BEVESPI AEROSPHERE Pressurised inhalation, suspension Ref.[51295] Active ingredients: Eformoterol Formoterol and Glycopyrronium bromide Glycopyrronium

Not for acute use

Bevespi Aerosphere is not indicated for the treatment of acute episodes of bronchospasm, i.e. as a rescue therapy.

Asthma

Bevespi Aerosphere should not be used to treat asthma.

Paradoxical bronchospasm

As with other inhalation therapy, administration of this medicinal product may result in paradoxical bronchospasm, which can be life-threatening. If paradoxical bronchospasm does occur, treatment with the medicinal product should be stopped and other treatments considered.

Cardiovascular effects

Cardiovascular effects, such as cardiac arrhythmias e.g. atrial fibrillation and tachycardia, may be seen after the administration of muscarinic receptor antagonists and sympathomimetics, including glycopyrronium or formoterol. Patients with clinically significant uncontrolled cardiovascular disease were excluded from clinical studies. Bevespi Aerosphere should be used with caution in patients with severe cardiovascular disorders, such as ischaemic heart disease, tachyarrhythmias or severe heart failure.

Caution should also be exercised in patients with thyrotoxicosis or known or suspected prolongation of the QTc interval (see section 4.5).

Hypokalaemia

β2-adrenergic agonists may produce significant hypokalaemia, which may increase the susceptibility to cardiac arrhythmias. 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 (see section 4.5).

Hyperglycaemia

Inhalation of high doses of β2-adrenergic agonists may produce increases in plasma glucose.

Anticholinergic activity

Due to its anticholinergic activity, Bevespi Aerosphere should be used with caution in patients with symptomatic prostatic hyperplasia, urinary retention or with narrow-angle glaucoma (see section 4.8).

Patients with severe renal impairment

As glycopyrronium is predominantly renally excreted, patients with severe renal impairment (creatinine clearance of <30 mL/min), including those with end-stage renal disease requiring dialysis, should only be treated with Bevespi Aerosphere if the expected benefit outweighs the potential risk (see section 5.2).

Patients with severe hepatic impairment

In patients with severe hepatic impairment, Bevespi Aerosphere should be used only if the expected benefit outweighs the potential risk (see section 5.2). These patients should be monitored for potential adverse reactions.

Pharmacokinetic interactions

No interaction studies have been performed with Bevespi Aerosphere; however, the potential for metabolic interactions is considered to be low based on in-vitro studies (see section 5.2).

Since glycopyrronium is eliminated mainly by the renal route, interactions could potentially occur with medicinal products affecting renal excretion mechanisms. In-vitro glycopyrronium is a substrate for the renal transporters OCT2 and MATE1/2K. The effect of cimetidine, a probe inhibitor of OCT2 and MATE1, on inhaled glycopyrronium disposition showed a limited increase in its total systemic exposure (AUC_0-t) by 22% and a slight decrease in renal clearance by 23% due to co-administration of cimetidine.

Pharmacodynamic interactions

Other antimuscarinics and sympathomimetics

Co-administration of Bevespi Aerosphere with other anticholinergic and/or long-acting β₂-adrenergic agonist containing medicinal products has not been studied and is not recommended as it may potentiate known inhaled muscarinic antagonist or β₂-adrenergic agonist adverse reactions (see sections 4.4 and 4.9).

Although no formal in-vivo interaction studies have been performed with Bevespi Aerosphere, studies indicate no clinical evidence of interactions when used concomitantly with other COPD medicinal products including short-acting β₂-adrenergic bronchodilators, methylxanthines, and oral and inhaled steroids.

Drug-induced hypokalaemia

Concomitant treatment with methylxanthine derivatives, steroids, or non-potassiumsparing diuretics may potentiate the possible initial hypokalaemic effect of β₂-adrenergic agonists, therefore, caution is advised in their concomitant use (see section 4.4).

β-adrenergic blockers

β-adrenergic blockers (including eye drops) can weaken or inhibit the effect of β₂-adrenergic agonists, such as formoterol. Concurrent use of either non-selective or selective β-adrenergic blockers should be avoided unless there are compelling reasons for their use. If β-adrenergic blockers are required (including eye drops), cardioselective β-adrenergic blockers are preferred, although they should also be administered with caution.

Other pharmacodynamic interactions

Bevespi Aerosphere should be administered with caution to patients being treated with medicinal products known to prolong the QTc interval (see section 4.4).

Pregnancy

There are no data on the use of Bevespi Aerosphere in pregnant women. Single-dose studies in humans found that very small amounts of glycopyrronium passed the placental barrier. In animal studies, formoterol and glycopyrronium, individually, have caused adverse effects in reproduction studies at very high doses/systemic exposure levels (see section 5.3).

Bevespi Aerosphere should only be used during pregnancy if the expected benefits outweigh the potential risks.

Breast-feeding

It is not known whether glycopyrronium or formoterol are excreted in human milk. Evidence of transfer of glycopyrronium and formoterol into maternal milk in rats has been reported.

Administration of Bevespi Aerosphere to women who are breast-feeding should only be considered if the expected benefit to the mother is greater than any possible risk to the infant (see section 5.3).

Fertility

Studies in rats have shown adverse effects on fertility only at dose levels higher than the maximum human exposure to formoterol (see section 5.3). Glycopyrronium did not cause any adverse effects on fertility in rats. It is unlikely that Bevespi Aerosphere administered at the recommended dose will affect fertility in humans.

Bevespi Aerosphere has no or negligible influence on the ability to drive and use machines. However dizziness and nausea are common side effects which should be taken into account when driving or using machines.

Summary of the safety profile

The safety profile is characterised by anticholinergic and β₂-adrenergic class effects related to the individual components of the combination. The most commonly reported adverse reactions in patients receiving Bevespi Aerosphere were headache (1.9%), nausea (1.4%), muscle spasms (1.4%), and dizziness (1.3%).

Tabulated list of adverse reactions

The tabulated list of adverse reactions is based on clinical trials and post-approval experience with Bevespi Aerosphere as well as experience with the individual components and related products.

The frequency of adverse reactions is defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) and not known (cannot be estimated from available data).

Table 1. Adverse reactions by frequency and system organ class (SOC):

¹ adverse reaction relates to formoterol
² adverse reaction relates to glycopyrronium

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.