4.1. Therapeutic indications

Symptomatic treatment of severe sialorrhoea (chronic pathological drooling) in children and adolescents aged 3 years and older with chronic neurological disorders.

4.2. Posology and method of administration

Sialanar should be prescribed by physicians experienced in the treatment of paediatric patients with neurological disorders.

Posology

Due to the lack of long-term safety data, Sialanar is recommended for short-term intermittent use (see section 4.4).

Paediatric population - children and adolescents aged 3 years and older

The dosing schedule for glycopyrronium is based on the weight of the child, starting with approximately 12.8 micrograms/kg per dose (equivalent to 16 micrograms/kg per dose glycopyrronium bromide), three times per day and increasing by the doses shown in Table 1 below, every 7 days. Dose titration should be continued until efficacy is balanced with undesirable effects and amended up or down, as appropriate, to a maximum individual dose of 64 micrograms/kg body weight glycopyrronium or 6 ml (1.9 mg glycopyrronium, equivalent to 2.4 mg glycopyrronium bromide) three times a day, whichever is less. Dose titrations should be conducted in discussion with the carer to assess both efficacy and undesirable effects until an acceptable maintenance dose is achieved.

Undesirable effects may be minimised by using the lowest effective dose necessary to control symptoms. It is important that the carer checks the dose volume in the syringe before administration. The maximum volume of the highest dose is 6 ml. In the event of a known anticholinergic adverse reaction occurring when the dose is increased, the dose should be reduced to the previous lower dose and the event monitored (see section 4.4). If the event does not resolve treatment should be discontinued. In the event of constipation, urinary retention or pneumonia (see section 4.8), treatment should be stopped and the prescribing physician contacted.

Younger children may be more susceptible to adverse reactions and this should be borne in mind when any dose adjustments are carried out.

Following the dose titration period, the child's sialorrhoea should be monitored, in conjunction with the carer at no longer than 3 monthly intervals, to assess changes in efficacy and/or tolerability over time, and the dose adjusted accordingly.

The Table 1 shows the dose in ml of solution to be given for each weight range at each dosing increase.

Table 1. Dosing table for children and adolescents with normal renal function

Weight

Dose level 1

Dose level 2

Dose level 3

Dose level 4

Dose level 5

Kg

(~12.8µg/kg)1

(~25.6µg/kg)1

(~38.4µg/kg)1

(~51.2µg/kg)1

(~64µg/kg)1

ml

ml

ml

ml

ml

13-17

0.6

1.2

1.8

2.4

3*

18-22

0.8

1.6

2.4

3.2

4*

23-27

1

2

3

4

5*

28-32

1.2

2.4

3.6

4.8

6*

33-37

1.4

2.8

4.2

5.6

6*

38-42

1.6

3.2

4.8

6*

6

43-47

1.8

3.6

5.4

6*

6

≥48

2

4

6*

6

6

1 refers to µg/kg glycopyrronium

*Maximum individual dose in this weight range

Special populations

Paediatric population (children aged < 3 years)

The safety and efficacy of glycopyrronium bromide in children aged from birth to < 3 years has not been established. No data are available.

Adult population

Sialanar is indicated for the paediatric population only. There is limited clinical trial evidence on the use of glycopyrronium in the adult population with pathological drooling.

Elderly

Sialanar is indicated for the paediatric population only. The elderly have a longer elimination half-life and reduced medicinal product clearance as well as limited data to support efficacy in short-term use. As such Sialanar should not be used in patients over the age of 65 years.

Hepatic impairment

Clinical studies have not been conducted in patients with hepatic impairment. Glycopyrronium is cleared predominantly from the systemic circulation by renal excretion and hepatic impairment is not thought to result in a clinically relevant increase in systemic exposure of glycopyrronium.

Renal impairment

Doses should be reduced by 30% in patients with mild to moderate renal impairment (eGFR <90 - ≥30 ml/min/1.73m2) (see Table 2). This medicinal product is contraindicated in patients with severe renal impairment (eGFR <30 ml/min/1.73m2), including those with end-stage renal disease requiring dialysis (see section 4.3).

Table 2. Dosing table for children and adolescents with mild to moderate renal impairment

Weight

Dose level 1

Dose level 2

Dose level 3

Dose level 4

Dose level 5

Kg

(~8.8µg/kg)1

(~17.6µg/kg)1

(~27.2µg/kg)1

(~36µg/kg)1

(~44.8µg/kg)1

ml

ml

ml

ml

ml

13-17

0.4

0.8

1.2

1.7

2.1*

18-22

0.6

1.1

1.7

2.2

2.8*

23-27

0.7

1.4

2.1

2.8

3.5*

28-32

0.8

1.7

2.5

3.4

4.2*

33-37

1

2

2.9

3.9

4.2*

38-42

1.1

2.2

3.4

4.2*

4.2

43-47

1.2

2.5

3.8

4.2*

4.2

≥48

1.4

2.8

4.2*

4.2

4.2

1 refers to µg/kg glycopyrronium

*Maximum individual dose in this weight range

Method of administration

For oral use only.

Co-administration with food results in a marked decrease in systemic medicinal product exposure (see section 5.2). Dosing should be at least one hour before or at least two hours after meals or at consistent times with respect to food intake. High fat food should be avoided. Where the child's specific needs determine that co-administration with food is required, dosing of the medicinal product should be consistently performed during food intake.

Insert the syringe adaptor into the neck of the bottle. Insert the end of the oral syringe into the syringe adaptor and ensure it is secure. Turn the bottle upside down. Gently pull down the plunger to the correct level (see Tables 1 and 2 for the correct dose). Turn the bottle upright. Remove the oral syringe. Place the oral syringe inside the child's mouth and press the plunger slowly to gently release the medicinal product. If the child is given the medicinal product through a feeding tube, flush the tube with 10 ml of water after you have given the medicinal product.

The oral syringe should be gently washed with warm water and allowed to dry after each use (i.e. three times per day). Do not use a dishwasher.

4.3. Contraindications

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

Pregnancy and breast-feeding.

Glaucoma.

Urinary retention.

Severe renal impairment (eGFR <30 ml/min/1.73m2), including those with end-stage renal disease requiring dialysis.

History of intestinal obstruction, ulcerative colitis, paralytic ileus, pyloric stenosis and myasthenia gravis.

Concomitant treatment with potassium chloride solid oral dose and anticholinergics (see section 4.5).

4.4. Special warnings and precautions for use

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:

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.

4.5. Interaction with other medicinal products and other forms of interaction

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.

4.6. Fertility, pregnancy and lactation

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).

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

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

Adverse reactions

Frequency category

Infections and infestations

Upper respiratory tract infection

Common

Pneumonia

Common

Urinary tract infection

Common

Psychiatric disorders

Irritability

Very common

Agitation

Common

Drowsiness

Common

Restlessness

Not known

Overactivity

Not known

Short attention span

Not known

Frustration

Not known

Mood variable

Not known

Temper tantrum

Not known

Intermittent explosive disorder

Not known

Sensitivity, shyness, and social withdrawal disorder specific to childhood or adolescence

Not known

Feeling sad

Not known

Crying

Not known

Fear

Not known

Nervous system disorders

Headache

Uncommon

Insomnia

Not known

Eye disorders

Mydriasis

Uncommon

Nystagmus

Uncommon

Angle-closure glaucoma

Not known

Photophobia

Not known

Dry eyes

Not known

Cardiac disorders

Flushing

Very common

Transient bradycardia

Not known

Respiratory, thoracic and mediastinal disorders

Nasal congestion

Very common

Epistaxis

Common

Reduced bronchial secretions

Very common

Sinusitis

Not known

Gastrointestinal disorders

Dry mouth

Very common

Constipation

Very common

Diarrhoea

Very common

Vomiting

Very common

Halitosis

Uncommon

Oesophageal candidiasis

Uncommon

Gastrointestinal motility disorder

Uncommon

Pseudo-obstruction

Uncommon

Nausea

Not known

Skin and subcutaneous tissue disorders

Rash

Common

Dryness of the skin

Not known

Inhibition of sweating

Not known

Renal and urinary disorders

Urinary retention

Very common

Urinary urgency

Not known

General disorders and administration site conditions

Pyrexia

Common

Dehydration

Uncommon

Thirst in hot weather

Uncommon

Angioedema

Not known

Allergic reaction

Not known

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:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

Overdose of glycopyrronium can result in anticholinergic syndrome, produced by the inhibition of cholinergic neurotransmission at muscarinic receptor sites. Clinical manifestations are caused by CNS effects, peripheral nervous system effects, or both. Common manifestations include flushing, dry skin and mucous membranes, mydriasis with loss of accommodation, altered mental status and fever. Additional manifestations include sinus tachycardia, decreased bowel sounds, functional ileus, urinary retention, hypertension, tremulousness and myoclonic jerking.

Management

Patients presenting with anticholinergic toxicity should be transported to the nearest emergency facility with advanced life support capabilities. Pre-hospital gastrointestinal decontamination with activated charcoal is not recommended because of the potential for somnolence and seizures and the resulting risk of pulmonary aspiration. At hospital, activated charcoal can be administered if the patient's airways can be adequately protected. Physostigmine salicylate is recommended when tachydysrhythmia with subsequent hemodynamic compromise, intractable seizure, severe agitation or psychosis is present.

Patients and/or parents/caregivers should be counselled to ensure an accurate dose is given each time, in order to prevent the harmful consequences of anticholinergic reactions of glycopyrronium seen with dosing errors or overdose.