Methimazole Dosing: Single Daily Dose is Preferred
For a healthy adult with newly diagnosed mild hyperthyroidism, methimazole should be given as a single daily dose of 15 mg, not divided into three doses. The FDA label's recommendation for three divided doses is outdated and contradicted by substantial clinical evidence demonstrating equal or superior efficacy with once-daily dosing 1.
Evidence Supporting Single Daily Dosing
Efficacy Comparable to Divided Dosing
Single daily dosing of 15 mg methimazole achieves euthyroidism in 93% of patients within 12 weeks, with a mean time to euthyroidism of 5.3 weeks—essentially identical to the 86% success rate and 5.6-week timeline seen with traditional divided dosing (10 mg three times daily) 2.
A long-term prospective study found no difference in clinical course, immunological response, or long-term remission rates between patients treated with 15 mg once daily versus 10 mg three times daily, with both groups achieving euthyroidism in approximately 5.6-5.8 weeks 3.
The single daily dose regimen controls hyperthyroidism in most patients, though propylthiouracil may achieve control slightly more rapidly than methimazole 4.
Superior Compliance and Safety Profile
Compliance with once-daily methimazole was 83.3% compared to only 53.3% with three-times-daily propylthiouracil, demonstrating the practical advantage of simplified dosing 5.
Adverse effects occurred in only 13% of patients on single daily dosing versus 24% with divided dosing, suggesting a better safety profile with the once-daily regimen 3.
When comparing 15 mg versus 30 mg single daily doses, the lower dose caused side effects in only 2 patients compared to 6 patients on the higher dose 2.
Recommended Dosing Algorithm
Initial Dosing Based on Disease Severity
For mild hyperthyroidism (your patient's presentation):
- Start with 15 mg methimazole once daily in the morning 1, 2.
- This dose is effective in 93% of patients and minimizes adverse effects 2.
For moderately severe hyperthyroidism:
For severe hyperthyroidism:
- The FDA label suggests 60 mg daily in divided doses, but single daily dosing studies have not extensively evaluated this severity level 1.
Maintenance Dosing
- Once euthyroid (typically within 5-8 weeks), gradually reduce to a maintenance dose of 5-15 mg daily 1, 3.
- Continue treatment for approximately 28 months on average before considering discontinuation 3.
Mechanism Supporting Once-Daily Dosing
- Perchlorate discharge tests performed 24 hours after a single 15 mg dose of methimazole showed greater than 10% discharge in 77% of patients, demonstrating that methimazole's duration of action extends well beyond 8 hours and supports once-daily dosing 2.
Comparative Efficacy: Methimazole vs. Propylthiouracil
A single daily dose of 15 mg methimazole is significantly more effective than 150 mg propylthiouracil once daily in reducing serum T3, T4, and free T4 levels after 4 weeks of treatment 6.
Methimazole also demonstrates superior reduction in thyrotropin receptor antibodies (TRAb) compared to propylthiouracil after 8 weeks of treatment 6.
Special Considerations for Cardiovascular Disease
If your patient has atrial fibrillation complicating thyrotoxicosis, add beta-blockers to control ventricular rate, or use non-dihydropyridine calcium channel antagonists if beta-blockers are contraindicated 7.
Normalize thyroid function before attempting cardioversion, as antiarrhythmic drugs and cardioversion are generally unsuccessful while thyrotoxicosis persists 7.
Consider antithrombotic therapy based on stroke risk factors, not just the presence of hyperthyroidism 7.
Common Pitfalls to Avoid
Do not reflexively follow the FDA label's three-times-daily dosing recommendation—this is based on older practice patterns and ignores decades of evidence supporting once-daily administration 1, 2, 3.
Avoid starting with 30 mg daily in mild hyperthyroidism, as 15 mg is equally effective with fewer side effects 2.
Do not assume poor compliance is due to disease severity—it is often due to the inconvenience of multiple daily doses 5.