma

Ultibro Breezhaler should not be used for the treatment of asthma due to the absence of data in thisindication.

Long-acting beta2-adrenergic agonists may increase the risk of asthma-related serious adverse events,including asthma-related deaths, when used for the treatment of asthma.

Ultibro Breezhaler is not indicated for the treatment of acute episodes of bronchospasm.

Immediate hypersensitivity reactions have been reported after administration of indacaterol orglycopyrronium, which are the active substances of Ultibro Breezhaler. If signs suggesting allergicreactions occur, in particular, angioedema (difficulties in breathing or swallowing, swelling of thetongue, lips and face) urticaria or skin rash, treatment should be discontinued immediately andalternative therapy instituted.

Administration of Ultibro Breezhaler may result in paradoxical bronchospasm which can belife-threatening. If this occurs, treatment should be discontinued immediately and alternative therapyinstituted.

Anticholinergic effects related to glycopyrronium

Narrow-angle glaucoma

No data are available in patients with narrow-angle glaucoma, therefore Ultibro Breezhaler should beused with caution in these patients.

Patients should be informed about the signs and symptoms of acute narrow-angle glaucoma andshould be informed to stop using Ultibro Breezhaler should any of these signs or symptoms develop.

Urinary retention

No data are available in patients with urinary retention, therefore Ultibro Breezhaler should be usedwith caution in these patients.

Patients with severe renal impairment

A moderate mean increase in total system exposure (AUClast) to glycopyrronium 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. In patients with severe renal impairment (estimatedglomerular filtration rate below 30 ml/min/1.73 m2), including those with end-stage renal diseaserequiring dialysis, Ultibro Breezhaler should be used only if the expected benefit outweighs thepotential risk (see section 5.2). These patients should be monitored closely for potential adversereactions.

Ultibro Breezhaler should be used with caution in patients with cardiovascular disorders (coronaryartery disease, acute myocardial infarction, cardiac arrhythmias, hypertension).

Beta2-adrenergic agonists may produce a clinically significant cardiovascular effect in some patientsas measured by increases in pulse rate, blood pressure, and/or symptoms. In case such effects occurwith this medicinal product, treatment may need to be discontinued. In addition, beta-adrenergicagonists have been reported to produce electrocardiographic (ECG) changes, such as flattening of the

T wave, prolongation of QT interval and ST segment depression, although the clinical significance ofthese observations is unknown. Therefore, long-acting beta2-adrenergic agonists (LABA) or

LABA-containing combination products such as Ultibro Breezhaler should be used with caution inpatients with known or suspected prolongation of the QT interval or treated with medicinal productsaffecting the QT interval.

Patients with unstable ischaemic heart disease, left ventricular failure, history of myocardial infarction,arrhythmia (excluding chronic stable atrial fibrillation), a history of long QT syndrome or whose QTc(Fridericia method) was prolonged (>450 ms) were excluded from the clinical trials, and thereforethere is no experience in these patient groups. Ultibro Breezhaler should be used with caution in thesepatient groups.

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 COPD, hypokalaemia may bepotentiated by hypoxia and concomitant treatment, which may increase the susceptibility to cardiacarrhythmias (see section 4.5).

Clinically relevant effects of hypokalaemia have not been observed in clinical studies of Ultibro

Breezhaler at the recommended therapeutic dose (see section 5.1).

Inhalation of high doses of beta2-adrenergic agonists may produce increases in plasma glucose. Uponinitiation of treatment with Ultibro Breezhaler plasma glucose should be monitored more closely indiabetic patients.

During long-term clinical studies, more patients on Ultibro Breezhaler experienced clinically notablechanges in blood glucose (4.9%) at the recommended dose than on placebo (2.7%). Ultibro Breezhalerhas not been investigated in patients for whom diabetes mellitus is not well controlled, thereforecaution and appropriate monitoring are advised in such patients.

General disorders

Ultibro Breezhaler should be used with caution in patients with convulsive disorders or thyrotoxicosis,and in patients who are unusually responsive to beta2-adrenergic agonists.

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

Concomitant administration of orally inhaled indacaterol and glycopyrronium, under steady-stateconditions of both active substances, did not affect the pharmacokinetics of either active substance.

No specific interaction studies were conducted with Ultibro Breezhaler. Information on the potentialfor interactions is based on the potential for each of its two active substances.

Beta-adrenergic blockers

Beta-adrenergic blockers may weaken or antagonise the effect of beta2-adrenergic agonists. Therefore

Ultibro Breezhaler should not be given together with beta-adrenergic blockers (including eye drops)unless there are compelling reasons for their use. Where required, cardioselective beta-adrenergicblockers should be preferred, although they should be administered with caution.

Anticholinergics

The co-administration of Ultibro Breezhaler with other anticholinergic-containing medicinal productshas not been studied and is therefore not recommended (see section 4.4).

Sympathomimetics

Concomitant administration of other sympathomimetics (alone or as part of combination therapy) maypotentiate the adverse events of indacaterol (see section 4.4).

Hypokalaemic treatment

Concomitant hypokalaemic treatment with methylxanthine derivatives, steroids, or non-potassium-sparing diuretics may potentiate the possible hypokalaemic effect of beta2-adrenergic agonists,therefore use with caution (see section 4.4).

To be taken into account with concomitant use

Metabolic and transporter based interactions

Inhibition of the key contributors of indacaterol clearance, CYP3A4 and P-glycoprotein (P-gp), raisesthe systemic exposure of indacaterol up to two-fold. The magnitude of exposure increases due tointeractions does not raise any safety concerns given the safety experience of treatment withindacaterol in clinical studies of up to one year at doses up to twice the maximum recommendedindacaterol dose.

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.

There are no data from the use of Ultibro Breezhaler in pregnant women available. Animal studies donot indicate direct or indirect harmful effects with respect to reproductive toxicity at clinically relevantexposures (see section 5.3).

Indacaterol may inhibit labour due to a relaxant effect on uterine smooth muscle. Therefore, Ultibro

Breezhaler should only be used during pregnancy if the expected benefit to the patient justifies thepotential risk to the foetus.

It is not known whether indacaterol, glycopyrronium and their metabolites are excreted in human milk.

Available pharmacokinetic/toxicological data have shown excretion of indacaterol, glycopyrroniumand their metabolites in the milk of lactating rats. The use of Ultibro Breezhaler by breast-feedingwomen should only be considered if the expected benefit to the woman is greater than any possiblerisk to the infant (see section 5.3).

Reproduction studies and other data in animals do 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.

However, the occurrence of dizziness may influence the ability to drive and use machines (seesection 4.8).

The presentation of the safety profile is based on the experience with Ultibro Breezhaler and theindividual active substances.

The safety experience with Ultibro Breezhaler was comprised of exposure of up to 15 months at therecommended therapeutic dose.

Ultibro Breezhaler showed similar adverse reactions to the individual components. As it containsindacaterol and glycopyrronium, the type and severity of adverse reactions associated with each ofthese components may be expected in the combination.

The safety profile is characterised by typical anticholinergic and beta-adrenergic symptoms related tothe individual components of the combination. Other most common adverse reactions related to themedicinal product (at least 3% of patients for Ultibro Breezhaler and also greater than placebo) werecough, nasopharyngitis and headache.

Adverse reactions detected during clinical trials and from post-marketing sources are listed by

MedDRA system organ class (Table 1). Within each system organ class, the adverse reactions areranked by frequency, with the most frequent reactions first. Within each frequency grouping, adversereactions are presented in order of decreasing seriousness. In addition, the corresponding frequencycategory for each adverse reaction is based on the following convention: very common (≥1/10);common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000, <1/1,000); very rare(<1/10,000); not known (cannot be estimated from the available data).

Table 1 Adverse reactions

Adverse reactions Frequency category

Upper respiratory tract infection Very common

Nasopharyngitis Common

Urinary tract infection Common

Sinusitis Common

Rhinitis Common

Hypersensitivity Common

Angioedema2 Uncommon

Hyperglycaemia and diabetes mellitus Common

Insomnia Uncommon

Dizziness Common

Headache Common

Paraesthesia Rare

Glaucoma1 Uncommon

Ischaemic heart disease Uncommon

Atrial fibrillation Uncommon

Tachycardia Uncommon

Palpitations Uncommon

Cough Common

Oropharyngeal pain including throat irritation Common

Paradoxical bronchospasm Uncommon

Dysphonia2 Uncommon

Epistaxis Uncommon

Dyspepsia Common

Dental caries Common

Gastroenteritis Uncommon

Dry mouth Uncommon

Pruritus/rash Uncommon

Musculoskeletal pain Uncommon

Muscle spasm Uncommon

Myalgia Uncommon

Pain in extremity Uncommon

Bladder obstruction and urinary retention Common

Pyrexia1 Common

Chest pain Common

Oedema peripheral Uncommon

Fatigue Uncommon1 Adverse reaction observed with Ultibro Breezhaler, but not with the individual components.2 Reports received from post-marketing experience; frequencies calculated, however, on the basis ofclinical trial data.

Cough was common, but usually of mild intensity.

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.

There is no information on clinically relevant overdosing with Ultibro Breezhaler.

An overdose could lead to exaggerated effects typical of beta2-adrenergic stimulants, i.e. tachycardia,tremor, palpitations, headache, nausea, vomiting, drowsiness, ventricular arrhythmias, metabolicacidosis, hypokalaemia and hyperglycaemia or could induce anticholinergic effects such as increasedintraocular pressure (causing pain, vision disturbances or reddening of the eye), obstipation ordifficulties in voiding. Supportive and symptomatic treatment is indicated. In serious cases, patientsshould be hospitalised. Use of cardioselective beta blockers may be considered for treating beta2-adrenergic effects, but only under the supervision of a physician and with extreme caution since theuse of beta-adrenergic blockers may provoke bronchospasm.

Pharmacotherapeutic group: Drugs for obstructive airway diseases, adrenergics in combination withanticholinergics, ATC code: R03AL04

Ultibro Breezhaler

When indacaterol and glycopyrronium are administered together in Ultibro Breezhaler, they provideadditive efficacy due to their different mode of action targeting different receptors and pathways toachieve smooth muscle relaxation. Due to the differential density of beta2-adrenoceptors and

M3-receptors in central versus peripheral airways, beta2-agonists should be more effective in relaxingperipheral airways, whilst an anticholinergic compound may be more effective in central airways.

Thus for bronchodilation in both peripheral and central airways of the human lung a combination of abeta2-adrenergic agonist and a muscarinic antagonist may be beneficial.

Indacaterol

Indacaterol is a long-acting beta2-adrenergic agonist for once-daily administration. Thepharmacological effects of beta2-adrenoceptor agonists, including indacaterol, are at least in partattributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyses the conversion ofadenosine triphosphate (ATP) to cyclic-3’, 5’-adenosine monophosphate (cyclic AMP). Increasedcyclic AMP levels cause relaxation of bronchial smooth muscle. In vitro studies have shown thatindacaterol has multi-fold greater agonist activity at beta2-receptors compared to beta1 andbeta3-receptors.

When inhaled, indacaterol acts locally in the lung as a bronchodilator. Indacaterol is a partial agonistat the human beta2-adrenergic receptor with nanomolar potency.

Although beta2-adrenergic receptors are the predominant adrenergic receptors in bronchial smoothmuscle and beta1-adrenergic 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. Their presence in the heart raises the possibility that even highly selective beta2-adrenergicagonists may have cardiac effects.

Glycopyrronium is an inhaled long-acting muscarinic receptor antagonist (anticholinergic) foronce-daily maintenance bronchodilator treatment of COPD. Parasympathetic nerves are the majorbronchoconstrictive neural pathway in airways, and cholinergic tone is the key reversible componentof airflow obstruction in COPD. Glycopyrronium works by blocking the bronchoconstrictor action ofacetylcholine on airway smooth muscle cells, thereby dilating the airways.

Glycopyrronium bromide is a high affinity muscarinic receptor antagonist. A greater than 4-foldselectivity for the human M3 receptors over the human M2 receptor has been demonstrated usingradioligand binding studies.

The combination of indacaterol and glycopyrronium in Ultibro Breezhaler showed a rapid onset ofaction within 5 minutes after dosing. The effect remains constant over the whole 24-h dosing interval.

The mean bronchodilator effect derived from serial FEV1 measurements over 24 h was 320 ml after26 weeks of treatment. The effect was significantly greater for Ultibro Breezhaler, when compared toindacaterol, glycopyrronium or tiotropium alone (difference 110 ml, for each comparison).

There was no evidence for tachyphylaxis to the effect of Ultibro Breezhaler over time when comparedto placebo or its monotherapy components.

Effects on heart rate

Heart rate effects in healthy volunteers were investigated after a single dose of 4 times therecommended therapeutic dose of Ultibro Breezhaler administered in four dose steps each separatedby one hour and compared to the effects of placebo, indacaterol, glycopyrronium and salmeterol.

The largest time-matched heart rate increase compared to placebo was +5.69 bpm (90% CI [2.71,8.66]), the largest decrease was -2.51 bpm (90% CI [-5.48, 0.47]). Overall the effect on heart rate overtime did not show a consistent pharmacodynamic effect of Ultibro Breezhaler.

Heart rate in COPD patients at supratherapeutic dose levels was investigated. There were no relevanteffects of Ultibro Breezhaler on mean heart rate over 24 h and heart rate assessed after 30 minutes, 4 hand 24 h.

A thorough QT (TQT) study in healthy volunteers with high doses of inhaled indacaterol (up to twicethe maximum recommended therapeutic dose) did not demonstrate a clinically relevant effect on the

QT interval. Similarly, for glycopyrronium no QT prolongation was observed in a TQT study after aninhaled dose of 8 times the recommended therapeutic dose.

The effects of Ultibro Breezhaler on QTc interval were investigated in healthy volunteers afterinhalation of Ultibro Breezhaler up to 4 times the recommended therapeutic dose in four dose stepseach separated by one hour. The largest time-matched difference versus placebo was 4.62 ms (90% CI0.40, 8.85 ms), the largest time-matched decrease was -2.71 ms (90% CI -6.97, 1.54 ms), indicatingthat Ultibro Breezhaler had no relevant impact on the QT interval, as was expected by the properties ofits components.

In COPD patients, supratherapeutic doses between 116 micrograms/86 micrograms and464 micrograms/86 micrograms of Ultibro Breezhaler showed a higher proportion of patients with

QTcF increases vs. baseline between 30 ms and 60 ms (ranging from 16.0% to 21.6% vs. 1.9% forplacebo), but there were no QTcF increases >60 ms from baseline. The highest dose level of464 micrograms/86 micrograms Ultibro Breezhaler also showed a higher proportion of absolute QTcFvalues >450 ms (12.2% vs. 5.7% for placebo).

Serum potassium and blood glucose

In healthy volunteers, after the administration of 4 times the recommended therapeutic dose of Ultibro

Breezhaler, the effect on serum potassium was very small (maximal difference -0.14 mmol/l whencompared to placebo). The maximal effect on blood glucose was 0.67 mmol/l.

The Ultibro Breezhaler clinical Phase III development programme included six studies in which over8,000 patients were enrolled: 1) a 26-week placebo- and active-controlled (indacaterol once daily,glycopyrronium once daily, open-label tiotropium once daily) study; 2) a 26-week active-controlled(fluticasone/salmeterol twice daily) study; 3) a 64-week active-controlled (glycopyrronium once daily,open-label tiotropium once daily) study; 4) a 52-week placebo-controlled study; 5) a 3-week placebo-and active-controlled (tiotropium once daily) exercise tolerance study; and 6) a 52-week active-controlled (fluticasone/salmeterol twice daily) study.

In four of these studies patients were enrolled who had a clinical diagnosis of moderate to severe

COPD. In the 64-week study patients were enrolled who had severe to very severe COPD with ahistory of ≥1 moderate or severe COPD exacerbation in the previous year. In the 52-week active-controlled study, patients were enrolled who had moderate to very severe COPD with a history of≥1 moderate or severe COPD exacerbation in the previous year.

Ultibro Breezhaler showed clinically meaningful improvements in lung function (as measured by theforced expiratory volume in one second, FEV1) in a number of clinical studies. In Phase III studies,bronchodilator effects were seen within 5 minutes after the first dose and were maintained over the24-hour dosing interval from the first dose. There was no attenuation of the bronchodilator effect overtime.

The magnitude of the effect was dependent on the degree of reversibility of airflow limitation atbaseline (tested by administration of a short-acting muscarinic antagonist bronchodilator and ashort-acting beta2-agonist bronchodilator): Patients with the lowest degree of reversibility at baseline(<5%) generally exhibited a lower bronchodilator response than patients with a higher degree ofreversibility at baseline (≥5%). At 26 weeks (primary endpoint), Ultibro Breezhaler increased trough

FEV1 by 80 ml in patients (Ultibro Breezhaler n=82; placebo n=42) with the lowest degree ofreversibility (<5%) (p=0.053) and by 220 ml in those patients (Ultibro Breezhaler n=392, placebon=190) with a higher degree of reversibility at baseline (≥5%) compared to placebo (p<0.001).

Trough and peak FEV1:

Ultibro Breezhaler increased post-dose trough FEV1 by 200 ml compared to placebo at the 26-weekprimary endpoint (p<0.001) and showed statistically significant increases compared to eachmonotherapy component treatment arm (indacaterol and glycopyrronium) as well as the tiotropiumtreatment arm, as shown in the below table.

Post-dose trough FEV1 (least squares mean) at day 1 and week 26 (primary endpoint)

Treatment difference Day 1 Week 26

Ultibro Breezhaler - placebo 190 ml (p<0.001) 200 ml (p<0.001)

Ultibro Breezhaler - indacaterol 80 ml (p<0.001) 70 ml (p<0.001)

Ultibro Breezhaler - glycopyrronium 80 ml (p<0.001) 90 ml (p<0.001)

Ultibro Breezhaler - tiotropium 80 ml (p<0.001) 80 ml (p<0.001)

The mean pre-dose FEV1 (average of the values taken at -45 and -15 minutes prior to the morningdose of study medication) was statistically significant in favour of Ultibro Breezhaler at week 26compared to fluticasone/salmeterol (least squares [LS] mean treatment difference 100 ml, p<0.001), atweek 52 compared to placebo (LS mean treatment difference 189 ml, p<0.001) and at all visits up toweek 64 compared to glycopyrronium (LS mean treatment difference 70-80 ml, p<0.001) andtiotropium (LS mean treatment difference 60-80 ml, p<0.001). In the 52-week active-controlled study,the mean pre-dose FEV1 was statistically significant in favour of Ultibro Breezhaler at all visits up toweek 52 compared to fluticasone/salmeterol (LS mean treatment difference 62-86 ml, p<0.001). Atweek 26, Ultibro Breezhaler produced statistically significant improvement in peak FEV1 compared toplacebo in the first 4 hours post dose (LS mean treatment difference 330 ml) (p<0.001).

FEV1 AUC:

Ultibro Breezhaler increased post-dose FEV1 AUC0-12 (primary endpoint) by 140 ml at 26 weeks(p<0.001) compared to fluticasone/salmeterol.

Symptomatic outcomes

Breathlessness:

Ultibro Breezhaler statistically significantly reduced breathlessness as evaluated by the Transitional

Dyspnoea Index (TDI); it demonstrated a statistically significant improvement in the TDI focal scoreat week 26 compared to placebo (LS mean treatment difference 1.09, p<0.001), tiotropium (LS meantreatment difference 0.51, p=0.007) and fluticasone/salmeterol (LS mean treatment difference 0.76,p=0.003). Improvements versus indacaterol and glycopyrronium were 0.26 and 0.21, respectively.

A statistically significantly higher percentage of patients receiving Ultibro Breezhaler responded witha 1 point or greater improvement in the TDI focal score at week 26 compared to placebo (68.1% and57.5% respectively, p=0.004). A higher proportion of patients demonstrated clinically meaningfulresponse at week 26 on Ultibro Breezhaler as compared to tiotropium (68.1% Ultibro Breezhalerversus 59.2% tiotropium, p=0.016) and fluticasone/salmeterol (65.1% Ultibro Breezhaler versus55.5% fluticasone/salmeterol, p=0.088).

Ultibro Breezhaler has also shown a statistically significant effect on health-related quality of lifemeasured using the St. George’s Respiratory Questionnaire (SGRQ) as indicated by a reduction in

SGRQ total score at 26 weeks compared to placebo (LS mean treatment difference -3.01, p=0.002)and tiotropium (LS mean treatment difference -2.13, p=0.009) and reductions versus indacaterol andglycopyrronium were -1.09 and -1.18, respectively. At 64 weeks, the reduction compared totiotropium was statistically significant (LS mean treatment difference -2.69, p<0.001). At 52 weeks,the reduction compared to fluticasone/salmeterol was statistically significant (LS mean treatmentdifference -1.3, p=0.003).

A higher percentage of patients receiving Ultibro Breezhaler responded with a clinically meaningfulimprovement in SGRQ score (defined as a decrease of at least 4 units from baseline) at week 26compared to placebo (63.7% and 56.6% respectively, p=0.088) and tiotropium (63.7% Ultibro

Breezhaler vs. 56.4% tiotropium, p=0.047), at week 64 compared to glycopyrronium and tiotropium(57.3% Ultibro Breezhaler versus 51.8% glycopyrronium, p=0.055; versus 50.8% tiotropium,p=0.051, respectively), and at week 52 compared to fluticasone/salmeterol (49.2% Ultibro Breezhalervs. 43.7% fluticasone/salmeterol, odds ratio: 1.30, p<0.001).

Daily activities

Ultibro Breezhaler demonstrated a statistically superior improvement versus tiotropium in thepercentage of “days able to perform usual daily activities” over 26 weeks (LS mean treatmentdifference 8.45%, p<0.001). At week 64, Ultibro Breezhaler showed numerical improvement overglycopyrronium (LS mean treatment difference 1.95%; p=0.175) and statistical improvement overtiotropium (LS mean treatment difference 4.96%; p=0.001).

COPD exacerbations

In a 64-week study comparing Ultibro Breezhaler (n=729), glycopyrronium (n=739) and tiotropium(n=737), Ultibro Breezhaler reduced the annualised rate of moderate or severe COPD exacerbations by12% compared to glycopyrronium (p=0.038) and by 10% compared to tiotropium (p=0.096). Thenumber of moderate or severe COPD exacerbations/patient-years was 0.94 for Ultibro Breezhaler(812 events), 1.07 for glycopyrronium (900 events) and 1.06 for tiotropium (898 events). Ultibro

Breezhaler also statistically significantly reduced the annualised rate of all COPD exacerbations (mild,moderate or severe) by 15% as compared to glycopyrronium (p=0.001) and 14% as compared totiotropium (p=0.002). The number of all COPD exacerbations/patient-years was 3.34 for Ultibro

Breezhaler (2,893 events), 3.92 for glycopyrronium (3,294 events) and 3.89 for tiotropium(3,301 events).

In the 52-week study comparing Ultibro Breezhaler (n=1,675) and fluticasone/salmeterol (n=1,679),

Ultibro Breezhaler met the primary study objective of non-inferiority in rate of all COPDexacerbations (mild, moderate or severe) compared to fluticasone/salmeterol. The number of all

COPD exacerbations/patient-years was 3.59 for Ultibro Breezhaler (4,531 events) and 4.03 forfluticasone/salmeterol (4,969 events). Ultibro Breezhaler further showed superiority in reducing theannualised rate of all exacerbations by 11% versus fluticasone/salmeterol (p=0.003).

Compared to fluticasone/salmeterol, Ultibro Breezhaler reduced the annualised rate of both moderateor severe exacerbations by 17% (p<0.001), and of severe exacerbations (requiring hospitalisation) by13% (not statistically significant, p=0.231). The number of moderate or severe COPDexacerbations/patient-years was 0.98 for Ultibro Breezhaler (1,265 events) and 1.19 forfluticasone/salmeterol (1,452 events). Ultibro Breezhaler prolonged time to first moderate or severeexacerbation with a 22% reduction in risk of an exacerbation (p<0.001) and prolonged time to firstsevere exacerbation with a 19% reduction in risk of an exacerbation (p=0.046).

The incidence of pneumonia was 3.2% in the Ultibro Breezhaler arm compared to 4.8% in thefluticasone/salmeterol arm (p=0.017). Time to first pneumonia was prolonged with Ultibro Breezhalercompared to fluticasone/salmeterol (p=0.013).

In another study comparing Ultibro Breezhaler (n=258) and fluticasone/salmeterol (n=264), for26 weeks, the number of moderate or severe COPD exacerbations/patient-years was 0.15 versus 0.18(18 events versus 22 events), respectively (p=0.512), and the number of all COPDexacerbations/patients-years (mild, moderate or severe) was 0.72 versus 0.94 (86 events versus113 events), respectively (p=0.098).

Over 26 weeks, Ultibro Breezhaler statistically significantly reduced the use of rescue medication(salbutamol) by 0.96 puffs per day (p<0.001) compared to placebo, 0.54 puffs per day (p<0.001)compared to tiotropium and 0.39 puffs per day (p=0.019) compared to fluticasone/salmeterol. Over64 weeks, this reduction was 0.76 puffs per day (p<0.001) compared to tiotropium. Over 52 weeks,

Ultibro Breezhaler reduced the use of rescue medication by 0.25 puffs per day compared tofluticasone/salmeterol (p<0.001).

Exercise tolerance

Ultibro Breezhaler, dosed in the morning, reduced dynamic hyperinflation and improved the length oftime exercise could be maintained from the first dose onwards. On the first day of treatment,inspiratory capacity under exercise was significantly improved (LS mean treatment difference 250 ml,p<0.001) compared to placebo. After three weeks of treatment, the improvement in inspiratorycapacity with Ultibro Breezhaler was greater (LS mean treatment difference 320 ml, p<0.001) andexercise endurance time increased (LS mean treatment difference 59.5 seconds, p=0.006) compared toplacebo.

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

Ultibro Breezhaler in all subsets of the paediatric population in chronic obstructive pulmonary disease(COPD) (see section 4.2 for information on paediatric use).

Ultibro Breezhaler

Following inhalation of Ultibro Breezhaler, the median time to reach peak plasma concentrations ofindacaterol and glycopyrronium was approximately 15 minutes and 5 minutes, respectively.

Based on the in vitro performance data, the dose of indacaterol delivered to the lung is expected to besimilar for Ultibro Breezhaler and indacaterol monotherapy product. Steady-state exposure toindacaterol after Ultibro Breezhaler inhalation was either similar or slightly lower than systemicexposure after indacaterol monotherapy product inhalation.

Following inhalation of Ultibro Breezhaler, the absolute bioavailability of indacaterol has beenestimated to range from 61 to 85% of the delivered dose, and that of glycopyrronium was about 47%of the delivered dose.

Steady-state exposure to glycopyrronium after Ultibro Breezhaler inhalation was similar to systemicexposure after glycopyrronium monotherapy product inhalation.

Indacaterol

Steady state concentrations of indacaterol were achieved within 12 to 15 days following once-dailyadministration. The mean accumulation ratio of indacaterol, i.e. AUC over the 24-h dosing interval onday 14 or day 15 compared to day 1, was in the range of 2.9 to 3.8 for once-daily inhaled dosesbetween 60 micrograms and 480 micrograms (delivered dose).

In patients with COPD, pharmacokinetic steady-state of glycopyrronium was reached within one weekof the start of treatment. The steady-state mean peak and trough plasma concentrations ofglycopyrronium at the recommended once-daily dosing regimen were 166 picograms/ml and8 picograms/ml, respectively. Steady-state exposure to glycopyrronium (AUC over the 24-hour dosinginterval) was about 1.4- to 1.7-fold higher than after the first dose.

Indacaterol

After intravenous infusion the volume of distribution of indacaterol during the terminal eliminationphase was 2557 litres indicating an extensive distribution. The in vitro human serum and plasmaprotein binding was about 95%.

After intravenous dosing, the steady-state volume of distribution of glycopyrronium was 83 litres andthe volume of distribution in the terminal phase was 376 litres. The apparent volume of distribution inthe terminal phase following inhalation was almost 20-fold larger, which reflects the much slowerelimination after inhalation. The in vitro human plasma protein binding of glycopyrronium was 38%to 41% at concentrations of 1 to 10 nanograms/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, a N-glucuronide ofindacaterol, and C- and N-dealkylated products were further metabolites identified.

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.

Oxidative metabolites were found in incubations with recombinant CYP1A1, CYP2D6, and CYP3A4.

CYP3A4 is concluded to be the predominant isoenzyme responsible for hydroxylation of indacaterol.

In vitro investigations further indicated that indacaterol is a low affinity substrate for the efflux pump

P-gp.

In vitro metabolism studies showed consistent metabolic pathways for glycopyrronium bromidebetween animals and humans. Hydroxylation resulting in a variety of mono- and bis-hydroxylatedmetabolites and direct hydrolysis resulting in the formation of a carboxylic acid derivative (M9) wereseen. In vivo, M9 is formed from the swallowed dose fraction of inhaled glycopyrronium bromide.

Glucuronide and/or sulfate conjugates of glycopyrronium were found in urine of humans afterrepeated inhalation, accounting for about 3% of the delivered dose.

Multiple CYP isoenzymes contribute to the oxidative biotransformation of glycopyrronium. Inhibitionor induction of the metabolism of glycopyrronium is unlikely to result in a relevant change of systemicexposure to the active substance.

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 OCT1 or OCT2. In vitroenzyme induction studies did not indicate a clinically relevant induction by glycopyrronium bromidefor any of the cytochrome P450 isoenzymes tested or for UGT1A1 and the transporters MDR1 and

MRP2.

Indacaterol

In clinical studies, the amount of indacaterol excreted unchanged via urine was generally lower than2.5% of the delivered dose. Renal clearance of indacaterol was, on average, between 0.46 and1.2 litres/hour. When compared with the serum clearance of indacaterol of 23.3 litres/hour, it isevident that renal clearance plays a minor role (about 2 to 5% of systemic clearance) in the eliminationof systemically available indacaterol.

In a human ADME study, indacaterol given orally was excreted into human faeces primarily asunchanged parent substance (54% of the dose) and, to a lesser extent, hydroxylated indacaterolmetabolites (23% of the dose).

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 12-15 days.

After intravenous administration of [3H]-labelled glycopyrronium bromide, the mean urinary excretionof radioactivity in 48 hours amounted to 85% of the dose. A further 5% of the dose was found in thebile.

Renal elimination of parent drug accounts for about 60 to 70% of total clearance of systemicallyavailable glycopyrronium whereas non-renal clearance accounts 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 following inhalation was in the range of 17.4 and24.4 litres/h. Active tubular secretion contributes to the renal elimination of glycopyrronium. Up to23% of the delivered dose was found in urine 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 sustained lungabsorption and/or transfer of glycopyrronium into the systemic circulation at and beyond 24 h afterinhalation.

Indacaterol

Systemic exposure to indacaterol increased with increasing (delivered) dose (120 micrograms to480 micrograms) in a dose proportional manner.

In COPD patients both systemic exposure and total urinary excretion of glycopyrronium atpharmacokinetic steady state increased about dose-proportionally over the (delivered) dose range of 44to 176 micrograms.

Ultibro Breezhaler

A population pharmacokinetic analysis of data in COPD patients after inhalation of Ultibro Breezhalerindicated no significant effect of age, gender and (lean body) weight on the systemic exposure toindacaterol and glycopyrronium. Lean body weight (which is a function of weight and height) wasidentified as a covariate. A negative correlation between systemic exposure and lean body weight (orbody weight) was observed; however, no dose adjustment is recommended due to the magnitude of thechange or the predictive precision of lean body weight.

Smoking status and baseline FEV1 had no apparent effect on systemic exposure to indacaterol andglycopyrronium after inhalation of Ultibro Breezhaler.

Indacaterol

A population pharmacokinetic analysis showed that there is no clinically relevant effect of age (adultsup to 88 years), sex, weight (32-168 kg) or race on the pharmacokinetics of indacaterol. It did notsuggest any difference between ethnic subgroups in this population.

A population pharmacokinetic analysis of data in COPD patients identified body weight and age asfactors contributing to inter-patient variability in systemic exposure. Glycopyrronium at therecommended dose can be safely used in all age and body weight groups.

Gender, smoking status and baseline FEV1 had no apparent effect on systemic exposure.

Ultibro Breezhaler:

Based on the clinical pharmacokinetic characteristics of its monotherapy components, Ultibro

Breezhaler can be used at the recommended dose in patients with mild and moderate hepaticimpairment. No data are available for subjects with severe hepatic impairment.

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 have not been conducted in patients with hepatic impairment. 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 of systemicexposure.

Ultibro Breezhaler:

Based on the clinical pharmacokinetic characteristics of its monotherapy components, Ultibro

Breezhaler can be used at the recommended dose in patients with mild to moderate renal impairment.

In patients with severe renal impairment or end-stage renal disease requiring dialysis, Ultibro

Breezhaler should be used only if the expected benefit outweighs the potential risk.

Indacaterol:

Due to the very low contribution of the urinary pathway to total body elimination of indacaterolmaleate, a study in renal impaired subjects was not performed.

Renal impairment has an impact on the systemic exposure to glycopyrronium bromide. A moderatemean increase in total systemic exposure (AUClast) of up to 1.4-fold was seen in subjects with mild andmoderate renal impairment and up to 2.2-fold in subjects with severe renal impairment and end-stagerenal disease. In COPD patients with mild and moderate renal impairment (estimated glomerularfiltration rate, eGFR ≥30 ml/min/1.73 m2) glycopyrronium bromide can be used at the recommendeddose.

Ultibro Breezhaler:

There were no major differences in total systemic exposure (AUC) for both compounds between

Japanese and Caucasian subjects. Insufficient pharmacokinetic data is available for other ethnicities orraces.

Indacaterol:

No difference between ethnic subgroups was identified. Limited treatment experience is available forthe black population.

There were no major differences in total systemic exposure (AUC) between Japanese and Caucasiansubjects. Insufficient pharmacokinetic data is available for other ethnicities or races.

Ultibro Breezhaler

Pre-clinical studies included in vitro and in vivo safety pharmacology assessments, repeated-doseinhalation toxicity studies in rats and dogs and an inhalation embryo-foetal development study in rats.

Increased heart rates were apparent in dogs at all doses of Ultibro Breezhaler and each monotherapycomponent. The effects on heart rate for Ultibro Breezhaler increased in magnitude and duration whencompared with the changes observed for each component alone consistent with an additive response.

Shortening of electrocardiograph intervals and decreased systolic and diastolic blood pressure werealso apparent. Indacaterol administered to dogs alone or in Ultibro Breezhaler was associated with asimilar incidence and severity of myocardial lesions. Systemic exposures (AUC) at theno-observed-adverse-effect level (NOAEL) for myocardial lesions were 64- and 59-fold higher than inhumans, for each component respectively.

No effects on the embryo or foetus were seen at any dose level of Ultibro Breezhaler during anembryo-foetal development study in rats. Systemic exposures (AUC) at theno-observed-adverse-effect level (NOAEL) were 79- and 126-fold higher than in humans, forindacaterol and glycopyrronium respectively.

Indacaterol

Effects on the cardiovascular system attributable to the beta2-agonistic properties of indacaterolincluded tachycardia, arrhythmias and myocardial lesions in dogs. Mild irritancy of the nasal cavityand larynx were seen in rodents. All these findings occurred at exposures sufficiently in excess ofthose anticipated in humans.

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-developmental rat study atan exposure 14-fold higher than in humans treated with indacaterol. Indacaterol and its metabolitestransferred rapidly into the milk of lactating rats.Indacaterol was not embryotoxic or teratogenic in ratsor rabbits.

Genotoxicity studies did not reveal any mutagenic or clastogenic potential. Carcinogenicity wasassessed in a two-year rat study and a six-month transgenic mouse study. Increased incidences ofbenign ovarian leiomyoma and focal hyperplasia of ovarian smooth muscle in rats were consistentwith similar findings reported for other beta2-adrenergic agonists. No evidence of carcinogenicity wasseen in mice. Systemic exposures (AUC) in rats and mice at the no-observed-adverse-effect levels inthese studies were at least 7- and 49-fold higher, respectively, than in humans treated with indacaterolonce a day at the maximum recommended therapeutic dose.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproductionand development.

Effects attributable to the muscarinic receptor antagonist properties of glycopyrronium bromideincluded mild to moderate increases in heart rate in dogs, lens opacities in rats and, reversible changesassociated with 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.

Glycopyrronium was not teratogenic in rats or rabbits following inhalation administration. Fertilityand pre- and post-natal development were not affected in rats. Glycopyrronium bromide and itsmetabolites did not significantly cross the placental barrier of pregnant mice, rabbits and dogs.

Glycopyrronium bromide (including its metabolites) was excreted into the milk of lactating rats andreached up to 10-fold higher concentrations in the milk than in the blood of the dam.

Genotoxicity studies did not reveal any mutagenic or clastogenic potential for glycopyrroniumbromide. Carcinogenicity studies in transgenic mice using oral administration and in rats usinginhalation administration revealed no evidence of carcinogenicity at systemic exposures (AUC) ofapproximately 53-fold higher in mice and 75-fold higher in rats than the maximum recommended doseonce daily for humans.

Lactose monohydrate

Magnesium stearate

Not applicable.

2 years

The inhaler in each pack should be disposed of after all capsules in that pack have been used.

Do not store above 25°C.

The capsules must always be stored in the original blister to protect from moisture and only removedimmediately before use.

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 either 6 or 10 hard capsules.

Single pack containing 6x1, 10x1, 12x1, 30x1 or 90x1 hard capsules, together with 1 inhaler.

Multipacks containing 96 (4 packs of 24x1) hard capsules and 4 inhalers.

Multipacks containing 150 (15 packs of 10x1) hard capsules and 15 inhalers.

Multipacks containing 150 (25 packs of 6x1) hard capsules and 25 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 Ultibro 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.

You should hear a noise If there is powder left inas the capsule is pierced. the capsule:

Only pierce the capsule * Close the inhaler.once. * Repeat steps 3a to 3c.

Powder Emptyremaining

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.

Important Information

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

* Do not push the capsule

Step 1d:through the foil to

Insert capsuleremove it from the

Never place a capsuleblister.

directly into the

* Do not swallow themouthpiece.capsule.

* Do not use the Ultibro

Breezhaler capsules withany other inhaler.

* Do not use the Ultibro

Breezhaler inhaler totake any other capsulemedicine.

Step 1e: * Never place the capsule

Close inhaler into 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 Ultibro Breezhaler Inhaler pack contains: Frequently Asked Cleaning the inhaler

* One Ultibro Breezhaler inhaler Questions Wipe the mouthpiece

* One or more blister cards, each containing either inside and outside with a6 or 10 Ultibro Breezhaler capsules to be used in Why didn’t the inhaler clean, dry, lint-free cloth tothe inhaler Capsule Mouthpiece make a noise when I remove any powderchamber inhaled? residue. Keep the inhaler

Cap

The capsule may be stuck dry. Never wash your

Screen

Side in the capsule chamber. If inhaler with water.buttons this happens, carefully

Ba se Blister loosen the capsule by

Inhaler Inhaler base Blister cardtapping the base of theinhaler. Inhale themedicine again byrepeating steps 3a to 3c.

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 3c. and inhalers that are nol onger 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.

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

EU/1/13/862/001-008

Date of first authorisation: 19 September 2013

Date of latest renewal: 22 May 2018

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

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