How should methimazole be started, dosed, and tapered in a newly diagnosed adult with Graves disease, including considerations for severe thyrotoxicosis, large goitre, ophthalmopathy, and pediatric patients?

How to Give Methimazole in Graves Disease

Start methimazole at 15 mg daily for mild hyperthyroidism, 30-40 mg daily for moderate disease, or 60 mg daily for severe hyperthyroidism, divided into three doses given every 8 hours, then taper to a maintenance dose of 5-15 mg daily once euthyroid. 1

Initial Dosing Strategy

Dose Selection Based on Disease Severity

• Mild hyperthyroidism: Start 15 mg daily divided into 3 doses (5 mg every 8 hours) 1
• Moderate hyperthyroidism: Start 30-40 mg daily divided into 3 doses 1
• Severe hyperthyroidism: Start 60 mg daily divided into 3 doses 1

The FDA-approved dosing divides the total daily dose into three administrations at 8-hour intervals 1. However, research demonstrates that once-daily dosing with 15 mg methimazole is highly effective for moderate disease and may improve adherence 2, 3. A single daily 15 mg dose achieved euthyroidism as effectively as 30 mg daily in comparative trials 3.

Alternative Regimen for Moderate-to-Severe Disease

For patients with free T4 ≥5 ng/dL, consider methimazole 15 mg daily plus inorganic iodine 38 mg daily initially, then discontinue iodine once free T4 normalizes 4. This combination achieved faster normalization (45% euthyroid by 30 days vs 25% with methimazole 30 mg alone) and caused fewer adverse effects requiring drug discontinuation (7.5% vs 14.8%) 4.

Adjunctive Therapy

Add a beta-blocker (propranolol or atenolol 25-50 mg daily) for symptomatic relief during the first 2-4 weeks until thyroid hormone levels normalize 5. Titrate to maintain heart rate <90 bpm if blood pressure tolerates 5.

Monitoring Protocol

Initial Phase (Until Euthyroid)

Check TSH and free T4 every 2-4 weeks after starting therapy until euthyroidism is achieved 5. For highly symptomatic patients with minimal free T4 elevations, consider adding T3 measurements 5.

Maintenance Phase

• Monitor thyroid function every 4-6 weeks initially after achieving euthyroidism 5
• Once stable, extend monitoring intervals to every 3 months 5
• Watch for transition to hypothyroidism, which requires dose adjustment 5

Tapering to Maintenance Dose

The maintenance dosage is 5-15 mg daily 1. The goal is maintaining free T4 or free T4 index in the high-normal range (0.8-1.6 ng/dL) using the lowest possible methimazole dose 5.

Long-Term Maintenance Strategy

For patients >35 years old, consider continuing low-dose methimazole (2.5-5 mg daily) long-term rather than discontinuing, as this prevents relapse more effectively than standard withdrawal protocols 6. In patients over 35, continuous low-dose therapy significantly reduced relapse risk compared to drug discontinuation 6.

A practical approach: maintain euthyroid status (normal free T4 and TSH) for at least 6 months on minimum maintenance dose (5 mg every other day) before considering discontinuation 7. This strategy predicted remission in 81% of patients 7.

Pediatric Dosing

Initial dose: 0.4 mg/kg body weight daily divided into 3 doses given every 8 hours 1. Maintenance dose: approximately half the initial dose 1.

Special Populations

Pregnancy

Use the lowest possible dose that maintains free T4 in the high-normal range 5. Monitor free T4 or free T4 index every 2-4 weeks throughout pregnancy 5. Methimazole is preferred over propylthiouracil after the first trimester due to PTU's hepatotoxicity risk, though PTU is preferred in the first trimester due to methimazole's teratogenic potential 5.

Severe or Life-Threatening Hyperthyroidism

For grade 3-4 hyperthyroidism:

• Hospitalize the patient and obtain endocrine consultation 5
• Provide aggressive beta-blockade, hydration, and supportive care 5
• Consider additional therapies including steroids, saturated solution of potassium iodide (SSKI), or higher-dose thionamides as directed by endocrinology 5

Critical Safety Monitoring

Monitor for agranulocytosis, which typically presents with sore throat and fever 5. Obtain a complete blood count immediately if these symptoms develop 5. This is the most serious adverse effect and requires immediate drug discontinuation.

Also monitor for cutaneous reactions and watch for development of hypothyroidism during treatment 5.

Common Pitfalls to Avoid

• Do not start thyroid hormone replacement before corticosteroids in patients with concurrent adrenal insufficiency, as this can precipitate adrenal crisis 8
• Lower initial doses (15 mg daily) cause significantly fewer adverse effects than higher doses (30 mg daily) while maintaining similar efficacy for mild-to-moderate disease 3, 4
• Negative thyroid antibodies (TBII or TSAb) at discontinuation do not reliably predict remission—11% of TBII-negative patients still relapsed 7