Product Monograph - Methimazole Tablets USP
INDICATIONS AND CLINICAL USE
- Methimazole tablets USP are indicated in the medical treatment of hyperthyroidism. Long-term therapy may lead to remission of the disease.
- Methimazole tablets USP may be used to ameliorate hyperthyroidism in preparation for subtotal thyroidectomy or radioactive iodine therapy.
- Methimazole tablets USP are 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
General
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”.
Carcinogenesis and Mutagenesis
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.
Endocrine and Metabolism
Lactose
Methimazole tablets USP contain lactose monohydrate. Patients with hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this product.
Hematologic
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 or plastic anemia (pancytopenia). The patient’s bone marrow function should be monitored. See Monitoring and Laboratory Tests.
Serious Warning and Precautions
Agranulocytosis (see Hematologic section below)
Liver toxicity (see Hepatic/Biliary/Pancreatic section below)
Anticoagulant Therapy
Treating patients with both methimazole and warfarin necessitates intensive and frequent monitoring, in particular when initiating, discontinuing or changing doses of methimazole, since alterations in the thyroid function affect the response to anticoagulation. See Drug-Drug Interactions.
Hepatic/Biliary/Pancreatic
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. Cholestatic jaundice has occurred rarely. Patients should be instructed to report symptoms of hepatic dysfunction such as jaundice, anorexia, pruritus, and/or right upper-quadrant pain. Their presence should prompt evaluation of liver function tests and discontinuation of methimazole. 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. See Monitoring and Laboratory Tests.
Skin
The drug should be discontinued in the presence of exfoliative dermatitis.
Special Populations
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.
Pediatrics: No formal studies have been conducted in the pediatric population.
Geriatrics: No formal studies have been conducted in the geriatric population.
Monitoring and Laboratory Tests
The patient’s liver function, hepatic transaminase levels, and the complete blood count should be closely monitored. See Boxed Warning and Hematologic section above. Because methimazole may cause hypoprothrombinemia and bleeding, prothrombin time/INR should also 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. Cholestatic jaundice, fulminant hepatitis, encephalopathy, hepatic necrosis and death have been rarely reported. (see Warning and precautions section)
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, anorexia, right upper-quadrant pain 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
Drug-Drug Interactions:
Increases and decreases in warfarin-induced anticoagulation have been reported in patients taking methimazole. In hyperthyroid patients, the metabolism of vitamin K clotting factors is increased, resulting in increased sensitivity to oral anticoagulants. Antithyroid drugs, by reducing the extent of hyperthyroidism, decrease the metabolism of clotting factors and thus reduce the effects of oral anticoagulants. On the other hand, patients on anticoagulant therapy who are euthyroid due to antithyroid agents may develop marked hypoprothrombinemia if the antithyroid medications are ceased and they become thyrotoxic again. Treating patients with both methimazole and warfarin necessitates intensive and frequent monitoring, in particular when initiating, discontinuing or changing doses of methimazole, since alterations in thyroid function affect the response to anticoagulation.
Drug-Food Interactions
Interactions with foods have not been studied.
Drug-Herb Interactions
Interactions with herbal products have not been studied.
Drug-Laboratory Test Interactions
Interactions with laboratory tests have not been studied.
DOSAGE AND ADMINISTRATION
Dosing Considerations
- Methimazole is administered orally.
- It is usually given in three equal doses a day at approximately eight-hour intervals.
Recommended Dose and Dosage Adjustment
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 ½ of the initial dose.
Missed Dose
No data is available.
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.
For management of suspected drug overdose, contact your regional Poison Control Centre.
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
Mechanism of Action
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.
Pharmacokinetics
Absorption: Methimazole is readily absorbed from the gastrointestinal tract.
Metabolism: It is metabolized rapidly and requires frequent administration.
Excretion: Methimazole is excreted in the urine.
STORAGE AND STABILITY
Store at room temperature (15 to 30 oC). Protect from light. Keep tightly closed.
DOSAGE FORMS, COMPOSITION AND PACKAGING
Methimazole tablets USP 5mg:
- Each round, white, scored tablet is debossed with ‘J94’ on one side and plain on the other side.
- Each tablet contains 5 mg methimazole.
- Available in bottles of 100.
Methimazole tablets USP 10mg:
- Each round, white tablet is debossed with ‘10’ on one side and plain on the other side.
- Each tablet contains 10 mg methimazole.
- Available in bottles of 100.
Methimazole tablets USP 20mg::
- Each round, white tablet is debossed with ‘20’ on one side and plain on the other side.
- Each tablet contains 20 mg methimazole.
- Available in bottles of 100.
Non-medicinal ingredients: Corn starch, lactose monohydrate, magnesium stearate, talc
PART II: SCIENTIFIC INFORMATION
PHARMACEUTICAL INFORMATION
Drug Substance
Proper name: Methimazole
Chemical name: 1-Methylimidazole-2-thiol
Molecular formula and molecular mass: C4H6N2S
114.16 g / mol
Structural formula:
Physicochemical properties:
Description: White to slightly cream-coloured crystalline powder.
It differs chemically from the drugs of the thiouracil series primarily because it has a five- instead of a six-membered ring.
Melting range: 143 - 146°C
Solubility: Freely soluble in water, alcohol and in acetone
CLINICAL TRIALS
No data is available.
DETAILED PHARMACOLOGY
No data is available.
TOXICOLOGY
No data is available.