Summary of Product Characteristics (SmPC) - Pyridostigmine, 60 mg tablets
1 NAME OF THE MEDICINAL PRODUCT
Pyridostigmine 60mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 60mg of pyridostigmine bromide.
Each tablet also contains lactose monohydrate.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Tablet
White to off white, flat faced, round, bevelled edges, uncoated tablet with cross scoring on one side and debossed ‘NM’ on the other side.
The tablet can be divided into four equal parts.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Myasthenia gravis, paralytic ileus and post-operative urinary retention.
4.2 Posology and method of administration
Posology
Myasthenia gravis
Adults
Doses of 30 to 120mg each 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 doses 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; 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.
Other Indications (paralytic ileus, post-operative urinary retention)
Adults
The usual dose is 1 to 4 tablets (60 – 240mg) per day
Paediatric population
The usual dose is 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 in elderly patients.
Renal Impairment
Pyridostigmine is mainly excreted unchanged in the urine, therefore lower doses may be required in patients with renal impairment and treatment should be based on titration of drug dosage to effect.
Hepatic impairment
There are no specific dosage recommendations for Pyridostigmine in patients with hepatic impairment.
Method of administration
Pyridostigmine should be taken with water. For oral use
4.3 Contraindications
Pyridostigmine should not be given to patients with mechanical gastro-intestinal or urinary obstruction.
Pyridostigmine is contra-indicated in patients with:
- known hypersensitivity to the drug and to 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 to patients with obstructive respiratory diseases like bronchial asthma and chronic obstructive pulmonary disease (COPD).
Care must be taken in patients with:
- Arrhythmias such as bradycardia and AV block (There is no evidence to suggest that pyridostigmine has any special effects on the elderly. However, 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 are taken by myasthenic patients it may be necessary to give atropine or other anticholinergic drugs to specifically counteract the muscarinic effects of Pyridostigmine while maintaining its nicotinergic effect.
In all patients the possibility of "cholinergic crisis", due to overdosage of pyridostigmine, 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 appropriate supportive measures, including respiratory assistance.
Pyridostigmine tablets contain lactose. The requirement for Pyridostigmine 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, the total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
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 the symptoms of myasthenia gravis.
Thymectomy
The need for Pyridostigmine 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.
Anti-arrhythmics:
Procainamide, quinidine, and propranolol have been shown to antagonize the effects of pyridostigmine. There have been some reports of propafenone also being able to antagonize the effects of pyridostigmine.
It should be noted that the lower gastro-intestinal motility caused by these drugs may affect the absorption of pyridostigmine bromide.
Antibacterials:
Aminogycoside antibiotics, clindamycin and also polymixins antagonize the effects of pyridostigmine.
Antimalarials:
Chloroquine and hydroxychloroquine, by nature of their ability to increase myasthenic symptoms have also been shown to antagonize the effects of pyridostigmine.
Lithium:
The anti-myasthenic effects of pyridostigmine are antagonized by lithium .
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).
Methylcellulose:
Methylcellulose has been reported to prevent the absorption of pyridostigmine so should not be dosed concomitantly with it.
Others:
Aminoglycoside antibiotics, local and some general anesthetics, 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 during pregnancy or lactation 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 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 overdose. Since Pyridostigmine bromide crosses the placenta barrier excessive doses of pyridostigmine bromide should be avoided; the newborn child should be monitored for possible effects.
Reproductive studies in rabbits and rats showed no teratogenic but embryo-/foetotoxic effects at doses toxic to the dam (see section 5.3).
Intravenous application of pyridostigmine bromide can induce contraction of the uterus (especially in the last period of pregnancy).
Lactation
The safety of pyridostigmine during lactation has not been established. Observations indicate that only negligible amounts of pyridostigmine 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
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 machinery.
4.8 Undesirable effects
As with cholinergic products, Pyridostigmine may have unwanted functional effects on the autonomic nervous system. Muscarine-like adverse effects may be exhibited as nausea, vomiting, increased salivation, 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 Yellow Card Scheme website at: 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 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, diaphoresis, hyperhydrosis and miosis. Nicotinic effects consist of muscular cramps, fasciculations and general weakness up to paralysis. Bradycardia and hypotension may also occur.
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.
Pyridostigmine treatment must be stopped immediately. Artificial ventilation should be instituted if respiration is severely depressed. Atropine sulphate 1 to 2mg 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
ATC code: N07 AA 02, Pharmacotherapeutic group: Nervous system, parasympathomimetics, anticholinesterases, pyridostigmine , ATC code: N07AA02 Pyridostigmine is an anticholinesterase. As an antagonist to cholinesterase, the enzyme which normally destroys acetylcholine, the action of pyridostigmine can briefly be described, therefore, as the potentiation of naturally occurring acetylcholine. Thus, it enhances the neuromuscular transmission in voluntary and involuntary muscles. Pyridostigmine has a more prolonged action than Prostigmin (neostigmine) although it is somewhat slower to take effect (generally taking 30 – 60 minutes). Because it has a weaker "muscarinic" action than Prostigmin, it is usually much better tolerated by myasthenic patients in whom the longer action is also an advantage. Although a positive correlation has been demonstrated between the plasma concentrations of pyridostigmine and its pharmacological effects as measured by a decrement in muscle response to repetitive nerve stimulation in a single muscle, this relationship is less clear when a global evaluation of muscular function in myasthenia gravis is used.
5.2 Pharmacokinetic properties
Oral pyridostigmine bromide is poorly absorbed by about 22-25%. The rate and extent of absorption show wide inter-individual differences. Administered in healthy volunteers at oral daily doses of 120 mg, 120-370 mg, and 180-1440 mg, the oral absolute 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 absolute 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 subjects, 1.76 L/kg in myasthenia gravis patients, and 0.53 to 1.1 L/kg in surgical patients.
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-methylpyridinium.
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. With oral use, 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 surgical patients, 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 to 4 h.
5.3 Preclinical safety data
There are no preclinical data of relevance to the prescriber, which are additional to those already included in other sections of the SmPC.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Silicon Dioxide
Lactose Monohydrate
Maize Starch
Purified Talc
Magnesium Stearate
6.2 Incompatibilities
Not applicable
6.3 Shelf life
36 months in amber glass bottle
36 months in white opaque HDPE bottle
6.4 Special precautions for storage
Do not store above 25°C. Store in the original container and keep container tightly closed to protect from moisture and light.
6.5 Nature and contents of container
Type III amber glass bottle with PP child-resistant closure or white opaque HDPE bottle, containing HDPE desiccant (silica gel) canister, with a PP child-resistant closure. Each bottle contains 200 tablets.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Teva UK Limited,
Ridings Point,
Whistler Drive,
Castleford,
WF10 5HX,
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 00289/2298
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
29/02/2012
10 DATE OF REVISION OF THE TEXT
12/02/2024