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Glycopyrronium Bromide 1 mg/5 ml Oral Solution

Last Updated on eMC 02-Feb-2017 View changes  | Colonis Pharma Ltd Contact details

1. Name of the medicinal product

Glycopyrronium Bromide 1 mg/5 ml Oral Solution

2. Qualitative and quantitative composition

Each 5 ml of oral solution contains 1 mg of glycopyrronium bromide

Excipient(s) with known effect:

Sorbitol (E420)

Sodium methyl parahydroxybenzoate (E219)

Sodium propyl parahydroxybenzoate (E217)

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Oral solution

Glycopyrronium Bromide 1 mg/5 ml oral solution is a clear, colourless, strawberry flavoured liquid.

4. Clinical particulars
4.1 Therapeutic indications

For use in adults as an add-on therapy in the treatment of peptic ulcer.

4.2 Posology and method of administration

Posology

The dosage of Glycopyrronium Bromide 1 mg/5 ml oral solution should be adjusted to the needs of the individual patient to assure symptomatic control with a minimum of adverse reactions. The recommended maximum daily dosage of Glycopyrronium Bromide is 8 mg (40 ml).

The recommended initial dosage of Glycopyrronium Bromide oral solution for adults is 1 mg (5 ml) three times daily (in the morning, early afternoon, and at bedtime). Some patients may require 2 mg (10 ml) at bedtime to assure overnight control of symptoms. For maintenance, a dosage of 1 mg (5 ml) twice a day is recommended.

The presence of high fat food reduces the oral bioavailability of Glycopyrronium Bromide if taken shortly after a meal. Therefore it should be taken at least one hour before or two hours after meals.

Paediatric population

Glycopyrronium Bromide oral solution is not recommended for use in children.

Method of administration

For oral use only.

The correct quantity of Glycopyrronium Bromide oral solution should be measured and administered using the dosage cup provided and then swallowed. The dosage cup should be washed after each use with clean water (do not put it in a dishwasher).

4.3 Contraindications

• Hypersensitivity to the active substance(s) 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

4.4 Special warnings and precautions for use

Glycopyrronium Bromide oral solution should be used with caution in the elderly.

It should also be used with caution in gastro-oesophageal reflux disease, ulcerative colitis, 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.

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 (especially children) 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 oral solution.

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

Patients with rare hereditary problems of fructose intolerance should not take this medicine. This is due to the presence of sorbitol (E420) in this medicine.

Glycopyrronium Bromide oral solution contains sodium propyl parahydroxybenzoate (E217) and sodium methyl parahydroxybenzoate (E219). These may cause allergic reactions (possibly delayed).

Paediatric population

Glycopyrronium Bromide is not recommended for use in children.

4.5 Interaction with other medicinal products and other forms of interaction

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)

Possibly increased antimuscarinic side-effects: tricyclic (related) antidepressants

Anticholinergic agents may delay absorption of other medication given concomitantly.

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

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

Concurrent use with parasympathomimetics may antagonise the effect.

Specific interactions

Domperidone/Metoclopramide: antagonism of effect on gastro-intestinal activity

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)

Topiramate and zonisamide: enhanced effect (reduction of sweating)

Inhaled anaesthetics: potential change to normal heart rhythm

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no, or limited, data from the use of glycopyrronium bromide in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of Glycopyrronium Bromide oral solution during pregnancy.

Breastfeeding

It is unknown whether Glycopyrronium Bromide or its metabolites are excreted in human milk.

A risk to the newborns/infants cannot be excluded.

Breast-feeding should be discontinued during treatment with Glycopyrronium Bromide oral solution.

Fertility

Animal studies do not indicate harmful effects with respect to fertility (see section 5.3). There are no data available in humans.

4.7 Effects on ability to drive and use machines

Glycopyrronium Bromide oral solution 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.

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.

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.

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 system, 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

In common with other anticholinergics, glycopyrronium bromide has gastrointestinal, genitourinary, cardiovascular, respiratory, and ophthalmic effects. Due to its limited passage across lipid membranes, CNS effects such as drowsiness are unlikely. Specific known effects of glycopyrronium bromide 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.

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.

The incidence of expected adverse events is dose-related. Therefore, dose is to 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.

Oral glycopyrronium bromide produces 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 about 74% lower than the Cmax observed under fasting conditions.

Distribution

Glycopyrronium bromide penetrates the blood-brain barrier poorly. Glycopyrronium bromide crosses the placenta to a limited extent; and 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 the serum in 5 minutes and almost 100% in 30 minutes. Urinary radioactivity was highest in the first 3 hours and 85% was excreted in the urine within 48 hours. Paper chromatography showed 80% of the radioactivity in bile and urine corresponding to unchanged glycopyrronium bromide. Following oral administration to mice, 7.6% was excreted in the urine and about 79% in the faeces.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity and toxicity to reproduction and development.

Studies for genotoxicity and carcinogenicity for glycopyrronium bromide are inadequate to form a conclusive decision on the potential for carcinogenicity. In silico assessments with glycopyrronium bromide demonstrate a lack of genotoxicity and mutagenicity, there was no evidence of pre-neoplastic or neoplastic lesions detected in rats treated with oral glycopyrronium bromide over 180 days (6 months).

The relevance of these findings to human risk is unknown.

6. Pharmaceutical particulars
6.1 List of excipients

Glycerol

Sorbitol (E420)

Sodium methyl parahydroxybenzoate (E219)

Sodium propyl parahydroxybenzoate (E217)

Citric acid monohydrate

Trisodium citrate dihydrate

Strawberry flavour:

Flavouring substance

Maltodextrin (maize)

Acacia (E414)

Triacetin (E1518)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

12 months.

Once opened, the product may be stored for up to 28 days at a maximum of 25°C. Other in use storage times and conditions are the responsibility of the user.

6.4 Special precautions for storage

Store below 25°C. Do not freeze.

Store in the original bottle. Keep bottle in the original carton in order to protect from light.

For storage conditions after first opening of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Glycopyrronium Bromide oral solution is supplied in a 150 ml amber type III glass bottle with a tamper evident, child resistant cap.

Each bottle is provided in a cardboard carton along with a polypropylene 15 ml dosage cup with graduations to allow the correct dose to be measured.

6.6 Special precautions for disposal and other handling

No special requirements for disposal.

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

7. Marketing authorisation holder

Colonis Pharma Limited

Quantum House

Hobson Industrial Estate

Burnopfield

County Durham

NE16 6EA

United Kingdom

8. Marketing authorisation number(s)

PL 41344/0010

9. Date of first authorisation/renewal of the authorisation

13/07/2016

10. Date of revision of the text

09/01/2017

Company contact details

Colonis Pharma Ltd

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Address

Quantum House, Hobson Industrial Estate, Burnopfield, County Durham, NE16 6EA

E-mail
Medical Information e-mail
Out of Hours contact
Telephone

Reporting of side effects: +44 (0) 1892 739404

Medical Information Direct Line

+44 (0) 1892 739403

Out of Hours Telephone

+44 (0) 1892 739404

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Active ingredients

glycopyrronium bromide

Legal categories

POM - Prescription Only Medicine

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