Pyridostigmine Bromide 12mg/ ml Oral Solution – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Pyridostigmine Bromide 12mg/ ml Oral Solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml contains 12mg pyridostigmine bromide.

Excipient(s) with known effect:

Each ml contains 3.04 mg sodium, 140 mg sorbitol, 3.84 mg propylene glycol, 1.27 mg sodium benzoate and 200mg glycerol.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Oral solution.

Clear, slightly viscous solution.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Adults:

Treatment of

• Myasthenia gravis and
• Paralytic ileus

Children:

Treatment of myasthenia gravis

4.2 Posology and method of administration

Posology

Myasthenia gravis

Adults

Doses of 30 to 120 mg (2.5 to 10ml of solution) 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 300 to 1200 mg pyridostigmine bromide (25 to 100ml of solution) but doses higher than these may be needed by some patients.

Paediatric Population

Children under 6 years old: An initial dose of 30 mg of pyridostigmine bromide (2.5ml of solution)

Children 6 to 12 years old: An initial dose of 60 mg (5ml of solution). Dosage should be increased gradually, in increments of 15 to 30mg (1.25 to 2.5ml of oral solution) daily, until maximum improvement is obtained. Total daily requirements are usually in the range 30 to 360 mg (2.5 to 30ml of solution).

Paralytic Ileus

Adults

The usual dose is 60 to 240 mg (5 to 20ml of solution) per day.

Special populations

Elderly

There are no specific dosage recommendations for pyridostigmine bromide in elderly patients.

Renal impairment

Pyridostigmine bromide 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 recommendation for pyridostigmine bromide in patinets with hepatic impairment.

Method of Administration

For oral use.

Oral administration

This medicine contains a plastic dosing pipette to measure the right amount of solution prescribed. The numbers up the side show how many millilitres (ml) of solution you have inside the pipette.

1. 1. Open the bottle: press the plastic screw cap down whilst turning the bottle anti-clockwise.
2. 2. Ensure the plunger of the pipette is fully depressed and insert it into the solution.
3. 3. Holding the body of the pipette with one hand, fill the pipette by drawing the plunger upwards with the opposite hand until the mark on the plunger corresponds to the amount prescribed by your doctor. The marks are at every 1ml and intermediate marks at 0.1ml.
4. 4. Remove the pipette from the bottle, place into your mouth and slide the plunger down. Drink the solution immediately.

If you need to take more solution to ensure you have the correct dose, wash the pipette first then repeat steps 2 to 4. When you have taken all of your dose, close the bottle, rinse the pipette thoroughly with water and dry. Replace the bottle and pipette back into the carton.

1. 1. Ensure that the enteral feeding tube is free from obstruction before administration.
2. 2. Flush the enteral tube with 5ml of water.
3. 3. Administer the required dose of Pyridostigmine Bromide 12mg/ml Oral Solution with a suitable measuring device. Do not use the dosing pipette provided.
4. 4. Flush the enteral tube with 5ml of water.

This product has not been tested with latex NG or latex PEG tubes and therefore should not be used with tubes made from latex.

4.3 Contraindications

Pyridostigmine bromide is contraindicated in patients with:

• Known hypersensitivity to the active substance, to bromides or to any of the excipients listed in section 6.1.
• Mechanical gastrointestinal or urinary obstruction

4.4 Special warnings and precautions for use

Extreme caution is required when administering pyridostigmine bromide 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 paitens may be more susceptiable to dysrhythmias than in the young adult)
• Recent coronary occlusion
• Hypotension
• Vagotonia
• Peptic ulcer
• Epilepsy or Parkinsonism
• Hyperthyroidism

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

When relatively large doses of pyridostigmine 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 pyridostigmine bromide.

In all patients the possibility of "cholinergic crisis", due to overdosage of pyridostigmine bromide, and its differentiation from "myasthenic crisis", due to increased severity of the 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.

Reduced dosage may be required for patients with impaired renal function (see section 4.2).

This medicinal product also contains:-

Excipient Content

per 5ml

Content per 100ml (Maximum Daily

Dose)

Sodium 15.2 mg 304 mg

Sorbitol 700 mg 14g

Propylene Glycol

19.2 mg 384 mg

Sodium Benzoate 6.35 mg 127 mg

Glycerol 1g 20g

.

Glycerol may cause headache, stomach upset and diarrhoea.

4.5 Interaction with other medicinal products and other forms of interaction

Immunosuppressant drugs

The requirement for pyridostigmine bromide could be decreased when additional therapy (steroids, immunosuppressant drugs) is given although peak plasma concentration and AUC of pyridostigmine may decrease by high doses of corticosteroids.

Anti-muscarinics

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.

Anti-malarials

Chloroquine and hydroxychloroquine, by nature of their ability to increase myasthenic symptoms have also been shown to antagonize the effects of pyridostigmine bromide.

Lithium

The anti-myasthenic effects of pyridostigmine bromide are antagonized by lithium.

Muscle relaxants

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

Methylcellulose

Methylcellulose can prevent the absorption of pyridostigmine bromide. Simultaneous administration with medicinal products containing methylcellulose as an excipient should be avoided.

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

Pregnancy

The safety of pyridostigmine bromide in pregnancy has not been established. Intravenous administration of anticholinesterases during pregnancy may lead to premature uterine contractions. The risk of premature contractions is especially high when the product is administered towards the end of the gestation period. It is unknown whether oral administration is also associated with an increased risk of premature uterine contractions.

Although the possible hazard to mother and child must be weighed against the potential benefits in every case, experience with pyridostigmine bromide has revealed no untoward effect of the drug on the course of pregnancy.

Animal studies revealed no teratogenic effects of orally administered pyridostigmine bromide. However, fetotoxicity and effects on the offspring have been observed (see sections 5.3).

Pyridostigmine bromide crosses the placenta barrier. Excessive doses of pyridostigmine should be avoided; the newborn child should be monitored for possible side effects.

As the severity of myasthenia gravis often fluctuates considerably, particular care is required to avoid cholinergic crisis due to overdosage of the drug.

Therefore, pyridostigmine bromide is not recommended during pregnancy unless strongly indicated.

Breast-feeding

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

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

Fertility

Non-clinical research in rats has shown no negative effect on reproductive behaviour (see section 5.3).

Pyridostigmine's safety in human fertility has not been established.

4.7 Effects on ability to drive and use machines

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

Do not drive or operate machines if this medicine affects your ability to see clearly.

4.8 Undesirable effects

Adverse reactions are listed below according to system organ class and frequency. Frequencies are defined according to the following convention: 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).

As with all cholinergic products, pyridostigmine may have unwanted functional effects on

the autonomic nervous system. Muscarine-like adverse effects may be exhibited as nausea, vomiting, diarrhoea, abdominal cramps, increased peristalsis and increased bronchial secretion, salivation, bradycardia and miosis.

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

As 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 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.

Signs of overdosage due to muscarinic effects may include abdominal cramps, increased peristalsis, diarrhoea, nausea and vomiting, increased bronchial secretions, 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.

In case of overdosage, discontinue treatment with pyridostigmine bromide 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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Nervous system, parasympathomimetics, anticholinesterases, pyridostigmine ATC code: N07AA02

Pyridostigmine bromide is an anticholinesterase. As an antagonist to cholinesterase, the enzyme which normally destroys acetylcholine, the action of pyridostigmine bromide can briefly be described, therefore, as the potentiation of naturally occurring acetylcholine. Thus, it enhances the neuro muscular transmission in voluntary and involuntary muscles. Pyridostigmine bromide has a more prolonged action than Prostigmin (neostigmine) although it is somewhat slower to take effect (generally taking 30 to 60 minutes).

5.2 Pharmacokinetic properties

Absorption

Pyridostigmine bromide was poorly absorbed by about 22-25%. The rate and extent of absorption show wide inter-individual differences. When administered in healthy volunteers at oral daily doses of 120 mg, 120-370 mg and 180-1440 mg the oral bioavailability of pyridostigmine bromide was 7.6%, 18.9% and 3-4% with Cmax of 40-80 μg/L, 20-100 μg/L and 180 μg/L at tmax of 3-4 h, 1.5-6 h and 1.5 h, respectively. This low and highly variable bioavailability across studies is attributed to the low absorption rate of pyridostigmine. In patients with myasthenia gravis, oral bioavailability may decrease to 3.3%.

Distribution

Pyridostigmine is not bound to plasma proteins. The apparent volume of distribution after intravenous administration was 1.03 L/kg to 1.43 L/Kg in healthy patients, 1.76 L/Kg in myasthenia gravis patients and 0.53 to 1.1 L/Kg in surgery. The concentration of pyridostigmine in breast milk has been found to be 36 to 113% compared to maternal plasma, which implies a very low dose to the nursing infant (about 0.1% of the dose per kilogram bodyweight taken by the mother).

Metabolism

Pyridostigmine is metabolized only to a small extent. It is hydrolised by plasma cholinesterases. The main metabolite of pyridostigmine is the hydrolysis product 3-hydroxy-N-methyl-pyridinium.

Elimination

Systemic (intravenous) pyridostigmine is mainly excreted by the kidneys (75 – 90%) as parent compound and as inactive metabolites at a ratio of about 4:1. A total of 5-15% of oral doses is dose-dependently excreted by the kidneys as parent compound, thus reflecting the low degree of oral pyridostigmine absorption. The total plasma clearance was very rapid with 0.65 L/h/kg in healthy subjects, 0.29-1.0 L/h/kg in myasthenic patients, and 0.52-0.98 L/h/kg in patients with surgery, respectively. After intravenous administration the apparent terminal elimination half-life was 1.51-1.74 h in healthy volunteers, 1.05 h in myasthenic patients and

0.38-1.86 h in surgical patients, respectively. With oral administration, this was 3-4 h.

5.3 Preclinical safety data

Subcutaneous injection of toxic doses of pyridostigmine bromide to rats caused symptoms such as salivation, convulsions, tremor and respiratory difficulties. On oral administration of toxic doses, rats died from acute respiratory failure. Histology revealed injury to neuromuscular synapses of the diaphragm. Long-term oral administration to rats led to an inhibition of plasma cholinesterase and RBC cholinesterase.

Standard in vitro and in vivo genotoxicity studies gave no indication of a clinically relevant genotoxic potential of pyridostigmine bromide.

Preclinical studies on carcinogenicity of pyridostigmine bromide have not been conducted.

Animal studies on reproductive toxicity have been conducted in rats following oral administration of pyridostigmine bromide. They revealed no effects on the male and female fertility. Embryotoxicity studies revealed increased rates of resorption and delayed ossification in the foetuses at maternally toxic doses. In a peri/postnatal study, the weight gain of the offspring of the treated dams was decreased.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Acesulfame potassium (E950)

Citric acid anhydrous (E330)

Glycerol (E422)

Hydroxyethyl cellulose 250 HX

Sodium benzoate (E211)

Trisodium citrate dihydrate (E331)

Sorbitol 70% solution (E420)

Purified water

Raspberry flavour

Propylene glycol (E1520)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Unopened: 3 years

Opened: Use within 28 days.

6.4 Special precautions for storage

Store below 25°C.

Keep the bottle in the outer carton in order to protect from light. For storage conditions after first opening the medicinal product, see section 6.3.

6.5 Nature and contents of container

Amber glass bottle with a tamper-evident, child-resistant, polypropylene closure with a low density polyethylene (LDPE) liner containing 150ml of solution.

The bottle is contained within an outer cardboard carton. Each carton also contains a 5ml polyethylene oral dosing pipette. The pipette is marked with a scale with markings at every 1ml and intermediate marks at every 0.1ml.

6.6 Special precautions for disposal

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Horizon Pharmaceuticals Limited

35 Grimwade Avenue

Croydon

CR0 5DJ

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 50956/0001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

03/04/2019

10 DATE OF REVISION OF THE TEXT

18/02/2022