What are the side effects of methimazole?

Methimazole Side Effects

Patients taking methimazole must be warned about potentially life-threatening agranulocytosis and instructed to immediately stop the medication and contact their physician if they develop fever, sore throat, mouth sores, pharyngitis, or malaise 1, 2.

Major (Life-Threatening) Side Effects

Agranulocytosis

• Occurs in 0.15-0.45% of patients 3
• 95% of cases occur within the first 100 days of therapy 1, 3
• Dose-dependent with methimazole, rarely occurs at low doses 1
• Routine white blood cell monitoring is NOT recommended because onset is sudden and unpredictable 1
• Obtain differential white blood cell count immediately during any febrile illness or at onset of pharyngitis 1
• Absolute contraindication to switch to propylthiouracil if agranulocytosis develops (50% cross-reactivity risk) 3

Hepatotoxicity

• Less common than with propylthiouracil, but can occur 2
• Presents with anorexia, pruritus, jaundice, pale stools, dark urine, right upper quadrant pain 1
• Stop medication if transaminases exceed 3 times upper limit of normal 2
• Moderate transaminase elevation (14-28% of patients) usually normalizes spontaneously in first 2 months 3

Vasculitis

• ANCA-positive vasculitis can occur 1, 2
• Manifestations include: leukocytoclastic cutaneous vasculitis, acute kidney injury, glomerulonephritis, pulmonary hemorrhage, CNS vasculitis, neuropathy 2
• Discontinue immediately if vasculitis suspected and initiate corticosteroids/immunosuppression as needed 2

First Trimester Teratogenicity

• Contraindicated in first trimester of pregnancy 2
• Causes aplasia cutis, choanal atresia, esophageal atresia, omphalocele, facial dysmorphism 2

Minor Side Effects

Cutaneous Reactions (5-10% of patients)

• Pruritic rash, urticaria 1, 3
• Can manage with concurrent antihistamines without stopping the drug 1
• If persistent, switch to radioactive iodine, surgery, or propylthiouracil (if other options refused) 1

Arthralgias/Myalgias (1-5% of patients)

• Joint or muscle/tendon pain 3
• Can be disabling despite being "minor" 3
• May be inaugural symptom of vasculitis—monitor closely 3

Gastrointestinal

• Abdominal pain, nausea, anorexia 1

Other Common Effects

• Fatigue 1
• Hypothyroidism (requires TSH monitoring and dose adjustment) 2

Monitoring Algorithm

Before Starting Treatment

• Baseline complete blood count with differential 1
• Baseline liver function tests (bilirubin, transaminases, alkaline phosphatase) 1

During Treatment

• No routine white blood cell monitoring recommended 1
• Check CBC immediately if fever, pharyngitis, mouth sores, or malaise develop 1
• Stop medication if absolute neutrophil count <1,000/mm³ (some suggest <800/mm³) 3
• Monitor thyroid function tests monthly initially, then every 2-4 months 1

Critical Patient Education Points

Patients must be instructed at EVERY visit to stop medication immediately and call physician if they develop 1:

• Fever or sore throat (agranulocytosis)
• Jaundice, pale stools, or dark urine (hepatotoxicity)
• Pruritic rash
• Arthralgias
• Abdominal pain
• Nausea or fatigue
• Pharyngitis or mouth sores

Special Populations

Children

• Same side effect profile as adults 1
• Younger age and lower baseline neutrophil count are risk factors for neutropenia 4
• Most adverse reactions occur within 3 months of starting treatment 4

Pregnancy

• Use propylthiouracil in first trimester instead 1
• Can use methimazole in second and third trimesters at lowest effective dose 2

Management of Side Effects

• Minor cutaneous reactions: Continue drug with antihistamines 1
• Persistent minor reactions: Stop and switch to radioactive iodine or surgery 1
• Serious allergic reaction: Never switch to propylthiouracil (cross-reactivity) 1
• Agranulocytosis: Stop immediately, never rechallenge with any thionamide 3