Glycopyrronium Other names: Glycopyrronium bromide

Inhalation use

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

Oral administration

Doses should be reduced by 30% in patients with mild to moderate renal impairment (eGFR <90 - ≥30 ml/min/1.73m²).

Dosing table for children and adolescents with mild to moderate renal impairment:

¹ refers to μg/kg glycopyrronium
^* Maximum individual dose in this weight range

Inhalation use

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, glycopyrronium should be used only if the expected benefit outweighs the potential risk. These patients should be monitored closely for potential adverse reactions.

Fertility

Oral administration

There are no data on the effects of glycopyrronium on male or female fertility. Reproductive performance in rats given glycopyrronium shows a decrease in the rate of conception and in survival rate at weaning. There are insufficient data in the public domain to adequately assess effects on the reproductive system in young adults.

Oral administration

Antimuscarinics such as glycopyrronium should be used with caution in patients with gastro-oesophageal reflux disease, pre-existing constipation and diarrhoea.

Inhalation use

Glycopyrronium bromide 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 glycopyrronium and to contact their doctor immediately should any of these signs or symptoms develop.

Inhalation use

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. Glycopyrronium should be used with caution in these patient groups.

Oral administration

Due to the low likelihood of benefit and the known adverse effect profile, glycopyrronium should not be given to children with mild to moderate sialorrhoea.

Oral administration

Glycopyrronium should be used with caution in patients with acute myocardial infarction, hypertension, coronary artery disease, cardiac arrhythmias and conditions characterised by tachycardia (including thyrotoxicosis, cardiac insufficiency, cardiac surgery) due to the potential increase in heart rate, blood pressure and rhythm disorders produced by its administration. The carer should be advised to measure the pulse rate if the child seems unwell and report very fast or very slow heart rate.

Oral administration

There are no data on the use of glycopyrronium in pregnant women. The assessment of reproductive endpoints for glycopyrronium is limited. Glycopyrronium is contraindicated during pregnancy.

Inhalation use

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

Oral administration

Safety in breast-feeding has not been established. Use while breast-feeding is contraindicated.

Inhalation use

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. 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.

Oral administration

Women of child-bearing potential

Effective contraception should be considered prior to treating women of childbearing age, where appropriate.

Fertility

There are no data on the effects of Sialanar on male or female fertility. Reproductive performance in rats given glycopyrronium shows a decrease in the rate of conception and in survival rate at weaning. There are insufficient data in the public domain to adequately assess effects on the reproductive system in young adults.

Inhalation use

Fertility

Reproduction studies and other data in animals do not indicate a concern regarding fertility in either males or females.

Oral administration

Glycopyrronium has moderate influence on the ability to drive and use machines. The anticholinergic effects of glycopyrronium may cause blurred vision, dizziness and other effects that may impair a patient's ability to perform skilled tasks such as driving, riding a bicycle and using machines. The undesirable effects are increased with increasing dose.

Inhalation use

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

Oral administration

Summary of the safety profile

Adverse reactions are common with glycopyrronium due to its known pharmacodynamic anticholinergic effects. The most common adverse reactions are dry mouth (11%), constipation (20%), diarrhoea (18%), vomiting (18%), urinary retention (15%), flushing (11%) and nasal congestion (11%).

Adverse reactions are more common with higher doses and prolonged use.

Tabulated list of adverse reactions

Adverse reactions reported in the literature for trials using glycopyrronium for sialorrhoea in the paediatric population (including 2 placebo controlled trials, an uncontrolled safety study using glycopyrronium for a 6 month period, and 3 supportive studies with adverse reaction data in the target population) are listed by MedDRA system organ class (Table 3). 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 3. List of adverse reactions:

Description of selected adverse reactions

Urinary retention

Urinary retention is a known adverse reaction associated with anticholinergic medicinal products (15%). Glycopyrronium treatment should be stopped until the urinary retention resolves.

Pneumonia

Pneumonia is a known adverse reaction associated with anticholinergic medicinal products (7.9%). Glycopyrronium treatment should be stopped until the pneumonia resolves.

Constipation

Constipation is a known adverse reaction associated with anticholinergic medicinal products (30%). Glycopyrronium treatment should be stopped until the constipation resolves.

Central nervous system

Although glycopyrronium has limited ability to cross the blood brain barrier, increased central nervous system effects have been reported in clinical trials (23%). Such effects should be discussed with the carer during treatment reviews and a dose reduction considered.

Cardiac disorders

Glycopyrronium is known to have an effect on heart rate and blood pressure at doses used during anaesthesia although clinical trials in children with chronic drooling have not shown this effect. An effect on the cardiovascular system should be considered when assessing tolerability.

Inhalation use

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 glycopyrronium. 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 glycopyrronium 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.