Methimazole

Methimazole readily crosses placental membranes and can cause fetal harm, particularly when administered in the first trimester of pregnancy. Rare instances of congenital defects, including aplasia cutis, craniofacial malformations (facial dysmorphism; choanal atresia) and gastrointestinal malformations (esophageal atresia with or without tracheoesophageal fistula; umbilical abnormalities) 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 the above congenital defects have been reported in offspring of patients treated with methimazole, it may be appropriate to use other agents in pregnant women requiring treatment for hyperthyroidism, particularly during organogenesis, in the first trimester of pregnancy. If methimazole is used, the lowest possible dose to control the maternal disease should be given.

Agranulocytosis is a potentially life-threatening adverse reaction of methimazole therapy. Patients should be instructed to immediately report to their physicians any symptoms suggestive 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), ANCA-positive vasculitis, hepatitis, or exfoliative dermatitis, and the patient’s bone marrow indices should be monitored.

Although there have been reports of hepatotoxicity (including acute liver failure) associated with methimazole, the risk of hepatotoxicity appears to be less with methimazole than with propylthiouracil, especially in the pediatric population. Symptoms suggestive of hepatic dysfunction (anorexia, pruritus, right upper quadrant pain, etc) should prompt evaluation of liver function (bilirubin, alkaline phosphatase) and hepatocellular integrity (ALT, AST). 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.

Methimazole can cause hypothyroidism necessitating routine monitoring of TSH and free T4 levels with adjustments in dosing to maintain a euthyroid state. Because the drug readily crosses placental membranes, methimazole can cause fetal goiter and cretinism when administered to a pregnant woman. For this reason, it is important that a sufficient, but not excessive, dose be given during pregnancy (see Precautions, Pregnancy).

Patients who receive methimazole should be under close surveillance and should be cautioned to report immediately any evidence of illness, particularly sore throat, skin eruptions, fever, headache, or general malaise. In such cases, white-blood-cell and differential counts should be obtained to determine whether agranulocytosis has developed. Particular care should be exercised with patients who are receiving additional drugs known to cause agranulocytosis.

Because methimazole may cause hypoprothrombinemia and bleeding, prothrombin time should be monitored during therapy with the drug, especially before surgical procedures.

Thyroid function tests should be monitored periodically during therapy. Once clinical evidence of hyperthyroidism has resolved, the finding of a rising serum TSH indicates that a lower maintenance dose of methimazole should be employed.

Due to potential inhibition of vitamin K activity by methimazole, the activity of oral anticoagulants (e.g., warfarin) may be increased; additional monitoring of PT/INR should be considered, especially before surgical procedures.

Hyperthyroidism may cause an increased clearance of beta blockers with a high extraction ratio. A reduced dose of beta-adrenergic blockers may be needed when a hyperthyroid patient becomes euthyroid.

Serum digitalis levels may be increased when hyperthyroid patients on a stable digitalis glycoside regimen become euthyroid; a reduced dosage of digitalis glycosides may be needed.

Theophylline clearance may decrease when hyperthyroid patients on a stable theophylline regimen become euthyroid; a reduced dose of theophylline may be needed.

In a 2 year study, rats were given methimazole at doses of 0.5, 3, and 18 mg/kg/day. These doses were 0.3, 2, and 12 times the 15 mg/day maximum human maintenance dose (when calculated on the basis of surface area). Thyroid hyperplasia, adenoma, and carcinoma developed in rats at the two higher doses. The clinical significance of these findings is unclear.

Due to the rare occurrence of congenital malformations associated with methimazole use, it may be appropriate to use other agents in pregnant women requiring treatment for hyperthyroidism, particularly in the first trimester of pregnancy (during organogenesis).

Patients should be advised that if they become pregnant or intend to become pregnant while taking an antithyroid drug, they should contact their physician immediately about their therapy.

In many pregnant women, the thyroid dysfunction diminishes as the pregnancy proceeds; consequently, a reduction in dosage of anti-thyroid therapy may be possible. In some instances, use of anti-thyroid therapy can be discontinued 2 or 3 weeks before delivery. Because the drug readily crosses placental membranes, methimazole can cause fetal goiter and cretinism when administered to a pregnant woman. For this reason, it is important that a sufficient, but not excessive, dose be given during pregnancy. (See WARNINGS)

Methimazole is excreted into breast milk. However, several studies found no effect on clinical status in nursing infants of mothers taking methimazole, particularly if thyroid function is monitored at frequent (weekly or biweekly) intervals. A long-term study of 139 thyrotoxic lactating mothers and their infants failed to demonstrate toxicity in infants who are nursed by mothers receiving treatment with methimazole.

Because of postmarketing reports of severe liver injury in pediatric patients treated with propylthiouracil, methimazole is the preferred choice when an antithyroid drug is required for a pediatric patient. (See DOSAGE AND ADMINISTRATION.)

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.

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.

To obtain up-to-date information about the treatment of overdose, a good resource is the certified Regional Poison Control Center. In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in the patient.

In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient’s medical status.

The initial daily dosage is 15 mg for mild hyperthyroidism, 30 to 40 mg for moderately severe hyperthyroidism, and 60 mg for severe hyperthyroidism, divided into 3 doses at 8-hour intervals. The maintenance dosage is 5 to 15 mg daily.

Initially, the daily dosage is 0.4 mg/kg of body weight divided into 3 doses and given at 8-hour intervals. The maintenance dosage is approximately 1/2 of the initial dose.