This information is intended for use by health professionals

1. Name of the medicinal product

Neostigmine Bromide Tablets 15 mg

2. Qualitative and quantitative composition

Each tablet contains 15 mg neostigmine bromide Ph.Eur.

3. Pharmaceutical form

Tablets

4. Clinical particulars
4.1 Therapeutic indications

Myasthenia gravis; paralytic ileus; post-operative urinary retention.

4.2 Posology and method of administration

Neostigmine bromide has a slower onset of effect when given orally than when given parenterally, but the duration of action is longer and the intensity of action more uniform.

To facilitate change of treatment from one route of administration to another, the following doses are approximately equivalent in effect:

0.5 mg intravenously = 1-1.5 mg intramuscularly or subcutaneously = 15 mg orally.

Myasthenia gravis

Adults: Doses of 1-2 tablets by mouth are given at intervals throughout the day when maximum strength is needed (for example, on rising and before mealtimes). The usual duration of action of a dose is two to four hours.

The total daily dose is usually in the range of 5-20 tablets but doses higher than these may be needed by some patients.

Newborn infants: Neostigmine bromide ampoules are recommended.

Older children: Children under 6 years old should receive an initial dose of half a tablet (7.5 mg) of Neostigmine Bromide; children 6-12 years old should receive one tablet (15 mg). Dosage requirements should be adjusted according to the response but are usually in the range of 15-90 mg orally per day.

The requirement for Neostigmine Bromide is usually markedly decreased after thymectomy, or when additional therapy (steroids, immunosuppressant drugs) is given.

When relatively large doses of neostigmine bromide are taken by myasthenic patients, it may be necessary to give atropine or other anticholinergic drugs to counteract the muscarinic effects. It should be noted that the slower gastro-intestinal motility caused by these drugs may affect the absorption of oral neostigmine bromide.

In all patients the possibility of 'cholinergic crisis', due to overdosage of neostigmine bromide, and its differentiation from 'myasthenic crisis', due to increased severity of disease, must be borne in mind. Both types of crisis are manifested by increased muscle weakness, but whereas myasthenic crisis may require more intensive anticholinesterase treatment, cholinergic crisis calls for immediate discontinuation of this treatment and institution of appropriate supportive measures, including respiratory assistance.

Other indications

Adults: The usual dose is 1 to 2 tablets orally.

Children: 2.5-15 mg orally.

The frequency of these doses may be varied according to the needs of the patient.

The elderly: There are no specific dosage recommendations for neostigmine bromide in elderly patients.

4.3 Contraindications

Neostigmine Bromide should not be given to patients with mechanical gastro-intestinal or urinary obstruction.

Neostigmine Bromide is contra-indicated in patients with known hypersensitivity to the drug and to bromides.

Neostigmine Bromide should not be used in conjunction with depolarising muscle relaxants such as suxamethonium as neuromuscular blockade may be potentiated and prolonged apnoea may result.

4.4 Special warnings and precautions for use

Extreme caution is required when administering Neostigmine Bromide to patients with bronchial asthma.

Care should also be taken in patients with bradycardia, recent coronary occlusion, hypotension, peptic ulcer, vagotonia, epilepsy or parkinsonism.

4.5 Interaction with other medicinal products and other forms of interaction

Neostigmine bromide should not be given during cyclopropane or halothane anaesthesia; however, it may be used after withdrawal of these agents.

4.6 Pregnancy and lactation

The safety of neostigmine bromide during pregnancy or lactation has not been established. Although the possible hazards to mother and child must therefore be weighed against the potential benefits in every case, experience with neostigmine bromide in pregnant patients with myasthenia gravis has revealed no untoward effect of the drug on the course of pregnancy.

As the severity of myasthenia gravis often fluctuates considerably, particular care is required to avoid cholinergic crisis, due to overdosage of the drug, but otherwise management is no different from that in non-pregnant patients.

Observations indicate that only negligible amounts of neostigmine bromide are excreted in breast milk; nevertheless, due regard should be paid to possible effects on the breast-feeding infant.

4.7 Effects on ability to drive and use machines

Not known.

4.8 Undesirable effects

There is no evidence to suggest that neostigmine bromide has any special effects in the elderly; however, elderly patients may be more susceptible to arrhythmias than the younger adult.

Side-effects and adverse reactions may include nausea and vomiting, increased salivation, diarrhoea and abdominal cramps.

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.

4.9 Overdose

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

Artificial ventilation should be instituted if respiration is severely depressed. Atropine sulphate 1 to 2 mg intravenously is an antidote to the muscarinic effects.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Neostigmine bromide is an antagonist to cholinesterase, the enzyme which normally destroys acetylcholine. The action of neostigmine bromide can briefly be described, therefore, as the potentiation of naturally occurring acetylcholine.

5.2 Pharmacokinetic properties

Neostigmine bromide is a quaternary ammonium compound and is poorly absorbed from the gastro-intestinal tract. Following parenteral administration as the methylsulphate, neostigmine is rapidly eliminated with a plasma half-life of 50-90 minutes and is excreted in the urine both as unchanged drug and metabolites. It is metabolised partly by hydrolysis of the ester linkage.

5.3 Preclinical safety data

Neostigmine has not been reported to have mutagenic or carcinogenic potential. In rats, acute and chronic exposure causes changes in the fine structure at the end-plate region of muscle.

6. Pharmaceutical particulars
6.1 List of excipients

Lactose

Maize starch

Talc

Magnesium stearate

6.2 Incompatibilities

None known.

6.3 Shelf life

Five years

6.4 Special precautions for storage

The recommended maximum storage temperature is 30°C. The tablets should be protected from light.

6.5 Nature and contents of container

Polypropylene tracer pots with HDPE caps, each containing 140 tablets.

6.6 Special precautions for disposal and other handling

None.

7. Marketing authorisation holder

Alliance Pharmaceuticals Limited

Avonbridge House,

Bath Road

Chippenham

Wiltshire

SN15 2BB

United Kingdom

8. Marketing authorisation number(s)

PL 16853/0142

9. Date of first authorisation/renewal of the authorisation

23rd October 1995

10. Date of revision of the text

15 January 2015