Glycopyrronium Bromide 200 Micrograms/Ml Solution For Injection
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Glycopyrronium Bromide 200 micrograms per ml Solution for Injection
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml of injection contains 200 micrograms (0.2mg) of Glycopyrronium Bromide.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
A clear and colourless sterile solution for Injection
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
To protect against the peripheral muscarinic actions of anticholinesterases such as Neostigmine and Pyridostigmine, used to reverse residual neuromuscular blockade produced by non-depolarising muscle relaxants.
As a pre-operative antimuscarinic agent to reduce salivary tracheobronchial and pharyngeal secretions and to reduce the acidity of the gastric contents.
As a pre-operative or intra-operative antimuscarinic to attenuate or prevent intra-operative bradycardia associated with the use of Suxamethonium or due to cardiac vagal reflexes.
4.2 Posology and method of administration
Glycopyrronium Bromide Injection is a sterile solution for intravenous or intramuscular administration.
Premedication
Adults and elderly patients:
200 to 400 micrograms (0.2mg to 0.4mg) intravenously or intramuscularly before the induction of anaesthesia. Alternatively, a dose of 4 to 5 micrograms/kg (0.004 to 0.005mg/kg) up to a maximum of 400 micrograms (0.4mg) may be used. Larger doses may result in profound and prolonged antisialogogue effect which may be unpleasant for the patient.
Paediatric population:
4 to 8 micrograms/kg (0.004 to 0.008mg/kg) up to a maximum of 200 micrograms (0.2mg) intravenously or intramuscularly before the induction of anaesthesia. Larger doses may result in profound and prolonged antisialogogue effect which may be unpleasant for the patient.
Intra-operative use Adults and elderly patients:
A single dose of 200 to 400 micrograms (0.2 to 0.4mg) by intravenous injection should be used. Alternatively, a single dose of 4 to 5 micrograms/kg (0.004 to 0.005mg/kg) up to a maximum of 400 micrograms (0.4mg) may be used. This dose may be repeated if necessary.
Paediatric population:
A single dose of 200 micrograms (0.2mg) by intravenous injection should be used. Alternatively, a single dose of 4 to 8 micrograms/kg by intravenous injection (0.004 to 0.008mg/kg) up to a maximum of 200 micrograms (0.2mg) may be used. This dose may be repeated if necessary.
Reversal of residual non-depolarising neuromuscular block
Adults and elderly patients:
200 micrograms (0.2mg) intravenously per 1000 micrograms (1mg) of Neostigmine or the equivalent dose of pyridostigmine. Alternatively, a dose of 10 to 15 micrograms/kg (0.01 to 0.015mg/kg) intravenously with 50 micrograms/kg (0.05mg/kg) Neostigmine or equivalent dose of pyridostigmine. Glycopyrronium Bromide Injection may be administered simultaneously from the same syringe with the anticholinesterase; as there are greater cardiovascular stability results from this method of administration.
Paediatric population:
10 micrograms/kg (0.01mg/kg) intravenously with 50 micrograms/kg (0.05mg/kg) Neostigmine or equivalent dose of pyridostigmine. Glycopyrronium Bromide Injection may be administered simultaneously from the same syringe with the anticholinesterase; as there are greater cardiovascular stability results from this method of administration.
4.3 Contraindications
Hypersensitivity to Glycopyrronium Bromide 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.
Anticholinesterase-antimuscarinic combinations such as neostigmine plus glycopyrronium should be avoided in patients with a prolonged QT interval.
4.4 Special warnings and precautions for use
Antimuscarinics should be used with caution (due to increased risk of side effects) in Down's syndrome, in children and in the elderly.
They should also be used with caution in gastro-oesophageal reflux disease, diarrhoea, ulcerative colitis, acute myocardial infarction, thyrotoxicosis, hypertension, congestive heart failure, 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, pyrexia (due to inhibition of sweating), pregnancy and breast feeding. As Glycopyrronium Bromide inhibits sweating, patients with increased temperature (especially children) should be observed closely.
Because of prolongation of renal elimination, repeated or large doses of Glycopyrronium Bromide should be avoided in patients with uraemia. Anticholinergic drugs can cause ventricular arrhythmias when administered during inhalation anaesthesia especially in association with the halogenated hydrocarbons.
Unlike atropine, Glycopyrronium Bromide is a quaternary ammonium compound and does not cross the blood-brain barrier. It is therefore less likely to cause postoperative confusion which is a particular concern in the elderly patients. Compared to atropine, Glycopyrronium Bromide has reduced cardiovascular and ocular effects.
This medicinal product contains less than 1 mmol sodium (23mg) per dose, i.e. essentially ‘sodium free’.
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 anticholingergics and corticosteroids may result in increased intraocular pressure.
Concurrent use of antocholinergic agents with slow-dissolving tablets of digoxin may cause increased serum digoxin levels.
Ritodrine: tachycardia
Increased antimuscarinic side-effects: amantadine; tricyclic antidepressants; antihistamines; clozapine; disopyramaide; MAOIs; nefopam; pethidine; phenothiazines (increased antimuscarinic side effects of phenothiazines but reduced plasma concentrations)
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
4.6 Fertility, pregnancy and lactation
Pregnancy:
For use as indicated, animal studies (see section 5.3) are of very limited relevance. Use in human pregnancy has not been systematically evaluated. This product should only be used in pregnancy if considered essential.
Breast-feeding:
May reach breast milk but in amounts probably too small to be harmful. Caution is advised when considering administration to a nursing mother.
4.7 Effects on ability to drive and use machines
Glycopyrronium Bromide 200 micrograms/ml Injection is used in anaesthesia. It is not anticipated that patients will be driving or operating machinery under its influence. However, systemic administration of antimuscarinics may cause blurred vision, dizziness and other effects that may impair a patient's ability to perform skilled tasks such as driving. These activities should not be undertaken until any disturbance of visual accommodation or balance has resolved.
4.8 Undesirable effects
Side effects of antimuscarinics such as Glycopyrronium Bromide are basically extensions of the fundamental pharmacological actions. These include difficulty in micturition, inhibition of sweating, constipation, transient bradycardia (followed by tachycardia, palpitations and arrythmias), reduced bronchial secretions, urinary urgency and retention, dilatation of the pupils with loss of accommodation, photophobia, dry mouth, 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.
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.
Overdose
4.9
Symptoms
Since Glycopyrronium Bromide is a quaternary ammonium agent, symptoms of overdosage are peripheral rather than central in nature.
Treatment
To combat the peripheral anticholinergic effects of Glycopyrronium Bromide a quaternary ammonium anticholinesterase such as Neostigmine methylsulfate may be given in a dose of 1000 micrograms (1.0mg) for each 1000 micrograms (1.0mg) of Glycopyrronium Bromide known to have been administered by the parenteral route.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Glycopyrronium bromide (ATC Code: A03AB02) is a quaternary ammonium antimuscarinic with peripheral effects similar to those of atropine. It is used similarly to atropine in anaesthetic practice. Given as a premedicant before general anaesthesia, it diminishes the risk of vagal inhibition of the heart and reduces salivary and bronchial secretions. Intra-operatively, it may be given to reduce bradycardia and hypotension induced by drugs such as suxamethonium, halothane or propofol. Glycopyrronium bromide may be used before, or with, anticholinesterases such as neostigmine to prevent their muscarinic adverse effects.
Antimuscarinic drugs are competitive inhibitors of the actions of acetylcholine at the muscarinic receptors of autonomic effector sites innervated by parasympathetic (cholinergic postganglionic) nerves, as well as being inhibitors of the action of acetylcholine on smooth muscle lacking 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.
Quaternary ammonium compounds are sparingly lipid soluble and do not readily pass lipid membranes such as the blood-brain barrier. Central effects are negligible.
5.2 Pharmacokinetic properties
Absorption
Following intravenous administration, onset of action occurs within one minute, with peak activity at around 5 minutes.
Following intramuscular injection, maximum plasma concentration and onset of action of Glycopyrronium Bromide is achieved within 30 minutes. Peak effects occur after approximately 30 - 45 minutes; vagal blocking effects last for 2 - 3 hours and antisialagogue effects persist for 7 - 8 hours. There is a faster absorption rate when Glycopyrronium Bromide is injected into the deltoid muscle rather than into the gluteal or vastus lateralis muscles.
Distribution
Cerebrospinal fluid levels of Glycopyrronium Bromide remain below detection level up to one hour after therapeutic dosing.
Elimination
Following either intravenous or intramuscular administration, 50% of Glycopyrronium Bromide is excreted in the urine in 3 hours in non-uraemic individuals; renal elimination is considerably prolonged in patients with uraemia. Appreciable amounts are excreted in bile. In 48 hours, 85% has been excreted into the urine. About 80% of the excreted amount is as unchanged Glycopyrronium Bromide or active metabolites. Although the elimination half-life of Glycopyrronium Bromide from plasma is within 75 minutes, quantifiable levels may remain up to 8 hours after administration.
5.3 Preclinical safety data
No further relevant information other than that which is included in other sections of the Summary of Product Characteristics.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sodium Chloride Hydrochloric Acid Water for Injections
6.2 Incompatibilities
Glycopyrronium Bromide Injection has been shown to be physically compatible with the following agents commonly used in anaesthetic practice: Butorphanol, Lorazepam, Droperical and Fentanyl Citrate, Levorphanol Tartrate, Pethidine Hydrochloride, Morphine Sulfate, Neostigmine, Promethazine and Pyridostigmine.
Glycopyrronium Bromide Injection has been shown to be physically incompatible with the following agents commonly used in anaesthetic practice: Diazepam, Dimenhydrinate, Methohexital Sodium, Pentazocine, Pentobarbital Sodium and Thiopental Sodium.
6.3 Shelf life
2 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Glycopyrronium Bromide Injection is presented in clear Type I ampoules of neutral glass containing 10 x 1ml ampoules or 10 x 3ml ampoules packed in a cardboard carton.
6.6 Special precautions for disposal
Keep out of the sight and reach of children.
If only part of an ampoule is used, discard the remaining solution.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Martindale Pharmaceuticals Ltd
T/A Martindale Pharma
Bampton Road
Harold Hill
Romford
Essex
RM3 8UG
UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 00156/0115
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation in: 7th September 2007
07/10/2016