XOTERNA BREEZHALER Inhalation powder, hard capsule Ref.[51241] Active ingredients: Glycopyrronium Indacaterol Indacaterol and Glycopyrronium bromide

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.

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 (AUC_last) 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.

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.

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).

Caution required with concomitant use

Hypokalaemic treatment

Concomitant hypokalaemic treatment with methylxanthine derivatives, steroids, or non-potassiumsparing 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 gly

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.

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).

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:

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.

Not applicable.