GLYCOPYRRONIUM BROMIDE 1 MG / 5ML ORAL SOLUTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Glycopyrronium Bromide 1mg/5ml Oral Solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5ml contains 1mg glycopyrronium bromide.

Excipients with known effect:

Sodium benzoate (E211)   3.55 mg/5ml

Glycerol (E422)           0.5 g/5ml

Sorbitol (E420)            2.45 g/5ml

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Oral solution

A clear colourless to straw-yellow solution

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 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, Glycopyrronium bromide oral solution 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 oral solution 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.

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

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

Paediatric population – children aged < 3 years

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

Adult population

Glycopyrronium Bromide 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 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 Glycopyrronium Bromide 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. Glycopyrrolate 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

Elimination of glycopyrrolate 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%.

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 use.

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 child’s specific needs determine that co-administration with food is required, dosing of the medicinal product should be consistently performed during food intake

The dosage syringe provided with the pack is for oral administration only. The correct quantity of Glycopyrronium Bromide oral solution should be measured and administered using the dosage syringe provided.

Instructions for use of the oral syringe:

1. To open the bottle, press the cap down and turn it anti-clockwise (figure 1).

2. Put the syringe adaptor into the bottle neck (figure 2).

3. Take the syringe and put it into the adaptor opening (figure 3).

4. Turn the bottle upside down (figure 4).

5. Fill the syringe with a small amount of solution by pulling the plunger down (figure 4A). Then push the plunger upward in order to remove any possible bubbles (figure 4B). Finally, pull the plunger down to the graduation mark corresponding to the quantity in millilitres (ml) prescribed by your doctor. The top flat edge of the piston should be in line with the graduation mark you are measuring to (Figure 4C).

6. Turn the bottle the right way up (Figure 5A).

7. Remove the syringe from the adaptor (Figure 5B).

8. Put the end of the syringe into your mouth and push the plunger slowly back in to take the medicine (Figure 6).

9. Wash the syringe with water and let it dry before you use it again.

10. Close the bottle with the plastic screw cap – leave the syringe adaptor in the bottle.

Suitable for administration via nasogastric (NG) or percutaneous endoscopic gastrostomy (PEG) tubes. For further instructions see section 6.6.

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 (see section 4.5);

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 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.

Lack of long-term safety data

Published safety data are not available beyond 24 weeks treatment duration. Given the limited longterm 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 (eg 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 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 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.

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

Sodium benzoate, may increase jaundice (yellowing of the skin and eyes) in newborn babies (up to 4 weeks old).

This medicine contains 2.45g sorbitol in 5ml. 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, this medicinal product contains less than 1 mmol sodium (23 mg) per maximum dose, i.e. 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.

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 paediatric 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

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

Glycopyrronium is contraindicated in 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 glycopyrronium on male or female fertility. Reproductive performance in rats given glycopyrronium shows a decrease in the rate of conception and in survival rate at weaning. There are insufficient data in the public domain to adequately assess effects on the reproductive system in young adults (see section 5.3).

4.7 Effects on ability to drive and use machines

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

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 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 Reaction Frequency

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 at: 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: Medicinal products for functional gastrointestinal disorders, synthetic anticholinergics, quaternary ammonium compounds. ATC Code: A03AB02.

Glycopyrronium is a quaternary ammonium antimuscarinic with peripheral effects similar to those of atropine.

Antimuscarinics are competitive inhibitors of the actions of acetylcholine at the muscarinic receptors of autonomic effector sites innervated by parasympathetic

(cholinergic postganglionic) nerves. They also inhibit the action of acetylcholine where smooth muscle lacks cholinergic innervation.

Salivation is primarily mediated by parasympathetic innervation of the salivary glands. 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 postganglionic cholinergic 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. Placebo controlled efficacy data includes patients with a treatment duration of 8 weeks. There is no placebo or comparator controlled data beyond 8 weeks.

Zeller et al 2012a evaluated the efficacy of glycopyrronium bromide oral solution (1 mg/5 mL) in managing problem drooling associated with cerebral palsy and other neurologic conditions. Thirty-eight patients aged 3–23 years weighing at least 27 lb (12.2 kg) with severe drooling (clothing damp 5–7 days/week) were randomized to eight-weeks treatment with glycopyrronium (n = 20), 20–100 ug/kg (not exceeding 3 mg in total) three times a day, or matching placebo (n = 18). The first four weeks were an individual titration period in fixed steps depending on response followed by 4-weeks maintenance treatment. 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 which rendered 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).

In addition, 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.

The safety and efficacy of glycopyrronium have been studied in an open labelled study with no control group over a 24-week period in children aged 3 to 18 years. At the week 24/exit visit, 52.3% (95% confidence interval 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.. The adverse event profile was consistent with the one seen with anticholinergics (see section 4.4 and 4.8).

5.2 Pharmacokinetic properties

Mean absolute oral bioavailability of glycopyrronium comparing a single 50 ug/kg oral dose and a single 5 ug/kg i.v. dose was low at approximately 3% (range 1.313.3%) 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.

The bioavailability of oral glycopyrronium in children was 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 ug/kg i.v. dose; distribution half-life was 2.2 ± 1.3 minutes. Following administration of 3H-labelled glycopyrronium more than 90% of the radiolabel disappeared from the 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 not specified) did not demonstrate linear pharmacokinetics of the medicinal product.

The volume of distribution, 0.64 ± 0.29 L/kg in adults is similar to that of total body water. Volume of distribution is somewhat higher in the paediatric population(s), 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 in the age range 0.19 – 14 years administered a 5 ug/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 significant shorter elimination half-life (ť/2, z) 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 ug single dose of glycopyrronium bromide resulted in an AUC of 2.39 ug.h/L (fasted). An AUC0–6 h of 8.64 ug.h/L was observed after 6 ug/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 detectable in the CSF of anaesthetised surgical patients or patients undergoing caesarean section following a 6 – 8 ug/kg i.v. dose. In the paediatric population 5 ug/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 being 0.83 ± 0.27 hours after i.v. administration, 75 minutes after i.m. administration and in the region of 2.5 – 4 h after oral (solution) administration, though again this was highly variable. That the latter two half-lives, and especially that for oral administration, are longer than for i.v. administration probably reflects 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 (known as flip-flop kinetics, characterized by Ka < Ke).

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. As this exceeds the glomerular filtration rate and it appears that 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 secretion by the base secretory mechanism.

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 (see Table 2) 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.

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.).

5.3 Preclinical safety data

Non-clinical data, including genotoxicity or carcinogenicity studies have not been performed for glycopyrronium.

Limited non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology or repeated dose toxicity.

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

Citric acid monohydrate (E330)

Sodium citrate (E331)

Sodium benzoate (E211)

Strawberry flavour

Liquid sorbitol (E420)

Glycerol (E422)

Purified water

6.2 Incompatibilities

Not applicable

6.3 Shelf life

24 months

Use within 1 month of opening the bottle.

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

Bottle: Amber (Type III glass)

Closure: HDPE, EPE wadded, child resistant closure

Dosing Syringe: Polypropylene body, purple HDPE plunger with a capacity of 10ml and dosage graduation at every 0.5ml

Bottle adaptor: Low Density Polyethylene

Pack size: 150 ml and 250 ml. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Instruction for administration via nasogastric (NG) or percutaneous endoscopic gastrostomy (PEG) tubes:

Ensure that the enteral feeding tube is free from obstruction before administration.

1. Flush the enteral tube with water, using the minimum flush volume required.

2. Administer the required dose of glycopyrronium bromide oral solution with a suitable measuring device.

3. Flush the enteral tube again, using the minimum flush volume required.

With respect to tubal administration, this product should be administered with silicone, PVC, polyurethane NG or PEG tubes only.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Rosemont Pharmaceuticals Ltd

Rosemont House

Yorkdale Industrial Park

Braithwaite Street

Leeds

LS11 9XE

UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 00427/0252

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

01/12/2021