GLYCOPYRRONIUM BROMIDE AND NEOSTIGMINE METILSULFATE 0.5 MG / 2.5 MG PER ML SOLUTION FOR INJECTION, ROBINUL NEOSTIGMINE INJECTION - summary of medicine characteristics

Robinul-Neostigmine 0.5mg/2.5mg per ml Solution for Injection,

Glycopyrronium Bromide and Neostigmine Metilsulfate 0.5mg/2.5mg per ml Solution for Injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1ml of solution contains 500 micrograms (0.5mg) of glycopyrrolate (glycopyrronium bromide) 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.

Solution for Injection.

Clear, colourless sterile solution for injection intended for parenteral administration presented in 1ml clear, type 1, Ph. Eur. glass ampoules.

4.1 Therapeutic indications

Reversal of residual non-depolarising (competitive) neuromuscular bloc­k.

4.2 Posology and method of administration

Posology

Adults and Elderly: 1 – 2ml 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)].

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

This medicine is for intravenous administration.

SUMMARY OF PRODUCT CHARACTERISTICS

4.3 Contraindications

Hypersensitivity to the two active substances or to any of the excipients listed in section 6.1.

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

This medicine 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 glycopyrronium should be avoided in patients with a prolonged QT interval.

SUMMARY OF PRODUCT CHARACTERISTICS

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 this medicine 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‘.

SUMMARY OF PRODUCT CHARACTERISTICS

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.

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 nondepolarising 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.

SUMMARY OF PRODUCT CHARACTERISTICS

4.8 Undesirable effects

Adverse events are which have been associated with this medicine 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 this medicine:

* Followed by tachycardia, palpitation and arrhythmias

Particularly in elderly

Tabulated list of adverse reactions for Neostigmine component of this medicine:

Tabulated list of adverse reactions for Glycopyrrolate- Neostigmine component of this medicine:

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 Robinul Injection (glycopyrrolate) 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.

SUMMARY OF PRODUCT CHARACTERISTICS

4.9 Overdose

Symptoms

Signs of neostigmine overdosage include (increased oropharyngeal secretions, bronchospasm, nausea, vomiting, diarrhoea, abdominal cramps (more marked with higher doses), increased bronchial secretions, lacrimation, excessive salivation and sweating, involuntary defecation and micturition, miosis, nystagmus, bradycardia or tachycardia, cardiospasm, 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 Robinul Injection (glycopyrrolate) 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.

SUMMARY OF PRODUCT CHARACTERISTICS

5.1. Pharmacodynamic properties

Pharmacotherapeutic group: Quaternary ammonium antimuscarinic

ATC Code: A03AB02

Mechanism of action:

Robinul (glycopyrrolate) is a quaternary ammonium anticholinergic agent. The quaternary ammonium moiety renders Robinul highly ionised at physiological pH and it thus penetrates the blood brain and placental barriers poorly. Robinul has a more gradual onset and longer duration of action than atropine.

Neostigmine metilsulfate is a quaternary ammonium anticholinesterase.

Robinul-Neostigmine Injection is associated with less initial tachycardia and better protection against the subsequent cholinergic effects of neostigmine than a mixture of atropine and neostigmine.

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 Robinul into the central nervous system. Administration of glycopyrrolate with neostigmine is associated with greater cardiostability than administration of glycopyrrolate and neostigmine metilsulfate separately.

This medicine can be used when atropine has been used as a pre-operative anticholinergic.

SUMMARY OF PRODUCT CHARACTERISTICS

5.2 Pharmacokinetic properties

Absorption and Biotransformation

Glycopyrrolate and Neostigmine Metilsulfate are routinely administered simultaneously to reverse residual non-depolarising (competitive) neuromuscular block. Numerous clinical studies which demonstrate this to be a safe and effective combination have been published. A number or pertinent clinical studies were included in the product licence application for Robinul Injection, approved in March 1981.

In the PL Application for Robinul Injection it was demonstrated that over 90% of the glycopyrrolate disappeared from serum within 5 minutes following intravenous administration.

The pharmacokinetics of neostigmine metilsulfate are described in Martindale. In one study, following intravenous administration, the plasma concentration declined to about 8% of its initial value after 5 minutes with a distribution half-life of less than one minute.

Elimination

The drug was rapidly excreted into bile with highest concentrations being found 30 to 60 minutes after dosing with some product being detected up to 48 hours after administration. Glycopyrrolate is also rapidly excreted into urine 85% of product was excreted within 48 hours. It has subsequently been confirmed in a single dose pharmacokinetic study using radioimmunological assay procedures that glycopyrrolate was rapidly distributed and/or excreted after intravenous administration. The terminal elimination phase was relatively slow with quantifiable plasma levels remaining up to 8 hours after administration. The elimination half-life was 1.7 hours.

Elimination half-life of neostigmine ranged from about 15 – 30 minutes. Trace amounts of neostigmine metilsulfate could be detected in the plasma after one hour.

In a study in non-myasthenic patients, the plasma half-life was 0.89 hours.

5.3 Preclinical safety data

No further relevant information other than that which is included in other sections of the Summary of Product Characteristics.

6.1

Disodium Hydrogen Phosphate Dodecahydrate

Citric Acid

Sodium Hydroxide

Water for Injections

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

Do not store above 25°C.

Keep the ampoules in the outer carton in order to protect from light.

6.5 Nature and contents of container

This medicine is presented in clear glass ampoules packed in cardboard cartons to contain 10 ampoules.