Glycopyrrolate-Neostigmine Injection
1.
NAME OF THE MEDICINAL PRODUCT
Glycopyrrolate and Neostigmine Metilsulfate 0.5mg / 2.5mg per ml Solution for Injection
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 1ml of solution contains 0.5mg of glycopyrrolate and 2.5mg of neostigmine metilsulfate.
Excipient with known effect
Each 1 ml contains 3 mg (0.13 mmol) sodium
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Solution for Injection.
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
Posology
Adults and Elderly: 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)].
Paediatric population: 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.
Method of administration
Glycopyrrolate-Neostigmine injection is for intravenous administration
4.3 Contraindications
Hypersensitivity to the two active substances or to any of the excipients listed in section 6.1.
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 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.
Breast-feeding
May reach breast milk but in amounts probably too small to be harmful.
4.7. Effects on ability to drive and use machines
This medicine may cause your eyesight to become weak and this could interfere with your ability to drive or operate machinery safely.
4.8 Undesirable effects
Adverse events are which have been associated with Glycopyrrolate-Neostigmine injection are given below, listed by system organ class and frequency.
Undesirable effects are especially likely to occur at treatment onset or at dose increase.
The undesirable effects are listed below by organ class and the following frequency convention:
Very common: (>1/10)
Common: (>1/100, <1/10)
Uncommon: (>1/1,000, <1/100)
Rare: (>1/10,000, <1/1,000)
Very rare: (<1/10,000),
Not known - cannot be estimated from the available data.”
Tabulated list of adverse reactions for Glycopyrrolate component of Glycopyrrolate-Neostigmine Injection:
|
System Organ Class |
Adverse reaction |
Frequency |
|
Nervous system disorders |
Confusion** Dizziness |
Not known |
|
Eye disorders |
dilatation of the pupils, photophobia, Angle closure glaucoma |
Not known |
|
Cardiac disorders |
Transient bradycardia* , |
Not known |
|
Respiratory, thoracic and mediastinal disorders |
Bronchial secretion reduced |
Not known |
|
Gastrointestinal Disorders |
Dry mouth, Constipation Nausea, vomiting |
Not known |
|
Skin and subcutaneous tissue disorders |
Flushing Dry skin |
Not known |
|
Renal and urinary disorders |
Micturition urgency Urinary retention |
Not known |
* Followed by tachycardia, palpitation and arrhythmias **Particularly in elderly
Tabulated list of adverse reactions for Neostigmine component of Gylcopyrolate-Neostigmine Injection:
|
System Organ Class |
Adverse reaction |
Frequency |
|
Cardiac disorders |
Bradycardia, cardiac dysrhythmias |
Not known |
|
Respiratory, thoracic and mediastinal disorders |
increased oropharyngeal secretions |
Not known |
|
Gastrointestinal Disorders |
increased gastrointestinal activity |
Not known |
Glycopyrrolate-Neostigmine component of injection can give rise to hypersensitivity, angioedema and anaphylactic reaction.
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 (0.2-0.6mg) or atropine 400-1200 micrograms (0.4-1.2mg).
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
Symptoms
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.
Management
The treatment of overdosage depends upon whether signs of anticholinesterase or anticholinergic overdosage are predominant presenting features 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
Pharmacotherapeutic group: Quaternary ammonium antimuscarinic ATC Code: A03AB02
Mechanism of action:
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
Absorption/Biotransformation:
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. Neostigmine metilsulfate is a quaternary ammonium anticholinesterase. Neostigmine undergoes hydrolysis by cholinesterases and is also metabolised in the liver.
Elimination
Glycopyrollate is excreted through bile and urine as unchanged drug.
Neostigmine 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
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3. Shelf Life
2 years.
6.4. Special precautions for storage
Store below 25°C. Keep the ampoule in the outer carton in order to 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.
Not all pack sizes may be marketed.
6.6. Special precautions for disposal and other handling
Keep this medicine 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
Mercury Pharma International Ltd 4045, Kingswood Road,
City West Business Park,
Co Dublin, Ireland
PL 02848/0200
OF
9. DATE OF FIRST AUTHORISATION/RENEWAL AUTHORISATION
3 March 1998
10 DATE OF REVISION OF THE TEXT
14/09/2016