Xoterna Breezhaler

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



 

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1. NAME OF THE MEDICINAL PRODUCT 
 

Xoterna Breezhaler 85 micrograms/43 micrograms inhalation powder hard capsules 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Each capsule contains 143 micrograms of indacaterol maleate equivalent to 110 micrograms of 

indacaterol and 63 micrograms of glycopyrronium bromide equivalent to 50 micrograms of 

glycopyrronium. 

 

Each delivered dose (the dose that leaves the mouthpiece of the inhaler) contains 110 micrograms of 

indacaterol  maleate equivalent to 85 micrograms of indacaterol and 54 micrograms of 

glycopyrronium bromide equivalent to 43 micrograms of glycopyrronium. 

 

Excipient(s) with known effect 

 

Each capsule contains 23.5 mg lactose (as monohydrate). 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Inhalation powder, hard capsule (inhalation powder). 

 

Capsules with transparent yellow cap and natural transparent body containing a white to almost white 

powder, with the product code “IGP110.50” printed in blue under two blue bars on the body and the 

company logo ( ) printed in black on the cap. 

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

Xoterna Breezhaler is indicated as a maintenance bronchodilator treatment to relieve symptoms in 

adult patients with chronic obstructive pulmonary disease (COPD). 

 

4.2 Posology and method of administration 

 

Posology 

 

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

Breezhaler inhaler. 

 

Xoterna Breezhaler is recommended to be administered at the same time of the day each day. If a dose 

is missed, it should be taken as soon as possible on the same day. Patients should be instructed not to 

take more than one dose in a day. 

 

Special populations 

 

Elderly population 

Xoterna Breezhaler can be used at the recommended dose in elderly patients (75 years of age and 

older). 

 

  



 

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Renal impairment 

Xoterna 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 it 

should be used only if the expected benefit outweighs the potential risk (see sections 4.4 and 5.2). 

 

Hepatic impairment 

Xoterna Breezhaler can be used at the recommended dose in patients with mild and moderate hepatic 

impairment. There are no data available for the use of Xoterna Breezhaler in patients with severe 

hepatic impairment, therefore caution should be observed in these patients (see section 5.2). 

 

Paediatric population 

There is no relevant use of Xoterna Breezhaler in the paediatric population (under 18 years) in the 

indication COPD. The safety and efficacy of Xoterna Breezhaler in children have not been established. 

No data are available. 

 

Method of administration 

 

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

 

The capsules must be administered only using the Xoterna Breezhaler inhaler (see section 6.6). The 

inhaler provided with each new prescription should be used. 

 

Patients should be instructed on how to administer the medicinal product correctly. Patients who do 

not experience improvement in breathing should be asked if they are swallowing the medicinal 

product rather than inhaling it. 

 

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

 

4.3 Contraindications 
 

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

 

4.4 Special warnings and precautions for use 

 

Xoterna Breezhaler should not be administered concomitantly with medicinal products containing 

other long-acting beta-adrenergic agonists or long-acting muscarinic antagonists, the 

pharmacotherapeutic groups to which the components of Xoterna Breezhaler belong (see section 4.5). 

 

Asthma 

 

Xoterna Breezhaler should not be used for the treatment of asthma due to the absence of data in this 

indication. 

 

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. 

 

Not for acute use 

 

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

 

Hypersensitivity 

 

Immediate hypersensitivity reactions have been reported after administration of indacaterol or 

glycopyrronium, which are the active substances of Xoterna Breezhaler. If signs suggesting allergic 

reactions occur, in particular, angioedema (difficulties in breathing or swallowing, swelling of the 

tongue, lips and face), urticaria or skin rash, treatment should be discontinued immediately and 

alternative therapy instituted. 



 

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Paradoxical bronchospasm 

 

Administration of Xoterna Breezhaler may result in paradoxical bronchospasm which can be 

life-threatening. If this occurs, treatment should be discontinued immediately and alternative therapy 

instituted. 

 

Anticholinergic effects related to glycopyrronium 

 

Narrow-angle glaucoma 

No data are available in patients with narrow-angle glaucoma, therefore Xoterna Breezhaler should be 

used with caution in these patients. 

 

Patients should be informed about the signs and symptoms of acute narrow-angle glaucoma and 

should be informed to stop using Xoterna Breezhaler should any of these signs or symptoms develop. 

 

Urinary retention 

No data are available in patients with urinary retention, therefore Xoterna Breezhaler should be used 

with 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 was 

seen in subjects with mild and moderate renal impairment and up to 2.2-fold in subjects with severe 

renal impairment and end-stage renal disease. In patients with severe renal impairment (estimated 

glomerular filtration rate below 30 ml/min/1.73 m2), including those with end-stage renal disease 

requiring dialysis, Xoterna Breezhaler should be used only if the expected benefit outweighs the 

potential risk (see section 5.2). These patients should be monitored closely for potential adverse 

reactions. 

 

Cardiovascular effects 

 

Xoterna Breezhaler should be used with caution in patients with cardiovascular disorders (coronary 

artery disease, acute myocardial infarction, cardiac arrhythmias, hypertension). 

 

Beta2-adrenergic agonists may produce a clinically significant cardiovascular effect in some patients 

as measured by increases in pulse rate, blood pressure, and/or symptoms. In case such effects occur 

with this medicinal product, treatment may need to be discontinued. In addition, beta-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, although the clinical significance of 

these observations is unknown. Therefore, long-acting beta2-adrenergic agonists (LABA) or 

LABA-containing combination products such as Xoterna Breezhaler should be used with caution in 

patients with known or suspected prolongation of the QT interval or treated with medicinal products 

affecting 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 therefore 

there is no experience in these patient groups. Xoterna Breezhaler should be used with caution in these 

patient groups. 

 

  



 

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Hypokalaemia 

 

Beta2-adrenergic agonists may produce significant hypokalaemia in some patients, which has the 

potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually 

transient, not requiring supplementation. In patients with severe COPD, hypokalaemia may be 

potentiated by hypoxia and concomitant treatment, which may increase the susceptibility to cardiac 

arrhythmias (see section 4.5). 

 

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

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

 

Hyperglycaemia 

 

Inhalation of high doses of beta2-adrenergic agonists may produce increases in plasma glucose. Upon 

initiation of treatment with Xoterna Breezhaler plasma glucose should be monitored more closely in 

diabetic patients. 

 

During long-term clinical studies, more patients on Xoterna Breezhaler experienced clinically notable 

changes in blood glucose (4.9%) at the recommended dose than on placebo (2.7%). Xoterna 

Breezhaler has not been investigated in patients for whom diabetes mellitus is not well controlled, 

therefore caution and appropriate monitoring are advised in such patients. 

 

General disorders 

 

Xoterna Breezhaler should be used with caution in patients with convulsive disorders or 

thyrotoxicosis, and in patients who are unusually responsive to beta2-adrenergic agonists. 

 

Excipients 

 

This medicinal product contains lactose. Patients with rare hereditary problems of galactose 

intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal 

product. 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

Concomitant administration of orally inhaled indacaterol and glycopyrronium, under steady-state 

conditions of both active substances, did not affect the pharmacokinetics of either active substance. 

 

No specific interaction studies were conducted with Xoterna Breezhaler. Information on the potential 

for interactions is based on the potential for each of its two active substances. 

 

Concomitant use not recommended 

 

Beta-adrenergic blockers 

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

Xoterna 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-adrenergic 

blockers should be preferred, although they should be administered with caution. 

 

Anticholinergics 

The co-administration of Xoterna Breezhaler with other anticholinergic-containing medicinal products 

has 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) may 

potentiate the adverse events of indacaterol (see section 4.4). 

 



 

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Caution required with concomitant use 

 

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), raises 

the systemic exposure of indacaterol up to two-fold. The magnitude of exposure increases due to 

interactions does not raise any safety concerns given the safety experience of treatment with 

indacaterol in clinical studies of up to one year at doses up to twice the maximum recommended 

indacaterol dose. 

 

Cimetidine or other inhibitors of organic cation transport 

In a clinical study in healthy volunteers, cimetidine, an inhibitor of organic cation transport which is 

thought to contribute to the renal excretion of glycopyrronium, increased total exposure (AUC) to 

glycopyrronium by 22% and decreased renal clearance by 23%. Based on the magnitude of these 

changes, no clinically relevant drug interaction is expected when glycopyrronium is co-administered 

with cimetidine or other inhibitors of the organic cation transport. 

 

4.6 Fertility, pregnancy and lactation 
 

Pregnancy 

 

There are no data from the use of Xoterna Breezhaler in pregnant women available. Animal studies do 

not indicate direct or indirect harmful effects with respect to reproductive toxicity at clinically relevant 

exposures (see section 5.3). 

 

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

Breezhaler should only be used during pregnancy if the expected benefit to the patient justifies the 

potential risk to the foetus. 

 

Breast-feeding 

 

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

Available pharmacokinetic/toxicological data have shown excretion of indacaterol, glycopyrronium 

and their metabolites in the milk of lactating rats. The use of Xoterna Breezhaler by breast-feeding 

women should only be considered if the expected benefit to the woman is greater than any possible 

risk to the infant (see section 5.3). 

 

Fertility 

 

Reproduction studies and other data in animals do not indicate a concern regarding fertility in either 

males or females. 

 

4.7 Effects on ability to drive and use machines 
 

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 (see 

section 4.8). 

 

  



 

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4.8 Undesirable effects 

 

The presentation of the safety profile is based on the experience with Xoterna Breezhaler and the 

individual active substances. 

 

Summary of the safety profile 

 

The safety experience with Xoterna Breezhaler was comprised of exposure of up to 15 months at the 

recommended therapeutic dose. 

 

Xoterna Breezhaler showed similar adverse reactions to the individual components. As it contains 

indacaterol and glycopyrronium, the type and severity of adverse reactions associated with each of 

these components may be expected in the combination. 

 

The safety profile is characterised by typical anticholinergic and beta-adrenergic symptoms related to 

the individual components of the combination. Other most common adverse reactions related to the 

medicinal product (at least 3% of patients for Xoterna Breezhaler and also greater than placebo) were 

cough, nasopharyngitis and headache. 

 

Tabulated summary of adverse reactions 

 

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 are 

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 corresponding frequency 

category 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 

Infections and infestations 

Upper respiratory tract infection Very common 

Nasopharyngitis Common 

Urinary tract infection Common 

Sinusitis Common 

Rhinitis Common 

Immune system disorders 

Hypersensitivity Common 

Angioedema2 Uncommon 

Metabolism and nutrition disorders 

Hyperglycaemia and diabetes mellitus Common 

Psychiatric disorders 

Insomnia Uncommon 

Nervous system disorders 

Dizziness Common 

Headache Common 

Paraesthesia Rare 

Eye disorders 

Glaucoma1 Uncommon 



 

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Cardiac disorders 

Ischaemic heart disease Uncommon 

Atrial fibrillation Uncommon 

Tachycardia Uncommon 

Palpitations Uncommon 

Respiratory, thoracic and mediastinal disorders 

Cough Common 

Oropharyngeal pain including throat irritation Common 

Paradoxical bronchospasm Uncommon 

Dysphonia2 Uncommon 

Epistaxis Uncommon 

Gastrointestinal disorders 

Dyspepsia Common 

Dental caries Common 

Gastroenteritis Uncommon 

Dry mouth Uncommon 

Skin and subcutaneous tissue disorders 

Pruritus/rash Uncommon 

Musculoskeletal and connective tissue disorders 

Musculoskeletal pain Uncommon 

Muscle spasm Uncommon 

Myalgia Uncommon 

Pain in extremity Uncommon 

Renal and urinary disorders 

Bladder obstruction and urinary retention Common 

General disorders and administration site conditions 

Pyrexia1 Common 

Chest pain Common 

Oedema peripheral Uncommon 

Fatigue Uncommon 
1 Adverse reaction observed with Xoterna Breezhaler, but not with the individual components. 
2 Reports received from post-marketing experience; frequencies calculated, however, on the basis of 

clinical trial data. 

 

Description of selected adverse reactions 

 

Cough was common, but usually of mild intensity. 

 

Reporting of suspected adverse reactions 

 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 

professionals are asked to report any suspected adverse reactions via the national reporting system 

listed in Appendix V. 

 

  



 

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4.9 Overdose 

 

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

 

An overdose could lead to exaggerated effects typical of beta2-adrenergic stimulants, i.e. tachycardia, 

tremor, palpitations, headache, nausea, vomiting, drowsiness, ventricular arrhythmias, metabolic 

acidosis, hypokalaemia and hyperglycaemia or could induce anticholinergic effects such as increased 

intraocular pressure (causing pain, vision disturbances or reddening of the eye), obstipation or 

difficulties in voiding. Supportive and symptomatic treatment is indicated. In serious cases, patients 

should 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 the 

use of beta-adrenergic blockers may provoke bronchospasm. 

 

 

5. PHARMACOLOGICAL PROPERTIES 
 

5.1 Pharmacodynamic properties 
 

Pharmacotherapeutic group: Drugs for obstructive airway diseases, adrenergics in combination with 

anticholinergics, ATC code: R03AL04 

 

Mechanism of action 

 

Xoterna Breezhaler 

When indacaterol and glycopyrronium are administered together in Xoterna Breezhaler, they provide 

additive efficacy due to their different mode of action targeting different receptors and pathways to 

achieve 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 relaxing 

peripheral 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 a 

beta2-adrenergic agonist and a muscarinic antagonist may be beneficial. 

 

Indacaterol 

Indacaterol is a long-acting beta2-adrenergic agonist for once-daily administration. The 

pharmacological effects of beta2-adrenoceptor agonists, including indacaterol, are at least in part 

attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyses the conversion of 

adenosine triphosphate (ATP) to cyclic-3’, 5’-adenosine monophosphate (cyclic AMP). Increased 

cyclic AMP levels cause relaxation of bronchial smooth muscle. In vitro studies have shown that 

indacaterol has multi-fold greater agonist activity at beta2-receptors compared to beta1 and 

beta3-receptors. 

 

When inhaled, indacaterol acts locally in the lung as a bronchodilator. Indacaterol is a partial agonist 

at the human beta2-adrenergic receptor with nanomolar potency. 

 

Although beta2-adrenergic receptors are the predominant adrenergic receptors in bronchial smooth 

muscle and beta1-adrenergic 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. Their presence in the heart raises the possibility that even highly selective beta2-adrenergic 

agonists may have cardiac effects. 

 

Glycopyrronium 

Glycopyrronium is an inhaled long-acting muscarinic receptor antagonist (anticholinergic) for 

once-daily maintenance bronchodilator treatment of COPD. Parasympathetic nerves are the major 

bronchoconstrictive neural pathway in airways, and cholinergic tone is the key reversible component 

of airflow obstruction in COPD. Glycopyrronium works by blocking the bronchoconstrictor action of 

acetylcholine on airway smooth muscle cells, thereby dilating the airways. 

 



 

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Glycopyrronium bromide is a high affinity muscarinic receptor antagonist. A greater than 4-fold 

selectivity for the human M3 receptors over the human M2 receptor has been demonstrated using 

radioligand binding studies. 

 

Pharmacodynamic effects 

 

The combination of indacaterol and glycopyrronium in Xoterna Breezhaler showed a rapid onset of 

action 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 after 

26 weeks of treatment. The effect was significantly greater for Xoterna Breezhaler, when compared to 

indacaterol, glycopyrronium or tiotropium alone (difference 110 ml, for each comparison). 

 

There was no evidence for tachyphylaxis to the effect of Xoterna Breezhaler over time when compared 

to placebo or its monotherapy components. 

 

Effects on heart rate 

Heart rate effects in healthy volunteers were investigated after a single dose of 4 times the 

recommended therapeutic dose of Xoterna Breezhaler administered in four dose steps each separated 

by 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 over 

time did not show a consistent pharmacodynamic effect of Xoterna Breezhaler. 

 

Heart rate in COPD patients at supratherapeutic dose levels was investigated. There were no relevant 

effects of Xoterna Breezhaler on mean heart rate over 24 h and heart rate assessed after 30 minutes, 

4 h and 24 h. 

 

QT interval 

A thorough QT (TQT) study in healthy volunteers with high doses of inhaled indacaterol (up to twice 

the 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 an 

inhaled dose of 8 times the recommended therapeutic dose. 

 

The effects of Xoterna Breezhaler on QTc interval were investigated in healthy volunteers after 

inhalation of Xoterna Breezhaler up to 4 times the recommended therapeutic dose in four dose steps 

each separated by one hour. The largest time-matched difference versus placebo was 4.62 ms (90% CI 

0.40, 8.85 ms), the largest time-matched decrease was -2.71 ms (90% CI -6.97, 1.54 ms), indicating 

that Xoterna Breezhaler had no relevant impact on the QT interval, as was expected by the properties 

of its components. 

 

In COPD patients, supratherapeutic doses between 116 micrograms/86 micrograms and 

464 micrograms/86 micrograms of Xoterna 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% for 

placebo), but there were no QTcF increases >60 ms from baseline. The highest dose level of 

464 micrograms/86 micrograms Xoterna Breezhaler also showed a higher proportion of absolute 

QTcF values >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 

Xoterna Breezhaler, the effect on serum potassium was very small (maximal difference –0.14 mmol/l 

when compared to placebo). The maximal effect on blood glucose was 0.67 mmol/l. 

 

  



 

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Clinical efficacy and safety 

 

The Xoterna Breezhaler clinical Phase III development programme included six studies in which over 

8,000 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 a 

history 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. 

 

Effects on lung function 

Xoterna Breezhaler showed clinically meaningful improvements in lung function (as measured by the 

forced 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 the 

24-hour dosing interval from the first dose. There was no attenuation of the bronchodilator effect over 

time. 

 

The magnitude of the effect was dependent on the degree of reversibility of airflow limitation at 

baseline (tested by administration of a short-acting muscarinic antagonist bronchodilator and a 

short-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 of 

reversibility at baseline (≥5%). At 26 weeks (primary endpoint), Xoterna Breezhaler increased trough 

FEV1 by 80 ml in patients (Xoterna Breezhaler n=82; placebo n=42) with the lowest degree of 

reversibility (<5%) (p=0.053) and by 220 ml in those patients (Xoterna Breezhaler n=392, placebo 

n=190) with a higher degree of reversibility at baseline (≥5%) compared to placebo (p<0.001). 

 

Trough and peak FEV1: 

Xoterna Breezhaler increased post-dose trough FEV1 by 200 ml compared to placebo at the 26-week 

primary endpoint (p<0.001) and showed statistically significant increases compared to each 

monotherapy component treatment arm (indacaterol and glycopyrronium) as well as the tiotropium 

treatment 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 

Xoterna Breezhaler – placebo 190 ml (p<0.001) 200 ml (p<0.001) 

Xoterna Breezhaler – indacaterol   80 ml (p<0.001)   70 ml (p<0.001) 

Xoterna Breezhaler – glycopyrronium   80 ml (p<0.001)   90 ml (p<0.001) 

Xoterna 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 morning 

dose of study medication) was statistically significant in favour of Xoterna Breezhaler at week 26 

compared to fluticasone/salmeterol (least squares [LS] mean treatment difference 100 ml, p<0.001), at 

week 52 compared to placebo (LS mean treatment difference 189 ml, p<0.001) and at all visits up to 

week 64 compared to glycopyrronium (LS mean treatment difference 70-80 ml, p<0.001) and 

tiotropium (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 Xoterna Breezhaler at all visits up to 

week 52 compared to fluticasone/salmeterol (LS mean treatment difference 62-86 ml, p<0.001). At 

week 26, Xoterna Breezhaler produced statistically significant improvement in peak FEV1 compared 

to placebo in the first 4 hours post dose (LS mean treatment difference 330 ml) (p<0.001). 

 



 

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FEV1 AUC: 

Xoterna 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: 

Xoterna Breezhaler statistically significantly reduced breathlessness as evaluated by the Transitional 

Dyspnoea Index (TDI); it demonstrated a statistically significant improvement in the TDI focal score 

at week 26 compared to placebo (LS mean treatment difference 1.09, p<0.001), tiotropium (LS mean 

treatment 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 Xoterna Breezhaler responded with 

a 1 point or greater improvement in the TDI focal score at week 26 compared to placebo (68.1% and 

57.5% respectively, p=0.004). A higher proportion of patients demonstrated clinically meaningful 

response at week 26 on Xoterna Breezhaler as compared to tiotropium (68.1% Xoterna Breezhaler 

versus 59.2% tiotropium, p=0.016) and fluticasone/salmeterol (65.1% Xoterna Breezhaler versus 

55.5% fluticasone/salmeterol, p=0.088). 

 

Health-related quality of life: 

Xoterna Breezhaler has also shown a statistically significant effect on health-related quality of life 

measured 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 and 

glycopyrronium were -1.09 and -1.18, respectively. At 64 weeks, the reduction compared to 

tiotropium 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 treatment 

difference -1.3, p=0.003). 

 

A higher percentage of patients receiving Xoterna Breezhaler responded with a clinically meaningful 

improvement in SGRQ score (defined as a decrease of at least 4 units from baseline) at week 26 

compared to placebo (63.7% and 56.6% respectively, p=0.088) and tiotropium (63.7% Xoterna 

Breezhaler vs. 56.4% tiotropium, p=0.047), at week 64 compared to glycopyrronium and tiotropium 

(57.3% Xoterna 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% Xoterna Breezhaler 

vs. 43.7% fluticasone/salmeterol, odds ratio: 1.30, p<0.001). 

 

Daily activities 

Xoterna Breezhaler demonstrated a statistically superior improvement versus tiotropium in the 

percentage of “days able to perform usual daily activities” over 26 weeks (LS mean treatment 

difference 8.45%, p<0.001). At week 64, Xoterna Breezhaler showed numerical improvement over 

glycopyrronium (LS mean treatment difference 1.95%; p=0.175) and statistical improvement over 

tiotropium (LS mean treatment difference 4.96%; p=0.001). 

 

COPD exacerbations 

In a 64-week study comparing Xoterna Breezhaler (n=729), glycopyrronium (n=739) and tiotropium 

(n=737), Xoterna Breezhaler reduced the annualised rate of moderate or severe COPD exacerbations 

by 12% compared to glycopyrronium (p=0.038) and by 10% compared to tiotropium (p=0.096). The 

number of moderate or severe COPD exacerbations/patient-years was 0.94 for Xoterna Breezhaler 

(812 events), 1.07 for glycopyrronium (900 events) and 1.06 for tiotropium (898 events). Xoterna 

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 to 

tiotropium (p=0.002). The number of all COPD exacerbations/patient-years was 3.34 for Xoterna 

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

(3,301 events). 

 

  



 

13 

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

Xoterna Breezhaler met the primary study objective of non-inferiority in rate of all COPD 

exacerbations (mild, moderate or severe) compared to fluticasone/salmeterol. The number of all 

COPD exacerbations/patient-years was 3.59 for Xoterna Breezhaler (4,531 events) and 4.03 for 

fluticasone/salmeterol (4,969 events). Xoterna Breezhaler further showed superiority in reducing the 

annualised rate of all exacerbations by 11% versus fluticasone/salmeterol (p=0.003). 

 

Compared to fluticasone/salmeterol, Xoterna Breezhaler reduced the annualised rate of both moderate 

or severe exacerbations by 17% (p<0.001), and of severe exacerbations (requiring hospitalisation) by 

13% (not statistically significant, p=0.231). The number of moderate or severe COPD 

exacerbations/patient-years was 0.98 for Xoterna Breezhaler (1,265 events) and 1.19 for 

fluticasone/salmeterol (1,452 events). Xoterna Breezhaler prolonged time to first moderate or severe 

exacerbation with a 22% reduction in risk of an exacerbation (p<0.001) and prolonged time to first 

severe exacerbation with a 19% reduction in risk of an exacerbation (p=0.046). 

 

The incidence of pneumonia was 3.2% in the Xoterna Breezhaler arm compared to 4.8% in the 

fluticasone/salmeterol arm (p=0.017). Time to first pneumonia was prolonged with Xoterna 

Breezhaler compared to fluticasone/salmeterol (p=0.013). 

 

In a another study comparing Xoterna Breezhaler (n=258) and fluticasone/salmeterol (n=264), for 

26 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 COPD 

exacerbations/patient-years (mild, moderate or severe) was 0.72 versus 0.94 (86 events versus 

113 events), respectively (p=0.098). 

 

Use of rescue medication 

Over 26 weeks, Xoterna 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. Over 

64 weeks, this reduction was 0.76 puffs per day (p<0.001) compared to tiotropium. Over 52 weeks, 

Xoterna Breezhaler reduced the use of rescue medication by 0.25 puffs per day compared to 

fluticasone/salmeterol (p<0.001). 

 

Exercise tolerance 

Xoterna Breezhaler, dosed in the morning, reduced dynamic hyperinflation and improved the length of 

time 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 inspiratory 

capacity with Xoterna Breezhaler was greater (LS mean treatment difference 320 ml, p<0.001) and 

exercise endurance time increased (LS mean treatment difference 59.5 seconds, p=0.006) compared to 

placebo. 

 

Paediatric population 

 

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

Xoterna Breezhaler in all subsets of the paediatric population in chronic obstructive pulmonary disease 

(COPD) (see section 4.2 for information on paediatric use). 

 

5.2 Pharmacokinetic properties 

 

Absorption 

 

Xoterna Breezhaler 

Following inhalation of Xoterna Breezhaler, the median time to reach peak plasma concentrations of 

indacaterol and glycopyrronium was approximately 15 minutes and 5 minutes, respectively. 

 

  



 

14 

Based on the in vitro performance data, the dose of indacaterol delivered to the lung is expected to be 

similar for Xoterna Breezhaler and indacaterol monotherapy product. Steady-state exposure to 

indacaterol after Xoterna Breezhaler inhalation was either similar or slightly lower than systemic 

exposure after indacaterol monotherapy product inhalation. 

 

Following inhalation of Xoterna Breezhaler, the absolute bioavailability of indacaterol has been 

estimated 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 Xoterna Breezhaler inhalation was similar to systemic 

exposure after glycopyrronium monotherapy product inhalation. 

 

Indacaterol 

Steady state concentrations of indacaterol were achieved within 12 to 15 days following once-daily 

administration. The mean accumulation ratio of indacaterol, i.e. AUC over the 24-h dosing interval on 

day 14 or day 15 compared to day 1, was in the range of 2.9 to 3.8 for once-daily inhaled doses 

between 60 micrograms and 480 micrograms (delivered dose). 

 

Glycopyrronium 

In patients with COPD, pharmacokinetic steady-state of glycopyrronium was reached within one week 

of the start of treatment. The steady-state mean peak and trough plasma concentrations of 

glycopyrronium at the recommended once-daily dosing regimen were 166 picrograms/ml and 

8 picograms/ml, respectively. Steady-state exposure to glycopyrronium (AUC over the 24-hour dosing 

interval) was about 1.4- to 1.7-fold higher than after the first dose. 

 

Distribution 

 

Indacaterol 

After intravenous infusion the volume of distribution of indacaterol during the terminal elimination 

phase was 2557 litres indicating an extensive distribution. The in vitro human serum and plasma 

protein binding was about 95%. 

 

Glycopyrronium 

After intravenous dosing, the steady-state volume of distribution of glycopyrronium was 83 litres and 

the volume of distribution in the terminal phase was 376 litres. The apparent volume of distribution in 

the terminal phase following inhalation was almost 20-fold larger, which reflects the much slower 

elimination after inhalation. The in vitro human plasma protein binding of glycopyrronium was 38% 

to 41% at concentrations of 1 to 10 nanograms/ml. 

 

Biotransformation 

 

Indacaterol 

After oral administration of radiolabelled indacaterol in a human ADME (absorption, distribution, 

metabolism, excretion) study, unchanged indacaterol was the main component in serum, accounting 

for about one third of total drug-related AUC over 24 hours. A hydroxylated derivative was the most 

prominent metabolite in serum. Phenolic O-glucuronides of indacaterol and hydroxylated indacaterol 

were further prominent metabolites. A diastereomer of the hydroxylated derivative, a N-glucuronide of 

indacaterol, 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, systemic 

exposure 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. 



 

15 

 

Glycopyrronium 

In vitro metabolism studies showed consistent metabolic pathways for glycopyrronium bromide 

between animals and humans. Hydroxylation resulting in a variety of mono- and bis-hydroxylated 

metabolites and direct hydrolysis resulting in the formation of a carboxylic acid derivative (M9) were 

seen. 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 after 

repeated inhalation, accounting for about 3% of the delivered dose. 

 

Multiple CYP isoenzymes contribute to the oxidative biotransformation of glycopyrronium. Inhibition 

or induction of the metabolism of glycopyrronium is unlikely to result in a relevant change of systemic 

exposure to the active substance. 

 

In vitro inhibition studies demonstrated that glycopyrronium bromide has no relevant capacity to 

inhibit CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4/5, the 

efflux transporters MDR1, MRP2 or MXR, and the uptake transporters OCT1 or OCT2. In vitro 

enzyme induction studies did not indicate a clinically relevant induction by glycopyrronium bromide 

for any of the cytochrome P450 isoenzymes tested or for UGT1A1 and the transporters MDR1 and 

MRP2. 

 

Elimination 

 

Indacaterol 

In clinical studies, the amount of indacaterol excreted unchanged via urine was generally lower than 

2.5% of the delivered dose. Renal clearance of indacaterol was, on average, between 0.46 and 

1.2 litres/hour. When compared with the serum clearance of indacaterol of 23.3 litres/hour, it is 

evident that renal clearance plays a minor role (about 2 to 5% of systemic clearance) in the elimination 

of systemically available indacaterol. 

 

In a human ADME study, indacaterol given orally was excreted into human faeces primarily as 

unchanged parent substance (54% of the dose) and, to a lesser extent, hydroxylated indacaterol 

metabolites (23% of the dose). 

 

Indacaterol serum concentrations declined in a multi-phasic manner with an average terminal half-life 

ranging from 45.5 to 126 hours. The effective half-life, calculated from the accumulation of 

indacaterol after repeated dosing ranged from 40 to 52 hours which is consistent with the observed 

time-to-steady state of approximately 12-15 days. 

 

Glycopyrronium 

After intravenous administration of [3H]-labelled glycopyrronium bromide, the mean urinary excretion 

of radioactivity in 48 hours amounted to 85% of the dose. A further 5% of the dose was found in the 

bile. 

 

Renal elimination of parent drug accounts for about 60 to 70% of total clearance of systemically 

available glycopyrronium whereas non-renal clearance accounts for about 30 to 40%. Biliary 

clearance contributes to the non-renal clearance, but the majority of non-renal clearance is thought to 

be due to metabolism. 

 

Mean renal clearance of glycopyrronium following inhalation was in the range of 17.4 and 

24.4 litres/h. Active tubular secretion contributes to the renal elimination of glycopyrronium. Up to 

23% of the delivered dose was found in urine as parent drug. 

 

Glycopyrronium plasma concentrations declined in a multi-phasic manner. The mean terminal 

elimination 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 lung 

absorption and/or transfer of glycopyrronium into the systemic circulation at and beyond 24 h after 

inhalation. 



 

16 

 

Linearity/non-linearity 

 

Indacaterol 

Systemic exposure to indacaterol increased with increasing (delivered) dose (120 micrograms to 

480 micrograms) in a dose proportional manner. 

 

Glycopyrronium 

In COPD patients both systemic exposure and total urinary excretion of glycopyrronium at 

pharmacokinetic steady state increased about dose-proportionally over the (delivered) dose range of 44 

to 176 micrograms. 

 

Special populations 

 

Xoterna Breezhaler 

A population pharmacokinetic analysis of data in COPD patients after inhalation of Xoterna 

Breezhaler indicated no significant effect of age, gender and (lean body) weight on the systemic 

exposure to indacaterol and glycopyrronium. Lean body weight (which is a function of weight and 

height) was identified as a covariate. A negative correlation between systemic exposure and lean body 

weight (or body weight) was observed; however, no dose adjustment is recommended due to the 

magnitude of the change or the predictive precision of lean body weight. 

 

Smoking status and baseline FEV1 had no apparent effect on systemic exposure to indacaterol and 

glycopyrronium after inhalation of Xoterna Breezhaler. 

 

Indacaterol 

A population pharmacokinetic analysis showed that there is no clinically relevant effect of age (adults 

up to 88 years), sex, weight (32-168 kg) or race on the pharmacokinetics of indacaterol. It did not 

suggest any difference between ethnic subgroups in this population. 

 

Glycopyrronium 

A population pharmacokinetic analysis of data in COPD patients identified body weight and age as 

factors contributing to inter-patient variability in systemic exposure. Glycopyrronium at the 

recommended 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. 

 

Patients with hepatic impairment 

Xoterna Breezhaler: 

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

Breezhaler can be used at the recommended dose in patients with mild and moderate hepatic 

impairment. 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 of 

indacaterol, nor did protein binding differ between mild and moderate hepatic impaired subjects and 

their healthy controls. Studies in subjects with severe hepatic impairment were not performed. 

 

Glycopyrronium: 

Clinical studies have not been conducted in patients with hepatic impairment. Glycopyrronium is 

cleared predominantly from the systemic circulation by renal excretion. Impairment of the hepatic 

metabolism of glycopyrronium is not thought to result in a clinically relevant increase of systemic 

exposure. 

 

  



 

17 

Patients with renal impairment 

Xoterna Breezhaler: 

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

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, Xoterna 

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 indacaterol 

maleate, a study in renal impaired subjects was not performed. 

 

Glycopyrronium: 

Renal impairment has an impact on the systemic exposure to glycopyrronium bromide. A moderate 

mean increase in total systemic exposure (AUClast) of up to 1.4-fold was seen in subjects with mild and 

moderate renal impairment and up to 2.2-fold in subjects with severe renal impairment and end-stage 

renal disease. In COPD patients with mild and moderate renal impairment (estimated glomerular 

filtration rate, eGFR ≥30 ml/min/1.73 m2) glycopyrronium bromide can be used at the recommended 

dose. 

 

Ethnicity 

 

Xoterna 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 or 

races. 

 

Indacaterol: 

No difference between ethnic subgroups was identified. Limited treatment experience is available for 

the black population. 

 

Glycopyrronium: 

There were no major differences in total systemic exposure (AUC) between Japanese and Caucasian 

subjects. Insufficient pharmacokinetic data is available for other ethnicities or races. 

 

5.3 Preclinical safety data 

 

Xoterna Breezhaler 

 

Pre-clinical studies included in vitro and in vivo safety pharmacology assessments, repeated-dose 

inhalation 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 Xoterna Breezhaler and each monotherapy 

component. The effects on heart rate for Xoterna Breezhaler increased in magnitude and duration 

when compared with the changes observed for each component alone consistent with an additive 

response. Shortening of electrocardiograph intervals and decreased systolic and diastolic blood 

pressure were also apparent. Indacaterol administered to dogs alone or in Xoterna Breezhaler was 

associated with a similar incidence and severity of myocardial lesions. Systemic exposures (AUC) at 

the no-observed-adverse-effect level (NOAEL) for myocardial lesions were 64- and 59-fold higher 

than in humans, for each component respectively. 

 

No effects on the embryo or foetus were seen at any dose level of Xoterna Breezhaler during an 

embryo-foetal development study in rats. Systemic exposures (AUC) at the 

no-observed-adverse-effect level (NOAEL) were 79- and 126-fold higher than in humans, for 

indacaterol and glycopyrronium respectively. 

 



 

18 

Indacaterol 

 

Effects on the cardiovascular system attributable to the beta2-agonistic properties of indacaterol 

included tachycardia, arrhythmias and myocardial lesions in dogs. Mild irritancy of the nasal cavity 

and larynx were seen in rodents. All these findings occurred at exposures sufficiently in excess of 

those anticipated in humans. 

 

Although indacaterol did not affect general reproductive performance in a rat fertility study, a decrease 

in the number of pregnant F1 offspring was observed in the peri- and post-developmental rat study at 

an exposure 14-fold higher than in humans treated with indacaterol. Indacaterol and its metabolites 

transferred rapidly into the milk of lactating rats.Indacaterol was not embryotoxic or teratogenic in rats 

or rabbits. 

 

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 in rats were consistent 

with similar findings reported for other beta2-adrenergic agonists. No evidence of carcinogenicity was 

seen in mice. Systemic exposures (AUC) in rats and mice at the no-observed-adverse-effect levels in 

these studies were at least 7- and 49-fold higher, respectively, than in humans treated with indacaterol 

once a day at the maximum recommended therapeutic dose. 

 

Glycopyrronium 

 

Non-clinical data reveal no special hazard for humans based on conventional studies of safety 

pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction 

and development. 

 

Effects attributable to the muscarinic receptor antagonist properties of glycopyrronium bromide 

included mild to moderate increases in heart rate in dogs, lens opacities in rats and, reversible changes 

associated with reduced glandular secretions in rats and dogs. Mild irritancy or adaptive changes in the 

respiratory tract were seen in rats. All these findings occurred at exposures sufficiently in excess of 

those anticipated in humans. 

 

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

and pre- and post-natal development were not affected in rats. Glycopyrronium bromide and its 

metabolites 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 and 

reached 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 glycopyrronium 

bromide. Carcinogenicity studies in transgenic mice using oral administration and in rats using 

inhalation administration revealed no evidence of carcinogenicity at systemic exposures (AUC) of 

approximately 53-fold higher in mice and 75-fold higher in rats than the maximum recommended dose 

once daily for humans. 

 

 

  



 

19 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Capsule content 

 

Lactose monohydrate 

Magnesium stearate 

 

6.2 Incompatibilities 
 

Not applicable. 

 

6.3 Shelf life 
 

2 years 

 

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

 

6.4 Special precautions for storage 

 

Do not store above 25°C. 

 

The capsules must always be stored in the original blister to protect from moisture and only removed 

immediately before use. 

 

6.5 Nature and contents of container 

 

Inhaler body and cap are made from acrylonitrile butadiene styrene, push buttons are made from 

methyl 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. 

 

6.6 Special precautions for disposal and other handling 
 

The inhaler provided with each new prescription should be used. The inhaler in each pack should be 

disposed of after all capsules in that pack have been used. 

 

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

requirements. 

 



 

20 

Instructions for handling and use 

 

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

  

 

 
  

 

 
Insert Pierce and release Inhale deeply Check capsule is empty 

 
  

 

 
   

 
   

  

 

 

 

 

 

 

 
Step 1a: 

Pull off cap 

Step 2a: 

Pierce capsule once 

Hold the inhaler upright. 

Pierce capsule by firmly 

pressing both side 

buttons at the same time. 

Step 3a: 

Breathe out fully 

Do not blow into the 

inhaler. 

Check capsule is empty 

Open the inhaler to see if 

any powder is left in the 

capsule. 

  

You should hear a noise 

as the capsule is pierced. 

Only pierce the capsule 

once. 

 

If there is powder left in 

the capsule: 

 Close the inhaler. 

 Repeat steps 3a to 3c. 

  
Powder Empty 

remaining 

 

Step 1b: 

Open inhaler 

 
Step 2b: 

Release side buttons 

Step 3b: 

Inhale medicine deeply 

Hold the inhaler as 

shown in the picture. 

Place the mouthpiece in 

your mouth and close 

your lips firmly around 

it. 

Do not press the side 

buttons. 

 

1 2 3 Check 



 

21 

  

  

 Breathe in quickly and as 

deeply as you can. 

During inhalation you 

will hear a whirring 

noise. 

You may taste the 

medicine as you inhale. 

 

Step 1c: 

Remove capsule 

Separate one of the 

blisters from the blister 

card. 

Peel open the blister and 

remove the capsule. 

Do not push the capsule 

through the foil. 

Do not swallow the 

capsule. 

 

 
Step 3c: 

Hold breath 

Hold your breath for up 

to 5 seconds. 

Remove empty capsule 

Put the empty capsule in 

your household waste. 

Close the inhaler and 

replace the cap. 

 
Step 1d: 

Insert capsule 

Never place a capsule 

directly into the 

mouthpiece. 

 

  Important Information 

 Xoterna Breezhaler 

capsules must always be 

stored in the blister card 

and only removed 

immediately before use. 

 Do not push the capsule 

through the foil to 

remove it from the 

blister. 

 Do not swallow the 

capsule. 

 Do not use the Xoterna 

Breezhaler capsules with 

any other inhaler. 

 Do not use the Xoterna 

Breezhaler inhaler to 

take any other capsule 

medicine. 

 Never place the capsule 

into your mouth or the 

mouthpiece of the 

inhaler. 

 Do not press the side 

buttons more than once. 

 Do not blow into the 

mouthpiece. 

 Do not press the side 

buttons while inhaling 

through the mouthpiece. 

 Do not handle capsules 

with wet hands. 

 Never wash your inhaler 

with water. 

 
Step 1e: 

Close inhaler 

 



 

22 

Your Xoterna Breezhaler Inhaler pack contains: 

 One Xoterna Breezhaler inhaler 

 One or more blister cards, each containing either 

6 or 10 Xoterna Breezhaler capsules to be used in 

the inhaler 

                  
 

 

 

Frequently Asked 

Questions 

 

Why didn’t the inhaler 

make a noise when I 

inhaled? 

The capsule may be stuck 

in the capsule chamber. If 

this happens, carefully 

loosen the capsule by 

tapping the base of the 

inhaler. Inhale the 

medicine again by 

repeating steps 3a to 3c. 

 

What should I do if there 

is powder left inside the 

capsule? 

You have not received 

enough of your medicine. 

Close the inhaler and 

repeat steps 3a to 3c. 

 

I coughed after inhaling 

– does this matter? 

This may happen. As long 

as the capsule is empty 

you have received enough 

of your medicine. 

 

I felt small pieces of the 

capsule on my tongue – 

does this matter? 

This can happen. It is not 

harmful. The chances of 

the capsule breaking into 

small pieces will be 

increased if the capsule is 

pierced more than once. 

Cleaning the inhaler 

Wipe the mouthpiece 

inside and outside with a 

clean, dry, lint-free cloth to 

remove any powder 

residue. Keep the inhaler 

dry. Never wash your 

inhaler with water. 

Disposing of the inhaler 

after use 

Each inhaler should be 

disposed of after all 

capsules have been used. 

Ask your pharmacist how 

to dispose of medicines 

and inhalers that are no 

longer required. 

 

 
 

7. MARKETING AUTHORISATION HOLDER 
 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

  

Base  

Side 

buttons 

Mouthpiece 

Blister 

Screen 

Capsule 

chamber 

Inhaler Inhaler base Blister card 



 

23 

8. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/13/863/001-008 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 

Date of first authorisation: 19 September 2013 

Date of latest renewal: 22 May 2018 

 

 

10. DATE OF REVISION OF THE TEXT 

 

 

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

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

 

  



 

24 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 

 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE 

SAFE AND EFFECTIVE USE OF THE MEDICINAL 

PRODUCT 

 



 

25 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer responsible for batch release 

 

Novartis Farmacéutica SA 

Ronda de Santa Maria 158 

08210 Barberà del Vallès, Barcelona 

Spain 

 

Novartis Pharma GmbH 

Roonstraße 25 

D-90429 Nuremberg 

Germany 

 

The printed package leaflet of the medicinal product must state the name and address of the 

manufacturer responsible for the release of the concerned batch. 
 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to medical prescription. 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

 Periodic safety update reports (PSURs) 
 

The requirements for submission of PSURs for this medicinal product are set out in the list of Union 

reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 

subsequent updates published on the European medicines web-portal. 

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

 Risk management plan (RMP) 
 

The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 

and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing 

authorisation and any agreed subsequent updates of the RMP. 

 

An updated RMP should be submitted: 

 At the request of the European Medicines Agency; 

 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 

an important (pharmacovigilance or risk minimisation) milestone being reached. 

 

  



 

26 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

  



 

27 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 
 

  



 

28 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON OF UNIT PACK 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Xoterna Breezhaler 85 micrograms/43 micrograms inhalation powder, hard capsules 

indacaterol/glycopyrronium 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each capsule contains 110 microgram indacaterol and 50 microgram glycopyrronium. The amount of 

indacaterol and glycopyrronium inhaled is 85 micrograms (equivalent to 110 micrograms of 

indacaterol maleate) and 43 micrograms (equivalent to 54 micrograms of glycopyrronium bromide), 

respectively. 

 

 

3. LIST OF EXCIPIENTS 

 

Also contains: lactose and magnesium stearate. 

See package leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Inhalation powder, hard capsule 

 

6 x 1 capsules + 1 inhaler 

10 x 1 capsules + 1 inhaler 

12 x 1 capsules + 1 inhaler 

30 x 1 capsules + 1 inhaler 

90 x 1 capsules + 1 inhaler 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

For use only with the inhaler provided in the pack. 

Do not swallow capsules. 

Read the package leaflet before use. 

Inhalation use 

Treatment for 90 days [90 x 1 capsules + 1 inhaler only]. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 



 

29 

8. EXPIRY DATE 

 

EXP 

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

 

 

9. SPECIAL STORAGE CONDITIONS 

 

Do not store above 25°C. 

Store the capsules in the original blister in order to protect from moisture and do not remove until 

immediately before use. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/13/863/001 6 capsules + 1 inhaler 

EU/1/13/863/007 10 capsules + 1 inhaler 

EU/1/13/863/002 12 capsules + 1 inhaler 

EU/1/13/863/003 30 capsules + 1 inhaler 

EU/1/13/863/004 90 capsules + 1 inhaler 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

 

  



 

30 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Xoterna Breezhaler 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC 

SN 

NN 

 



 

31 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON OF MULTIPACK (INCLUDING BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Xoterna Breezhaler 85 micrograms/43 micrograms inhalation powder, hard capsules 

indacaterol/glycopyrronium 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each capsule contains 110 microgram indacaterol and 50 microgram glycopyrronium. The amount of 

indacaterol and glycopyrronium inhaled is 85 micrograms (equivalent to 110 micrograms of 

indacaterol maleate) and 43 micrograms (equivalent to 54 micrograms of glycopyrronium bromide), 

respectively. 

 

 

3. LIST OF EXCIPIENTS 

 

Also contains: lactose and magnesium stearate. 

See package leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Inhalation powder, hard capsule 

 

Multipack: 96 (4 packs of 24 x 1) capsules + 4 inhalers. 

Multipack: 150 (15 packs of 10 x 1) capsules + 15 inhalers. 

Multipack: 150 (25 packs of 6 x 1) capsules + 25 inhalers. 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

For use only with the inhaler provided in the pack. 

Do not swallow capsules. 

Read the package leaflet before use. 

Inhalation use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 



 

32 

8. EXPIRY DATE 

 

EXP 

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

 

 

9. SPECIAL STORAGE CONDITIONS 

 

Do not store above 25°C. 

Store the capsules in the original blister in order to protect from moisture and do not remove until 

immediately before use. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/13/863/005 Multipack comprising 4 packs (24 capsules + 1 inhaler) 

EU/1/13/863/008 Multipack comprising 15 packs (10 capsules + 1 inhaler) 

EU/1/13/863/006 Multipack comprising 25 packs (6 capsules + 1 inhaler) 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

 

  



 

33 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Xoterna Breezhaler 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC 

SN 

NN 

 
  



 

34 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Xoterna Breezhaler 85 micrograms/43 micrograms inhalation powder, hard capsules 

indacaterol/glycopyrronium 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each capsule contains 110 microgram indacaterol and 50 microgram glycopyrronium. The amount of 

indacaterol and glycopyrronium inhaled is 85 micrograms (equivalent to 110 micrograms of 

indacaterol maleate) and 43 micrograms (equivalent to 54 micrograms of glycopyrronium bromide), 

respectively. 

 

 

3. LIST OF EXCIPIENTS 

 

Also contains: lactose and magnesium stearate. 

See package leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Inhalation powder, hard capsule 

 

24 x 1 capsules + 1 inhaler. Component of a multipack. Not to be sold separately. 

10 x 1 capsules + 1 inhaler. Component of a multipack. Not to be sold separately. 

6 x 1 capsules + 1 inhaler. Component of a multipack. Not to be sold separately. 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

For use only with the inhaler provided in the pack. 

Do not swallow capsules. 

Read the package leaflet before use. 

Inhalation use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 



 

35 

8. EXPIRY DATE 

 

EXP 

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

 

 

9. SPECIAL STORAGE CONDITIONS 

 

Do not store above 25°C. 

Store the capsules in the original blister in order to protect from moisture and do not remove until 

immediately before use. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/13/863/005 Multipack comprising 4 packs (24 capsules + 1 inhaler) 

EU/1/13/863/008 Multipack comprising 15 packs (10 capsules + 1 inhaler) 

EU/1/13/863/006 Multipack comprising 25 packs (6 capsules + 1 inhaler) 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

 

  



 

36 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Xoterna Breezhaler 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 
  



 

37 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

INNER LID OF OUTER CARTON OF UNIT PACK AND OF INTERMEDIATE CARTON OF 

MULTIPACK 

 

 

1. OTHER 

 

1  Insert 

2  Pierce and release 

3  Inhale deeply 

Check  Check capsule is empty 

 

Read the leaflet before use. 

  



 

38 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTERS 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Xoterna Breezhaler 85 mcg/43 mcg inhalation powder 

indacaterol/glycopyrronium 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

Inhalation use only 

 

  



 

39 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 



 

40 

Package leaflet: Information for the user 
 

Xoterna Breezhaler 85 micrograms/43 micrograms inhalation powder, hard capsules 

indacaterol/glycopyrronium 

 

Read all of this leaflet carefully before you start using this medicine because it contains 

important information for you. 
- Keep this leaflet. You may need to read it again. 

- If you have any further questions, ask your doctor, pharmacist or nurse. 

- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 

- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 

 

What is in this leaflet 
 

1. What Xoterna Breezhaler is and what it is used for 

2. What you need to know before you use Xoterna Breezhaler 

3. How to use Xoterna Breezhaler 

4. Possible side effects 

5. How to store Xoterna Breezhaler 

6. Contents of the pack and other information 

Instructions for use of Xoterna Breezhaler inhaler 

 

 

1. What Xoterna Breezhaler is and what it is used for 

 

What Xoterna Breezhaler is 

This medicine contains two active substances called indacaterol and glycopyrronium. These belong to 

a group of medicines called bronchodilators. 

 

What Xoterna Breezhaler is used for 

This medicine is used to make breathing easier for adult patients who have breathing difficulties due to 

a lung disease called chronic obstructive pulmonary disease (COPD). In COPD the muscles around the 

airways tighten. This makes breathing difficult. This medicine blocks the tightening of these muscles 

in the lungs, making it easier for air to get in and out of the lungs. 

 

If you use this medicine once a day, it will help to reduce the effects of COPD on your everyday life. 

 

 

2. What you need to know before you use Xoterna Breezhaler 
 

Do not use Xoterna Breezhaler 
- if you are allergic to indacaterol or glycopyrronium or any of the other ingredients of this 

medicine (listed in section 6). 

 

Warnings and precautions 
Talk to your doctor, pharmacist or nurse before using Xoterna Breezhaler if any of the following 

applies to you: 

- you have asthma - this medicine should not be used as a treatment for asthma. 

- you have heart problems. 

- you have seizure or fits. 

- you have thyroid gland problems (thyrotoxicosis). 

- you have diabetes. 

- you are using any medicines for your lung disease which contain active substances similar 

(same class) to those in Xoterna Breezhaler (see section “Other medicines and Xoterna 

Breezhaler”). 



 

41 

- you have kidney problems. 

- you have severe liver problems. 

- you have an eye problem called narrow-angle glaucoma. 

- you have difficulty passing urine. 

If any of the above applies to you (or you are not sure), talk to your doctor, pharmacist or nurse 

before using this medicine. 
 

During treatment with Xoterna Breezhaler 

- Stop using this medicine and seek medical help immediately if you experience any of the 

following: 

- eye pain or discomfort, temporary blurring of vision, visual halos or coloured images in 

association with red eyes – these may be signs of an acute attack of narrow-angle 

glaucoma. 

- difficulty breathing or swallowing, swelling of the tongue, lips or face, skin rash, itching 

and hives (signs of an allergic reaction). 

- tightness of the chest, coughing, wheezing or breathlessness immediately after using this 

medicine – these may be signs of a condition called paradoxical bronchospasm. 

- Tell your doctor immediately if your COPD symptoms such as breathlessness, wheezing or 

cough do not improve or get worse. 

 

Xoterna Breezhaler is used as an ongoing treatment for your COPD. Do not use this medicine to treat 

a sudden attack of breathlessness or wheezing. 

 

Children and adolescents 
Do not give this medicine to children or adolescents below the age of 18 years. This is because it has 

not been studied in this age group. 

 

Other medicines and Xoterna Breezhaler 

Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 

In particular, please tell your doctor or pharmacist if you are using: 

- any medicines that may be similar to Xoterna Breezhaler (contain similar active substances). 

- medicines called beta blockers that may be used for high blood pressure or other heart problems 

(such as propranolol), or for an eye problem called glaucoma (such as timolol). 

- medicines that lower the amount of potassium in your blood. These include: 

- steroids (such as prednisolone), 

- diuretics (water tablets) used for high blood pressure (such as hydrochlorothiazide), 

- medicines for breathing problems (such as theophylline). 

 

Pregnancy and breast-feeding 
There are no data on the use of this medicine in pregnant women and it is not known whether the 

active substances of this medicine pass into human milk. Indacaterol, one of the active substances in 

Xoterna Breezhaler, may prevent labour due to its effect on the uterus. 

 

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 

your doctor or pharmacist for advice before using this medicine. You should not use Xoterna 

Breezhaler unless your doctor tells you to do so. 

 

Driving and using machines 

It is unlikely that this medicine will affect your ability to drive and use machines. However, this 

medicine may cause dizziness (see section 4). If you feel dizzy while taking this medicine, do not 

drive or use machines. 

 

Xoterna Breezhaler contains lactose 

This medicine contains lactose (23.5 mg per capsule). If you have been told by your doctor that you 

have an intolerance to some sugars, contact your doctor before using this medicine. 

 

  



 

42 

Ask your doctor or pharmacist for advice before using any medicine. 

 

 

3. How to use Xoterna Breezhaler 

 

Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 

or pharmacist if you are not sure. 

 

How much Xoterna Breezhaler to use 

The usual dose is to inhale the content of one capsule each day. 

You only need to inhale once a day because the effect of this medicine lasts for 24 hours. Do not use 

more than your doctor tells you to use. 

 

Elderly (age 75 years and over) 

You can use this medicine if you are aged 75 years and over at the same dose as for other adults. 

 

When to inhale Xoterna Breezhaler 

Use this medicine at the same time each day. This will also help you to remember to use it. 

You can inhale Xoterna Breezhaler any time before or after food or drink. 

 

How to inhale Xoterna Breezhaler 

- Xoterna Breezhaler is for inhalation use. 

- In this pack, you will find an inhaler and capsules (in blisters) that contain the medicine as 

inhalation powder. Only use the capsules with the inhaler provided in this pack (Xoterna 

Breezhaler inhaler). The capsules should remain in the blister until you need to use them. 

- Peel the backing away from the blister to open it - do not push the capsule through the foil. 

- When you start a new pack, use the new Xoterna Breezhaler inhaler that is supplied in the pack. 

- Dispose of the inhaler ineach pack after all capsules in that pack have been used. 

- Do not swallow the capsules. 

- Please read the instructions at the end of this leaflet for more information on how to use the 

inhaler. 

 

If you use more Xoterna Breezhaler than you should 

If you have inhaled too much of this medicine or if someone else accidentally uses your capsules, you 

must immediately either tell your doctor or go to the nearest emergency unit. Show the pack of 

Xoterna Breezhaler. Medical attention may be needed. You may notice that your heart is beating faster 

than usual, or you may have a headache, feel drowsy, feel nauseous or have to vomit, or you may 

notice visual disturbances, feel constipated or have difficulty when passing urine. 

 

If you forget to use Xoterna Breezhaler 

If you forget to inhale a dose at the usual time, inhale one as soon as possible that day. Then, inhale 

the next dose as usual the next day. Do not inhale more than one dose on the same day. 

 

How long to continue your treatment with Xoterna Breezhaler 

 Keep using Xoterna Breezhaler for as long as your doctor tells you. 

 COPD is a long-term disease and you should use Xoterna Breezhaler every day and not only 

when you have breathing problems or other symptoms of COPD. 

If you have questions about how long to continue your treatment with this medicine, talk to your 

doctor or pharmacist. 

 

If you have further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 

 

 



 

43 

4. Possible side effects 

 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

 

Some side effects may be serious: 

 

Common (may affect up to 1 in 10 people) 

 difficulty breathing or swallowing, swelling of tongue, lips or face, urticaria, skin rash – these 

may be signs of an allergic reaction. 

 feeling tired or very thirsty, having an increased appetite without gaining weight and passing 

more urine than usual – these may be signs of high level of sugar in the blood (hyperglycaemia). 

 

Uncommon (may affect up to 1 in 100 people) 

 crushing chest pain with increased sweating – this may be a serious heart problem (ischaemic 

heart disease). 

 swelling mainly of the tongue, lips, face or throat (possible signs of angioedema). 

 difficulty breathing with wheezing or coughing. 

 eye pain or discomfort, temporary blurring of vision, visual halos or coloured images in 

association with red eyes – these may be signs of glaucoma. 

 irregular heartbeat. 

 

If you get any of these serious side effects, seek medical help immediately. 

 

Other side effects may include: 

 

Very common (may affect more than 1 in 10 people) 

 blocked nose, sneezing, cough, headache with or without fever - these may be signs of an upper 

respiratory tract infection. 

 

Common 

 combination of sore throat and runny nose - these may be signs of nasopharyngitis. 

 painful and frequent urination – these may be signs of a urinary tract infection called cystitis. 

 feeling of pressure or pain in the cheeks and forehead – these may be signs of inflammation of 

the sinuses called sinusitis. 

 runny or stuffy nose. 

 dizziness. 

 headache. 

 cough. 

 sore throat. 

 upset stomach, indigestion. 

 dental caries. 

 difficulty and pain when passing urine – these may be signs of a bladder obstruction or urinary 

retention. 

 fever. 

 chest pain. 

 

  



 

44 

Uncommon 

 difficulty sleeping. 

 fast heart beat. 

 palpitations – signs of abnormal heart beat. 

 voice alteration (hoarseness). 

 nose bleeds. 

 diarrhoea or stomach ache. 

 dry mouth. 

 itching or rash. 

 pain that affects the muscles, ligaments, tendons, joints and bones. 

 muscle spasm. 

 muscle pain, aches or tenderness. 

 pain in arms or legs. 

 swollen hands, ankles and feet. 

 tiredness. 

 

Rare (may affect up to 1 in 1000 people) 

 tingling or numbness. 

 

Reporting of side effects 

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. You can also report side effects directly via the national reporting 

system listed in Appendix V. By reporting side effects you can help provide more information on the 

safety of this medicine. 

 

 

5. How to store Xoterna Breezhaler 

 

Keep this medicine out of the sight and reach of children. 

 

Do not use this medicine after the expiry date which is stated on the carton and blister after “EXP”. 

The expiry date refers to the last day of that month. 

 

Do not store above 25°C. 

 

Store the capsules in the original blister in order to protect from moisture and do not remove until 

immediately before use. 

 

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

 

Do not use this medicine if you notice that the pack is damaged or shows signs of tampering. 

 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 

throw away medicines you no longer use. These measures will help protect the environment. 

 

 

  



 

45 

6. Contents of the pack and other information 

 

What Xoterna Breezhaler contains 

- The active substances are indacaterol (as maleate) and glycopyrronium bromide. Each capsule 

contains 143 micrograms of indacaterol maleate equivalent to 110 micrograms of indacaterol 

and 63 micrograms of glycopyrronium bromide equivalent to 50 micrograms of 

glycopyrronium. The delivered dose (the dose that leaves the mouthpiece of the inhaler) is 

equivalent to 85 micrograms of indacaterol (equivalent to 110 micrograms of indacaterol 

maleate) and 43 micrograms of glycopyrronium (equivalent to 54 micrograms of 

glycopyrronium bromide). 

- The other ingredients of the inhalation powder are lactose monohydrate and magnesium stearate 

(see section 2 under “Xoterna Breezhaler contains lactose”). 

 

What Xoterna Breezhaler looks like and contents of the pack 

 

Xoterna Breezhaler 85 micrograms/43 micrograms inhalation powder, hard capsules are transparent 

and yellow and contain a white to almost white powder. They have the product code “IGP110.50” 

printed in blue under two blue bars on the body and the company logo ( ) printed in black on the cap. 

 

In this pack, you will find a device called an inhaler together with capsules in blister strips. Each 

blister contains either 6 or 10 hard capsules. 

 

The following pack sizes are available: 

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 available in your country. 

 

Marketing Authorisation Holder 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

Manufacturer 

Novartis Farmacéutica SA 

Ronda de Santa Maria 158 

08210 Barberà del Vallès, Barcelona 

Spain 

 

Novartis Pharma GmbH 

Roonstraße 25 

D-90429 Nuremberg 

Germany 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

België/Belgique/Belgien 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Lietuva 

SIA „ovartis Baltics Lietuvos filialas 

Tel: +370 5 269 16 50 

 



 

46 

България 

Novartis Bulgaria EOOD 

Тел: +359 2 489 98 28 

 

Luxembourg/Luxemburg 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Česká republika 

Novartis s.r.o. 

Tel: +420 225 775 111 

 

Magyarország 

Novartis Hungária Kft. 

Tel.: +36 1 457 65 00 

Danmark 

Novartis Healthcare A/S 

Tlf: +45 39 16 84 00 

 

Malta 

Novartis Pharma Services Inc. 

Tel: +356 2122 2872 

Deutschland 

Novartis Pharma GmbH 

Tel: +49 911 273 0 

 

Nederland 

Novartis Pharma B.V. 

Tel: +31 88 04 52 111 

Eesti 

SIA Novartis Baltics Eesti filiaal 

Tel: +372 66 30 810 

 

Norge 

Novartis Norge AS 

Tlf: +47 23 05 20 00 

Ελλάδα 

Novartis (Hellas) A.E.B.E. 

Τηλ: +30 210 28 11 712 

ή 

INNOVIS PHARMA ΑΕΒΕ 

Τηλ: +30 210 66 64 805-6 

 

Österreich 

Novartis Pharma GmbH 

Tel: +43 1 86 6570 

España 

Ferrer Internacional, S.A. 

Tel: +34 93 600 37 00 

 

Polska 

Novartis Poland Sp. z o.o. 

Tel.: +48 22 375 4888 

France 

Novartis Pharma S.A.S. 

Tél: +33 1 55 47 66 00 

 

Portugal 

Laboratório Medinfar - Produtos Farmacêuticos, 

S.A. 

Tel: +351 21 499 7400 

Hrvatska 

Novartis Hrvatska d.o.o. 

Tel. +385 1 6274 220 

 

România 

Novartis Pharma Services Romania SRL 

Tel: +40 21 31299 01 

Ireland 

Novartis Ireland Limited 

Tel: +353 1 260 12 55 

 

Slovenija 

Novartis Pharma Services Inc. 

Tel: +386 1 300 75 50 

Ísland 

Vistor hf. 

Sími: +354 535 7000 

 

Slovenská republika 

Novartis Slovakia s.r.o. 

Tel: +421 2 5542 5439 

 

  



 

47 

Italia 

Alfasigma S.p.A. 

Tel: +39 06 91 39 4666 

Suomi/Finland 

Novartis Finland Oy 

Puh/Tel: +358 (0)10 6133 200 

 

Κύπρος 

Novartis Pharma Services Inc. 

Τηλ: +357 22 690 690 

 

Sverige 

Novartis Sverige AB 

Tel: +46 8 732 32 00 

 

Latvija 

SIA Novartis Baltics 

Tel: +371 67 887 070 

 

United Kingdom 

Novartis Pharmaceuticals UK Ltd. 

Tel: +44 1276 698370 

 

 

This leaflet was last revised in 

 

 

Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency web site: 

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

  



 

48 

 

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

 

 

 

 

Insert Pierce and release Inhale deeply Check capsule is empty 

 
  

 

 
   

 
   

  

 

  

 

  

 

 
Step 1a: 

Pull off cap 

Step 2a: 

Pierce capsule once 

Hold the inhaler upright. 

Pierce capsule by firmly 

pressing both side 

buttons at the same time. 

Step 3a: 

Breathe out fully 

Do not blow into the 

inhaler. 

Check capsule is empty 

Open the inhaler to see if 

any powder is left in the 

capsule. 

  

You should hear a noise 

as the capsule is pierced. 

Only pierce the capsule 

once. 

 

 

If there is powder left in 

the capsule: 

 Close the inhaler. 

 Repeat steps 3a to 3c. 

 
Powder Empty 

remaining 
 

Step 1b: 

Open inhaler 

  
Step 2b: 

Release side buttons 

Step 3b: 

Inhale medicine deeply 

Hold the inhaler as 

shown in the picture. 

Place the mouthpiece in 

your mouth and close 

your lips firmly around 

it. 

Do not press the side 

buttons. 

 

1 
 

2 
 

3 
 

Check 
 



 

49 

 

 

 Breathe in quickly and as 

deeply as you can. 

During inhalation you 

will hear a whirring 

noise. 

You may taste the 

medicine as you inhale. 

 

Step 1c: 

Remove capsule 

Separate one of the 

blisters from the blister 

card. 

Peel open the blister and 

remove the capsule. 

Do not push the capsule 

through the foil. 

Do not swallow the 

capsule. 

 

 
Step 3c: 

Hold breath 

Hold your breath for up 

to 5 seconds. 

Remove empty capsule 

Put the empty capsule in 

your household waste. 

Close the inhaler and 

replace the cap. 

 
Step 1d: 

Insert capsule 

Never place a capsule 

directly into the 

mouthpiece. 

 

  Important Information 

 Xoterna Breezhaler 

capsules must always be 

stored in the blister card 

and only removed 

immediately before use. 

 Do not push the capsule 

through the foil to 

remove it from the 

blister. 

 Do not swallow the 

capsule. 

 Do not use the Xoterna 

Breezhaler capsules with 

any other inhaler. 

 Do not use the Xoterna 

Breezhaler inhaler to 

take any other capsule 

medicine. 

 Never place the capsule 

into your mouth or the 

mouthpiece of the 

inhaler. 

 Do not press the side 

buttons more than once. 

 Do not blow into the 

mouthpiece. 

 Do not press the side 

buttons while inhaling 

through the mouthpiece. 

 Do not handle capsules 

with wet hands. 

 Never wash your inhaler 

with water. 

  
Step 1e: 

Close inhaler 

 



 

50 

Your Xoterna Breezhaler Inhaler pack contains: 

 One Xoterna Breezhaler inhaler 

 One or more blister cards, each containing either 

6 or 10 Xoterna Breezhaler capsules to be used in 

the inhaler 

 

                  
 

 

 

 

Frequently Asked 

Questions 

 

Why didn’t the inhaler 

make a noise when I 

inhaled? 

The capsule may be stuck 

in the capsule chamber. If 

this happens, carefully 

loosen the capsule by 

tapping the base of the 

inhaler. Inhale the 

medicine again by 

repeating steps 3a to 3c. 

 

What should I do if there 

is powder left inside the 

capsule? 

You have not received 

enough of your medicine. 

Close the inhaler and 

repeat steps 3a to 3c. 

 

I coughed after inhaling 

– does this matter? 

This may happen. As long 

as the capsule is empty 

you have received enough 

of your medicine. 

 

I felt small pieces of the 

capsule on my tongue – 

does this matter? 

This can happen. It is not 

harmful. The chances of 

the capsule breaking into 

small pieces will be 

increased if the capsule is 

pierced more than once. 

Cleaning the inhaler 

Wipe the mouthpiece 

inside and outside with a 

clean, dry, lint-free cloth to 

remove any powder 

residue. Keep the inhaler 

dry. Never wash your 

inhaler with water. 

Disposing of the inhaler 

after use 

Each inhaler should be 

disposed of after all 

capsules have been used. 

Ask your pharmacist how 

to dispose of medicines 

and inhalers that are no 

longer required. 

 

 

 

Base 

Cap 

Side 

buttons 

Mouthpiece 

Blister 

Screen 

Capsule 

chamber 

Inhaler Inhaler base Blister card 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET