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

Summary of Product Characteristics Updated 12-Nov-2018 | Martindale Pharma, an Ethypharm Group Company

1. Name of the medicinal product

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

2. Qualitative and quantitative composition

Each 1ml of solution contains Glycopyrronium Bromide (Glycopyrrolate) 0.5mg and Neostigmine Metilsulfate 2.5mg.

Excipient with known effect:

This medicine contains less than 1 mmol sodium (23 mg) per 1ml essentially 'sodium free'

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

A clear and colourless sterile solution for Injection.

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

1-2ml intravenously over a period of 10 to 30 seconds (equivalent to Glycopyrronium Bromide 0.5mg with Neostigmine Metilsulfate 2.5mg to Glycopyrronium Bromide 1mg with Neostigmine Metilsulfate 5mg). Alternatively 0.02ml/kg intravenously over a period of 10 to 30 seconds may be used, (equivalent to Glycopyrronium Bromide 0.01mg/kg with Neostigmine Metilsulfate 0.05mg/kg), dose may be repeated (total maximum 2ml)

Paediatric population:

0.02ml/kg intravenously over a period of 10 to 30 seconds (equivalent to Glycopyrronium Bromide 0.01mg/kg with Neostigmine Metilsulfate 0.05mg/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

For intravenous injection

4.3 Contraindications

Hypersensitivity to the Glycopyrronium Bromide or Neostigmine Metilsulfate or to any of the excipients listed in section 6.1.

Glycopyrronium Bromide and Neostigmine Metilsulfate Injection should not be given to patients with known hypersensitivity to either of the two active ingredients or given to patients with mechanical obstruction of the gastrointestinal or urinary tracts. In addition, this product 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.

4.4 Special warnings and precautions for use

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

Administration of anticholinesterase agents to patients with intestinal anastomoses may produce rupture of the anastomosis or leakage of intestinal contents.

Although Glycopyrronium Bromide and Neostigmine Metilsulfate 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 or thyrotoxicosis.

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.

Use with caution in patients with epilepsy or Parkinson's disease.

This product should be used cautiously in pyrexial patients due to inhibition of sweating.

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

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.

The use of Neostigmine in pregnant patients with myasthenia gravis has revealed no untoward effect of the drug on the course of pregnancy.

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

Not applicable.

4.8 Undesirable effects

The Glycopyrronium Bromide component of Glycopyrrolate - Neostigmine Metilsulfate Injection can give rise to a dry mouth, difficulty in micturition, cardiac dysrhythmias, and disturbances of visual accommodation and inhibition of sweating.

The Neostigmine component of Glycopyrronium Bromide and Neostigmine Metilsulfate Injection can give rise to nausea, vomiting, increased salivation, diarrhoea, abdominal cramps (more marked with higher doses); signs of overdosage include bronchoconstriction, increased bronchial secretions, lacrimation, excessive sweating, involuntary defecation and micturition, miosis, nystagmus, bradycardia, photophobia, heart block, arrhythmias, hypotension, agitation, excessive dreaming, and weakness eventually leading to fasciculation and paralysis.

Glycopyrronium-Neostigmine component of injection can give rise to hypersensitivity, angioedema and anaphylactic reaction. Their frequency is not known

Hypersensitivity

If severe Neostigmine induced muscarinic side effects occur (bradycardia, hypotension, increased or pharyngeal secretions, decreased cardiac conduction rate, bronchospasm or increased gastrointestinal activity etc), these may be treated by the intravenous administration of Glycopyrronium Bromide Injection 200 – 600 micrograms (0.2 – 0.6mg) or atropine 400 – 1200 micrograms (0.4 – 1.2mg).

Reporting of suspected adverse reactions

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

The treatment of overdosage depends on whether signs of anticholinesterase or anticholinergic overdose is the predominant presenting feature.

Signs of Neostigmine overdosage include those of muscarinic effects (nausea, vomiting, increased salivation, diarrhoea, abdominal cramps (more marked with higher doses); signs of overdosage include bronchoconstriction, increased bronchial secretions, lacrimation, excessive sweating, involuntary defecation and micturition, miosis, nystagmus, bradycardia, heart block, arrhythmias, hypotension, agitation, excessive dreaming, and weakness eventually leading to fasciculation and paralysis.) may be treated by administration of Glycopyrronium Bromide Injection 0.2 – 0.6mg or atropine 0.4 – 1.2mg. In severe cases, respiratory depression may occur, artificial ventilation may be necessary in such patients.

Signs of Glycopyrronium Bromide overdose (tachycardia, ventricular irritability etc.) may be treated by intravenous administration of Neostigmine Metilsulfate 1.0mg for each 1.0mg of Glycopyrronium Bromide known to have been administered. As Glycopyrronium Bromide 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 Glycopyrronium Bromide overdosage.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anticholinesterases

ATC code: N07AA51

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

Neostigmine Metilsulfate is a quaternary ammonium anticholinesterase.

Glycopyrronium Bromide and Neostigmine Metilsulfate 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 Glycopyrronium Bromide into the central nervous system. Administration of Glycopyrronium Bromide with Neostigmine Metilsulfate is associated with greater cardiostability than administration of Glycopyrronium Bromide and Neostigmine Metilsulfate separately.

5.2 Pharmacokinetic properties

Absoprtion

Glycopyrronium Bromide 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.

Over 90% of the Glycopyrronium Bromide disappears from serum within 5 minutes following intravenous administration. The drug is 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.

Distribution

Glycopyrronium Bromide is also rapidly excreted into urine with the highest concentrations being found within 3 hours of administration. Over 85% of product is excreted within 48 hours. It has subsequently been confirmed in a single dose pharmacokinetic study using radio immunological assay procedures that Glycopyrronium Bromide 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.

Neostigmine Metilsulfate is extensively hydrolyzed in the blood. 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

Elimination half-life 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. Pharmaceutical particulars
6.1 List of excipients

Citric Acid

Sodium Hydroxide

Citric Acid Solution

Water for Injections

Sodium Phosphate

6.2 Incompatibilities

Do not mix Glycopyrronium Bromide and Neostigmine Metilsulfate Injection with any other preparation.

6.3 Shelf life

12 months.

6.4 Special precautions for storage

Do not store above 25°C.

Keep the container in the outer carton to protect from light.

6.5 Nature and contents of container

Glycopyrronium Bromide 0.5mg/ml and Neostigmine Metilsulfate 2.5mg/ml Solution for Injection is presented in clear Type I ampoules of neutral glass containing 10 x 1ml ampoules packed in a cardboard carton.

6.6 Special precautions for disposal and other handling

Do not dilute.

If only part of an ampoule is used, discard the remaining solution. Keep out of the sight and reach of children.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Martindale Pharmaceuticals Ltd

T/A Martindale Pharma

Bampton Road

Harold Hill

Romford

Essex

RM3 8UG

UK

8. Marketing authorisation number(s)

PL 00156/0116

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 7th September 2007

10. Date of revision of the text

07/11/2018

Company Contact Details
Martindale Pharma, an Ethypharm Group Company
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Bampton Road, Harold Hill, Romford, Essex, RM3 8UG

Telephone

+44 (0)1277 266 600

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