Consumer medicine information

Neostigmine Injection BP

Neostigmine methylsulfate

BRAND INFORMATION

Brand name

Neostigmine Injection BP

Active ingredient

Neostigmine methylsulfate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Neostigmine Injection BP.

What is in this leaflet

This leaflet answers some of the common questions people ask about Neostigmine Injection. It does not contain all the information that is known about Neostigmine 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 Injection against the benefits they expect it will have for you.

If you have any concerns about being given this medicine, ask your doctor or pharmacist.

Keep this leaflet.

You may need to read it again.

What Neostigmine is for

Neostigmine Injection increases movement of the muscles in the body.

It can be used:

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

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

Your doctor will have explained why you are being treated with Neostigmine 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 Injection is not addictive.

Before you are given Neostigmine

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

When you must not use it

You should not be given Neostigmine Injection if you are pregnant or 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 Injection from breast milk if you are breastfeeding.

You must not be given Neostigmine Injection if:

  • you are sensitive to neostigmine
  • 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 Injection if you have the following medical conditions:

  • blockage of the intestines or urinary tract
  • peritonitis

Neostigmine 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
  • heart disease or other heart problems
  • epilepsy
  • low blood pressure
  • Parkinson's disease
  • stomach ulcer
  • kidney problems
  • Addison's disease
  • an overactive thyroid gland

It may not be safe for you to be given Neostigmine 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 buy at the chemist, supermarket or health food shop.

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

  • corticosteroids
  • atropine
  • antibiotics
  • medicine for heart problems including beta-blockers
  • lithium
  • chloroquine, hydroxychloroquine
  • quinine

These medicines may affect the way Neostigmine 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 Injection is given

Neostigmine Injection will be given to you by injection 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 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 be given Neostigmine Injection.

Neostigmine Injection helps most people with muscle weakness but may have unwanted side-effects in a few people.

All medicines can 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:

  • 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 Injection.

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

  • 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.

Some people may get other side effects while being given Neostigmine Injection.

Storage

Neostigmine 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 °C and protected from light.

Disposal

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

Product description

Neostigmine Injection is a clear, colourless solution.

It contains neostigmine methylsulfate 0.5 or 2.5 mg/mL as the active ingredient, plus

Sodium chloride

Sodium phosphate-monobasic dihydrate (E339)

Sodium phosphate-dibasic dodecahydrate (E339)

Water for Injections.

Polyamp® DuoFit® ampoules

0.5mg/mL pack of 10

2.5mg/mL pack of 50

Manufacturer

AstraZeneca Pty Ltd
ABN 54 009 682 311
Alma Road
NORTH RYDE NSW 2113

Tel: 1 800 805 342

This leaflet was prepared in

October 2004.

Australian Registration Number

0.5mg/mL ampoule 11973

2.5mg/mL ampoule 11976

BRAND INFORMATION

Brand name

Neostigmine Injection BP

Active ingredient

Neostigmine methylsulfate

Schedule

S4

 

1 Name of Medicine

Neostigmine methylsulfate.

6.7 Physicochemical Properties

The chemical name for neostigmine methylsulfate is (3-dimethyl-carbamoxyloxy) trimethylanilinium methyl sulfate. Empirical formula C13H22N2O6S, MW: 334.4.

Chemical structure.


CAS number.

51-60-5.

2 Qualitative and Quantitative Composition

1 mL sterile solution of pH 4.5 - 6.5 containing 0.5 mg of neostigmine methylsulfate.
1 mL sterile solution of pH 4.5 - 6.5 containing 2.5 mg of neostigmine methylsulfate.
Excipients with known effect: sodium chloride, monobasic sodium phosphate, dibasic sodium phosphate dodecahydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Injection solution. Clear, colourless solution.

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.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Metabolism.

The major site of uptake is in the liver. 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.

4 Clinical Particulars

4.1 Therapeutic Indications

Neostigmine is indicated for:
Reversal of the effects of nondepolarising neuromuscular blocking agents (e.g. tubocurarine, pancuronium etc).
Prophylaxis and treatment of postoperative intestinal atony and urinary retention.
Treatment of myasthenia gravis during acute exacerbations, when the condition is severe or in neonates.

4.3 Contraindications

Mechanical obstruction of intestinal or urinary tract.
Known hypersensitivity to neostigmine.
Peritonitis.

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.
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 may be advisable. Atropine sulfate should always be available along with other antishock 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).
Neostigmine should not be given whilst anaesthesia with cyclopropane and halothane continues but may be used after withdrawal of these agents.
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 the elderly.

No data available.

Paediatric use.

No 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 respiratory depression with extended periods of apnoea may occur.

Atropine.

Atropine 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.

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, chloroquinine, 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.

4.8 Adverse Effects (Undesirable Effects)

Adverse reactions generally associated with neostigmine overdosage are:

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 defaecation.

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 of suspected adverse reactions.

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.

4.2 Dose and Method of Administration

Neostigmine Injection BP 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 Injection BP is given, a syringe of atropine sulfate 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 Injection BP 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 Injection BP 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.

Adults.

A single dose of neostigmine 0.5 to 2.5 mg (0.05 - 0.07 mg/kg) to be administered simultaneously (in separate syringes) with atropine sulfate 0.6 - 1.2 mg (0.02 to 0.03 mg/kg) 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.

Children.

The suggested dose in children is 0.05 mg/kg and atropine sulfate 0.02 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 in separate syringes, but in patients with bradycardia, the pulse rate should be increased to about 80 beats/minute with atropine before administering neostigmine.
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 Injection BP or lead to re-curarisation 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.

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.

4.9 Overdose

For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).
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.

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium chloride, monobasic sodium phosphate, dibasic sodium phosphate dodecahydrate and 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. Neosotigmine Injection should be protected from light.

6.5 Nature and Contents of Container

1 mL polyethylene ampoules (Polyamp DuoFit) in packs of 10 (0.5 mg/mL) or 50 (2.5 mg/mL).

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes