Methimazole

Approved Indications:

• Hyperthyroidism (including Graves’ disease)
• Used to manage hyperthyroidism by reducing thyroid hormone production.
• Toxic Multinodular Goiter
• Thyroid Storm (Thyrotoxic Crisis)
• Used as part of combination therapy in acute management.
• Preparation for Thyroidectomy or Radioactive Iodine Therapy
• Given prior to definitive therapy to normalize thyroid function.

Clinically Accepted Off-label Uses:

• Amiodarone-induced Hyperthyroidism
• As part of management in selected cases.
• Subclinical Hyperthyroidism (in elderly or high-risk patients)
• During Pregnancy (Second and Third Trimesters)
• Preferred over propylthiouracil in later pregnancy stages to minimize hepatotoxicity risk.

Route: Oral
Formulations Available: 5 mg, 10 mg tablets

Adults:

• Initial Dose:
• Mild hyperthyroidism: 15 mg/day (divided doses)
• Moderate: 30–40 mg/day (divided doses)
• Severe: up to 60 mg/day (divided doses)
• Maintenance Dose: 5–15 mg/day (once daily)

Pediatrics:

• Initial Dose: 0.4–0.7 mg/kg/day divided into 3 doses
• Maintenance: 0.2–0.4 mg/kg/day once or twice daily
• Maximum dose: Typically not exceeding 30 mg/day

Pregnancy:

• Use only when clinically indicated.
• First trimester: Avoid due to risk of congenital malformations.
• Second/third trimester: 5–30 mg/day in divided doses (use lowest effective dose).

Renal/Hepatic Impairment:

• Use with caution. No exact dose adjustment guidelines; monitor closely for toxicity.

Duration of Therapy:

• Typically 12–18 months, then reassess for remission or plan definitive treatment.

Methimazole is a thionamide antithyroid agent that inhibits the enzyme thyroid peroxidase, which catalyzes the iodination of tyrosine residues on thyroglobulin and the coupling of iodotyrosines. These steps are essential for the synthesis of thyroxine (T4) and triiodothyronine (T3). By blocking this process, methimazole reduces the production of active thyroid hormones, thereby controlling hyperthyroidism. It does not affect circulating thyroid hormones or thyroid hormone release.

• Absorption: Rapid and nearly complete oral absorption
• Bioavailability: ~93%
• Distribution: Widely distributed, accumulates in the thyroid gland
• Protein Binding: ~0–10%
• Metabolism: Hepatic (extensively metabolized)
• Half-life: 4–6 hours; duration of action may persist up to 24 hours due to accumulation in the thyroid
• Excretion: Primarily renal, <10% excreted unchanged in urine

• Pregnancy:
• Previously FDA Category D
• Crosses placenta and can cause congenital anomalies (especially in 1st trimester: aplasia cutis, choanal/esophageal atresia).
• Use propylthiouracil in 1st trimester, switch to methimazole in 2nd and 3rd.
• Lactation:
• Excreted in small amounts in breast milk.
• Considered safe during breastfeeding at doses ≤20 mg/day.
• Monitor infant thyroid function if breastfeeding.

• Class: Antithyroid Agent
• Subclass: Thionamide Derivative

• Known hypersensitivity to methimazole or other thionamides
• History of agranulocytosis with prior methimazole use
• Severe liver disease (relative contraindication)
• First trimester of pregnancy (unless no alternative)

• Agranulocytosis: Life-threatening; may occur suddenly (monitor WBC if fever/sore throat)
• Hepatotoxicity: Risk of liver injury, monitor liver function tests
• Teratogenicity: Avoid in early pregnancy
• Vasculitis: Rarely causes ANCA-positive vasculitis
• Monitoring:
• Baseline and periodic CBC, liver enzymes, and thyroid function (TSH, FT4, FT3)
• Signs requiring immediate discontinuation:
• Fever, sore throat, jaundice, fatigue, rash, dark urine

Common:

• Skin: Rash, urticaria, pruritus
• GI: Nausea, vomiting, mild stomach upset
• Musculoskeletal: Arthralgia

Serious/Rare:

• Agranulocytosis (0.1–0.5%)
• Hepatitis or cholestatic jaundice
• Aplastic anemia
• Lupus-like syndrome
• Vasculitis (including ANCA-associated)

Timing:

• Agranulocytosis typically occurs within first 3 months
• Hepatotoxicity may occur early or late in treatment

• Warfarin: Methimazole may increase the anticoagulant effect by reducing vitamin K-dependent clotting factors.
• Theophylline: Decreased clearance in hyperthyroid patients corrected with methimazole.
• Beta-blockers: Enhanced effect due to normalized thyroid state.
• Digitalis: Dose adjustment may be required as thyroid levels normalize.
• No known significant CYP450 interactions.

• ATA Guidelines (2023):
• Continue methimazole as first-line agent for long-term treatment of hyperthyroidism.
• Monitor for agranulocytosis, especially within 90 days of initiation.
• FDA Safety Updates:
• Emphasized teratogenic risks in the first trimester.

• Storage Temperature: 20°C to 25°C (68°F to 77°F); excursions permitted to 15–30°C
• Humidity & Light: Store in a dry place, protect from moisture
• Handling Precautions: Keep container tightly closed
• No refrigeration or reconstitution required