Consumer medicine information

Neostigmine Juno Solution for Injection

Neostigmine methylsulfate

BRAND INFORMATION

Brand name

Neostigmine Juno

Active ingredient

Neostigmine methylsulfate

Schedule

What is in this leaflet

This leaflet answers some of the common questions about Neostigmine Juno Solution for Injection. It does not contain all the information that is known about Neostigmine Juno Solution for Injection. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor will have weighed the risks of you being given Neostigmine Juno Solution for Injection against the benefits they expect it will have for you.

If you have any concerns about this medicine talk to your doctor or pharmacist.

Keep this leaflet. You may need to read it again.

What Neostigmine Juno is used for

Neostigmine Juno Solution for Injection increases movement of the muscles in the body.

It can be used:

To reverse the effects of medicines that are used to stop muscles moving;
To activate the muscles in the bladder, stomach and intestines following surgery
For myasthenia gravis.

Neostigmine is known as a cholinesterase inhibitor. It works by stopping a chemical called acetylcholine, which stimulates muscles movement, from breaking down.

Your doctor will have explained why you are being treated with Neostigmine Juno Solution for Injection.

Follow all directions given to you by your doctor carefully. They may differ from the information contained in this leaflet.

Your doctor may prescribe this medicine for another use. Ask your doctor if you want more information.

Neostigmine Juno Solution for Injection is not addictive.

Before you are given Neostigmine Juno

You may already have been given Neostigmine Juno Solution for Injection. Your doctor will have considered the situation carefully and decided to use it. However, if any of any of the following applies to you, tell your doctor immediately.

When you must not use it

You should not be given Neostigmine Juno Solution for Injection if you are breastfeeding unless your doctor says so. Ask your doctor about the risks and benefits involved.

It may make your baby arrive early if you are given it in the last weeks before your baby is due.

Your baby can take in very small amounts of Neostigmine Juno Solution for Injection from breast milk if you are breastfeeding.

You must not be given Neostigmine Juno Solution for Injection if:

You are sensitive to neostigmine
You have an allergy to any ingredient listed at the end of this leaflet or any other related medicines.
If you have an allergic reaction, you may get a skin rash, hayfever, asthma or feel faint.

You should not be given Neostigmine Juno Solution for Injection if you have the following medical conditions:

Blockage of the intestines or urinary tract
Peritonitis

Neostigmine Juno Solution for Injection will only be used if the solution is clear, the package is undamaged and the use by (expiry) date marked on the pack has not been passed.

Before you are given it

You must tell your doctor if you have any of these medical conditions:

Recent surgery involving the intestine or bladder
Other intestinal or bladder problems
Asthma or any difficulty with breathing
Heart disease or other heart problems
Any obstruction to your coronary arteries
Epilepsy
Low blood pressure
Parkinsons disease
Stomach ulcer
Kidney problems
Addison’s disease
An overactive thyroid gland

It may not be safe for you to be given Neostigmine Juno Solution for Injection if you have any of these conditions.

Taking other medicines

You must tell your doctor if you are taking any other medicines, including medicines that you can buy at the chemist, supermarket or health food shop.

Some medicines and Neostigmine Juno Solution for Injection may interfere with each other. These include:

Corticosteroids
Atropine or glycopyrrolate
Antibiotics
Medicine for heart problems including beta blockers
Lithium
Chloriquinine, hydroxychloroquinine
Quinine

These medicines may affect the way Neostigmine Juno Solution for Injection works. Your doctor or pharmacist can tell you what to do if you are taking any of these medicines.

If you have not told your doctor about any of these things, tell them before you are given any Neostigmine.

How Neostigmine Juno is given

Neostigmine Juno Solution for Injection will be given to you by a doctor or a specially trained nurse.

It may be given just under the skin, into a muscle, or directly into the bloodstream. The dose you will be given will be carefully worked out depending on the procedure and your body weight.

Overdose

The doctor or nurse giving you Neostigmine Juno Solution for Injection will be experienced in its use, so it is extremely unlikely that you will be given too much. However, the first signs of overdose can be nausea, vomiting, muscle cramps, sweating, increased saliva and changes in heart rate.

Side Effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are receiving Neostigmine Juno Solution for Injection.

Neostigmine Juno Solution for Injection helps most people with muscle weakness but may have some unwanted side effects in a few people.

All medicines have side effects. Sometimes they are serious, most of the time they are not.

You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

Shivering
Low oxygen levels
Muscle weakness
Difficulty speaking or breathing
Nausea and vomiting
Diarrhoea
Stomach cramps or flatulence
Involuntary urination or defecation
Sweating
Increased saliva or mucous production
Faintness, dizziness or weakness
Changes in vision
Muscle cramps or twitching
Drowsiness or restlessness
Increased secretion of tears from the eyes
Headache
Slurred speech
Agitation or fear
Itching

These are all mild side effects of Neostigmine Juno Solution for Injection.

Tell your doctor or nurse immediately or go to casualty at your nearest hospital if you notice any of the following:

General weakness
Inability to smile, swallow or speak
Slowed heart rate or palpitations
Shortness of breath, tightness in the chest or wheezing
Severe rash
Irritation
Swollen face
Convulsions

These are all serious side effects. You may need urgent medical attention.

Tell your doctor if you notice anything else that is making you feel unwell.

Storage

Neostigmine Juno Solution for Injection will be stored by your doctor or pharmacist under the recommended conditions.

It should be kept in a cool, dry place where the temperature stays below 25 degrees C.

Disposal

Any Neostigmine Juno Solution for Injection which is not used will be disposed of in a safe manner by your doctor or pharmacist.

Product description

Neostigmine Juno Solution for Injection is a clear, colourless solution presented in clear glass ampoules.

It contains neostigmine methylsulfate 2.5 mg/ml as the active ingredient, plus sodium chloride and water for injections.

Sponsor

Juno Pharmaceuticals Pty Ltd
42 Kelso Street,
Cremorne,
VIC 3121
[email protected].

This leaflet was prepared in August 2021.

Australian Registration Number: 2.5 mg/ml ampoule AUSTR 219054

Published by MIMS November 2021

BRAND INFORMATION

Brand name

Neostigmine Juno

Active ingredient

Neostigmine methylsulfate

Schedule

1 Name of Medicine

Neostigmine methylsulfate.

2 Qualitative and Quantitative Composition

Neostigmine Juno injection contains 2.5 mg neostigmine methylsulfate in 1 mL solution.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Neostigmine Juno Solution for Injection is a clear, colourless sterile solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Neostigmine is indicated for:
Reversal of the effects of non-depolarising neuromuscular blocking agents.
Prophylaxis and treatment of post-operative intestinal atony and urinary retention.
Treatment of myasthenia gravis during acute exacerbations, when the condition is severe or in neonates.

4.2 Dose and Method of Administration

Neostigmine Juno Solution for Injection can be given as an intramuscular (IM), intravenous (IV) or subcutaneous (SC) injection. The following doses are approximately equivalent in effect: 0.5 mg IV = 1.0-1.5 mg IM or SC.
When Neostigmine Juno Solution for Injection is given, a syringe of atropine sulfate or glycopyrrolate should be available to counteract severe cholinergic reactions, if they occur. Do not mix atropine with other drugs in the same syringe as compatibility data are not available.
Neostigmine Juno Solution for Injection in ampoules contains no antimicrobial agent. It should be used once and any residue discarded.

Antagonist to nondepolarising neuromuscular blockade.

Usually, reversal of neuromuscular blockade with Neostigmine Juno Solution for Injection should not be attempted until spontaneous recovery from paralysis is evident. It is recommended that the patient be well ventilated and patent airway maintained until complete recovery of normal respiration is affirmed.
Neostigmine should be administered when the first twitch response is substantially greater than 10% of baseline, or when a second twitch is present.
Adequacy of the reversal of the neuromuscular block needs to be based on a clinical assessment of the patient and not train-of-four responses alone, unless quantitative (numeric) assessment is made of neuromuscular function.
Patients should be monitored for clinical signs of residual blockade (e.g. difficulty maintaining a patent airway, generalised weakness, inadequate ventilatory effort) following cessation of the anaesthetic and extubation.

Adults.

A single dose of neostigmine 0.5 to 2.5 mg (0.04-0.07 mg/kg) to be administered simultaneously with atropine sulfate 0.6-1.2 mg (0.02 to 0.03 mg/kg) or glycopyrrolate 0.2 mg intravenously per 1 mg neostigmine or 0.008 mg/kg glycopyrrolate intravenously with 0.04 mg/kg neostigmine by slow IV injection over 1 minute is generally adequate for complete reversal of nondepolarising muscle relaxants within 5 to 15 minutes. The maximum recommended dose of neostigmine in adults is 5 mg as excess of this dose of neostigmine may produce depolarising neuromuscular block.

Children.

The suggested dose in children is 0.04 mg/kg and atropine sulfate 0.02 mg/kg or glycopyrrolate 0.008 mg/kg by slow IV injection over 1 minute. Maximum recommended dose of neostigmine in children is 2.5 mg.
The two drugs are often given simultaneously, but in patients with bradycardia, the pulse rate should be increased to about 80 beats/minute e.g. with atropine before administering neostigmine.
Neostigmine and glycopyrrolate may be given in the same syringe.
The speed of recovery from neuromuscular blockade is primarily determined by the intensity of the block at the time of antagonism. It is also influenced by other factors including the presence of drugs (e.g. anaesthetic drugs, antibiotics and antiarrhythmic drugs) and physiological changes (e.g. electrolyte and acid-base imbalance, renal impairment). These factors may prevent successful reversal with Neostigmine Juno Solution for Injection or lead to recurarisation after apparently successful reversal. It is imperative that the patients should not be left unattended until these possibilities have been excluded.

Myasthenia gravis.

Adults.

1 mg to 2.5 mg given as an IM or SC injection at intervals throughout the day when greater strength may be needed (e.g. mornings and before meals) giving a total daily dose of 5 to 20 mg. Duration of action of a single dose is 2 to 4 hours.

Neonates.

0.05-0.25 mg as an IM injection every 2-4 hours, half an hour before feeding. Treatment is not usually required beyond 8 weeks of age. Because the condition is usually self-limiting the daily dosage should gradually be reduced until the drug can be withdrawn.

Older children.

0.2 to 0.5 mg by injection as required. Dosage should be adjusted according to response.
When large doses of neostigmine are given to myasthenic patients, atropine sulfate may be required to counteract the muscarinic side effects.

Intestinal atony.

Prophylaxis.

0.25 mg as an IM or SC injection before or immediately after the operation, repeated every 4 to 6 hours, for 2 to 3 days.

Treatment.

0.5 mg as an IM or SC injection repeated at intervals of 4 to 6 hours.

Urinary retention.

Prophylaxis.

0.25 mg as an IM or SC injection as for intestinal atony.

Treatment.

0.5 mg as an IM or SC injection and apply heat to lower abdomen. After patient has voided continue 0.5 mg SC or IM every 3 hours for at least 5 injections. If there has been no urinary response within one hour of the first dose, the patient should be catheterised.

Dosage adjustment.

Renal impairment.

The duration of effect may be prolonged in patients with renal impairment since neostigmine is excreted mostly in the urine. Dosage adjustment may be needed for patients in renal failure.

Elderly.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy.

4.3 Contraindications

Mechanical obstruction of intestinal or urinary tract.
Known hypersensitivity to neostigmine.
Peritonitis (when used to promote peristalsis).
This medicine should not be given in conjunction with suxamethonium as neostigmine potentiates the depolarising myoneural blocking effects of this agent.

4.4 Special Warnings and Precautions for Use

Neostigmine should be used with extreme caution in patients who have undergone recent intestinal or bladder surgery and in patients with bronchial asthma.
Administration of neostigmine to patients with intestinal anastomosis may produce rupture of the anastomosis or leakage of intestinal contents.
Neostigmine alone induces significant bronchoconstriction.
Use with caution in patients with, cardiac disease and cardiovascular disorders including arrhythmias, bradycardia, recent myocardial infarction or coronary occlusion, and hypotension as well as in patients with epilepsy, vagotonia, parkinsonism, peptic ulceration, renal impairment, Addison's disease or hyperthyroidism.
With large doses, simultaneous parenteral administration of atropine sulfate or glycopyrrolate may be advisable. Atropine sulfate or glycopyrrolate should always be available along with other anti-shock medications (adrenaline) in case of hypersensitivity to neostigmine.
Neostigmine may prolong the depolarising neuromuscular blocking action of depolarising muscle relaxants such as suxamethonium and prolonged apnoea may result (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Neuromuscular function monitoring must be available for every patient in whom neuromuscular blockade has been induced and should be used whenever the anaesthetist is considering extubation following the use of non-depolarising neuromuscular blockade.
Re-administration of muscle relaxant shortly after use of neostigmine should be done with caution: competing at the neuromuscular junction there may be increased levels of acetylcholine and neostigmine has some direct postsynaptic cholinomimetic effects, thus resistance to muscle relaxation may be seen. There will still be some previously administered relaxant in the patient, thus prolonged recovery may also be seen.
The administration of sugammadex after neostigmine reversal may increase muscle relaxation as all muscle relaxant is removed and the neuromuscular inhibition by neostigmine is revealed.
As the severity of myasthenia gravis can fluctuate considerably, care is required to avoid cholinergic crisis due to overdosage with neostigmine (see Section 4.9 Overdose).

Use in renal impairment.

Use neostigmine with caution in patients with renal impairment. Neostigmine is excreted mostly in the urine. Please also see Section 4.2 Dose and Method of Administration.

Use in the elderly.

In a study of 59 patients over 65 years of age (32 with cardiovascular disease) receiving neostigmine 50 microgram/kg with glycopyrronium 10 microgram/kg, compared to previous studies in healthy adults, the initial increase in heart rate is higher, the subsequent falls in heart rate are less in elderly patients and the incidence of cardiac dysrhythmias was higher. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy.

Paediatric use.

Limited literature data available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Corticosteroids.

Corticosteroids may decrease the anticholinesterase effects of neostigmine. Conversely anticholinesterase effects may increase after stopping corticosteroids.

Depolarising muscle relaxants.

Neostigmine may prolong the Phase I block of depolarising muscle relaxants such as suxamethonium. Prolonged muscle paralysis with extended periods of apnoea may occur unless IPPV (intermittent positive pressure ventilation) is maintained.

Atropine or glycopyrrolate.

Atropine or glycopyrrolate reverses the muscarinic effects of neostigmine. This interaction is used to counteract the muscarinic symptoms of neostigmine toxicity, however masking the signs of overdosage can lead to inadvertent induction of cholinergic crisis with the use of atropine or glycopyrrolate.

Aminoglycosides, local/general anaesthetics, antiarrhythmic agents.

Anticholinesterase agents can be effective in reversing neuromuscular block induced by aminoglycoside antibiotics. Aminoglycoside antibiotics, local and some general anaesthetics, antiarrhythmic agents and other drugs that interfere with neuromuscular transmission should be used cautiously, if at all, in patients with myasthenia gravis. The dose of neostigmine may need to be increased accordingly.
Quinine, chloroquine, hydroxychloroquine, beta-blockers and lithium may reduce the effectiveness of treatment with neostigmine.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category B2)
The maternal need for neostigmine may be absolute in the context of myasthenia gravis. Cholinergic effects in the neonate are rare.
The safety of neostigmine in pregnancy has not been established with respect to possible adverse effects on foetal development. Anticholinesterase agents may cause uterine irritability and induce premature labour when given IV to pregnant women near term. Therefore neostigmine should not be used in pregnant women or those likely to become pregnant unless the expected benefits outweigh any potential risk.
Evidence indicates that only negligible amounts of neostigmine enter the breast milk; nevertheless, the possibility of adverse effects on the breast-feeding infant should be considered.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Inadequate reversal.

Studies have shown ~31% to 50% of patients have clinically significant residual neuromuscular blockade with train-of-four ratios less than 0.90 following surgery.
Patients with train-of-four ratios less than 0.90 are at increased risk for hypoxemic events, impaired control of breathing during hypoxia, airway obstruction, postoperative pulmonary complications (there is an increase in the risk of aspiration) and symptoms of muscle weakness.
Clinical signs include:
Weakness (head lift, handgrip, eye-opening, or tongue protrusion).
Inability to smile, swallow, speak, cough, track objects with eyes; or inability to perform a deep or vital capacity breath.
Symptoms also include blurry vision, diplopia, facial weakness, facial numbness, and general weakness.

Adverse reactions.

Adverse reactions in a study in 14 healthy volunteers receiving neostigmine 2.5 mg with glycopyrrolate 450 microgram repeated after 1/4 h in 9 of the volunteers included: muscle weakness 14 (100%), blurred vision 13 (93%), abdominal cramping 13 (93%), dry mouth 11 (79%), nausea 11 (79%), vomiting 1 (7%), none of these were seen in the 7 subjects receiving saline placebo. See Table 1.

Postmarketing.

Cardiovascular.

Cardiac arrhythmias (especially bradycardia), hypotension, syncope, cardiac arrest.

Central nervous system.

Headache, dizziness, convulsions, loss of consciousness, coma, drowsiness, restlessness, ataxia, slurred speech, agitation and fear.

Gastrointestinal.

Nausea, vomiting, diarrhoea, abdominal cramps, flatulence, increased peristalsis and involuntary defecation.

Genitourinary.

Involuntary urination or desire to urinate.

Musculoskeletal.

Muscle cramps, fasciculation, general weakness and paralysis.

Respiratory.

Increased oral, pharyngeal and bronchial secretions, dyspnoea, bronchospasm, respiratory depression, respiratory arrest, tight chest and wheezing.

Allergic.

Allergic reactions including anaphylaxis.

Skin.

Rash and urticaria.

Other.

Increased sweating and salivation, miosis, vision changes, nystagmus and lacrimation.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Overdosage with neostigmine can cause cholinergic crisis, which is characterised by increasing muscle weakness. Myasthenic crisis is due to an increase in severity of the disease and may be difficult to distinguish from cholinergic crisis on a symptomatic basis. Cholinergic crisis can lead to respiratory paralysis, which may result in death, while myasthenic crisis is extreme muscle weakness. The differentiation between the two crises is extremely important as treatment is different for each. The two types of crises can be differentiated by the use of edrophonium and clinical judgement.

Symptoms.

Signs of overdosage due to muscarinic effects may include abdominal cramps, increased peristalsis, diarrhoea, nausea and vomiting, increased bronchial secretion, salivation, diaphoresis and miosis. Nicotinic effects consist of muscular cramps, fasciculations and general weakness. Bradycardia and hypotension may also occur.

Treatment.

The treatment of cholinergic crisis requires the discontinuation of all cholinergic medication. The immediate use of atropine is also recommended, muscarinic effects are controlled with IV atropine sulfate (1 to 2 mg) followed by IM atropine sulfate every 2 to 4 hours. Assistance of ventilation may be required if respiration is severely depressed.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Neostigmine is an anticholinesterase agent which inhibits reversibly the hydrolysis of acetylcholine by competing with acetylcholine for attachment to acetylcholinesterase. As a result acetylcholine accumulates at cholinergic synapses and its effects are prolonged and exaggerated. Neostigmine is therefore capable of producing a generalised cholinergic response, including miosis, increased tonus of intestinal and skeletal musculature, constriction of bronchi and ureters, bradycardia and stimulation of salivary and sweat glands.
In addition neostigmine is used mainly for its direct cholinomimetic effect on skeletal muscle and to a lesser extent to increase the activity of smooth muscle.
Because of its quaternary ammonium structure, in moderate doses, neostigmine does not cross the blood-brain barrier to produce CNS effects. Extremely high doses, however produce CNS stimulation followed by CNS depression.

Pharmacodynamics.

In healthy volunteers glycopyrrolate/neostigmine in combination produces muscle weakness in a dose related fashion, affecting handgrip strength, single twitch height, dysphagia and to some extent diplopia.
Neostigmine-induced weakness with characteristics of phase-1 depolarising neuromuscular blockade was evidenced by fasciculations of multiple muscle groups, depression of the single twitch height, no fade in train-of-four and increased neuromuscular blockade after the second dose of anticholinesterase agent and muscle weakness.
Thus residual post-operative weakness may be both inadequate reversal and neostigmine induced weakness (especially with large doses).
Respiratory muscle weakness produces decreased volumes (FEV₁ and FVC).

Clinical trials.

Only literature data available.

5.2 Pharmacokinetic Properties

Distribution.

The major site of uptake of neostigmine is the liver.
Because of its quaternary ammonium structure, in moderate doses, neostigmine does not cross the blood-brain barrier to produce CNS effects.

Metabolism.

Neostigmine is excreted in urine as unchanged drug (50%) and metabolites. It is metabolised partly by the hydrolysis of the ester linkage and partly by microsomal enzymes in the liver.

Excretion.

Approximately 80% of a single IM dose of neostigmine is excreted in the urine in 24 hours, about 50% as unchanged drug and the remainder as metabolites. Following IV administration the elimination half-life ranges from 47 to 60 minutes and after IM administration 50 to 91 minutes.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

No data available.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium chloride, water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Product is for single use in one patient only. Discard any residue.

6.5 Nature and Contents of Container

Neostigmine Juno Solution for Injection is available as 2.5 mg neostigmine methylsulfate in 1 mL colourless type 1 glass ampoules in cartons of 10 or 50 ampoules.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical Name: (3-dimethyl-carbamoxyloxy) trimethylanilinium methyl sulfate.

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Neostigmine Juno Solution for Injection

Neostigmine methylsulfate

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