Is methimazole (antithyroid medication) typically administered in 3 divided doses?

Methimazole Dosing: Single Daily Dose vs. Divided Doses

No, methimazole is NOT required to be given in 3 divided doses—current evidence strongly supports once-daily dosing as equally effective and potentially safer than the traditional divided dosing regimen. 1, 2, 3

FDA-Approved Dosing vs. Clinical Practice

The FDA label for methimazole states that the total daily dosage is "usually given in 3 divided doses at approximately 8-hour intervals," with initial dosing of 15 mg for mild hyperthyroidism, 30-40 mg for moderate disease, and 60 mg for severe hyperthyroidism. 1 However, this traditional divided dosing approach has been superseded by substantial clinical evidence supporting once-daily administration.

Evidence Supporting Single Daily Dosing

Efficacy of Once-Daily Dosing

• Single daily dosing achieves euthyroidism in 91-93% of patients, comparable to divided dosing regimens. 3
• The mean time to achieve euthyroidism with single daily dosing (15-30 mg once daily) is approximately 5.3 weeks, which is not significantly different from divided dosing (5.6 weeks). 3
• In a study of 47 patients with initial hyperthyroidism, all patients became euthyroid using single daily dose methimazole, with a mean time of 16.7 weeks. 2

Safety Advantages of Once-Daily Dosing

• Lower doses given once daily result in fewer adverse effects. Side effects occurred in only 2 patients (4.7%) treated with 15 mg single daily dose compared to 6 patients (18.8%) treated with 30 mg single daily dose. 3
• The risk of agranulocytosis is dose-dependent, making lower starting doses preferable. 4
• Starting doses should not exceed 15-20 mg/day to minimize complications. 4

Recommended Dosing Strategy

Initial Dosing

• For mild to moderate hyperthyroidism: Start with 15 mg once daily. 4, 3
• For moderate to severe hyperthyroidism: Consider 15 mg methimazole + inorganic iodine 38 mg/day as an alternative to 30 mg methimazole alone, as this combination achieves faster normalization of thyroid function (45.3% vs. 24.8% achieving normal fT4 within 30 days) with fewer adverse effects requiring discontinuation (7.5% vs. 14.8%). 5
• For severe hyperthyroidism: 30 mg once daily may be used, though higher doses carry increased risk of adverse effects. 3

Maintenance Dosing

• Maintenance dosing typically ranges from 5-15 mg daily, which can be administered as a single daily dose. 1

Pharmacologic Rationale

• Perchlorate discharge tests performed 24 hours after a single dose of methimazole demonstrate persistent thyroid inhibition, with 77% of patients showing >10% discharge after 15 mg and 74% after 30 mg, supporting the drug's prolonged duration of action. 3
• The mean percent discharge values (41.5% for 15 mg and 35.4% for 30 mg) indicate sustained antithyroid effect throughout the 24-hour dosing interval. 3

Common Pitfalls to Avoid

• Avoid starting with doses >20 mg/day unless dealing with severe thyrotoxicosis, as this increases the risk of dose-dependent adverse effects including agranulocytosis. 4
• Do not use propylthiouracil as first-line therapy except during the first trimester of pregnancy or in patients with adverse reactions to methimazole, due to risk of severe liver failure. 4
• Recognize that the FDA label's recommendation for divided dosing reflects older practice patterns rather than current evidence-based medicine. 1, 2, 3