1 Name of Medicine
Glycopyrronium bromide (glycopyrrolate).
2 Qualitative and Quantitative Composition
Glycopyrronium-AFT 1 mL ampoule contains glycopyrronium bromide (glycopyrrolate) 0.2 mg as the active ingredient.
For the full list of excipients, see Section 6.1 List of Excipients.
3 Pharmaceutical Form
Clear, colourless solution for injection, free from visible particles and fibres.
4.1 Therapeutic Indications
As a preoperative antimuscarinic to reduce salivary, tracheobronchial and pharyngeal secretions, and to reduce the acidity and volume of the gastric contents.
As a preoperative or intra-operative antimuscarinic to attenuate or prevent intra-operative bradycardia associated with the use of suxamethonium or due to cardiac vagal reflexes.
To protect against the peripheral muscarinic actions (e.g. bradycardia and excessive secretions) of anticholinesterases such as neostigmine or pyridostigmine given to reverse neuromuscular blockade produced by non-depolarising muscle relaxants.
4.2 Dose and Method of Administration
For intramuscular or intravenous administration.
Pre-anaesthetic use.
Adults.
0.2 mg to 0.4 mg intravenously or intramuscularly before the induction of anaesthesia.
Alternatively, a dose of 0.004 to 0.005 mg/kg up to a maximum of 0.4 mg may be used. Larger doses may result in profound and prolonged antisialogogue effect, which may be unpleasant for the patient.
Children (see Section 4.3 Contraindications).
1 month to 12 years of age 0.004 to 0.008 mg/kg up to a maximum of 0.2 mg 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.
Intraoperative use.
When used to treat arrhythmias associated with traction reflexes, the usual attempts should be made to determine the aetiology of the arrhythmia, and the surgical or anaesthetic manipulations necessary to correct parasympathetic imbalance should be performed.
Adults.
In those situations where intraoperative use is indicated, a single dose of 0.2 to 0.4 mg (or 0.004 to 0.005 mg/kg up to a maximum of 0.4 mg) by intravenous injection should be used. This dose may be repeated if necessary.
Children (1 month to 12 years of age).
In those situations where intraoperative use is indicated, a single dose of 0.004 to 0.008 mg/kg or up to a maximum of 0.2 mg by intravenous injection should be used. This dose may be repeated if necessary.
Reversal of neuromuscular blockade.
Adults.
0.2 mg intravenously per 1 mg neostigmine or the equivalent dose of pyridostigmine. Alternatively, a dose of 0.01-0.015 mg intravenously with 0.05 mg/kg neostigmine or equivalent dose of pyridostigmine. Glycopyrronium-AFT may be administered simultaneously from the same syringe with the anticholinesterase; greater cardiovascular stability results from this method of administration.
Children (1 month to 12 years of age).
0.01 mg/kg intravenously with 0.05 mg/kg neostigmine or the equivalent dose of pyridostigmine. Glycopyrronium-AFT may be administered simultaneously from the same syringe with the anticholinesterase; greater cardiovascular stability results from this method of administration.4.3 Contraindications
Known hypersensitivity to glycopyrronium bromide (glycopyrrolate) or any of the inactive ingredients (see Section 4.8 Adverse Effects (Undesirable Effects)).
4.4 Special Warnings and Precautions for Use
Glycopyrronium-AFT should be used with caution, if at all, in patients with glaucoma or asthma.
Glycopyrronium-AFT should be used with caution in patients with any of the following conditions: obstructive uropathy, obstructive disease of the gastrointestinal tract, paralytic ileus, intestinal atony, unstable cardiovascular status in acute haemorrhage, severe ulcerative colitis and toxic megacolon complicating ulcerative colitis, autonomic neuropathy and prostatic hypertrophy.
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.
In the case of ulcerative colitis, large doses of Glycopyrronium-AFT may suppress intestinal motility resulting in production of paralytic ileus perhaps precipitating or aggravating toxic megacolon.
Hiatus hernia associated with reflux oesophagitis may be aggravated following administration of this medicine.
Use with caution in patients with coronary artery disease; congestive heart failure; cardiac arrhythmias; hypertension or hyperthyroidism since an increase in heart rate may occur. Investigate any tachycardia before giving glycopyrronium bromide (glycopyrrolate) as an increase in heart rate may occur.
In the presence of fever, as in high environmental temperature, and physical exercise, reduced sweating can occur with Glycopyrronium-AFT causing, heat prostration (fever and heat stroke). Use very cautiously when the ambient temperature is high and in pyrexic patients, especially children and the elderly, who have a tendency to sweat less.
Large doses of quaternary ammonium anticholinergic compounds have been shown to block end-plate nicotinic receptors. This should be considered before using glycopyrronium bromide (glycopyrrolate) in patients with myaesthenia gravis.
Use in hepatic impairment.
No data available.
Use in renal impairment.
The duration of effect of Glycopyrronium-AFT may be prolonged in patients with renal impairment since glycopyrronium bromide (glycopyrrolate) is excreted mostly in urine as unchanged drug. Dosage adjustment may be needed for patients in renal failure.
Use in the elderly.
Clinical studies of glycopyrronium bromide (glycopyrrolate) did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy.
Paediatric use.
Arrythmias associated with the use of glycopyrronium bromide (glycopyrrolate) intravenously as a premedication or during anaesthesia appear to be more likely in paediatric patients than in adults.
Infants, patients with Down's syndrome, and paediatric patients with spastic paralysis or brain damage may experience an increased response to anticholinergics, thus increasing the potential for side effects.
A paradoxical reaction characterised by hyperexcitability may occur in paediatric patients taking large doses of anticholinergics including glycopyrronium bromide (glycopyrrolate). Infants and young children are especially susceptible to the toxic effects of anticholinergics.
Safety and effectiveness of long-term IV use has not been established in paediatric patients. Long-term use of Glycopyrronium-AFT is therefore not recommended in paediatric patients.
Effects on laboratory tests.
No data available.4.5 Interactions with Other Medicines and Other Forms of Interactions
The use of glycopyrronium bromide (glycopyrrolate), like atropine, with or within several hours of ritodrine hydrochloride administration may result in a drug interaction causing tachycardia.
The intravenous administration of any anticholinergic in the presence of cyclopropane anaesthesia can result in ventricular arrhythmias; therefore, caution should be observed if Glycopyrronium-AFT is used during cyclopropane anaesthesia. If the drug is given in small incremental doses of 0.1 mg or less, the likelihood of producing ventricular arrhythmias is reduced.
Anticholinergic agents may delay absorption of other medications given concomitantly.
Excessive cholinergic blockade can occur if Glycopyrronium-AFT is given concomitantly with belladonna alkaloids or other synthetic anticholinergic agents (such as antiparkinsonism agents), phenothiazines, tricyclic antidepressants, disopyramide, procainamide, quinidine, some antihistamines, narcotic analgesics such as pethidine, thioxanthenes, butyrophenones or amantadine.
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.
Glycopyrronium-AFT is compatible for mixing and injection with pethidine hydrochloride; morphine sulfate; droperidol plus fentanyl citrate; hydroxyzine; neostigmine; promethazine and pyridostigmine. Glycopyrronium-AFT may be mixed with 4%-10% glucose in water or saline, or it may be administered via the tubing of a running infusion of physiological saline, glucose, or lactated Ringer's solution.
Since the stability of glycopyrronium bromide (glycopyrrolate) is questionable above a pH of 6.0, do not inject Glycopyrronium-AFT at the same intramuscular site or combine it in the same syringe with: thiopentone sodium; chloramphenicol; diazepam; dimenhydrinate; methohexitone sodium; pentazocine lactate; pentobarbitone sodium; quinalbarbitone; or sodium bicarbonate. A gas will evolve or a precipitate may form.
Mixing with dexamethasone, sodium phosphate or a buffered solution of lactated Ringer's solution will result in a pH higher than 6.0.
4.6 Fertility, Pregnancy and Lactation
Effects on fertility.
Long-term studies in animals have not been performed to evaluate the mutagenic potential of glycopyrronium bromide (glycopyrrolate).
(Category B2)
Clinically the safe use of glycopyrronium bromide (glycopyrrolate) has not been established. Single-dose studies in humans found that only very small amounts of glycopyrronium bromide (glycopyrrolate) passed the placental barrier. Therefore, the drug should not be used in pregnant women or those likely to become pregnant, unless the expected benefits outweigh any potential risk.
Reproduction studies in rats and rabbits did not reveal any teratogenic effects from glycopyrronium bromide (glycopyrrolate). Diminished rates of conception and of survival of 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 (glycopyrrolate). The significance of this for humans is not clear.
Anticholinergic agents may suppress lactation. It is not known whether glycopyrronium bromide (glycopyrrolate) is excreted in human milk.
Therefore, it is not recommended for nursing mothers unless the expected benefits outweigh any potential risk.4.7 Effects on Ability to Drive and Use Machines
In the ambulatory patient Glycopyrronium-AFT 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 Adverse Effects (Undesirable Effects)
Reporting suspected adverse effects.
Reporting suspected adverse reactions after registration 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 at https://www.tga.gov.au/reporting-problems (Australia) or https://nzphvc.otago.ac.nz/reporting (New Zealand).
The following reported adverse reactions are extensions of Glycopyrronium-AFT fundamental pharmacological actions:
Cardiovascular.
Tachycardia, ventricular fibrillation, bradycardia, palpitation and arrhythmia, hypertension, hypotension, cardiac arrest, heart block, prolonged QTc interval.
Dermatological.
Flushing and inhibition of sweating. Severe allergic reactions or drug idiosyncrasies including urticaria and other dermal manifestations, pruritus, dry skin.
Gastrointestinal.
Nausea, vomiting, dry mouth, constipation, taste alterations, including loss of taste.
Genitourinary.
Urinary hesitancy and retention, impotence.
Ocular.
Blurred vision due to mydriasis, cycloplegia, photophobia, increased ocular tension.
Nervous system.
Inhibition of transmission at neuromuscular junction, headache, nervousness, drowsiness, dizziness, seizure, insomnia, some degree of mental confusion, especially in the elderly, hyperexcitability in children.
Pregnancy and perinatal.
Suppression of lactation.
Respiratory system.
Respiratory arrest.
General.
Hyperpyrexia, bloated feeling, anaphylaxis/anaphylactoid reaction, hypersensitivity. Injection site reactions including pruritus, oedema, erythema, pain have been reported rarely.4.9 Overdose
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia) or the National Poisons Centre on 0800 POISON (0800 764766) (New Zealand).
The signs and symptoms of overdosage reflect the pharmacological effects of glycopyrronium bromide (glycopyrrolate). These may include hypotension, respiratory failure and a curare-like action, i.e. neuromuscular blockade leading to muscular weakness and possibly paralysis.
Treatment should be symptomatic.
Dialysis is of no value because of low plasma concentrations of the drug.
To combat peripheral anticholinergic effects a quaternary ammonium anticholinesterase such as neostigmine methylsulfate may be given intravenously in increments of 0.25 mg in adults.
This dosage may be repeated every five to ten minutes until anticholinergic over-activity is reversed or up to a maximum of 2.5 mg. Proportionately smaller doses should be used in children. Indication for repetitive doses of neostigmine should be based on close monitoring of the decrease in heart rate and the return of bowel sounds.
In the unlikely event that CNS symptoms (excitement, restlessness, convulsions, psychotic behaviour) occur, physostigmine (which does cross the blood-brain barrier) should be used. Physostigmine 0.5 to 2.0 mg should be slowly administered intravenously and repeated as necessary up to a total of 5 mg in adults. Proportionately smaller doses should be used in children.
Fever should be treated symptomatically. In the event of a curare-like effect on respiratory muscles, artificial respiration should be instituted and maintained until effective respiratory action returns.
5 Pharmacological Properties
5.1 Pharmacodynamic Properties
Mechanism of action.
Glycopyrronium bromide (glycopyrrolate) is a synthetic anticholinergic agent. 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. Doses which produce marked antisialogogue actions have little effect on heart rate, visual accommodation, or pupil size.
Glycopyrronium bromide (glycopyrrolate) antagonises muscarinic symptoms (e.g. bronchorrhoea, bronchospasm, bradycardia, and intestinal hypermotility) induced by cholinergic drugs such as anticholinesterases.
The highly polar quaternary ammonium group of glycopyrronium bromide (glycopyrrolate) limits its passage across lipid membranes, such as the blood-brain barrier, in contrast to atropine sulfate and hyoscine hydrobromide, which are non-polar tertiary amines that penetrate lipid barriers easily.
Clinical trials.
No data available.
5.2 Pharmacokinetic Properties
Absorption.
Peak effects occur approximately 30 to 45 minutes after intramuscular administration. The vagal blocking effects persist for 2 to 3 hours and the antisialogogue effects persist up to 7 hours, periods longer than for atropine. With intravenous injection, the onset of action is generally evident within one minute.
Distribution.
Pharmacokinetic studies in normal volunteers given a single intravenous infusion of 0.4 mg glycopyrronium bromide (glycopyrrolate) showed that the drug undergoes a rapid distribution/elimination phase (t1/2 = 5 min) followed by a more prolonged termination elimination phase (t1/2 = 1.7 hr). The peak plasma concentration immediately following the end of the infusion was 26.4 mg/mL (+7.6), and the volume of distribution was 0.158+0.28 L/kg, which suggests that glycopyrronium bromide (glycopyrrolate), is not widely distributed to the tissues.
Metabolism.
No data available.
Excretion.
Excretion is via the urine and bile. Radioactivity studies have shown that 85% is excreted in the urine within 48 hours, over 80% of this being unchanged drug.
5.3 Preclinical Safety Data
Genotoxicity.
No data available.
Carcinogenicity.
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of glycopyrronium bromide (glycopyrrolate).6 Pharmaceutical Particulars
6.1 List of Excipients
Excipients include water for injections, sodium chloride and hydrochloric acid (for pH adjustment).
6.2 Incompatibilities
Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
6.3 Shelf Life
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). In New Zealand, information on the shelf life can be found on Therapeutic Products Database. The expiry date can be found on the packaging.
6.4 Special Precautions for Storage
Store below 25°C. Protect from light.
Product is for single use in one patient only. Discard any residue.
6.5 Nature and Contents of Container
Glycopyrronium-AFT is supplied in 1 mL flint OPC glass ampoule with green colour dot. Available in packs of 5 and 10 ampoules.
6.6 Special Precautions for Disposal
Any unused medicine or waste material should be disposed of in accordance with local requirements.
6.7 Physicochemical Properties
Chemical structure.
CAS number.
596-51-0.
Molecular formula: C19H28BrNO3.
Molecular mass: 398.33.
The chemical name(s) for glycopyrronium bromide (glycopyrrolate) is: Pyrrolidinium, 3- [(cyclopentylhydroxyphenylacetyl) oxy]-1,1-dimethyl- bromide. 3-Hydroxy-1,1- dimethylpyrrolidinium bromide α -cyclopentylmandelate.
Glycopyrronium bromide (glycopyrrolate) is White or almost white, crystalline powder. It is freely soluble in water, soluble in ethanol (96%), very slightly soluble in methylene chloride.7 Medicine Schedule (Poisons Standard)
Prescription only Medicine (Schedule 4).
Summary Table of Changes
