What are the potential side effects of methimazole in an adult patient with a history of thyroid disorders, particularly Graves' disease?

Side Effects of Methimazole

Methimazole can cause several potentially serious adverse reactions, with agranulocytosis being the most life-threatening, typically occurring within the first 3-6 months of therapy, along with hepatotoxicity, skin reactions, and vasculitis that require immediate drug discontinuation. 1

Life-Threatening Adverse Reactions

Agranulocytosis

• Agranulocytosis is the most serious side effect and is potentially life-threatening, requiring immediate discontinuation of methimazole 2, 1
• Patients must be instructed to immediately report fever or sore throat, as these are cardinal symptoms of agranulocytosis 2, 1
• This reaction typically presents within the first few months of therapy, with 75% of adverse reactions occurring during the first 6 months of treatment 3
• Leukopenia, thrombocytopenia, and aplastic anemia (pancytopenia) may also occur and require drug discontinuation 1

Hepatotoxicity

• Hepatotoxicity, including acute liver failure, can occur with methimazole, though the risk appears lower than with propylthiouracil, especially in pediatric populations 1
• Symptoms suggestive of hepatic dysfunction (anorexia, pruritus, right upper quadrant pain) should prompt immediate evaluation of liver function tests 1
• Drug treatment should be discontinued promptly if hepatic transaminase values exceed 3 times the upper limit of normal 1
• Hepatitis has been reported as an adverse reaction to thioamide therapy 2

Vasculitis

• Cases of severe vasculitis have been reported, including leukocytoclastic cutaneous vasculitis, acute kidney injury with glomerulonephritis, alveolar/pulmonary hemorrhage, CNS vasculitis, and neuropathy 1
• Most cases are associated with ANCA-positive vasculitis 1
• If vasculitis is suspected, discontinue therapy immediately and initiate appropriate intervention, which may include corticosteroids, immunosuppressant therapy, and plasmapheresis 1
• Thrombocytopenia is also reported as a side effect 2

Common Adverse Reactions

Dermatologic Reactions

• Skin reactions are the most prominent adverse effect, comprising 68% of all registered reactions 3
• Cutaneous reactions should be monitored throughout therapy 4
• These reactions typically occur early in treatment, with most adverse events happening within the first 6 months 3

Musculoskeletal Complaints

• Myalgia, arthralgia, and arthritis are well-known adverse reactions 5
• Rare cases of methimazole-induced myositis have been reported, which may present with eosinophilic myositis and fasciitis 5
• Resolution of myositis symptoms may occur after stopping methimazole 5

Pregnancy-Related Concerns

First Trimester Teratogenicity

• Methimazole crosses the placental membranes and can cause fetal harm when administered in the first trimester of pregnancy 1
• Rare instances of congenital defects include aplasia cutis, craniofacial malformations (facial dysmorphism, choanal atresia), gastrointestinal malformations (esophageal atresia with or without tracheoesophageal fistula), omphalocele, and abnormalities of the omphalomesenteric duct 1
• Because of first trimester teratogenicity risk, propylthiouracil is preferred in the first trimester, while methimazole is preferred in the second and third trimesters 2
• If methimazole must be used during pregnancy, the lowest possible dose to control maternal disease should be given 1

Fetal Thyroid Effects

• Methimazole can cause fetal goiter and cretinism when administered to pregnant women 1
• Suppression of fetal and neonatal thyroid function can occur with thioamide therapy for Graves' disease, though it is usually transient and rarely requires treatment 2

Thyroid-Related Side Effects

Hypothyroidism

• Methimazole can cause hypothyroidism, necessitating routine monitoring of TSH and free T4 levels with dosing adjustments to maintain a euthyroid state 1
• Transition to hypothyroidism can occur during treatment and requires dose adjustment 6, 4

Timing and Frequency of Adverse Reactions

• Ten percent of patients experience adverse drug reactions, with 75% occurring during the first 6 months of therapy 3
• After 24 months on low-dose methimazole (5 mg/day), no further adverse drug reactions were recorded in one prospective study 3
• Side effects are more frequent at higher doses (30 mg/day) compared to lower doses (15 mg/day), with adverse effects requiring discontinuation occurring in 14.8% versus 7.5% of patients respectively 7
• Side effects occurred in only 2 patients treated with 15 mg single daily dose compared to 6 patients treated with 30 mg single daily dose 8

Critical Monitoring Recommendations

• No hepatic or bone marrow affection was recorded in patients maintained on long-term low-dose methimazole (5 mg/day) after 24 months, though these severe reactions must still be kept in mind 3
• Patients should be monitored with thyroid function tests every 2-4 weeks until euthyroidism is achieved 6, 4
• Monitor for adverse effects including cutaneous reactions throughout therapy 4