This information is intended for use by health professionals

1. Name of the medicinal product

Assicco 1mg Tablets

Glycopyrronium Bromide 1mg Tablets

2. Qualitative and quantitative composition

Each 1mg tablet contains 1mg of Glycopyrronium Bromide

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Tablets

The tablets are white to off white capsule shaped, flat, bevelled edge, scored tablets engraved with “I 21” (1mg) or “I 22” (2mg) on the scored side and plain on the other side.

The tablet can be divided into equal doses.

4. Clinical particulars
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

Glycopyrronium bromide tablets are recommended for short-term intermittent use (see section 4.4 and 5.1).

Glycopyrronium bromide tablets should be prescribed by physicians experienced in the treatment of patients with neurological disorders.

Posology

The dosing schedule for Glycopyrronium bromide 1mg and 2mg tablets is based on the weight of the child with an initial dosing of 0.02 mg/kg to be given orally three times daily and titrated in increments of 0.02 mg/kg every 7 days based on therapeutic response and adverse reactions. The maximum recommended dose is 0.1 mg/kg three times daily not to exceed 1.5-3 mg per dose based upon weight (see Table).

During a four-week titration period, dose should be increased no more frequently than weekly using the titration schedule to minimise anticholinergic adverse events. Increase of dose should occur only after it is clear that the dose level is well tolerated and monitoring of the increase is in place. Prior to each dose increase, a review of the tolerability of the current dose level should be made with the patient's caregiver.

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

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.

Dosing table for children and adolescents aged 3 years and older (week intervals between increased dose increments)

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

0.6 mg

0.9 mg

1.2 mg

1.5 mg

18-22

0.4 mg

0.8 mg

1.2 mg

1.6 mg

2.0 mg

23-27

0.5 mg*

1.0 mg

1.5 mg

2.0 mg

2.5 mg

28-32

0.6 mg

1.2 mg

1.8 mg

2.4 mg

3.0 mg

33-37

0.7 mg

1.4 mg

2.1 mg

2.8 mg

3.0 mg

38-42

0.8 mg

1.6 mg

2.4 mg

3.0 mg

3.0 mg

43-47

0.9 mg

1.8 mg

2.7 mg

3.0 mg

3.0 mg

≥48

1.0 mg

2.0 mg

3.0 mg

3.0 mg

3.0 mg

* 0.5mg dose can be achieved by taking ½ of a 1mg tablet.

For doses which cannot be achieved using the tablet formulation, other pharmaceutical forms of glycopyrronium bromide are available.

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

Adult population

Glycopyrronium Bromide tablets are 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 population

Glycopyrronium Bromide tablets are 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 Glycopyrronium Bromide tablets should not be used in patients over the age of 65 years.

Renal Impairment

Elimination of glycopyrronium is severely impaired in patients with renal failure. Glycopyrronium is contraindicated in those with severe renal failure (see section 4.3). For patients with Mild to moderate renal impairment (eGFR <90 - ≥30 ml/min/1.73m2) doses should be reduced by 30%.

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.

Other licensed glycopyrronium products are not all interchangeable on a milligram-for-milligram basis due to differences in bioavailability; please refer to the approved posology of the product if changing between products.

Method of administration

For oral administration only.

For patients who cannot swallow tablets, other pharmaceutical forms can be used.

Co-administration with food results in a marked decrease in systemic medicinal product exposure. 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 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).

In exceptional circumstances it may not be possible to administer the tablets orally, please refer to recommendations in section 6.6.

4.3 Contraindications

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

• 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

• Pregnancy and breast-feeding

• Concomitant treatment with (see section 4.5);

o potassium chloride solid oral dose

o anticholinergics

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:

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 evaluation, the prescriber should decide if treatment should be discontinued or if it should be continued at a lower dose.

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, Glycopyrronium bromide tablets 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. 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

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

Glycopyrronium can cause thickening of secretions, which may increase the risk of respiratory infection and pneumonia. Glycopyrronium 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 e.g. Intraventicular shunt, brain tumour, encephalitis.

Children below the age of 3 years

Glycopyrronium Bromide is not recommended for use 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.

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.

Patients with rare hereditary problems of galactose intolerance, the total lactase deficiency, glucose-galactose malabsorption or fructose intolerance should not take this medicine. This is due to the presence of sorbitol (E420) in this medicine.

This medicinal product contains less than 1 mmol sodium (23 mg) per maximum dose, i.e. essentially is '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.

Contraindications of concomitant use

Concomitant use of the following medicinal products is contraindicated (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 GI 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

Concomitant use of the following medicinal products should 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: may have additive anticholinergic effects. A reduction in anticholinergic and/or antihistamine dosage 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: may have additive anticholinergic effects. A reduction in anticholinergic and/or tricyclic antidepressants and MAOIs dosage 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

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

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 Glycopyrronium Bromide tablets 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 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 efficacy of the medicinal product should be balanced against the adverse reactions and the dose monitored regularly and adjusted as necessary. The most common anticholinergic adverse reactions in the placebo-controlled studies (see section 5.1) related to the gastrointestinal system and were dry mouth, constipation, diarrhoea and vomiting, all of which occurred at a rate of ≥15%. The safety profile is further characterised by other symptoms, related to the anticholinergic effects at a rate of ≥15%, including urinary retention, flushing and nasal congestion.

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

Tabulated summary 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 event data in the target population) are listed by MedDRA system organ class (Table below). 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).

Tabulated list of adverse reactions

Adverse reaction

Frequency

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 withdrawn until the urinary retention resolves.

Pneumonia

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

Constipation

Constipation is a known adverse reaction associated with anticholinergic medicinal products (30%). Glycopyrronium treatment should be withdrawn 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.

Haematology and chemistry

A decrease of >10% from the normal reference range at baseline for absolute neutrophil (11.2%) and red blood cell (11.1%) count, and increases >10% from the normal reference range at baseline for monocyte (16.7%) and absolute monocyte (11.2%) counts has been seen. Decreases >10% from the normal reference range at baseline were observed for carbon dioxide (15.1%), bicarbonate (13.3%), and creatinine (10.7%) concentrations.

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

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.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Synthetic anticholinergics, quaternary ammonium compounds;

ATC code: A03AB02

Mechanism of action

Glycopyrronium bromide is a synthetic muscarinic anticholinergic agent that binds competitively to the muscarinic acetylcholine receptor. Like other anticholinergic (antimuscarinic) agents, it inhibits the action of acetylcholine on structures innervated by postganglionic cholinergic nerves and on smooth muscles that respond to acetylcholine but lack cholinergic innervation. These peripheral cholinergic receptors are present in the autonomic effector cells of smooth muscle, cardiac muscle, the sinoatrial node, the atrioventricular node, exocrine glands and, to a limited degree, in the autonomic ganglia. Thus, it diminishes the volume and free acidity of gastric secretions and controls excessive pharyngeal, tracheal, and bronchial secretions.

Aside from differences in the CNS actions, the spectrum of pharmacological actions by glycopyrronium bromide is qualitatively similar to that of the naturally occurring alkaloids atropine and scopolamine, but differs with regard to duration and intensity. Within the peripheral nervous system, glycopyrronium bromide acts as a potent competitive antagonist at muscarinic receptors and attenuates physiological processes regulated by the parasympathetic nervous system, including predictable actions within the respiratory tract, gastrointestinal tract, and heart. The highly polar quaternary ammonium group of glycopyrronium bromide limits its passage across lipid membranes, such as the blood-brain barrier.

Pharmacodynamic effects

Glycopyrronium competitively inhibits cholinergic muscarinic receptors in salivary glands and other peripheral tissues, thus indirectly reducing the rate of salivation. Glycopyrronium has little effect on cholinergic stimuli at nicotinic acetylcholine receptors, on structures innervated by sympathetic postganglionic neurons, and on smooth muscles that respond to acetylcholine but have no cholinergic innervation. Peripheral antimuscarinic effects that are produced as the dose increases are: decreased production of secretions from the salivary, bronchial and sweat glands; dilatation of the pupils (mydriasis) and paralysis of accommodation (cyclopegia); increased heart rate; inhibition of micturition and reduction in gastrointestinal tone; inhibition of gastric acid secretion. Specific effects include dryness of the mouth, reduced bronchial secretions, dilation of pupils with loss of accommodation, photophobia, flushing, inhibition of sweating, transient bradycardia followed by tachycardia with palpitations and arrhythmias, urinary urgency and retention, reduced gastrointestinal motility and tone.

Due to its limited passage across lipid membranes, CNS effects such as drowsiness are unlikely.

Clinical efficacy and safety

The medicinal use of glycopyrronium bromide for its anticholinergic effects is well-established. Studies published in the scientific literature demonstrate reduction in gastric secretions and acidity, and delayed gastric emptying by glycopyrronium bromide in peptic ulcer patients. Some efficacy of glycopyrronium bromide as monotherapy was shown in peptic ulcer healing, recurrence rate of duodenal ulcer, chronic gastric ulcer, duodenal ulcer, peptic ulcer, gastrointestinal disorders and acid-peptic disease. Published studies of glycopyrronium bromide in adults as add-on therapy with antacids in the treatment of peptic ulcer also demonstrate some efficacy.

Placebo-controlled efficacy data for sialorrhoea in children includes patients with a treatment duration of 8 weeks. There is no placebo or comparator-controlled data beyond 8 weeks.

Zeller et al 2012 evaluated the efficacy of glycopyrronium bromide oral solution (1 mg/5mL) in managing problem drooling associated with cerebral palsy and other neurological conditions.

Thirty-eight patients aged 3-23 years weighing at least 12.2 kg with severe drooling (clothing damp 5-7 days/week) were randomized to 8 weeks treatment with glycopyrronium (n = 20), 20-100 μg/kg (not exceeding 3 mg in total), or matching placebo (n = 18) tds. The first 4 weeks were an individual titration period in fixed steps depending on response, followed by 4-weeks maintenance treatment.

The primary efficacy endpoint was responder rate, defined as percentage showing ≥3-point improvement on the modified Teacher's Drooling Scale (mTDS). The primary analysis population was revised to only comprise patients with an age of 3 -16 years with 19 patients in the glycopyrrolate oral solution group an 17 in the placebo group. Responder rate was defined as at least a 3-point improvement in modified Teacher's Drooling Scale (mTDS).

Treatment

At least a 3-point improvement in mTDS

Mean improvement in mTDS

Glycopyrronium

14 of 19 patients (73.7%)

3.94 points

(SD: 1.95; 95%; CI: 2.97–4.91)

Placebo

3 of 17 patients (17.6%)

0.71 points

(SD: 2.14; 95% CI: –0.43–1.84)

p value

p = 0.0011

p <0.0001

84% of physicians and 100% of parents/caregivers regarded glycopyrrolate as worthwhile compared with 41% and 56%, respectively, for placebo (p≤0.014). Most frequently reported treatment-emergent adverse events (glycopyrrolate vs placebo) were dry mouth, constipation, vomiting and nasal congestion.

In a separate study by Zeller et al (2012), the safety and efficacy of glycopyrronium were studied in an open-labelled study without a control group over a 24-week period in children aged 3-18 years At the week 24 exit visit, 52.3% (95% CI 43.7–60.9) of patients (n=130) had an at least three point decrease in mTDS from baseline and were classified as responders to treatment with oral glycopyrrolate solution with 83.5% of parents/caregivers and 85.8% of investigators rating oral glycopyrrolate solution as worthwhile. The adverse event profile was consistent with that seen with anticholinergics (see section 4.4 and 4.8).

The incidence of expected adverse anticholinergic effects is dose-related. Therefore, dose should be titrated to achieve an optimal balance of effectiveness with minimal anticholinergic-associated adverse events.

5.2 Pharmacokinetic properties

Absorption

Glycopyrronium bromide is poorly absorbed from the gastrointestinal tract. Oral glycopyrronium bromide has low oral bioavailability; a mean of approximately 3% is found in plasma.

Mean absolute oral bioavailability of glycopyrronium comparing a single 50 μg/kg oral dose and a single 5 μg/kg i.v. dose was low at approximately 3% (range 1.3–13.3%) in children aged 7–14 years undergoing intraocular surgery (n = 6) due to the medicinal product's low lipid solubility. Data from sparse PK sampling in children suggests dose proportional PK.

Therapeutic doses of oral glycopyrronium bromide produce low plasma concentrations (Cmax 0.318 ± 0.190 ng/ml) lasting up to 12 hours.

Food effect data indicate that the mean Cmax under fed high-fat meal conditions is ~75% lower than the Cmax observed under fasting conditions.

Distribution

The bioavailability of oral glycopyrronium in children is between that of adults under fed and fasted conditions. Co-administration with food results in a marked decrease in systemic glycopyrronium exposure.

In adults, distribution of glycopyrronium was rapid following a single 6 μg/kg i.v. dose; distribution half-life was 2.2 ± 1.3 minutes. Following administration of 3H-labelled glycopyrronium >90% of the radiolabel disappeared from plasma in 5 minutes, and almost 100% within 30 minutes, reflecting rapid distribution. Analyses of population pharmacokinetic data from healthy adults and children with cerebral palsy-associated chronic moderate to severe drooling who received glycopyrronium (route of administration and dosages unspecified) did not demonstrate linear pharmacokinetics of the medicinal product.

The volume of distribution (Vd), 0.64 ± 0.29 L/kg in adults is similar to that of total body water. Vd is somewhat higher in the paediatric population in the range 1.31 to 1.83 L/kg.

The PK of glycopyrronium has been shown to be essentially independent of age in children 0.19-14 years administered a 5 μg/kg i.v. single-dose. In most paediatric subjects, plasma glycopyrronium vs. time plots are reported to show a triexponential curve; adults generally show a biexponential curve. Modest changes in volume of distribution (Vss) and clearance (Cl) have been observed in children between 1 and 3 years of age, leading to a statistically significantly shorter elimination half-life (t½) than that observed in younger (<1 year of age; p = 0.037) or older (>3 years of age; p = 0.042) groups.

In a study in healthy adults, a 2000 μg single dose of glycopyrronium bromide resulted in an AUC of 2.39 μg.h/L (fasted). An AUC0-6 h of 8.64 μg.h/L was observed after 6 μg/kg i.v. glycopyrronium.

Based upon theoretical physicochemical considerations, the quaternary ammonium compound glycopyrronium would be expected to have low central bioavailability. No glycopyrronium was detected in the CSF of anaesthetised surgical patients or patients undergoing caesarean section following a 6-8 μg/kg i.v. dose. In the paediatric population 5 μg/kg i.v. glycopyrronium has low central bioavailability, except in the case where the blood brain barrier has been compromised (e.g. a shunt infection).

The primary route of elimination of glycopyrronium is via renal excretion, mainly as unchanged medicinal product. Approximately 65% of an i.v. dose is renally excreted within the first 24 hours. A small proportion (~5%) is eliminated in the bile.

The elimination half-life of glycopyrronium appears to be dependent on route of administration: 0.83 ± 0.27 hours after i.v. administration, 75 minutes after i.m. administration and ~2.5-4 h after oral (solution) administration, though this was highly variable. The latter two half-lives, and especially that for oral administration, are longer than for i.v. administration probably reflecting the complex absorption and distribution of glycopyrronium by each route. It is possible that prolonged absorption after oral administration translates into elimination being faster than absorption (flip-flop kinetics).

The total body clearance of the medicinal product following an i.v. dose is relatively high at between 0.54 ± 0.14 L/h/kg and 1.14 ± 0.31 L/h/kg. Since this exceeds the glomerular filtration rate and more than 50% of the dose is excreted unchanged in the urine, it is probable that the renal elimination of glycopyrronium involves both glomerular filtration and proximal tubular basal secretion.

A mean increase in total systemic exposure (AUClast) of up to 1.4 fold was seen in adult subjects with mild and moderate renal impairment (GFR ≥30mL/min/1.73m2) and up to 2.2 fold in subjects with severe renal impairment or end stage renal disease (estimated GFR <30 mL/min/1.73m2). A 30% dose reduction is required for patients with mild to moderate renal impairment. Glycopyrronium is contraindicated in patients with severe renal impairment.

Baseline characteristics (age, weight, gender and race) do not affect the pharmacokinetics of glycopyrronium.

Glycopyrronium bromide penetrates the blood-brain barrier poorly. Glycopyrronium bromide crosses the placenta to a limited extent; it is not known whether it is distributed into milk.

Biotransformation

In adult patients who underwent surgery for cholelithiasis and were given a single IV dose of tritiated glycopyrronium bromide, approximately 85% of total radioactivity was excreted in urine and < 5% was present in T-tube drainage of bile. In both urine and bile, > 80% of the radioactivity corresponded to unchanged drug. These data suggest a small proportion of i.v. glycopyrronium bromide is excreted as one or more metabolites.

Elimination

A study using intravenous 3H-glycopyrronium bromide in humans showed the disappearance of more than 90% from serum in 5 minutes and almost 100% in 30 minutes. Urinary radioactivity was highest in the first 3 h and 85% was excreted in the urine within 48 h. 80% of the radioactivity in bile and urine was unchanged glycopyrronium bromide. Following oral administration to mice, 7.6% was excreted in the urine and ~79% in the faeces.

Impaired hepatic function is not expected to affect the pharmacokinetics of glycopyrronium since the majority of the medicinal product is eliminated through the kidneys.

Co-administration with food results in a marked decrease in systemic glycopyrronium exposure (see section 4.2.).

Different formulations of glycopyrronium differ in bioavailability and should not be regarded as interchangeable (see section 4.2).

5.3 Preclinical safety data

Genotoxicity studies did not reveal any mutagenic or clastogenic potential for glycopyrronium bromide. Carcinogenicity studies in transgenic mice using oral administration and in rats using inhalation administration revealed no evidence of carcinogenicity.

The single dose toxicity of glycopyrronium has been tested in a range of investigations, although only limited experimental details are available. Upon oral administration, high LD50 values of 550 mg/kg in mice and above 1,000 mg/kg in rats were reported. In rats at higher doses (1500-2000 mg/kg) tremors, clonic and tonic convulsions and laboured breathing were observed prior to death, resulting from respiratory failure.

Chronic oral administration of glycopyrronium at doses of 4, 16 and 64 mg/kg for up to 27 weeks in dogs produced mydriasis, cycloplegia, xerostomia, emesis, occasional lacrimation, injection of sclera and rhinorrhoea.

Extrapolation of safety margins to the paediatric population is not possible, as no exposure data are available from repeated dose toxicology studies and no studies in juvenile animals have been performed with glycopyrronium.

Data on reproductive endpoints for glycopyrronium are very limited. A reduction in corpora lutea was observed in female rats administered glycopyrronium. No effects on fertility were observed in male rats. Reproductive performance in rats given glycopyrronium shows a decrease in the rate of conception and in survival rate at weaning. The significance of the non-clinical findings for humans is not clear, and the lack of human data on the medicinal product leads to glycopyrronium being contraindicated in pregnant women. There are insufficient data in the public domain to adequately assess effects on the reproductive system in young adults, and safety in human pregnancy has not been established.

6. Pharmaceutical particulars
6.1 List of excipients

Lactose Monohydrate

Dibasic calcium phosphate

Povidone

Sodium starch glycolate

Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

None

6.5 Nature and contents of container

Aluminium blisters of 10, 14, 28, 30, 56, 60, 90 and 112 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No Special requirements for disposal.

For patients where oral administration of tablet is not possible, or not desired, administration by tablet solubilisation, and subsequent administration as an extemporaneous oral dispersion, or by administration via a nasogastric tube or a percutaneous endoscopic gastrostomy (PEG) tube can be used. Such dispersions should be administered as following. For dose recommendations see section 4.2.

Dispersion of a tablet is achieved as follows, using water as a dispersant medium and a 60 ml oral syringe as the vessel for dispersion.

- Remove the plunger from the syringe and introduce a single tablet into the syringe barrel, replace the plunger and depress to just above the tablet

- Draw up the required volume of water - 10-30 ml either of potable or purified is suitable, dependent on any patient fluid intake restrictions, and manually shake the syringe assembly for 30 seconds

- Allow to stand for 5 minutes and manually shake for another 30 seconds

- Allow to stand for a further 5 minutes and manually shake for another 30 seconds

- Allow to stand for a final 5 minutes and manually shake for another 30 seconds.

The tablet dispersion should be administered immediately after preparation. The dispersion is opaque, with some visible heavy particulates that are an inactive ingredient. The whole of the dispersion, including residue, is to be administered. The studies conducted with the nasogastric and PEG tubes evaluated three types of tubing, polyvinylchloride, polyurethane and silicone, and concluded that there were no significant differences evident between the three types of tubing with more than 90% overall recovery. Filtration studies prior to analysis were performed to evaluate if undissolved residues contained significant amounts of glycopyrronium bromide and concluded that there was no significant decrease in the amount recovered. Filtered and unfiltered samples both showed overall recovery of more than 90%.

Administration may be by the following routes:

- Orally, as an aqueous dispersion. Following administration of the dispersion, the oral syringe is rinsed with a further water, a minimum of 10 ml that should also be taken to ensure complete dosing.

- Via either a nasogastric tube, or PEG tube. Tubes made of polyvinylchloride, polyurethane, or silicon are suitable. There are no data available on tubes made of latex; such tubes should not be used. Immediately following administration of the initial dispersion, by connection of the oral syringe to the tube, the oral syringe is disconnected and rinsed with a further 10 ml of water, which should also be administered, in order to ensure complete dosing.

Such dispersions should not be used to provide doses below that of the tablet used to prepare the dispersion, since there are no data available to support such dose subdivision. Dispersion should be administered immediately following preparation. There are no data available to show that the medicine could be co-administered with food when administered through enteral tubes and this should be avoided as recommended.

7. Marketing authorisation holder

Morningside Healthcare Ltd,

Unit C, Harcourt Way,

Leicester, LE19 1WP

United Kingdom

8. Marketing authorisation number(s)

1mg PL 20117/0094; 2mg PL 20117/0095

9. Date of first authorisation/renewal of the authorisation

06/02/2014

10. Date of revision of the text

18/03/2021