TOVANOR Inhalation powder, hard capsule Ref.[6836] Active ingredients: Glycopyrronium

Not for acute use

Tovanor Breezhaler is a once-daily, long-term maintenance treatment and is not indicated for the initial treatment of acute episodes of bronchospasm, i.e. as a rescue therapy.

Hypersensitivity

Immediate hypersensitivity reactions have been reported after administration of Tovanor Breezhaler. If signs suggesting allergic reactions occur, in particular, angioedema (including 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 Tovanor 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 effect

Tovanor Breezhaler should be used with caution in patients with narrow-angle glaucoma or urinary retention.

Patients should be informed about the signs and symptoms of acute narrow-angle glaucoma and should be informed to stop using Tovanor Breezhaler and to contact their doctor immediately should any of these signs or symptoms develop.

Patients with severe renal impairment

A moderate mean increase in total systemic exposure (AUC_last) 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, Tovanor 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.

Patients with a history of cardiovascular disease

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 for males or >470 ms for females) were excluded from the clinical trials, and therefore the experience in these patient groups is limited. Tovanor Breezhaler should be used with caution in these patient groups.

Excipients

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

The co-administration of Tovanor Breezhaler with other anticholinergic-containing medicinal products has not been studied and is therefore not recommended.

Although no formal drug interaction studies have been performed, Tovanor Breezhaler has been used concomitantly with other medicinal products commonly used in the treatment of COPD without clinical evidence of drug interactions. These include sympathomimetic bronchodilators, methylxanthines, and oral and inhaled steroids.

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 organic cation transport.

Concomitant administration of glycopyrronium and orally inhaled indacaterol, a beta₂-adrenergic agonist, under steady-state conditions of both active substances did not affect the pharmacokinetics of either medicinal product.

Pregnancy

There are no data from the use of Tovanor Breezhaler in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). Glycopyrronium should only be used during pregnancy if the expected benefit to the patient justifies the potential risk to the foetus.

Breast-feeding

It is unknown whether glycopyrronium bromide is excreted in human milk. However, glycopyrronium bromide (including its metabolites) was excreted in the milk of lactating rats (see section 5.3). The use of glycopyrronium 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 (see section 5.3).

Glycopyrronium has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most common anticholinergic adverse reaction was dry mouth (2.4%). The majority of the reports of dry mouth were suspected to be related to the medicinal product and were mild, with none being severe.

The safety profile is further characterised by other symptoms related to the anticholinergic effects, including signs of urinary retention, which were uncommon. Gastrointestinal effects including gastroenteritis and dyspepsia were also observed. Adverse reactions related to local tolerability included throat irritation, nasopharyngitis, rhinitis and sinusitis.

Tabulated summary of adverse reactions

Adverse reactions reported during the first six months of two pooled pivotal Phase III trials of 6 and 12 months duration 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 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Table 1. Adverse reactions:

¹ More frequent for glycopyrronium than placebo in the 12 months database only.
² Reports have been received from post-approval marketing experience in association with the use of Tovanor Breezhaler. These were reported voluntarily from a population of uncertain size, and it is therefore not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Therefore the frequency was calculated from clinical trial experience.
³ Seen more frequently for glycopyrronium than placebo in elderly >75 years only.

Description of selected adverse reactions

In the pooled 6-month database the frequency of dry mouth was 2.2% versus 1.1%, of insomnia 1.0% versus 0.8%, and of gastroenteritis 1.4% versus 0.9%, for Tovanor Breezhaler and placebo respectively.

Dry mouth was reported mainly during the first 4 weeks of treatment with a median duration of four weeks in the majority of patients. However in 40% of cases symptoms continued for the entire 6-month period. No new cases of dry mouth were reported in months 7-12.

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.