Intestinal atony, atonic constipation. Myasthenia gravis.

Adults
Intestinal atony, atonic constipation
1 sugar-coated tablet a required, e.g. at intervas of 4 hours.
Central and peripheral pareses (dose-finding)
1-6 sugar-coated tablets daily depending on the severity of the patient’s condition.
Myasthenia gravis
1-3 sugar-coated tablets 2-4 times daily, or higher doses if required.
Special dosage instructions
It is important to remember that the full effect of the treatment appears gradually, usually within 15-30 minutes.
Elderly patients
No special dosage instructions.
Patients with hepatic impairment
No special dosage instructions.
Patients with renal impairment
Pyridostigmine is mainly excreted unchanged through the kidneys. In patients with renal disease associated with impaired renal clearance, lower doses may therefore be indicated. The dose should always be ad-justed to the effect.
Children
The 10-mg tablet is not suitable for use in paediatric patients. The age-appropriate dosage strength should
be prepared individually under GMP conditions (in the hospital's pharmacy, for instance).
The required dose must be carefully titrated when used in paediatrics.
In cases of neonatal myasthenia, treatment with neostigmine (Prostigmin) is generally preferred. However,
if this appears unsuitable due to excessive cholinergic side effects, then Mestinon can be administered. In
these cases, the following recommendation serves as a rough guideline: every 4-6 hours S mg per os in the
form of the appropriately prepared tablet dose, 30-60 minutes before meals. This dose should be gradually
reduced until the medication can be withdrawn..

Treatment beyond the eighth week of life is required only in extremely rare cases of congenital and familial
infantile myasthenia.
Myasthenia gravis
In myasthenia gravis, one dose is effective for approximately four hours during the day whilst, at night (ow-ing to reduced physical activity), a longer duration of effect of around 6 hours can be expected.
It is recommended that the times of administration be chosen so that the maximum effect coincides with the most strenuous physical exertion, e.g. when getting up and at mealtimes.
Because of the similarity of clinical symptoms when the product is ineffective (myasthenic crisis) or in case of overdose (cholinergic crisis), investigation with a suitable test (e.g. with edrophonium chloride), consid-ering the necessary precautions, is required after a higher dose, if the corresponding symptoms occur.

Great caution is required when Mestinon is given to patients with obstructive lung disease such as bron-chial asthma or chronic obstructive pulmonary disease (COPD). Caution is also required in the case of car-diac arrhythmias such as bradycardia and atrioventricular block (elderly patients may tend more to arrhyth-mias than young adults); decompensated heart failure; recent coronary occlusion; hypotension; vagotonia; renal disease; gastric ulcer; gastrointestinal surgery; epilepsy or parkinsonism; hyperthyroidism; diabetes mellitus.
If relatively high doses are taken by myasthenia gravis patients, administration of atropine or other anticho-linergic agents may be necessary to counteract the muscarinic effect.
The possibility of a “cholinergic crisis” because of a pyridostigmine bromide overdose must be distinguished from a “myasthenic crisis” because of worsening of the disease in the differential diagnosis in all patients. Both types of crisis are expressed as increased muscle weakness. However, while the anticholinesterase treatment must be increased in a myasthenic crisis, the treatment must be discontinued immediately with a cholinergic crisis and suitable supportive measures, including respiratory support, must be instituted.
Mestinon is mainly excreted unchanged through the kidneys. Mestinon should therefore be used with cau-tion in renal failure. Lower doses may therefore be required for patients with renal disease. The required dose should be determined individually according to the effect.
Mestinon should be used with caution if suxamethonium chloride is present in high overdosage as, instead of the desired abolishing of the neuromuscular blockade, this may be intensified.
The Mestinon requirement may be diminished following thymectomy.
Patients with rare hereditary problems such as fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase deficiency should not take this medicinal product.

Drugs with an immunosuppressive action
The required dose of Mestinon may be reduced with concomitant administration of drugs such as steroids or immunosuppressants. Neverthertheless, a new addition of corticosteroids may initially aggravate the symptoms of myasthenia gravis.
Methylcellulose

Methylcellulose inhibits the absorption of pyridostigmine bromide. Concomitant administration of medici-nal products that contain methyl cellulose as an excipient should therefore be avoided.
Drugs with an antimuscarinic action
Atropine and scopolamine counteract the muscarinic effect of pyridostigmine. It should be noted that the diminished gastrointestinal mobility caused by these drugs can delay the absorption of pyridostigmine bro-mide.
Muscle relaxants
Pyridostigmine bromide antagonises the action of curare-type non-depolarising muscle relaxants (e.g. pan-curonium and vecuronium). Pyridostigmine bromide can prolong the effect of the depolarising muscle re-laxant suxamethonium (see “Special warnings and precautions”).
Other interactions
Aminoglycoside antibiotics, local and some systemic anaesthetics, antiarrhythmic agents and other drugs that influence neuromuscular transmission can interact with pyridostigmine bromide.

Fertility
Nonclinical investigations in rats have not shown any negative effects on reproductive behavior
Pregnancy
The safet of pyridostigmine bromide during pregnancy and lactation has not been studied.
Although the potential risk for mother and child must be weighed against the potential benefit in every case, experience to date of administration of pyridostigmine bromide to pregnant patients with myasthenia gravis has not shown any negative effects of the drug on the course of the pregnancy.
As the severity of myasthenia gravis often fluctuates considerably in pregnancy, particular care is required to avoid cholinergic crisis due to overdose.
Pyridostigmine crosses the placental barrier. Excessively high doses of pyridostigmine during pregnancy should be avoided and the newborn should be examined for possible side effects.
In animal studies of developmental toxicity in rats and rabbits, pyridostigmine bromide did not show any teratogenic effects after oral administration. By contrast, in the maternal toxic dose range, there was an increased rate of absorption and delayed ossification in the foetuses. In a peri- and postnatal study in rats, the weight gain in the offspring of treated mothers was reduced (see “Preclinical data”).
Intravenous use of pyridostigmine bromide can trigger uterine contractions (especially when used at the end of pregnancy). Whether there is also a risk of triggering premature labour with oral use is unknown.
During pregnancy, this medication should only be used strictly as indicated after a thorough consideration of the benefit-risk relationship, with careful dosing and under medical supervision.
Lactation
There is insufficient information on whether pyridostigmine bromide has effects on newborns and infants. Observations indicate that only negligible amounts of pyridostigmine bromide pass into breast milk. If treatment is required, the baby should be monitored for possible effects or should be weaned.

No study results are available in this regard.
In case of inadequate compensation of the underlying disease or parasympathicotonic effects after a rela-tive overdose of Mestinon/Mestinon retard (miosis, disorders of accommodation), visual acuity and there-fore the ability to react and drive and use machines may be impaired.

Like all cholinergic drugs, Mestinon can have undesirable functional effects on the autonomic nervous sys-tem.
Muscarine-type side effects can manifest themselves as nausea, vomiting, diarrhoea, stomach cramps, in-creased peristalsis and bronchial secretion, salivation and lacrimation as well as bradycardia and miosis. Nicotine-type side effects consist mainly of muscle spasms, muscle twitches and muscle weakness.
Within the organ system, the undesirable effects are listed according to the following frequencies:
very common (>1/10), common (<1/10, >1/100), uncommon (<1/100, >1/1000), rare (<1/1000, >1/10,000), very rare (<1/10,000). Frequency unknown (cannot be estimated from the available data) The following un-desirable effects were observed. However, their frequency is unknown.
Immune system disorders
Frequency unknown: Drug hypersensitivity
Psychiatric disorders
Frequency unknown: In the presence of organic brain changes, psychopathological symptoms including psychosis can occur during treatment with Mestinon or pre-existing symptoms may be increased.
Nervous system disorders
Frequency unknown: Syncope
Eye disorders
Frequency unknown: miosis, increased lacrimation, accommodation disorders. (e.g. blurred vision)
Cardiac disorders
Frequency unknown: arrhythmia (including bradycardia, tachycardia, AV block), Prinzmetal angina
Vascular disorders
Frequency unknown: Flushing, hypotension (see “Overdose”)
Respiratory, thoracic and mediastinal disorders
Frequency unknown: increased bronchial secretion in combination with bronchial obstruction.
Gastrointestinal disorders
Frequency unknown: nausea, vomiting, diarrhoea, abdominal symptoms (e.g. discomfort pain, cramps etc.), increased peristalsis, increased salivation.
Skin and subcutaneous tissue disorders
Rare: rash
Frequency unknown: hyperhidrosis. urticaria
Like other bromine-containing medications, Mestinon can lead in rare cases to rashes, which usually disap-pear rapidly after the drug is discontinued. Further use of Mestinon or other bromine-containing prepara-tions is then contraindicated.
Musculoskeletal and connective tissue disorders
Frequency unknown: increased muscle weakness, muscle twitches, tremor and muscle cramps, diminished muscle tone.
Renal and urinary disorders
Frequency unknown: increased urinary urgency.

As the symptoms may be signs of a cholinergic crisis, the treating doctor should be consulted without delay so that the cause of the symptoms and signs can be investigated (see “Overdose”).

To reports any side effect(s):
Saudi Arabia:
• The National Pharmacovigilance Centre (NPC):
- Fax: +966-11-205-7662
- Call NPC at +966-11-2038222, Ext 2317-2356-2340
- SFDA Call Center: 19999
- E-mail: npc.drug@sfda.gov.sa
- Website: https://ade.sfda.gov.sa/
Other GCC States:
o Please contact the relevant competent authority.

4.9 Overdose
Pyridostigmine may cause cholinergic crisis. The signs of overdose due to muscarinic effects can include abdominal cramps, increased peristalsis, diarrhoea, diaphoresis, nausea, vomiting, increased bronchial se-cretion, bronchospasm, salivation, hyperhidrosis and miosis.
Nicotinic side effects are expressed as muscle cramps, muscle twitches and general weakness including pa-ralysis, which may produce apnoea and cerebral anoxia in particularly severe cases. Hypotension including cardiovascular collapse and bradyarrhythmia including cardiac arrest can also occur.
Central nervous system effects can include excitation, confusion, slurred speech, nervousness, irritation and visual hallucinations. Convulsions and coma may occur. Countermeasures consist of the immediate dis-continuation of Mestinon or other cholinergic agents. Artificial ventilation should be initiated if there is se-vere respiratory depression. 1-2 mg atropine sulphate is given slowly intravenously as a specific antidote. If necessary, this dose can be repeated at intervals of 5 to 30 minutes.

5.1 Pharmacodynamic properties
ATC code: N07AA02
Pyridostigmine, the active ingredient of Mestinon, is a cholinesterase inhibitor. It is characterised by the gentle onset, smooth course, comparatively long duration and gradual decline of its cholinergic action.
Pyridostigmine has an antagonistic effect on non-depolarising muscle relaxants only. It has a synergistic ef-fect on depolarising muscle relaxants.

Absorption
Peroral 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 bioavaila-bility across studies is attributed to the low absorption rate of pyridostigmine. In patients with myasthenia gravis, oral bioavailability may decrease to 3.3%.
Distribution
Peak plasma concentrations are reached approximately 1½-2 hours after administration of 120 mg pyri-dostigmine in the fasting state. The increase in active substance is delayed when taken with food.
The distribution volume averages 1.4 l·kg -1 of body weight after intravenous administration.
Pyridostigmine is not noticeably bound to plasma proteins and does not cross the blood-brain barrier.

With myasthenia gravis, blood plasma levels of 20-60 ng·ml -1 are required in order to obtain the desired therapeutic effect.
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 body-weight 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
Mean values of around 1.5 hours are given for the elimination half-life. This can, however, be prolonged up to three times over in individual cases. Mean plasma clearance in healthy subjects is given as 0.36- 0.65 l·kg-1·h-1. No confirmed data are available regarding the potential accumulation of unchanged pyri-dostigmine or active metabolites. Since the dosage must, in any case, be adjusted individually, this point is devoid of practical significance. Pyridostigmine is largely (75-81%) eliminated unchanged via the kidneys. One part (18-21%) appears as the 3-hydroxy-N-methyl-pyridine metabolite in the urine. Other unidentified metabolites account for 1-4%.
Kinetics in specific patient populations
Impaired liver function has no relevant effect on the kinetics of pyridostigmine. In the case of age- or dis-ease-induced renal failure, the elimination half-life can increase approximately four-fold; plasma clearance can be reduced to approximately one-fifth.

Subcutaneous injection of pyridostigmine bromide to rats in toxic dosages leads to salivation, twitching, tremor and respiratory difficulties, among other things. With p.o. administration of toxic doses, the rats died of acute respiratory failure. Damage to the neuromuscular synapses of the diaphragm was detectable histologically. Longer-term oral administration to rats led to inhibition of plasma cholinesterase and eryth-rocyte acetylcholinesterase.
In rats, an inhibition of acetylcholinesterase in erythrocytes with tremor was noted after three months of treatment with ≥ 15 mg/kg. At 60 mg/kg, mortality amounted to 10% of animals treated. Clinicochemical changes were also found in this group. Treatment-related haematology, post-mortem or histopathology findings occurred in none of the dosage groups.
Standard in-vitro and in-vivo tests of genetic toxicology yielded no evidence of a clinically relevant geno-toxic potential of pyridostigmine bromide.
Preclinical studies on the carcinogenicity of pyridostigmine bromide were not conducted.
Animal studies on the reproductive toxicity of pyridostigmine bromide were conducted in rats after oral administration. No effects on male and female fertility were seen. At high doses, post-implantation losses were noted, possibly caused by the cholinergic stimulation of the maternal animals. In studies on develop-mental toxicity, there was an increased resorption rate in rats and rabbits after oral administration in the maternal toxic dose range and delayed ossification in the rat foetuses. In a peri-/postnatal study in rats, the weight gain in the progeny of treated maternal animals was reduced.

Excipients:
Maize starch:
23.200 mg / tablet
Magnesium stearate:
0.800 mg/ tablet
Pregelatinised starch:
7.500 mg/ tablet
Povidone K30:
20.000 mg/ tablet
Silica, colloidal anhydrous:
42.500 mg/ tablet
Talc:
6.000 mg/ tablet
Coating components:
Acacia spray-dried gum:
1.473 mg/ tablet
Iron oxide red (E 172) CI 77491:
0.010 mg/ tablet
Iron oxide yellow (E 172) CI 77492:
0.006 mg/ tablet
Light liquid paraffin:
0.008 mg/ tablet
Hard paraffin:
0.047 mg/ tablet
Rice starch:
14.583 mg/ tablet
Sucrose crystalline:
161.569 mg/ tablet
Talc:
12.304 mg/ tablet

Not applicable

Store in closed original packaging at store below 30°C and out of the reach of children.

Packed in glass bottle & PE Screw cap
Sugar-coated tablets containing 60 mg: 20

No special requirements.