Glycopyrrolate USP, solution for injection, glycopyrronium bromide 200 mcg/ml
Glycopyrronium Bromide 200 micrograms per ml Solution for Injection is a sterile, clear and colourless isotonic solution, free from visible particles. 1 ml solution contains: Glycopyrrolate USP corresponding to Glycopyrronium bromide 200 micrograms. It is presented in two ampoule sizes:
0.2 mg in 1 ml
0.6 mg in 3 ml
Pharmacotherapeutic group
A03AB02: member of A03AB - synthetic anticholinergics, quaternary ammonium compounds, a subset of A03A - drugs for functional bowel disorders.
Glycopyrrolate (or glycopyrronium bromide) 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. Glycopyrrolate antagonises muscarinic symptoms (e.g. bronchorrhoea, bronchospasm, bradycardia, and intestinal hypermotility) induced by cholinergic medicines such as anticholinesterases. 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.
Absorption
Pharmacokinetic studies in normal volunteers given a single intravenous infusion of 0.4 mg glycopyrrolate yielded a peak plasma concentration immediately following the end of the infusion of 26.4 +- 7.6 mg/ml.
Please refer to the Medsafe website (www.medsafe.govt.nz) for the most recent version of this prescribing information.
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NEW ZEALAND DATA SHEET
Glycopyrrolate USP, solution for injection, glycopyrronium bromide 200 mcg/ml
Distribution
The highly polar quaternary ammonium group of 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. From studies in normal volunteers given a single intravenous infusion of 0.4 mg glycopyrrolate, the volume of distribution was 0.158 +- 0.28 litres/kg, suggesting that glycopyrrolate is not widely distributed to the tissues.
Biotransformation
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 medicine.
Elimination
Pharmacokinetic studies in normal volunteers given a single intravenous infusion of 0.4 mg glycopyrrolate showed that the medicine undergoes a rapid distribution/elimination phase (t
1/2
= 5 minutes) followed by a more prolonged termination elimination phase (t1/2 = 1.7 hours).
In anaesthesia
Glycopyrrolate is indicated for use as a preoperative antimuscarinic to reduce salivary, tracheobronchial and pharyngeal secretions; to reduce the volume and free acidity of gastric secretions, and to block cardiac vagal inhibitory reflexes during induction of anaesthesia and intubation when indicated. Glycopyrronium Bromide 200 micrograms per ml Solution for Injection may be used intraoperatively to counteract drug-induced or vagal traction reflexes with the associated arrhythmias. Glycopyrrolate protects against the peripheral muscarinic effects (e.g. bradycardia and excessive secretions) of cholinergic agents such as neostigmine and pyridostigmine given to reverse the neuromuscular blockade due to non-depolarising muscle relaxants.
In peptic ulcer
For use in adults as adjunctive therapy for the treatment of peptic ulcer when rapid anticholinergic effect is desired or when oral medication is not tolerated.
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.
Please refer to the Medsafe website (www.medsafe.govt.nz) for the most recent version of this prescribing information.
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NEW ZEALAND DATA SHEET
Glycopyrrolate USP, solution for injection, glycopyrronium bromide 200 mcg/ml
Children (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.
All age groups
Refer to Contraindications. Larger doses may result in profound and prolonged anti- sialogogue 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.
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.
All age groups
Glycopyrrolate may be administered simultaneously from the same syringe with the anticholinesterase; greater cardiovascular stability results from this method of administration.
For intramuscular or intravenous administration.
Known hypersensitivity to glycopyrrolate, or any of the inactive ingredients.
Please refer to the Medsafe website (www.medsafe.govt.nz) for the most recent version of this prescribing information.
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NEW ZEALAND DATA SHEET
Glycopyrrolate USP, solution for injection, glycopyrronium bromide 200 mcg/ml
Glycopyrrolate should be used with caution, if at all, in patients with glaucoma or asthma. Glycopyrrolate 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 medicine would be inappropriate and possibly harmful. In the case of ulcerative colitis, large doses of glycopyrrolate may suppress intestinal motility resulting in production of paralytic ileus perhaps precipitating or aggravating toxic megacolon. In the ambulatory patient glycopyrrolate 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 medicine. 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 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 glycopyrrolate 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 glycopyrrolate in patients with myaesthenia gravis. The duration of effect of glycopyrrolate may be prolonged in patients with renal impairment since glycopyrrolate is excreted mostly in urine as unchanged medicine. Dosage adjustment may be needed for patients in renal failure. The use of anticholinergic agents in the treatment of gastric ulcer may produce a delay in gastric emptying due to antral stasis.
Please refer to the Medsafe website (www.medsafe.govt.nz) for the most recent version of this prescribing information.
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NEW ZEALAND DATA SHEET
Glycopyrrolate USP, solution for injection, glycopyrronium bromide 200 mcg/ml
Arrhythmias associated with the use of 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 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 glycopyrrolate is therefore not recommended in paediatric patients.
Clinical studies of 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.
Use in pregnancy
Assigned Category B2 in the Australian Categorisation of risk system. Category B2 refers to medicines which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed. Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of foetal damage. Clinically the safe use of glycopyrrolate has not been established. Single-dose studies in humans found that only very small amounts of glycopyrrolate passed the placental barrier. Therefore, the medicine 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 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 glycopyrrolate. The significance of this for humans is not clear.
Please refer to the Medsafe website (www.medsafe.govt.nz) for the most recent version of this prescribing information.
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NEW ZEALAND DATA SHEET
Glycopyrrolate USP, solution for injection, glycopyrronium bromide 200 mcg/ml
Use in lactation
Anticholinergic agents may suppress lactation. It is not known whether glycopyrrolate is excreted in human milk. Therefore, it is not recommended for nursing mothers unless the expected benefits outweigh any potential risk.
Do not operate or drive heavy machinery until instructed by a physician.
Long-term studies in animals have not been performed to evaluate the carcinogenic or mutagenic potential of glycopyrrolate.
The following reported adverse reactions are extensions of glycopyrrolate's 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.
Please refer to the Medsafe website (www.medsafe.govt.nz) for the most recent version of this prescribing information.
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NEW ZEALAND DATA SHEET
Glycopyrronium Bromide 200 micrograms per ml Solution for Injection
Glycopyrrolate USP, solution for injection, glycopyrronium bromide 200 mcg/ml
General
Hyperpyrexia, bloated feeling, anaphylaxis/anaphylactoid reaction, hypersensitivity. Injection site reactions including pruritus, oedema, erythema, pain have been reported rarely.
The use of 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 glycopyrrolate is used during cyclopropane anaesthesia. If the medicine 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 glycopyrrolate 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.
The signs and symptoms of overdosage reflect the pharmacological effects of 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 medicine.
Please refer to the Medsafe website (www.medsafe.govt.nz) for the most recent version of this prescribing information.
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NEW ZEALAND DATA SHEET
Glycopyrrolate USP, solution for injection, glycopyrronium bromide 200 mcg/ml
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.
Contact the National Poisons Centre by telephoning 0800 POISON or 0800 764 766 for further advice on overdose management.
Glycopyrronium Bromide 200 micrograms per ml Solution for Injection is compatible for mixing and injection with pethidine hydrochloride; morphine sulfate; droperidol plus fentanyl citrate; hydroxyzine; neostigmine; promethazine and pyridostigmine. Glycopyrronium Bromide 200 micrograms per ml Solution for Injection 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 Ringers solution.
Since the stability of glycopyrrolate is questionable above a pH of 6.0, do not inject glycopyrrolate 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 ringers solution will result in a pH higher than 6.0.
Store at or below 25degC.
Please refer to the Medsafe website (www.medsafe.govt.nz) for the most recent version of this prescribing information.
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NEW ZEALAND DATA SHEET
Glycopyrrolate USP, solution for injection, glycopyrronium bromide 200 mcg/ml
Opened container
For single use only. Store the neat or diluted solution between 2 to 8degC. Do not use if more than 24 hours has elapsed since the solution was opened and/or diluted. Do not use if visible particles are present.
Prescription Medicine
0.2 mg in 1 ml
Packs of 10 ampoules.
0.6 mg in 3 ml
Packs of 10 ampoules.
Sodium chloride, water for injections. Solution is adjusted to pH 2.5 with hydrochloric acid.
Max Health Limited P O Box 65-231 Mairangi Bay Auckland 0754 Telephone: 09 476 9469 Fax: 09 476 0972
12 December 2012 Version 1. Revisions to the previous version are indicated by ( *).
Please refer to the Medsafe website (www.medsafe.govt.nz) for the most recent version of this prescribing information.
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