PRODUCT MONOGRAPH

MESTINON

Tablets, 60 mg

MESTINON -SR (Slow-Release) Tablets, 180 mg

(Pyridostigmine Bromide Tablets)

Antimyasthenic - Cholinergic

Valeant Canada LP Prepared: September 28, 2004

2150 St-Elzear Blvd W Laval, Revised: September 9, 2014

Quebec H7L 4A8,

Canada

Control#: 171984

PRODUCT MONOGRAPH

MESTINON Tablets, 60 mg

MESTINON -SR (Slow-Release) Tablets, 180 mg

(Pyridostigmine Bromide Tablets)

Antimyasthenic - Cholinergic

ACTIONS:

Pyridostigmine is a cholinergic agent which acts primarily by the inhibition of

cholinesterase. It enhances cholinergic action by facilitating the transmission of

impulses across neuromuscular junctions. It also has a direct cholinomimetic effect on

skeletal muscle and possibly on autonomic ganglion cells and neurons of the central

nervous system. Because of its quaternary ammonium structure, moderate doses of

pyridostigmine do not cross the blood-brain barrier to produce CNS effects. Extremely

high doses, however, produce CNS stimulation followed by CNS depression, in

addition to a depolarizing neuromuscular blockade.

Pyridostigmine is an analog of neostigmine. However, it differs from neostigmine in

certain clinically significant respects; for example, pyridostigmine is more effectively

absorbed from the alimentary tract than is neostigmine; with equipotent doses,

pyridostigmine has a slower onset and longer duration of action, and produces fewer

gastrointestinal side effects than neostigmine. After oral administration, Mestinon

generally has an onset of action of 20 minutes and a duration of action of

approximately 6 hours; as for Mestinon -SR, it has an onset of action of 30 to 60

minutes and a duration of action of 6 to 12 hours.

INDICATIONS:

Mestinon and

Mestinon -SR are indicated for the symptomatic treatment of

myasthenia gravis. In acute myasthenic crises where difficulty in breathing and

swallowing is present, the parenteral form should be used. The patient can be

transferred to the oral form as soon as it can be tolerated.

CONTRAINDICATIONS:

Mestinon and Mestinon -SR are contraindicated in patients with known

hypersensitivity to anticholinesterase agents. Because of the presence of the bromide

ion, they should not be used in patients with a prior history of reaction to bromides.

They are also contraindicated in patients with peritonitis or mechanical obstruction of

the intestinal or urinary tract.

WARNINGS:

Mestinon and Mestinon -SR should be used with caution in patients with epilepsy,

bronchial asthma, bradycardia, recent coronary occlusion, vagotonia, hyperthyroidism,

cardiac arrhythmias or peptic ulcer. Large oral doses of the drug should be avoided in

patients with megacolon or decreased gastrointestinal motility. In these patients, the

drug may accumulate and result in toxicity when gastrointestinal motility is restored.

PRECAUTIONS:

General:

Although failure of patients to show clinical improvement may reflect underdosage, it

can also be indicative of overdosage. It is important to differentiate between

myasthenic crisis and cholinergic crisis caused by overdosage of Mestinon or

Mestinon -SR. Both conditions result in extreme muscle weakness but require

radically different treatment. (See Overdosage Section)

Information for Patients:

Complete restoration of muscle strength is rare in myasthenia gravis, and patients

should be cautioned not to increase their dose, in an attempt to relieve their symptoms,

without consulting their physician. The patient should be encouraged to keep a daily

record of his or her condition to assist the physician in determining an optimal

therapeutic regimen.

Drug Interactions:

Atropine antagonizes the muscarinic effects of pyridostigmine and this interaction may

be utilized to counteract the effects of pyridostigmine. (See Overdosage Section)

Pyridostigmine bromide does not antagonize, and in fact may prolong the phase I block

of depolarizing muscle relaxants such as succinylcholine or decamethonium.

Certain antibiotics, especially neomycin, streptomycin and kanamycin, have a mild but

definite nondepolarizing blocking action which may accentuate neuromuscular block.

These antibiotics should be used in the myasthenic patient only where definitely

indicated, and then careful adjustment should be made of adjunctive anticholinesterase

dosage.

Local and some general anesthetics, antiarrhythmic agents and other drugs that

interfere with neuromuscular transmission should be used cautiously, if at all, in

patients with myasthenia gravis; the dose of pyridostigmine bromide may have to be

increased accordingly.

In severe myasthenia gravis, neostigmine has been used in combination with

pyridostigmine to provide the benefits of short and long-term activity; because of the

possibility of reduced intestinal motility and increased toxicity, this combination

should be used only under strict medical supervision.

Carcinogenesis, Mutagenesis and Impairment of Fertility:

Carcinogenicity and mutagenicity studies have not been performed with

pyridostigmine bromide.

A fertility and general reproductive performance study was performed in rats at

dosages of 15 and 40 mg/kg/day. There were no adverse effects on pregnancy rate,

average number of implantation sites, average number of embryos per dam, percent

resorptions, duration of gestation, litter size, pup viability or pup growth.

Pregnancy:

Teratogenic effects: Pregnancy category B

Reproductive studies have been performed in rats at dosages up to 40 mg/kg/day (2

times the maximum recommended human dose; 4.6 times the average recommended

dose). These studies have revealed no evidence of impaired fertility or harm to the

fetus due to pyridostigmine bromide. There are, however, no adequate and well

controlled studies in pregnant women. However, pyridostigmine bromide, like other

cholinesterase inhibitors, contains a quaternary ammonium and, therefore, would be

expected to cross the placenta only to a limited extent. Because animal reproductive

studies are not always predictive of human response, this drug should be used during

pregnancy only if clearly needed.

Non-teratogenic effects:

Of newborn infants whose mothers have received anticholinesterase drugs for

treatment of myasthenia gravis, 10 to 20 percent were observed to have transient

muscular weakness.

Nursing Mothers:

It is not known whether pyridostigmine bromide is excreted in human milk. Because

many drugs are excreted in human milk, and because of the potential for serious

adverse reactions from pyridostigmine in nursing infants, a decision should be made

whether to discontinue nursing or to discontinue the drug, taking into account the

importance of the drug to the mother.

Pediatric Use:

See Dosage and Administration Section.

ADVERSE REACTIONS:

Side effects are generally due to an exaggeration of pharmacological effects of which

increased salivation and fasciculation are the most common. Abdominal cramps and

diarrhea may also occur.

The following additional adverse reactions have been reported following the use of

Mestinon and Mestinon -SR:

Respiratory: Increased bronchial secretions.

Gastrointestinal: Nausea, vomiting, increased peristalsis.

Musculoskeletal: Muscle cramps.

Dermatologic: Urticaria, rash.

Miscellaneous: Miosis, diaphoresis, weakness, allergic reactions.

SYMPTOMS AND TREATMENT OF OVERDOSAGE:

As is true of all anticholinesterase agents, overdosage of Mestinon or Mestinon -SR

can cause cholinergic crisis, which is characterized by increasing muscle weakness and

which, through involvement of the muscles of respiration, may result in death.

Myasthenic crisis, due to an increase in the severity of the disease, is also accompanied

by extreme muscle weakness, and thus may be difficult to distinguish from cholinergic

crisis on a symptomatic basis. However, such differentiation is extremely important,

because increases in the dose of pyridostigmine bromide or other drugs in this class in

the presence of cholinergic crisis or of a refractory or "insensitive" state could have

grave consequences. The two types of crises may be differentiated by the use of

Tensilon (edrophonium chloride) as well as by clinical judgment.

Treatment of the two conditions differs radically. Whereas the presence of

myasthenic crisis requires more intensive anticholinesterase therapy, cholinergic

crisis calls for the prompt withdrawal of all drugs of this type. The immediate use of

atropine in cholinergic crisis is also recommended. A syringe containing 1 mg of

atropine sulfate should be immediately available to be given in aliquots intravenously

to counteract severe cholinergic reactions.

Atropine also may be used to abolish or minimize gastrointestinal side effects or other

muscarinic reactions; but such use, by masking signs of overdosage, can lead to

inadvertent induction of cholinergic crisis.

DOSAGE AND ADMINISTRATION:

The dosage, route and frequency of administration depend on the requirements and

clinical response of the patients. The dosage schedule should be adjusted for each

patient and changed as the need arises. Dosage requirements in patients with

myasthenia gravis may vary from day to day, according to remissions and

exacerbations of the disease and the physical and emotional stress suffered by the

patient. Larger portions of the label daily dose may be given at times when the patient

is more prone to fatigue (afternoon, mealtimes, etc.).

In the initial treatment of myasthenia gravis, oral Mestinon and Mestinon -SR should

be started at a dosage smaller than that required to produce maximum strength, and

daily dosage gradually increased at intervals of 48 hours or more. Changes in oral

dosage may take several days to show results. When a further increase in dosage

produces no corresponding increase in muscle strength, dosage should be reduced to

the previous level so that the patient receives the smallest dose necessary to produce

maximum strength.

Note: For information on a diagnostic test for myasthenia gravis, and for the

evaluation and stabilization of anticholinesterase therapy, see Product Monograph on

Tensilon (edrophonium chloride injection).

The immediate effect of a Mestinon -SR 180 mg tablet is about equal to that of a 60

mg conventional tablet; however, the duration of drug action, although varying in

individual patients, averages 2 ½ times that of a 60 mg dose. One to three 180 mg

tablets, once or twice daily (180 mg to 1.08 g a day), will usually be sufficient to

control symptoms; however, the needs of individual patients may vary markedly from

this average. For optimal control, it may be necessary to use conventional tablets or

syrup in conjunction with Mestinon -SR therapy. Mestinon -SR tablets are

particularly useful for bedtime administration in patients who are very weak upon

awakening.

Mestinon and Mestinon -SR tablets should be swallowed whole. Do not crush.

However, in certain cases, Mestinon and Mestinon -SR tablets, can be cut in half; but

Mestinon -SR tablets should not be crushed or quartered since this would destroy too

much of the sustained release matrix.

Due to the slow-release mechanism of the tablet, the matrix may pass through the

intestinal system intact. However, it should be noted that the medicinal ingredient has

been released through the gastro-intestinal tract over an 8 to 12 hour passing time and

only the matrix is rejected.

HOW SUPPLIED:

Mestinon , white, flat compressed tablet, cross-scored on one side and embossed

MESTINON 60 - V on the other contains 60 mg of pyridostigmine bromide.

Nonmedicinal ingredients: lactose, silicone dioxide and stearic acid. Energy: 4.6 kJ

(1.1 kcal). Gluten-, paraben-, sodium-, sulfite- and tartrazine-free. Bottles of 100.

Mestinon -SR capsule-shaped, flattened on two sides with a single score on one face,

light straw coloured tablets, embossed MES V 180, each containing 180 mg

pyridostigmine bromide. Nonmedicinal ingredients: calcium phosphate, carnauba

wax, isopropyl alcohol and magnesium stearate. Energy: 2.3 kJ (0.5 kcal). Gluten-,

lactose-, paraben-, sodium-, sulfite-, and tartrazine-free. Bottles of 30. Store in a dry

place between 15 and 30°C (59 and 86°F), in a well-closed container with the

desiccant enclosed.

Note: Because of the hygroscopic nature of the Mestinon and Mestinon -SR tablets,

mottling may occur. This does not affect their efficacy.

CHEMISTRY AND PHARMACOLOGY:

Chemical Name: 3-Hydroxy-1-methylpyridinium bromide dimethylcarbamate

Structural Formula:

Molecular Formula: C

BrN

Molecular Weight: 261.12 Daltons

Description: Pyridostigmine Bromide is a hygroscopic, white or practically

white, crystalline powder having an agreeable, characteristic

odour. It is freely soluble in water, in alcohol, and in chloroform;

slightly soluble in solvent hexane; and practically insoluble in

ether.

Pharmacology:

Pyridostigmine inhibits the hydrolysis of acetylcholine by competing with

acetylcholine for attachment to acetylcholinesterase at sites of cholinergic transmission.

The pyridostigmine-enzyme complex is hydrolysed at a much slower rate than the

acetylcholine-enzyme complex, resulting in accumulation of acetylcholine at

cholinergic synapses with prolonged and exaggerated effects. The generalized

cholinergic responses produced by pyridostigmine include miosis, increased tonus of

intestinal and skeletal musculature, constriction of bronchi and ureters, bradycardia,

and stimulation of secretion by salivary and sweat glands.

O N

Following oral administration of Mestinon -SR, the mean peak pyridostigmine plasma

concentration is reached by 2 hours. The remainder of the dose is released over 8-12

hours. When administered concomitantly with food, the time to reach mean peak

plasma concentration can be increased to about 3 hours; however, the extent of

absorption of pyridostigmine is not affected.

Pyridostigmine does not bind to plasma protein. The drug has been reported to cross

the placenta and, after large oral doses, to decrease fetal plasma cholinesterase activity.

Animals administered radioactive-labelled pyridostigmine orally showed presence of

radioactivity in most tissues except brain, fat, thymus, and intestinal wall.

In a comparative pharmacokinetic study, determined in 10 healthy subjects given

pyridostigmine bromide (4 mg i.v. over 30 minutes, and 60 mg orally), the oral

availability as measured by the AUC ratio was 11.5% to 18.9% (=14.3%). The mean

of the plasma level decline after oral dosing was 200 minutes, twice as long as the

terminal elimination t

after intravenous infusion (97 minutes), indicating that

absorption may proceed at a slower rate than elimination.

Pyridostigmine not only undergoes hydrolysis by cholinesterases but is also

metabolized by microsomal enzymes in the liver. The major metabolite of

pyridostigmine is 3-hydroxy-N-methylpyridinium. Patients with severe myasthenia

gravis appear to metabolize and excrete the drug faster than patients having a milder

form of the disease. Pyridostigmine and its metabolites are excreted in the urine by

tubular secretion. Approximately 10% of the administered dose is excreted in the urine

as intact drug in 24 hours, but a considerable individual variation in urinary excretion

patterns has been shown by patients with myasthenia gravis.

TOXICITY:

The acute toxicity of pyridostigmine bromide in mice and in rats is summarized in the

following table:

ACUTE TOXICITY

ANIMAL

ROUTE

S.E.

SYMPTOMS

Mice

i.v.

i.m.

2.0 0.8 mg/kg

3.25 0.2 mg/kg

Tremors, Straub reaction,

exophthalmia

Tremors, exophthalmia, salivation

(watery), lacrimation, respiratory

failure

Rats

i.v.

i.m.

2.25 0.2 mg/kg

3.4 0.3 mg/kg

Tremors, piloerection,

lacrimation, bloody tears,

respiratory failure

Salivation, tremors, lacrimation,

bloody tears

The LD

for pyridostigmine in rats fed by the oral route is reported to be 86 mg/kg

body weight.

An assessment of the morphological changes in rats caused by pyridostigmine has

shown that respiratory failure occurred within 1 hour and resulted in death in four of

the six animals that received a single oral dose of 80 mg/kg body weight. No

spontaneous death occurred in animals given a single dose of 20 to 40 mg of

Pyridostigmine per kg of body weight, although these doses caused a marked reduction

of the acetylcholinesterase activity in the whole blood and in the erythrocytes. The

histological findings in the skeletal muscles of these animals revealed, particularly in

the diaphragm, unequivocal, severe lesions within 24 hours, characterized by

disseminated single fibre necrosis or necrosis of grouped fibres associated with

infiltrates of polymorphonuclear neutrophilic granulocytes, lymphoid and histiocytic

cells. The staining of the motor endplates in areas where necrosis occurred revealed

marked changes of the nerve endings: their ramifications were mostly rarefied,

shortened, and plump.

REFERENCES:

1. American Hospital Formulary Service, Washington, D.C., The American

Society of Hospital Pharmacists, 1982.

2. Aquilonius S.M., et al. Pharmacokinetics and oral bioavailability of

pyridostigmine in man. Eur J Clin Pharmacol 1980;18:423-428.

3. Kornfeld P. et al. Metabolism of

C labeled pyridostigmine in myasthenia

gravis. Neurology 1970; 20:634-641.

4. Chan K. et al. The isolation and determination of neostigmine, pyridostigmine

and their metabolites in human biological fluids. J Pharmacol Methods 1978;

1:311-320.

5. Kornfeld P. et al. Studies in myasthenia gravis: pyridostigmine-C

metabolism

after thymectomy. Neurology 1975; 25:998-999.

6. Somani S.M. et al. Pyridostigmine metabolism in man. Clin Pharmacol Therap

1972; 13:393-399.

7. Hoar R.M. and Woo D. Reproduction studies of pyridostigmine bromide in

rats. RCR N-22291, February 11, 1970.

8. Adamsons Jr. K., and Joelson I. The effects of pharmacologic agents upon the

fetus and newborn. Am J Obst and Gynecol 1966; 96:437-460.

9. McNall P.G., and Jafarnia M. Management of myasthenia gravis in the

obstetrical patient. Am J Obst and Gynecol 1965; 92:518-525.

10. Breyer-Pfatt U., et al. Pyridostigmine kinetics in heathy subjects and patients

with myasthenia gravis. Clin Pharmacol Therap 1985; 37:495-501.

11. Fromherz K., and Pellmont B. Pharmakologische Wirkungen des MESTINON

"Roche" (Dimethylcarbaminsaureester des-1-Methyl-3-oxypyridinium-bromid;

Pyridotigmin bromid). Schweiz Med Wschr 1953; 49:1187-1190.

12. Gebbers J-O, et al. Acute toxicity of pyridostigmine in rats: histological

findings. Arch Toxicol 1986; 58:271-275.