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

Posology

Glycopyrronium Bromide is recommended for short-term intermittent use (see section 4.4 and 5.1)

The dosage must be measured and administered with the graduated syringe included in the pack.

The dosing schedule for Glycopyrronium Bromide is based on the weight of the child with the initial dosing of 0.02 mg/kg to be given orally three times daily and titrate in increments of 0.02 mg/kg every 5-7 days based on therapeutic response and adverse reactions.

The maximum recommended dosage is 0.1 mg/kg three times daily not to exceed 1.5-3 mg per dose based upon weight. For greater detail, see Table 1.

During the four-week titration period, dosing can be increased with the recommended dose titration schedule while ensuring that the anticholinergic adverse events are tolerable. Prior to each increase in dose, review the tolerability of the current dose level with the patient's caregiver.

In the event of a known anticholinergic adverse event (AE) occurring when the dose is increased, the dose should be reduced to the previous lower dose and the event monitored. If the AE does not resolve treatment should be discontinued.

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

Table 1: Dosing tables for children and adolescents aged 3 years and older

Weight

Dose Level 1

Dose Level 2

Dose Level 3

Dose Level 4

Dose Level 5

kg

(~0.02 mg/kg)

(~0.04 mg/kg)

(~0.06 mg/kg)

(~0.08 mg/kg)

(~0.1 mg/kg)

13-17

0.3 mg

1.5 ml

0.6 mg

3 ml

0.9 mg

4.5 ml

1.2 mg

6 ml

1.5 mg

7.5 ml

18-22

0.4 mg

2 ml

0.8 mg

4 ml

1.2 mg

6 ml

1.6 mg

8 ml

2.0 mg

10 ml

23-27

0.5 mg

2.5 ml

1.0 mg

5 ml

1.5 mg

7.5 ml

2.0 mg

10 ml

2.5 mg

12.5 ml

28-32

0.6 mg

3 ml

1.2 mg

6 ml

1.8 mg

9 ml

2.4 mg

12 ml

3.0 mg

15 ml

33-37

0.7 mg

3.5 ml

1.4 mg

7 ml

2.1 mg

10.5 ml

2.8 mg

14 ml

3.0 mg

15 ml

38-42

0.8 mg

4 ml

1.6 mg

8 ml

2.4 mg

12 ml

3.0 mg

15 ml

3.0 mg

15 ml

43-47

0.9 mg

4.5 ml

1.8 mg

9 ml

2.7 mg

13.5 ml

3.0 mg

15 ml

3.0 mg

15 ml

≥48

1.0 mg

5 ml

2.0 mg

10 ml

3.0 mg

15 ml

3.0 mg

15 ml

3.0 mg

15 ml

Glycopyrronium Bromide is not recommended for use in children younger than 3 years.

Adult population

There is limited clinical evidence on the use of glycopyrronium in the adult population with pathological drooling.

Elderly population

Glycopyrronium Bromide 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 this medicine should not be used in patients over the age of 65 years.

Hepatic Impairment

Clinical studies have not been evaluated in patients with hepatic impairment. Glycopyrrolate is eliminated largely from the renal excretion and hepatic impairment is not thought to result in an increase in a systemic exposure of Glycopyrronium.

Renal impairment

Elimination of glycopyrronium is severely impaired in patients with mild to moderate renal impairment (eGFR <90 - ≥ 30 ml/min/1.73m2) therefore doses should be reduced by 30% (see Table 2). This medicine is contraindicated in severe renal impairment (eGFR < 30 ml/min/1. 73m2) (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

(~0.01 mg/kg)*

(~0.03 mg/kg)*

(~0.04 mg/kg)*

(~0.06 mg/kg)*

(~0.07 mg/kg)*

13-17

1.1 ml

2.1 ml

3.2 ml

4.2 ml

5.3 ml1

18-22

1.4 ml

2.8 ml

4.2 ml

5.6 ml

7.0 ml1

23-27

1.8 ml

3.5 ml

5.3 ml

7.0 ml

8.8 ml1

28-32

2.1 ml

4.2 ml

6.3 ml

8.4 ml

10.5 ml1

33-37

2.5 ml

4.9 ml

7.4 ml

9.8 ml

10.5 ml1

38-42

2.8 ml

5.6 ml

8.4 ml

10.5 ml1

10.5 ml

43-47

3.2 ml

6.3 ml

9.5 ml

10.5 ml1

10.5 ml

≥48

3.5 ml

7.0 ml

10.5 ml

10.5 ml

10.5 ml

*refers to mg/kg glycopyrronium bromide

1Maximum individual dose in this weight range

Administration with food

High fat food should be avoided. The presence of high fat food reduces the oral bioavailability of Glycopyrronium Bromide if given shortly after a meal. Therefore, it should be given at least one hour before or two hours after meals. If the patient's specific needs determine that co-administration with food is required, dosing of the medicinal product should be consistently performed during food intake (see section 5.2).

Method of administration

Glycopyrronium bromide products with different strengths are available. Proper dose adjustment is required, if switching products, to avoid overdose and anticholinergic toxicity (see section 4.8 and 4.9).

For oral use and use with nasogastric and or PEG tubes.

The correct quantity of Glycopyrronium Bromide should be measured and administered using the syringe included in the pack.

Nasogastric feeding tubes, if used, should be flushed with 20 ml of water immediately after dosing. See Section 6.6 for instructions for use.

4.3. Contraindications

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

In common with other antimuscarinics:

• Angle-closure glaucoma

• Myasthenia gravis (large doses of quaternary ammonium compounds have been shown to antagonise end plate nicotinic receptors)

• Pyloric stenosis

• Paralytic ileus

• Prostatic enlargement

• Urinary retention

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

• Intestinal obstruction

• Potassium chloride solid oral dose products

• Anticholinergic medicines

4.4. Special warnings and precautions for use

Anticholinergic effects

Anticholinergic effects such as urinary retention, constipation and overheating due to inhibition of sweating are dose dependent. 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.

Lack of long-term safety data

Safety data are not available beyond 24 weeks treatment duration. Given the limited long- term safety data available and the uncertainties around the long term use of the product, the 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 potential benefit and the known adverse effect profile, Glycopyrronium Bromide should not be given to children with mild to moderate sialorrhoea.

Cardiac disorders

Glycopyrronium Bromide should be used with caution in patients with acute myocardial infarction, hypertension, conditions characterised by tachycardia (including hyperthyroidism, cardiac insufficiency, cardiac surgery) because of the increase in heart rate produced by its administration, coronary artery disease and cardiac arrhythmias.

Due to the potential change to normal heart rhythm, Glycopyrronium Bromide should be used with caution in patients receiving inhalation anaesthesia.

Gastro-intestinal disorders

Glycopyrronium Bromide should be used with caution in patients with gastro- oesophageal reflux disease, ulcerative colitis, pre-existing constipation, and diarrhoea.

Diarrhoea may be an early symptom of incomplete intestinal obstruction, especially in patients with ileostomy or colostomy. In this instance treatment with this drug would be inappropriate and possibly harmful.

As glycopyrronium bromide inhibits sweating, patients with increased temperature should be observed closely. In the presence of a high environmental temperature, heat prostration (fever and heat stroke due to decreased sweating) can occur with use of Glycopyrronium Bromide.

Dental

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

CNS adverse events

Increased central nervous system 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; fearfulness. 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 eg. Intraventicular shunt, brain tumour, encephalitis.

Renal disorders

Because of prolongation of renal elimination, repeated or large doses of Glycopyrronium Bromide should be avoided in patients with uraemia.

Paediatric population – children younger than 3 years

Glycopyrronium Bromide is not recommended for use in children younger than 3 years of age.

Growth and development

The effects of glycopyrronium on the reproductive system have not been investigated. Whilst clinical studies do not report any short or long-term effect of glycopyrronium on neurodevelopment or growth, no studies have been conducted to specifically address these issues.

Excipient Warnings

Sorbitol

This medicine contains 875 mg sorbitol in each 5 ml which is equivalent to 175mg/1 ml. Sorbitol is a source of fructose. If your doctor has told you that you (or your child) have an intolerance to some sugars or if you have been diagnosed with hereditary fructose intolerance (HFI), a rare genetic disorder in which a person cannot break down fructose, talk to your doctor before you (or your child) take or receive this medicine. Sorbitol may cause gastrointestinal discomfort and mild laxative effect.

Sodium Benzoate

This medicine contains 4 mg sodium benzoate in each 5 ml which is equivalent to 0.80 mg/ml.

Information on Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per 1 ml, that is to say essentially 'sodium-free'.

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.

Contraindication of concomitant use

Concomitant use of the following medicinal products is contraindicated (see section 4.3)

• Potassium chloride solid oral dose products: 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 GI bleeding and small bowel ulceration, stenosis, perforation, and obstruction has been observed.

• Anticholinergic medicines: 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 including dose adjustment

Class interactions

Many drugs have antimuscarinic effects; concomitant use of two or more of such drugs can increase side-effects such as dry mouth, urine retention and constipation. Concomitant use can also lead to confusion in the elderly. The Glycopyrronium Bromide dosage may need to be decreased in patients receiving two or more antimuscarinic drugs concomitantly.

Increased antimuscarinic side-effects: amantadine; tricyclic antidepressants; antihistamines; clozapine; disopyramide; MAOIs; nefopam; memantine; phenothiazines (increased antimuscarinic side effects of phenothiazines but reduced plasma concentrations). The Glycopyrronium Bromide dosage may need to be decreased in patients receiving two or more antimuscarinic drugs concomitantly.

Concurrent administration of anticholinergics and corticosteroids may result in increased intraocular pressure.

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 (see contraindications).

Concurrent use with slow-dissolving tablets of digoxin, atenolol or metformin may result in increased serum levels of these medicines.

Skeletal muscle relaxants: Concurrent use of anticholinergics after administration of skeletal muscle relaxants may potentiate systemic anticholinergic effects.

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

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.

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

Topiramate and zonisamide: glycopyrronium may potentiate the effects of oligohidrosis and hyperthermia associated with the use of topiramate, particularly in paediatric patients.

Levodopa: absorption of levodopa possibly reduced.

Haloperidol: effects of haloperidol possibly reduced.

Nitrates: possibly reduced effect of sublingual nitrates (failure to dissolve under the tongue owing to dry mouth).

Inhaled anaesthetics: potential change to normal heart rhythm

4.6. Fertility, pregnancy and lactation

Women of child-bearing potential

Women of childbearing potential have to use effective contraception during the treatment.

Pregnancy

There is limited amount of data (less than 300 pregnancy outcomes) from the use of glycopyrronium bromide in pregnant women. The assessment of reproductive endpoints for glycopyrronium is limited (see section 5.3). Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of glycopyrronium bromide during pregnancy.

Breastfeeding

Available toxicological data in animals have shown excretion of glycopyrronium bromide and its metabolites in milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue from glycopyrronium bromide therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

There are no data on the effects of Glycopyrronium Bromide 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

Glycopyrronium Bromide may influence the ability to drive and use machines because it may produce drowsiness or blurred vision. In this event, the patient should be warned not to engage in activities requiring mental alertness such as operating a motor vehicle or other machinery, or performing hazardous work while taking this drug.

4.8. Undesirable effects

Glycopyrronium bromide may produce the following effects, which are extensions of its fundamental pharmacological actions: dry mouth, diminished gastrointestinal motility, difficulty in micturition, increased body temperature and inhibition of sweating.

Side-effects of antimuscarinics include difficulty swallowing, difficulty talking, thirst, constipation, transient bradycardia (followed by tachycardia, palpitation and arrhythmias), reduced bronchial secretions, urinary urgency and retention, dilatation of the pupils with loss of accommodation, photophobia, flushing, and dryness of the skin.

Other side-effects that occur less frequently include confusion (particularly in the elderly), nausea, vomiting, drowsiness, dizziness and angle-closure glaucoma.

Summary of the safety profile

The highest incidence of adverse reactions associated with Glycopyrronium Bromide therapy is related to its anticholinergic properties1 i.e. dry mouth (13%), constipation (16%), diarrhoea (9.4%), nasal congestion (8.4%), vomiting (11.4%), urinary retention (5.4%) etc.

Pulmonary undesirable effects including upper respiratory infection and pneumonia have been reported. The incidence rate cannot be calculated from the available data (See Section 4.4).

There is no data on the long-term use of the product. (see section 4.4).

Tabulated list of adverse reactions

Adverse reactions associated with Glycopyrronium bromide obtained from published studies1 are tabulated below according to the following convention: Very common (>1/10); Common (>1/100, <1/10); Uncommon (>1/1,000, <1/100); Unknown (cannot be estimated from the available data)

System Organ Class/ Adverse reaction

Frequency

Immune system disorder

Allergic reaction

Uncommon

Nervous system disorder

Headache

Unknown

Somnolence

Unknown

Drowsiness

Unknown

Seizure (worsening)

Uncommon

Dizziness

Uncommon

Insomnia

Uncommon

Gastrointestinal disorder

Dry mouth

Very common

Constipation

Very common

Diarrhoea

Very common

Vomiting

Very common

Pseudo-obstruction

Uncommon

Gastrointestinal mobility disorder

Uncommon

Eosophageal candidiasis

Uncommon

Breath odour

Uncommon

Nausea

Unknown

Infections and infestations

Upper respiratory infection

Unknown

Pneumonia

Common

Otitis media

Unknown

Streptoccocal pharyngitis

Unknown

Urinary tract infection

Unknown

Psychiatric disorder

Behavioural changes2

Very common

Eye disorder

Nystagmus

Uncommon

Mydriasis

Unknown

Blurred vision

Unknown

Angle-closure glaucoma

Unknown

Photophobia

Unknown

Dry Eyes

Unknown

Cardiac disorder

Flushing

Very common

Angioedema

Unknown

Transient bradycardia

Unknown

Respiratory, thoracic and mediastinal disorders

Nasal congestion

Very common

Reduced bronchial secretions

Very common

Epistaxis

Unknown

Sinusitis

Unknown

Skin and subcutaneous tissue disorder

Rash

Unknown

Hives

Uncommon

Skin dryness

Unknown

Sweat inhibition

Unknown

Renal and urinary disorders

Urinary retention

Common

Urinary urgency

Uncommon

General disorders and administration site conditions

Pyrexia

Common

Dehydration

Uncommon

Thirst

Uncommon

1 Frequency categories are assigned from the pooled data from the following published studies: double blinded placebo controlled trials Mier et al. and Zeller et al. 2012a, one retrospective review Bachrach et al., and three one open –label studies Zeller et al 2012b, Stern and Blasco et al. with a total of 297 patients exposed to glycopyrromium.

2 Behavioural changes include agitation, drowsiness, restlessness, overactivity, short attention span, frustration, irritability, mood changes, temper outbursts, explosive behaviour, excessive sensitivity, seriousness, sadness, frequent crying, fearfulness.

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 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

Since glycopyrronium bromide is a quaternary ammonium agent, symptoms of overdosage are peripheral rather than central in nature. Theoretically, with overdosage, a curare-like action may occur, i.e. neuro-muscular blockade leading to muscular weakness and possible paralysis. Furthermore, the likelihood of experiencing anticholinergic side effects is increased.

Treatment of overdose is symptomatic and supportive.

• To guard against further absorption of the drug, use gastric lavage, cathartics and/or enemas.

• To combat peripheral anticholinergic effects (residual mydriasis, dry mouth, etc.), utilise a quaternary ammonium anticholinesterase, such as neostigmine. Proportionately smaller doses should be used in children.

• To combat hypotension, use pressor amines (norepinephrine, metaraminol) i.v. and supportive care.

• To combat respiratory depression, administer oxygen; utilise a respiratory stimulant such as Doxapram hydrochloride i.v. and artificial respiration.