4.1. Therapeutic indications

Myasthenia gravis, paralytic ileus and post-operative urinary retention.

4.2. Posology and method of administration

Myasthenia gravis

Adults

Doses of 30 to 120mg 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 3 to 4 hours in the daytime but a longer effect (6 hours) is often obtained with a dose taken on retiring for bed.

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

Paediatric population

Children under 6 years old should receive an initial dose of half a tablet (30mg) of Pyridostigmine Tablets; children 6 – 12 years old should receive one tablet (60mg). Dosage should be increased gradually, in increments of 15 – 30mg daily, until maximum improvement is obtained. Total daily requirements are usually in the range to 30 – 360mg.

Paralytic ileus and post-operative urinary retention

Adults

The usual dose is 1 to 4 tablets (60 – 240mg) per day.

Paediatric population

The usual daily dose is a quarter to one tablet (15 – 60mg per day).

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

Special populations

Elderly

There are no specific dosage recommendations for Pyridostigmine Tablets in elderly patients.

Renal impairment

Pyridostigmine is mainly excreted unchanged by the kidney, therefore lower doses may be required in patients with renal disease and treatment should be based on titration of drug dosage to effect.

Hepatic impairment

There are no specific dosage recommendations for Pyridostigmine Tablets in patients with hepatic impairment.

Method of administration

Pyridostigmine Tablets should be taken with water. For oral use.

4.3. Contraindications

Pyridostigmine Tablets are contraindicated in patients with:

- Hypersensitivity to the active substance, bromides or to any of the excipients listed in section 6.1.

- Mechanical gastro-intestinal or urinary obstruction

4.4. Special warnings and precautions for use

Extreme caution is required when administering Pyridostigmine Tablets to patients with obstructive respiratory diseases like bronchial asthma and chronic obstructive pulmonary disease (COPD).

Care should also be taken in patients with:

- Arrhythmias such as bradycardia and AV block (elderly patients may be more susceptible to dysrhythmias than the young adult)

- Recent coronary occlusion

- Hypotension

- Vagotonia

- Peptic ulcer

- Epilepsy or Parkinsonism

- Hyperthyroidism

- Renal impairment

When relatively large doses of Pyridostigmine Tablets are taken by myasthenic patients it may be necessary to give atropine or other anticholinergic drugs to specifically counteract the muscarinic effects of Pyridostigmine Tablets while maintaining its nicotinergic effect.

In all patients the possibility of "cholinergic crisis", due to overdosage of Pyridostigmine Tablets, and its differentiation from "myasthenic crisis", due to increased severity of the disease, must be considered. 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.

The requirement for Pyridostigmine Tablets is usually markedly decreased after thymectomy or when additional therapy (steroids, immunosuppressant drugs) is given (see section 4.5).

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine since it contains lactose.

4.5. Interaction with other medicinal products and other forms of interaction

Immunosuppressant drugs

The requirement for pyridostigmine bromide could be decreased by concomitant use with corticosteroids or immunosuppressant drugs. Nevertheless, a new addition of corticosteroids may initially aggravate the symptoms of myasthenia gravis.

Thymectomy

The need for Pyridostigmine Tablets may be decreased after thymectomy (see section 4.4).

Methylcellulose

Methylcellulose and medicine containing methylcellulose as excipients can completely inhibit absorption of pyridostigmine bromide.

Antimuscarinics

Atropine and hyoscine antagonise the muscarinic effects of pyridostigmine bromide. It should be noted that the slower gastro-intestinal motility caused by these drugs may affect the absorption of pyridostigmine bromide.

Muscle Relaxants

Pyridostigmine antagonises the effect of non-depolarising muscle relaxants (e.g. pancuronium and vecuronium). Pyridostigmine may prolong the effect of depolarising muscle relaxants (e.g. suxamethonium).

Others

Aminoglycoside antibiotics, local and some general anaesthetics, antiarrhythmic agents, and other drugs that interfere with neuromuscular transmission may interact with pyridostigmine bromide.

4.6. Fertility, pregnancy and lactation

Fertility

Nonclinical investigations in rats have not shown any negative effects on reproductive behaviour.

Pregnancy

The safety of pyridostigmine bromide during pregnancy has not been established.

Although the possible hazards to mother and child must be weighed against the potential benefits in every case, experience with pyridostigmine bromide in pregnant patients with myasthenia gravis has revealed no untoward effect of the medicinal product on the course of pregnancy. As the severity of myasthenia gravis often fluctuates considerably in pregnancy, particular care is required to avoid cholinergic crisis due to overdose. Since pyridostigmine bromide crosses the placenta barrier excessive dose of pyridostigmine should be avoided; the newborn child should be monitored for possible effects.

Reproductive studies in rabbits and rats showed no teratogenic but embryo-/fetotoxic effects at doses toxic to the dam (see section 5.3).

Intravenous administration of pyridostigmine bromide can induce contraction of the uterus (especially in the last period of pregnancy).

Lactation

The safety of pyridostigmine bromide during lactation has not been established. Observations indicate that only negligible amounts of pyridostigmine is excreted in breast milk. Nevertheless, due regard should be paid to possible effects on the breast-fed infant.

4.7. Effects on ability to drive and use machines

Due to miosis and accommodation disorders caused by pyridostigmine bromide or an inadequate treatment of Myasthenia gravis, pyridostigmine may impair visual acuity and consequently the ability to react as well as the ability to drive and use machines.

4.8. Undesirable effects

As with all cholinergic products, pyridostigmine bromide may have unwanted functional effects on the autonomic nervous system. Muscarine-like adverse effects may be exhibited as nausea, vomiting, diarrhoea, abdominal cramps, increased peristaltic and increased bronchial secretion, salivation, bradycardia and miosis.

The primary nicotinic effects are muscle spasms, fasciculation and muscular weakness.

Within the system organ classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000), Not known (cannot be estimated from the available data).

The following undesirable effects were observed whereas the frequency of undesirable effect is not known:

Immune system disorders

Frequency not known: Drug hypersensitivity

Nervous system disorders

Frequency not known: Syncope

Eye disorders

Frequency not known: Miosis, increased lacrimation, accommodation disorders (e.g. blurred vision)

Cardiac disorders

Frequency not known: Arrhythmia (including bradycardia, tachycardia, AV block), Prinzmetal angina, as well as syncope and hypotension (see section 4.9)

Vascular disorders

Frequency not known: Flushing, hypotension

Respiratory, thoracic and mediastinal disorders

Frequency not known: Increased bronchial secretion combined with bronchoconstriction

Gastrointestinal disorders

Frequency not known: Nausea, vomiting, diarrhoea, gastrointestinal hypermotility, salivary hypersecretion, abdominal symptoms (e.g. discomfort pain, cramps etc.)

Skin and subcutaneous tissue disorders

Frequency not known: Rash (disappears usually soon after ceasing of medication. Bromide containing medicines should no longer be used), hyperhydrosis, urticaria

Musculoskeletal and connective tissue disorders

Frequency not known: Increased muscle weakness fasciculation, tremors and muscle cramps or muscle hypotonia (see section 4.9)

Renal and urinary disorders

Frequency not known: Urinary urgency

Because these symptoms may be an indication of cholinergic crisis, the physician should be notified immediately to clarify the diagnosis (see section 4.9)

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

4.9. Overdose

Overdosage may lead to “cholinergic crisis” characterised by severe muscarinic and nicotinic symptoms of marked muscle weakness. Cardiovascular and respiratory failure may occur.

Pyridostigmine bromide may cause cholinergic crisis. Signs of overdosage due to muscarinic effects may include abdominal cramps, increased peristalsis, diarrhoea, nausea and vomiting, increased bronchial secretions, bronchospasm, salivation, hyperhydrosis and miosis. Nicotinic effects consist of muscular cramps, fasciculations and general weakness up to paralysis.

Hypotension up to cardiovascular collapse, bradyarrhythmia, up to cardiac arrest may also occur.

Central nervous system effects may include agitation, confusion, slurred speech, nervousness, irritation, visual hallucinations. Convulsions and coma may occur.

Treatment with Pyridostigmine Tablets must be stopped immediately. Artificial ventilation should be instituted if respiration is severely depressed. Atropine sulphate 1 to 2 mg intravenously is an antidote to the muscarinic effects. Doses may be repeated every 5 to 30 minutes as needed.