6111 Royalmount Ave., Suite 102 Jan. 18, 2001 Montreal, Quebec H4P 2T4 Date of Revision:

May 30, 2007

Control No. 105662

PART I: HEALTH PROFESSIONAL INFORMATION. 3 SUMMARY OF PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 6 DRUG INTERACTIONS 6 OVERDOSAGE 7 STORAGE AND STABILITY 8 DOSAGE FORMS, COMPOSITION AND PACKAGING 8 PART II: SCIENTIFIC INFORMATION 9 PHARMACEUTICAL INFORMATION 9 PART III: CONSUMER INFORMATION 10

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY OF PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Tapazole(r) (methimazole) is indicated in the medical treatment of hyperthyroidism. Long- term therapy may lead to remission of the disease. Tapazole(r) may be used to ameliorate hyperthyroidism in preparation for subtotal thyroidectomy or radioactive iodine therapy. Tapazole(r) is also used when thyroidectomy is contraindicated or not advisable.

CONTRAINDICATIONS

Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph. Nursing mothers, as the drug is excreted in breast milk.

WARNINGS AND PRECAUTIONS

Patients who receive methimazole should be under close surveillance. Physicians should encourage patients to immediately report any evidence of illness or unusual clinical symptoms, particularly sore throat, skin eruptions, fever, headache or general malaise. In such cases, white blood cell and differential counts should be made to determine whether agranulocytosis has developed. Particular care should be exercised with patients who are receiving additional drugs known to cause agranulocytosis. The development of arthralgias should prompt drug discontinuation, since this symptom may indicate a severe transient migratory polyarthritis known as "the antithyroid arthritis syndrome".

Rats treated for 2 years with methimazole demonstrated thyroid hyperplasia and thyroid adenoma and carcinoma formation. Such findings are seen with continuous suppression of thyroid function by sufficient doses of a variety of antithyroid agents. Pituitary adenomas have also been observed.

Agranulocytosis is potentially the most serious side effect of therapy with methimazole. Patients should be instructed to report to their physicians any symptoms of agranulocytosis, such as fever or sore throat. Leukopenia, thrombocytopenia, and aplastic anemia (pancytopenia) may also occur. The drug should be discontinued in the presence of agranulocytosis, aplastic anemia (pancytopenia), hepatitis, or exfoliative dermatitis. The patient's bone marrow function should be monitored.

Due to the similar hepatic toxicity profiles of methimazole and propylthiouracil, attention is drawn to the severe hepatic reactions, which have occurred with both drugs. There have been rare reports of fulminant hepatitis, hepatic necrosis, encephalopathy and death. Symptoms suggestive of hepatic dysfunction (anorexia, pruritis, right upper quadrant pain, etc.) should prompt evaluation of liver function. Drug treatment should be discontinued promptly in the event of clinically significant evidence of liver abnormality, including hepatic transaminase values exceeding 3 times the upper limit of normal.

Pregnant Women:

Methimazole can cause fetal harm when administered to a pregnant woman. Methimazole readily crosses the placental membranes and can induce goiter and even cretinism in the developing fetus. In addition, rare instances of aplasia cutis, as manifested by scalp defects have occurred in infants born to mothers who received methimazole during pregnancy. If methimazole is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be warned of the potential hazard to the fetus.

Since scalp defects have not been reported in offspring of patients treated with propylthiouracil, this agent may be preferable to methimazole in pregnant women requiring treatment with antithyroid drugs. Methimazole used judiciously is an effective drug in the treatment of hyperthyroidism complicated by pregnancy. In many pregnant women, the thyroid dysfunction diminishes as the pregnancy proceeds; consequently, a reduction in dosage may be possible. In some instances, use of methimazole can be discontinued 2 or 3 weeks before delivery.

Nursing Women:

Methimazole is excreted in human breast milk and its use is contraindicated in nursing mothers.

PediatricsGeriatrics: Monitoring and Laboratory Tests

Because methimazole may cause hypoprothrombinemia and bleeding, prothrombin time should be monitored during therapy with the drug, especially before surgical procedures. Periodic monitoring of thyroid function is warranted. A laboratory result indicating elevated TSH warrants a decrease in the dosage of methimazole.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Adverse reactions occur in less than 1 percent of patients. Serious adverse reactions (which occur less frequently than the minor less serious adverse reactions) include inhibition of myelopoiesis (agranulocytosis, granulocytopenia and thrombocytopenia), aplastic anemia, drug fever, a lupus-like syndrome, insulin autoimmune syndrome (which can result in hypoglycemic coma), hepatitis (jaundice may persist for several weeks after discontinuation of the drug), periarteritis and hypoprothrombinemia. Nephritis occurs very rarely. Less serious adverse reactions include skin rash, urticaria, nausea, vomiting, epigastric distress, arthralgia, paresthesia, loss of taste, abnormal loss of hair, myalgia, headache, pruritus, drowsiness, neuritis, edema, vertigo, skin pigmentation, jaundice, sialadenopathy and lymphadenopathy.

Abnormal Hematologic and Clinical Chemistry Findings

It should be noted that about 10% of patients with untreated hyperthyroidism have leucopenia (white-blood-cell count of less than 4,000/mm3), often with relative granulopenia.

DRUG INTERACTIONS

The activity of anticoagulants may be potentiated by the anti-vitamin K activity attributed to methimazole.

DOSAGE AND ADMINISTRATION

Methimazole is administered orally. It is usually given in three equal doses a day at approximately eight-hour intervals.

Adult:

The initial daily dose is 15 mg for mild hyperthyroidism, 30 to 40 mg for moderately severe hyperthyroidism and 60 mg for severe hyperthyroidism, divided into three doses at eight- hour intervals. The maintenance dosage is 5 to 15 mg daily.

Pediatric:

Initially, the daily dosage is 0.4 mg/kg of body weight divided into three doses and given at eight-hour intervals. The maintenance dosage is approximately 1/2 of the initial dose.

OVERDOSAGE

Symptoms

: Symptoms may include nausea, vomiting, epigastric distress, headache, fever, joint pain, pruritus and edema. Aplastic anemia (pancytopenia) or agranulocytosis may be manifested in hours to days. Less frequent events are hepatitis, nephrotic syndrome, exfoliative dermatitis, neuropathies and CNS stimulation or depression. Although not well studied, methimazole- induced agranulocytosis is generally associated with doses of 40 mg or more in patients older than 40 years of age.

No information is available on the median lethal dose of the drug or the concentration of methimazole in biologic fluids associated with toxicity and/or death.

Treatment:

In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.

Protect the patient's airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient's vital signs, blood gases, serum electrolytes, etc. The patient's bone marrow function should be monitored. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient's airway when employing gastric emptying or charcoal. Forced diuresis, peritoneal dialysis, hemodialysis or charcoal hemoperfusion have not been established as beneficial for an overdose of methimazole.

ACTION AND CLINICAL PHARMACOLOGY

Methimazole inhibits the synthesis of thyroid hormones and thus is effective in the treatment of hyperthyroidism. The drug does not inactivate existing thyroxine and triiodo-thyroxine that are stored in the thyroid or circulating in the blood, nor does it interfere with the effectiveness of thyroid hormones given by mouth or by injection. The actions and use of methimazole are similar to those of propylthiouracil. On a weight basis, the drug is at least ten times as potent as propylthiouracil, but methimazole may be less consistent in action.

Absorption: Metabolism: Excretion:

STORAGE AND STABILITY

Store at room temperature (15 to 30 oC). Protect from light. Keep tightly closed.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Tapazole(r) 5 mg tablets: Each round, white, scored tablet is debossed with 'J94' on one side and plain on the other side.

Route of Administration	Dosage Form / Strength	Clinically Relevant Non-medicinal Ingredients
Oral	Tablet 5, 10 and 20 mg	Lactose monohydrate For a complete listing see Dosage Forms, Composition and Packaging section.

PRODUCT MONOGRAPH

Antithyroid Agent

PALADIN LABS INC.