Glycopyrronium Bromide 1mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Glycopyrronium Bromide 1mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 1mg of Glycopyrronium Bromide For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Tablets
White to off white round scored uncoated tablet engraved with “GP” & “1” on either side of score line and plain on the other.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
For use in adults as add-on therapy in the treatment of peptic ulcer.
4.2 Posology and method of administration
Posology
The dosage of Glycopyrronium Bromide 1 mg or 2 mg Tablets should be adjusted to the needs of the individual patient to assure symptomatic control with a minimum of adverse reactions. The presently recommended maximum daily dosage of Glycopyrronium Bromide is 8 mg.
Glycopyrronium Bromide 1mg Tablets.
The recommended initial dosage of Glycopyrronium Bromide 1 mg Tablets for adults is one tablet three times daily (in the morning, early afternoon, and at bedtime). Some patients may require two tablets at bedtime to assure overnight control of symptoms. For maintenance, a dosage of one tablet twice a day is frequently adequate.
Glycopyrronium Bromide 2mg Tablets.
The recommended dosage of Glycopyrronium Bromide 2 mg Tablets for adults is one tablet two or three times daily at equally spaced intervals.
Paediatric population
Glycopyrronium Bromide Tablets are not recommended for use in children.
Method of administration For oral administration
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 block end plate nicotinic receptors); paralytic ileus; pyloric stenosis; prostatic enlargement.
4.4 Special warnings and precautions for use
Glycopyrronium Bromide Tablets should be used with caution in the elderly.
They 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 their administration, coronary artery disease and cardiac arrhythmias.
Diarrhoea may be an early symptom of incomplete intestinal obstruction, especially in patients with ileostomy or colostomy. In this instance treatment with this drug would be inappropriate and possibly harmful.
As Glycopyrronium Bromide inhibits sweating, patients with increased temperature should be observed closely. In the presence of a high environmental temperature, heat prostration (fever and heat stroke due to decreased sweating) can occur with use of Glycopyrronium Bromide tablets.
Because of prolongation of renal elimination, repeated or large doses of Glycopyrronium Bromide should be avoided in patients with uraemia.
Large doses of quaternary anticholinergic compounds have been shown to block end plate nicotinic receptors. This should be considered before using Glycopyrronium Bromide in patients with myasthenia gravis.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Paediatric population Not applicable
4.5 Interaction with other medicinal products and other forms of interaction
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.
Anticholinergic agents may delay absorption of other medication given concomitantly.
Concurrent administration of anticholinergics and corticosteroids may result in increased intraocular pressure.
Concurrent use of anticholinergic agents with slow-dissolving tablets of digoxin may cause increased serum digoxin levels.
Increased antimuscarinic side-effects: amantadine; tricyclic antidepressants; antihistamines; clozapine; disopyramide; MAOIs; nefopam; pethidine; phenothiazines (increased antimuscarinic side effects of phenothiazines but reduced plasma concentrations)
Possibly increased antimuscarinic side-effects: tricyclic (related) antidepressants Domperidone/Metoclopramide: antagonism of effect on gastro-intestinal activity Ketoconazole: reduced absorption of ketoconazole Levodopa: absorption of levodopa possibly reduced Memantine: effects possibly enhanced by memantine
Nitrates: possibly reduced effect of sublingual nitrates (failure to dissolve under the tongue owing to dry mouth)
Parasympathomimetics: antagonism of effect
Ritodrine: tachycardia
Paediatric population Not applicable
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no or limited amount of 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 Tablets 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 Tablets.
Fertility
Reproduction studies in rats revealed no teratogenic effects from Glycopyrronium Bromide; however, the potent anticholinergic action of this agent resulted in diminished rates of conception and of survival at weaning, in a dose-related manner. Other studies in dogs suggest that this may be due to diminished seminal secretion which is evident at high doses of Glycopyrronium Bromide.
No data are available in humans.
4.7 Effects on ability to drive and use machines
Glycopyrronium Bromide tablets 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, difficulty in micturition, inhibition of sweating. Side-effects of antimuscarinics include 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.
Side-effects that occur occasionally include confusion (particularly in the elderly), nausea, vomiting, and giddiness; very rarely, angle-closure glaucoma may occur.
Paediatric population Not applicable
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.
The symptoms of overdosage of Glycopyrronium Bromide are peripheral in nature rather than central. Treatment 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.) - utilize a quaternary ammonium anticholinesterase, such as neostigmine methylsulfate in increments of 0.25mg in adults. The dose may be repeated every 5 - 10 minutes until anticholinergic over-activity is reversed or up to a maximum of 2.5mg. 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; utilize a respiratory stimulant such as Doxapram hydrochloride i.v.; 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 quaternary ammonium antimuscarinic agent and like other anticholinergic 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. Glycopyrronium Bromide antagonizes muscarinic symptoms (e.g. bronchorrhea, bronchospasm, bradycardia and intestinal hypermotility) induced by cholinergic drugs such as the anticholinesterases.
The highly polar quaternary ammonium group of Glycopyrronium Bromide limits its passage across lipid membranes, such as the blood-brain barrier, in contrast to atropine sulphate and scopolamine hydrobromide, which are non-polar tertiary amines which penetrate lipid barriers easily.
Pharmacodynamic effects
In common with other cholinergics, Glycopyrronium Bromide has gastrointestinal, genitourinary, cardiovascular, respiratory, and ophthalmic effects. Some antimuscarinic agents such as atropine cross the blood brain barrier to cause CNS effects such as drowsiness. In contrast, Glycopyrronium Bromide does not, so drowsiness is not a common adverse event. Specific known effects of Glycopyrronium Bromide include xerostomia, diminished gastrointestinal motility, decreased perspiration, increased body temperature, urinary retention, pupil dilation, loss of focusing accommodation, and increased heart rate. These expected effects of antimuscarinic drugs make them useful in treating certain conditions such as gastric ulcers, excess perspiration, overactive bladder, and pupil dilation during ophthalmologic examination. Treatment of drooling, is also a potential therapeutic use for the xerostomic effect of Glycopyrronium Bromide.
Clinical efficacy and safety
Glycopyrronium Bromide, like other anticholinergic (antimuscarinic) agents, 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 sino-atrial 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. Glycopyrronium Bromide antagonizes muscarinic symptoms (e.g., bronchorrhoea, bronchospasm, bradycardia, and intestinal hypermotility) induced by cholinergic drugs such as the anticholinesterases. The highly polar quaternary ammonium group of Glycopyrronium Bromide limits its passage across lipid membranes, such as the blood-brain barrier, in contrast to atropine sulphate and scopolamine hydrobromide, which are non-polar tertiary amines which penetrate lipid barriers easily.
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; about 10 to 25% is absorbed after an oral dose. Oral Glycopyrronium Bromide has low oral bioavailability, a median of 3.3% is found in plasma.
Oral Glycopyrronium Bromide (2 mg) produces low plasma concentrations (Cmax 190 - 440 pg/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 IV Glycopyrronium Bromide is excreted as one or more metabolites.
Elimination
Glycopyrronium Bromide is excreted largely unchanged in the urine. Approximately 65-80% of an IV Glycopyrronium Bromide dose was eliminated unchanged in urine in adults. In two studies, after IV administration to paediatric patients ages 1-14 years, mean clearance values ranged from 1.01- 1.41 L/kg/hr (range 0.32 - 2.22 L/kg/hr). In adults, IV clearance values were 0.54 ± 0.14 L/kg/hr.
5.3 Preclinical safety data
Acute toxicity of Glycopyrronium Bromide was studied in mice and rats. Following intraperitoneal administration, the LD50 was estimated to be 107 mg/kg in mice and 196 mg/kg in rats. Following oral dosing, the LD50 was estimated to be 1150 mg/kg in rats. Chronic oral administration 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. There were no changes in organ weight and histopathology showed no drug-related changes.
Although reproduction studies in rats and rabbits revealed no teratogenic effects from Glycopyrronium Bromide, safety in human pregnancy and lactation has not been established. Diminished rates of conception and of survival at weaning were observed in rats, in a dose-related manner. Studies in dogs suggest that this may be due to diminished seminal secretion which is evident at high doses of Glycopyrronium Bromide. The significance of this for man is not clear.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Calcium hydrogen phosphate dihydrate
Lactose anhydrous
Povidone
Sodium starch glycolate Magnesium stearate
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
After first opening: 3 months
6.4 Special precautions for storage
None
6.5 Nature and contents of container
Tablets are packed in a white HDPE bottle with a child resistant closure containing 10, 14, 28, 30, 56, 60, 90 and 100 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No Special requirements for disposal.
7 MARKETING AUTHORISATION HOLDER
Kinedexe UK Ltd Unit 15 Moorcroft Harlington Road Uxbridge UB8 3HD, UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 44710/0017
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
20/04/2016
10 DATE OF REVISION OF THE TEXT
20/04/2016