Glycopyrronium Bromide/ Neostigmine Metilsulfate

Registered South African indications:

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

Registered South African contraindications

• Hypersensitivity to active ingredient or any of the excipients in this combination product
• Should not be given to patients with mechanical obstruction of the gastrointestinal or urinary tracts
• Should not be given in conjunction with depolarising muscle relaxants, such as suxamethonium, as neostigmine potentiates the depolarising myoneural blocking effects of this agent

Contraindications registered in other jurisdictions

• Hypersensitivity to active ingredient or any of the excipients in this combination product
• Should not be administered to patients with mechanical obstruction of the gastrointestinal or urinary tracts
• Should not be administered concurrently with suxamethonium, as neostigmine enhances the depolarising myoneural blocking effects of suxamethonium
• Anticholinesterase-antimuscarinic combinations, such as neostigmine plus glycopyrronium, should be avoided in patients with a prolonged QT interval

South African recommendations

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Hepatic impairment

Renal function consideration

• Neostigmine metilsulfate is primarily excreted by the kidneys, necessitating careful administration in patients with impaired renal function

Elderly patients

• While glycopyrronium offers benefits in reducing the risk of postoperative confusion, caution is still advised when using glycopyrronium bromide/ neostigmine metilsulfate in elderly patients due to their generally increased sensitivity to medications

Asthma and bronchospasm

• Use cautiously in patients with asthma or bronchospasm, as it may worsen the condition

Severe bradycardia

• Patients with severe bradycardia should be closely monitored when given glycopyrronium bromide/ neostigmine metilsulfate due to potential aggravation of the condition

Intestinal anastomoses

• There's a risk of rupture or leakage at the site of intestinal anastomoses when administering anticholinesterase agents like glycopyrronium bromide/ neostigmine metilsulfate

Cardiovascular conditions

• Exercise caution in individuals with coronary artery disease, congestive heart failure, cardiac dysrhythmias, hypertension, hyperthyroidism or thyrotoxicosis, and cardiac insufficiency due to potential adverse effects

Epilepsy and Parkinson's disease

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

Pyrexia

• Special care is required when administering to pyrexial patients, especially children, as it may inhibit sweating

Prostatic hypertrophy and other antimuscarinic concerns

• Care is advised when administering to individuals with conditions sensitive to antimuscarinic effects, such as prostatic hypertrophy, paralytic ileus, pyloric stenosis, and closed-angle glaucoma

Cardiovascular and gastrointestinal caution

• Patients with hypotension, peptic ulceration, or vagotonia should use this medicine cautiously

Inhalation anaesthesia risks

• During procedures involving inhalation anaesthesia, especially with halogenated hydrocarbons, glycopyrronium bromide/ neostigmine metilsulfate's anticholinergic properties may increase the risk of ventricular dysrhythmias

Myasthenia gravis

• In those with myasthenia gravis, large doses of quaternary ammonium compounds like glycopyrronium, found in glycopyrronium bromide/ neostigmine metilsulfate, could block nicotinic muscle end plate receptors. It is crucial to carefully assess the risk of administering glycopyrronium bromide/ neostigmine metilsulfate in this patient group to avoid inducing a cholinergic crisis

Blood-brain barrier

• Glycopyrronium, as a quaternary ammonium compound, does not cross the blood-brain barrier, making it less likely to cause postoperative confusion, a common concern among elderly patients

Reduced side effects

• Glycopyrronium bromide (glycopyrrolate) is associated with fewer cardiovascular and ocular side effects compared to other medications in its class

Combination with neostigmine

• When given before or alongside neostigmine metilsulfate, glycopyrronium helps prevent bradycardia, excessive salivation, and other muscarinic effects caused by neostigmine

Sodium content

• Glycopyrronium bromide/ neostigmine metilsulfate is essentially sodium-free, containing less than 1mmol sodium (23mg) per ampoule

Ability to drive or use machines

• May cause the eyesight to become weak, which could interfere with the ability to drive or operate machinery safely

Recommendations in other jurisdictions

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment

Elderly patients

• Glycopyrrolate is less likely to cause postoperative confusion compared to atropine, which is a particular concern in the elderly patients

Respiratory caution

• Use with extreme caution in patients with bronchospasm

Cardiovascular conditions

• Patients with severe bradycardia, arrhythmias, recent myocardial infarction, hypotension, coronary artery disease, congestive heart failure, cardiac dysrhythmias, hypertension, and thyrotoxicosis and cardiac insufficiency should be monitored closely as glycopyrrolate may affect cardiovascular stability

Gastrointestinal risks

• Caution is advised in patients with vagotonia and peptic ulceration
• Administration of anticholinesterase agents to patients with intestinal anastomosis may produce rupture of the anastomosis or leakage of intestinal contents

Epilepsy and Parkinson's disease

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

Temperature regulation

• As glycopyrrolate inhibits sweating, patients with increased temperature (especially children) should be observed closely

Prostatic and ocular precautions

• Like other antimuscarinic drugs, glycopyrrolate should be used cautiously in patients with prostatic hypertrophy, paralytic ileus, pyloric stenosis, and closed-angle glaucoma

Anaesthetic interactions

• When used during inhalation anesthesia, especially with halogenated hydrocarbons, there's an increased risk of ventricular arrhythmias

Myasthenia gravis

• Patients with this condition should be evaluated carefully as glycopyrrolate in large doses can block nicotinic muscle end plate receptors, potentially triggering a cholinergic crisis

Reduced cardiovascular and ocular effects

• Glycopyrrolate has fewer cardiovascular and ocular side effects than atropine, offering a safer profile for certain patients

Sodium content

• This medicinal product is essentially sodium-free, containing less than 1 mmol sodium (23mg) per dose

Ability to drive or use machines

• May cause your eyesight to become weak and this could interfere with your ability to drive or operate machinery safely

Forms avail. in SA and covered in this monograph: inj

South African registered indications and dosages

Reversal of residual non-depolarising (competitive) neuromuscular block

Glycopyrronium Bromide/ Neostigmine Metilsulfate
0.5/2.5 (mg/ml)

• IV: 1-2ml, given over 10-30sec (equivalent to 0.5/2.5 - 1/5 (mg/ml)) OR 0.02ml/kg, given over 10-30sec (equivalent to 0.01mg/kg glycopyrronium bromide and 0.05mg/kg neostigmine metilsulfate); Repeat 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

Paed. forms avail. in SA and covered in this monograph: inj

South African registered indications and dosages

Reversal of residual non-depolarising (competitive) neuromuscular block

Glycopyrronium Bromide/ Neostigmine Metilsulfate
0.5/2.5 (mg/ml)

• IV: 0.02ml/kg, given over 10-30sec (equivalent to 0.01mg/kg glycopyrronium bromide and 0.05mg/kg neostigmine metilsulfate) OR Dilute to 10ml with water for injections and admin. 1ml/5kg bodyweight

Pregnancy

South African recommendations

• Caution
• There are no data from the use of glycopyrronium bromide or neostigmine metilsulfate in pregnant women
• Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity
• Anticholinesterase medicines, including neostigmine may cause uterine irritability and induce premature labour when administered to pregnant women near term
• Neostigmine metilsulfate should be given to a pregnant woman with caution

Recommendations in other jurisdictions

• Caution
• For use as indicated, animal studies are of very limited relevance
• Use in human pregnancy has not been systematically evaluated

Breastfeeding

South African recommendations

• Caution
• It is unknown whether glycopyrronium bromide is excreted in human milk
• The amount of neostigmine metilsulfate distributed into breastmilk is very small, but breastfed infants need to be monitored. Glycopyrronium bromide (including its metabolites) was excreted in the milk of lactating rats
• The amount of glycopyrronium bromide/ neostigmine metilsulfate excreted in breastmilk following a standard single dose is not expected to have any influence on the baby

Recommendations in other jurisdictions

• Caution
• May reach breast milk but in amounts probably too small to be harmful

Fertility

South African recommendations

• Reproduction studies and other data in animals do not indicate a concern regarding fertility in either males or females
• In a fertility and early embryonic development study in rats, male rats were treated for 28 days prior to mating and female rats were treated for 14 days prior to mating with intravenous neostigmine metilsulfate (human equivalent doses of 1,6, 4 and 8,1 mcg/kg/day, based on body surface area)
• No adverse effects were reported at any dose

Recommendations in other jurisdictions

• No information available

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no dose adjustment recommended

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no information available

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no dose adjustment recommended

Combination products may have additional pharmacological effects not accounted for by the action of the individual ingredients

Glycopyrronium Bromide/ Neostigmine Metilsulfate

Immune System Disorders

Not known

• Hypersensitivity
• Angioedema
• Anaphylactic reaction

Glycopyrronium Bromide

Nervous System Disorders

Not known

• Confusion (particularly in the elderly)
• Dizziness

Eye Disorders

Not known

• Accommodation disorder
• Dilatation of the pupils
• Photophobia
• Angle closure glaucoma

Cardiac Disorders

Not known

• Transient bradycardia (followed by tachycardia, palpitation and arrhythmias)
• Cardiac dysrhythmias

Respiratory, Thoracic and Mediastinal Disorders

Not known

• Reduced bronchial sectretion

Gastrointestinal Disorders

Not known

• Dry mouth
• Constipation
• Nausea and vomiting

Skin and Subcutaneous Tissue Disorders

Not known

• Flushing
• Dry skin
• Inhibition of sweating

Renal and Urinary Disorders

Not known

• Difficulty in micturition
• Micturition urgency
• Urinary retention

Neostigmine Metilsulfate

Cardiac Disorders

Not known

• Bradycardia
• Cardiac dysrhythmias

Respiratory, Thoracic and Mediastinal Disorders

Not known

• Increased oropharyngeal secretions

Gastrointestinal Disorders

Not known

• Nausea
• Vomiting
• Increased salivation
• Increased gastrointestinal activity (more marked at higher doses)
• Diarrhoea

• Depolarising muscle relaxants
• Suxamethonium
• Monoamine oxidase inhibitors
• Amantadine
• Clozapine
• Tricyclic antidepressants
• Nefopam
• Anticholinesterase agents
• Non-depolarising muscle relaxants
• Aminoglycoside antibiotics
• Antiarrhythmic agents
• Chloroquine
• Hydroxychloroquine
• Antimuscarinic agents
• Clindamycin
• Lithium
• Polymyxins
• Procainamide
• Propafenone
• Propanolol
• Quinidine

• Blood pressure
• Heart rate
• Respiratory status

Specific cases may require

• Electrocardiogram (ECG) (as clinically indicated)
• Train-of-four monitoring
• Renal function
• Hepatic function

Additional observations

• Anticholinergic effects

Glycopyrronium Bromide
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, like other anticholinergic (antimuscarinic) agents, inhibits the action of acetylcholine on structures innervated by postganglionic, cholinergic nerves and on smooth muscles that respond to acetylcholine, but lack cholinergic innervation. These peripheral cholinergic receptors are present in the autonomic effector cells of smooth muscle, cardiac muscle, the sinoatrial node, the atrioventricular node, exocrine glands, and, to a limited degree, in the autonomic ganglia. Thus, it diminishes the volume and free acidity of gastric secretion and controls excessive pharyngeal, tracheal, and bronchial secretions. Glycopyrronium bromide antagonises muscarinic symptoms (e.g. bronchorrhoea, bronchospasm, bradycardia, and intestinal hypermotility) induced by cholinergic medicines such as the anticholinesterases. Glycopyrronium bromide has a more gradual onset and longer duration of action than atropine.

Neostigmine Metilsulfate
Neostigmine metilsulphate is a quaternary ammonium anticholinesterase.  The combination of glycopyrronium bromide and neostigmine metilsulfate 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 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.

Combination Glycopyrronium/Neostigmine

Powder of Injection (per ml) 0,5 mg and 2,5 mg

• Cholstyq