Glycopyrrolate-Neostigmine Injection
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Glycopyrrolate-Neostigmine Injection.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 1ml of solution contains 0.5mg of glycopyrrolate USP and 2.5mg of neostigmine metilsulfate BP/PhEur.
3. PHARMACEUTICAL FORM
Clear, colourless sterile solution for injection intended for parenteral administration presented in 1ml clear, type 1, Ph.Eur. glass ampoules.
4 CLINICAL PARTICULARS
4.1. Therapeutic Indications
Reversal of residual non-depolarising (competitive) neuromuscular block.
4.2. Posology and Method of Administration
Glycopyrrolate-Neostigmine injection is for intravenous administration.
Adults and older patients: 1-2 ml intravenously over a period of 10-30 seconds [equivalent to neostigmine metilsulfate 2500 micrograms (2.5mg) with glycopyrrolate 500 micrograms (0.5mg) to neostigmine metilsulfate 5000 micrograms (5mg) with glycopyrrolate 1000 micrograms (1mg)].
Alternatively 0.02ml/kg intravenously over a period of 10-30 seconds may be used [equivalent to neostigmine metilsulfate 50 micrograms/kg (0.05mg/kg) with glycopyrrolate 10 micrograms/kg (0.01mg/kg)].
Children: 0.02ml/kg intravenously over a period of 10-30 seconds [equivalent to neostigmine metilsulfate 50 micrograms/kg (0.05mg/kg) with glycopyrrolate 10 micrograms/kg (0.01mg/kg)]. Alternatively, dilute to 10ml with Water for Injections BP or Sodium Chloride injection BP 0.9% w/v and administer 1ml per 5kg bodyweight.
These doses may be repeated if adequate reversal of neuromuscular blockade is not achieved. Total doses in excess of 2ml are not recommended as this dose of neostigmine may produce depolarising neuromuscular block.
4.3 Contra-Indications
Glycopyrrolate-Neostigmine Injection should not be given to patients with known hypersensitivity to either of the two active ingredients or any of the excipients.
Glycopyrrolate-Neostigmine Injection should not be given in conjunction with suxamethonium as neostigmine potentiates the depolarising myoneural blocking effects of this agent.
4.4 Special Warnings and Special-Precautions for Use
Administer with caution to patients with bronchospasm, or severe bradycardia. Administration of anticholinesterase agents to patients with intestinal anastomosis may produce rupture of the anastomosis or leakage of intestinal contents. Although Glycopyrrolate-Neostigmine Injection has been shown to have less impact on the cardiovascular system than atropine with neostigmine metilsulfate, use with caution in patients with coronary artery disease, congestive heart failure, cardiac dysrhythmias, hypertension, thyrotoxicosis and cardiac insufficiency. Use with caution in patients with epilepsy or Parkinsonism. As glycopyrrolate - inhibits sweating, patients with increased temperature (especially children) should be observed closely.
In common with other antimuscarinic drugs caution is advised in patients with prostatic hypertrophy, paralytic ileus, pyloric stenosis and closed angle glaucoma.
Anticholinergic drugs can cause ventricular arrhythmias when administered during inhalation anaesthesia especially in association with the halogenated hydrocarbons.
Quaternary ammonium compounds in large dose have been shown to block the nicotinic muscle end plate receptors. This must be evaluated prior to its administration in patients with myasthenia gravis.
Unlike atropine, glycopyrrolate 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, glycopyrrolate has reduced cardiovascular and ocular effects.
Neostigmine metilsulfate: Glycopyrronium or alternatively atropine, given before or with neostigmine, prevents bradycardia, excessive salivation, and other muscarinic effects of neostigmine.
4.5 Interactions with other Medicinal Products and other Forms of Interaction
Neostigmine potentiates the depolarising myoneural blocking effects of suxamethonium (see contra-indications above).
There is increased risk of antimuscarinic side effects in patients taking drugs with antimuscarinic effects such as MAOIs, amantadine, clozapine, tricyclic antidepressants and nefopam.
4.6 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.
Lactation:
May reach breast milk but in amounts probably too small to be harmful.
4.7. Effects on Ability to Drive and Use Machines
Not relevant as the product is for intra-operative use.
4.8 Undesirable effects
The glycopyrrolate component of Glycopyrrolate-Neostigmine Injection can give rise to dry mouth, constipation, transient bradycardia (followed by tachycardia, palpitation and arrhythmias), reduced bronchial secretions, urinary urgency and retention, dilatation of the pupils, 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.
The neostigmine component of Glycopyrrolate-Neostigmine Injection can give rise to bradycardia, increased oropharyngeal secretions, cardiac dysrhythmias and increased gastrointestinal activity.
If severe neostigmine-induced muscarinic side effects occur (bradycardia, increased oropharyngeal secretions, decreased cardiac conduction rate, increased sweating ,bronchospasm or increased gastrointestinal activity etc), these may be treated by the intravenous administration of Glycopyrrolate Injection 200-600 micrograms (0.20.6mg) or atropine 400-1200 micrograms (0.4-1.2mg).
4.9 Overdose
The treatment of overdosage depends upon whether signs of anticholinesterase or anticholinergic overdosage are predominant presenting features. Signs of neostigmine overdosage include nausea, vomiting, diarrhoea, excessive salivation and sweating, increased oropharyngeal secretions, miosis, bradycardia or tachycardia, cardiospasm, bronchospasm, incoordination, muscle cramps, fasciculation and paralysis.
This may be treated by the administration of Glycopyrrolate Injection 200-600 micrograms (0.2-0.6mg) or atropine 400-1200 micrograms (0.4-1.2mg). In severe cases, respiratory depression may occur and artificial ventilation may be necessary in such patients. Signs of glycopyrrolate overdosage (tachycardia, ventricular irritability etc) may be treated by the administration of neostigmine metilsulfate 1000 micrograms (1.0mg) for each 1000 micrograms (1.0mg) of glycopyrrolate known to have been administered. As glycopyrrolate is a quaternary ammonium agent, symptoms of overdosage are peripheral rather than central in nature; centrally acting anticholinesterase drugs such as physostigmine are therefore unnecessary to treat glycopyrrolate overdosage.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Glycopyrrolate is a quaternary ammonium anticholinergic agent. Glycopyrrolate has a more gradual onset and longer duration of action than atropine. Neostigmine metilsulfate is a quaternary ammonium anticholinesterase. Glycopyrrolate-Neostigmine Injection is associated with less initial tachycardia and better protection against the subsequent cholinergic effects of neostigmine metilsulfate than a mixture of atropine and neostigmine metilsulfate. In addition, residual central anticholinergic effects are minimised due to the limited penetration of Glycopyrrolate into the central nervous system. Administration of glycopyrrolate with neostigmine metilsulfate is associated with greater cardiostability than administration of glycopyrrolate and neostigmine metilsulfate separately.
Glycopyrrolate-Neostigmine Injection can be used when atropine has been used as a pre-operative anticholinergic.
5.2. Pharmacokinetic Properties
Glycopyrrolate is a quaternary ammonium anti-muscarinic agent. The quaternary ammonium moiety renders glycopyrrolate highly ionised at physiological pH and it thus penetrates the blood brain and placental barriers poorly. Excretion is through bile and urine as unchanged drug.
Neostigmine metilsulfate is a quaternary ammonium anticholinesterase. Neostigmine undergoes hydrolysis by cholinesterases and is also metabolised in the liver. It is rapidly eliminated and is excreted in the urine both as unchanged drug and metabolites.
5.3 Pre-clinical Safety Data
Although reproduction studies in rats and rabbits revealed no teratogenic effects from glycopyrrolate, 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 glycopyrrolate. The significance of this for man is not clear.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Disodium Hydrogen Phosphate Dodecahydrate BP/PhEur. Citric Acid Monohydrate BP/Ph.Eur.
Sodium Hydroxide BP/ Ph.Eur.
Water for Injections BP/ Ph.Eur.
6.2. Incompatibilities
Do not mix Glycopyrrolate Neostigmine Injection with any other product.
6.3. Shelf Life
2 years.
6.4. Special Precautions for Storage
Store below 25°C. Protect from light.
6.5. Nature and Content of Container
Glycopyrrolate Neostigmine Injection is presented in clear glass ampoules packed in cardboard cartons to contain 5 or 10 ampoules.
6.6. Instructions for Use, Handling and Disposal
Keep out of reach of children.
If only part of an ampoule is used, discard the remaining solution.
7 MARKETING AUTHORISATION HOLDER
Mercury Pharma International Ltd 4045, Kingswood Road,
City West Business Park,
Co Dublin, Ireland
8. MARKETING AUTHORISATION NUMBER
PL 02848/0200
9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION
3 March 1998
10 DATE OF REVISION OF THE TEXT
23/08/2012