SIALANAR Oral solution Ref.[27652] Active ingredients: Glycopyrronium

Anticholinergic effects

Anticholinergic effects such as urinary retention, constipation and overheating due to inhibition of sweating may be dose dependent and difficult to assess in a disabled child. Monitoring by physicians and caregivers is required with adherence to the management instructions below:

Management of important anticholinergic side effects

The carer should stop treatment and seek advice from the prescriber in the event of:

• constipation
• urinary retention
• pneumonia
• allergic reaction
• pyrexia
• very hot weather
• changes in behaviour

After evaluating the event, the prescriber will decide if treatment should remain stopped or if this should continue at a lower dose (see section 4.2).

Lack of long-term safety data

Published safety data are not available beyond 24 weeks treatment duration. Given the limited long-term safety data available and the uncertainties around the potential risk for carcinogenicity, total treatment duration should be kept as short as possible. If continuous treatment is needed (e.g. in a palliative setting) or the treatment is repeated intermittently (e.g. in the non palliative setting treating chronic disease) benefits and risks should be carefully considered on a case by case basis and treatment should be closely monitored.

Mild to moderate sialorrhoea

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

Cardiac disorders

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 (see section 4.8). The carer should be advised to measure the pulse rate if the child seems unwell and report very fast or very slow heart rate.

Gastro-intestinal disorders

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

Dental disorders

Since reduced salivation can increase the risk of oral cavities and periodontal diseases, it is important that patients receive adequate daily dental hygiene and regular dental health checks.

Respiratory disorders

Glycopyrronium can cause thickening of secretions, which may increase the risk of respiratory infection and pneumonia (see section 4.8). Glycopyrronium should be discontinued if pneumonia is present.

Central nervous system (CNS) adverse reactions

Increased CNS effects have been reported in clinical trials including: irritability, drowsiness, restlessness, overactivity, short attention span, frustration, mood changes, temper outbursts or explosive behaviour, excessive sensitivity, seriousness or sadness, frequent crying episodes and fearfulness (see section 4.8). Behavioural changes should be monitored.

As a consequence of its quaternary charge glycopyrronium has limited ability to penetrate the blood brain barrier, although the extent of penetration is unknown. Caution should be exercised in children with compromised blood brain barrier, e.g. intraventricular shunt, brain tumour, encephalitis.

Children below the age of 3 years

Sialanar is not recommended in children below the age of 3 years since there is very limited data on the efficacy and safety of glycopyrronium in this age group.

Excipients with known effect

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per maximum dose, that is to say essentially ‘sodium free’.

Sodium benzoate

This medicinal product contains 2.3 mg sodium benzoate (E211) in each ml.

No interaction studies have been performed.

Paediatric population

There are limited data available relating to interactions with other medicinal products in the paediatric age group.

The following medicinal product interaction information is relevant to glycopyrronium.

Contraindications of concomitant use (see section 4.3)

Potassium chloride solid oral dose

Glycopyrronium may potentiate the risk of upper gastrointestinal injury associated with oral solid formulations of potassium chloride due to increased gastrointestinal transit time creating a high localized concentration of potassium ions. An association with upper gastrointestinal bleeding and small bowel ulceration, stenosis, perforation, and obstruction has been observed.

Anticholinergics

Concomitant use of anticholinergics may increase the risk of anticholinergic side effects. Anticholinergics may delay the gastrointestinal absorption of other anticholinergics administered orally and also increase the risk of anticholinergic side effects.

Concomitant use to be considered with caution

Antispasmodics

Glycopyrronium may antagonize the pharmacologic effects of gastrointestinal prokinetic active substances such as domperidone and metoclopramide.

Topiramate

Glycopyrronium may potentiate the effects of oligohidrosis and hyperthermia associated with the use of topiramate, particularly in pediatric patients.

Sedating antihistamines

Sedating antihistamines may have additive anticholinergic effects. A reduction in anticholinergic and/or antihistamine dose may be necessary.

Neuroleptics/antipsychotics

The effects of active substances such as phenothiazines, clozapine and haloperidol may be potentiated. A reduction in anticholinergic and/or neuroleptic/antipsychotic dose may be necessary.

Skeletal muscle relaxants

Use of anticholinergics after administration of botulinum toxin may potentiate systemic anticholinergic effects.

Tricyclic antidepressants and MAOIs

Tricyclic antidepressants and MAOIs may have additive anticholinergic effects. A reduction in anticholinergic and/or tricyclic antidepressants and MAOIs dose may be necessary.

Opioids

Active substances such as pethidine and codeine may result in additive central nervous system and gastrointestinal adverse effects, and increase the risk of severe constipation or paralytic ileus and CNS depression. If concomitant use cannot be avoided, patients should be monitored for potentially excessive or prolonged CNS depression and constipation.

Corticosteroids

Steroid-induced glaucoma may develop with topical, inhaled, oral or intravenous, steroid administration. Concomitant use may result in increased intraocular pressure via an open- or a closed-angle mechanism.

Other

Medicinal products with anticholinergic properties (e.g. antihistamines, antidepressants) may cause cumulative parasympatholytic effects including dry mouth, urinary retention, constipation and confusion, and an increased risk of anticholinergic intoxication syndrome.

Women of child-bearing potential

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

Pregnancy

There are no data on the use of Sialanar in pregnant women. The assessment of reproductive endpoints for glycopyrronium is limited (see section 5.3). Glycopyrronium is contraindicated during pregnancy (see section 4.3).

Breast-feeding

Safety in breast-feeding has not been established. Use while breast-feeding is contraindicated (see section 4.3).

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 (see section 5.3).

Sialanar 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.

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 (see section 4.4).

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 (see section 4.4).

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.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.