- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
PosologyThe 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 populationGlycopyrronium Bromide oral solution is not recommended for use in children.
Method of administrationFor 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).
• 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
Paediatric populationGlycopyrronium Bromide is not recommended for use in children.
Class interactionsMany 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) antidepressantsAnticholinergic 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 interactionsDomperidone/Metoclopramide: antagonism of effect on gastro-intestinal activityLevodopa: absorption of levodopa possibly reducedHaloperidol: effects of haloperidol possibly reducedNitrates: 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
PregnancyThere 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.
BreastfeedingIt 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.
FertilityAnimal studies do not indicate harmful effects with respect to fertility (see section 5.3). There are no data available in humans.
Reporting of suspected adverse reactionsReporting 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.
• 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.
Mechanism of actionGlycopyrronium 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 effectsIn 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 safetyThe 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.
AbsorptionGlycopyrronium 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.
DistributionGlycopyrronium 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.
BiotransformationIn 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.
EliminationA 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.
Colonis Pharma Ltd
Quantum House, Hobson Industrial Estate, Burnopfield, County Durham, NE16 6EA
Reporting of side effects: +44 (0) 1892 739403
+44 (0) 1892 739403
+44 (0) 1892 739403