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

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

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

Inhalation powder, hard capsule

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.

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

Posology

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

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

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

Renal impairment

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

Hepatic impairment

Ultibro 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 Ultibro 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 Ultibro Breezhaler in the paediatric population (under 18 years) in the indication COPD. The safety and efficacy of Ultibro 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 Ultibro Breezhaler inhaler (see section 6.6).

Patients should be instructed on how to administer the product correctly. Patients who do not experience improvement in breathing should be asked if they are swallowing the medicine rather than inhaling it.

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

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

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

Asthma

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

Long-acting beta_2-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

Ultibro 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 components of Ultibro 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

In clinical studies with Ultibro Breezhaler, paradoxical bronchospasm was not observed. However, paradoxical bronchospasm has been observed with other inhalation therapy and 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 Ultibro 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 Ultibro Breezhaler should any of these signs or symptoms develop.

Urinary retention

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

Ultibro 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 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. Ultibro 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 Ultibro 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 Ultibro Breezhaler plasma glucose should be monitored more closely in diabetic patients.

During clinical studies, more patients on Ultibro Breezhaler experienced clinically notable changes in blood glucose (4.1%) at the recommended dose than on placebo (2.3%). Ultibro Breezhaler has not been investigated in patients for whom diabetes mellitus is not well controlled.

General disorders

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

Excipients

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Concomitant administration of orally inhaled indacaterol and glycopyrronium, under steady-state conditions of both components, did not affect the pharmacokinetics of either component.

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

Concomitant use not recommended

Beta-adrenergic blockers

Beta-adrenergic blockers may weaken or antagonise the effect of beta₂-adrenergic agonists. Therefore Ultibro Breezhaler should not be given together with beta-adrenergic blockers (including eye drops) unless there are compelling reasons for their use. Where required, cardioselective beta-adrenergic blockers should be preferred, although they should be administered with caution.

Anticholinergics

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

Sympathomimetic agents

Concomitant administration of other sympathomimetic agents (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-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.

Pregnancy

There are no data from the use of Ultibro 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, Ultibro 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 Ultibro 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.