This information is intended for use by health professionals

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 and Neostigmine Injection should not be given to patients with mechanical obstruction of the gastrointestinal or urinary tracts.

Glycopyrrolate-Neostigmine Injection should not be given in conjunction with suxamethonium as neostigmine potentiates the depolarising myoneural blocking effects of this agent.

Anticholinesterase-antimuscarinic combinations such as neostigmine plus glycopyrrolate should be avoided in patients with a prolonged QT interval.

4.4 Special warnings and precautions for use

Administer with caution to patients with bronchospasm (extreme caution), or severe bradycardia arrhythmias, recent myocardial infarction, hypotension, vagotonia, peptic ulceration, hyperthyroidism or renal impairment. 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.

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

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.

Anticholinesterase drugs enhance neuromuscular transmission in voluntary and involuntary muscle in myasthenia gravis.

Non-depolarizing neuromuscular block induced by the muscle relaxants used in anesthesia; neuromuscular block induced by aminoglycoside antibiotics and antiarrhythmic agents.

Aminoglycosides -Effects of Neostigmine antagonised by aminoglycosides

Chloroquine and Hydroxychloroquine - effects of Neostigmine may be diminished because of potential for Chloroquine and Hydroxychloroquine to increase symptoms of myasthenia gravis

Many drugs have antimuscarinic effects; concomitant use of two or more such drugs can increase side-effects such as dry mouth, urine retention, and constipation; concomitant use can also lead to confusion in the elderly.

Clindamycin - Effects of Neostigmine antagonised by Clindamycin

Lithium - Effects of Neostigmine antagonised by lithium

Muscle Relaxants, non-depolarising - Neostigmine antagonises effects of non- depolarising muscle relaxants

Polymyxins - Effects of Neostigmine antagonised by polymyxins

Procainamide - Effects of Neostigmine antagonised by Procainamide

Propafenone -Effects of Neostigmine possibly antagonised by Propafenone

Propranolol -Effects of Neostigmine antagonised by Propranolol

Quinidine -Effects of Neostigmine antagonised by Quinidine

Suxamethonium -Neostigmine enhances effects of Suxamethonium

Antimuscarinics - Effects of parasympathomimetics antagonised by antimuscarinics

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

Accommodation disorder, dilatation of the pupils, photophobia, Angle closure glaucoma

Not known

Cardiac disorders

Transient bradycardia* , Cardiac dysrhythmias

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

Inhibition of sweating

Not known

Renal and urinary disorders

Difficulty in micturition

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

Nausea, vomiting, increased salivation, increased gastrointestinal activity (more marked and higher doses), diarrhea

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Symptoms

Signs of neostigmine overdosage include nausea, vomiting, diarrhoea, abdominal cramps (more marked with higher doses), increased bronchial secretions, lacrimation, excessive salivation and sweating, involuntary defecation and micturition, increased oropharyngeal secretions, miosis, nystagmus, bradycardia or tachycardia, cardiospasm, bronchospasm, incoordination, muscle cramps, heart block, arrhythmias, hypotension, agitation, excessive dreaming, and weakness eventually leading to fasciculation and paralysis.

Signs of glycopyrrolate overdosage include tachycardia, venticular irritability etc.

Management

The treatment of overdosage depends upon whether signs of anticholinesterase or anticholinergic overdosage are predominant presenting features

Signs of neostigmine overdosage 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 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.

Neostigmine is used mainly for its effects on skeletal muscle in myasthenia gravis and in anaesthesia for termination of the effects of competitive neuromuscular blocking drugs.

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 and 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 Preclinical 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/Ph.Eur.

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

18 Months

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 contents 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 Pharmaceuticals Ltd,

Capital House, 85 King William Street,

London EC4N 7BL, UK

8. Marketing authorisation number(s)

PL 12762/0580

9. Date of first authorisation/renewal of the authorisation

3 March 1998

10. Date of revision of the text

20/08/2019