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Methimazole

Pronunciation

(meth IM a zole)

Index Terms

  • MMI
  • Thiamazole

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Tapazole: 5 mg, 10 mg [scored]

Generic: 5 mg, 10 mg

Brand Names: U.S.

  • Tapazole

Pharmacologic Category

  • Antithyroid Agent
  • Thioamide

Pharmacology

Inhibits the synthesis of thyroid hormones by blocking the oxidation of iodine in the thyroid gland; blocks synthesis of thyroxine and triiodothyronine (T3); does not inactivate circulating T4 and T3

Absorption

Almost complete (Clark 2006)

Distribution

Concentrated in thyroid gland

Metabolism

Hepatic

Excretion

Urine

Onset of Action

Antithyroid: 12 to 18 hours (Clark 2006)

Time to Peak

Serum: 1 to 2 hours (Clark 2006)

Duration of Action

36 to 72 hours (Clark 2006)

Half-Life Elimination

4 to 6 hours (Clark 2006)

Protein Binding

Plasma: None (Cooper 2005)

Use: Labeled Indications

Hyperthyroidism: Treatment of hyperthyroidism in patients with Graves’ disease or toxic multinodular goiter (surgery or radioactive iodine therapy is not appropriate); amelioration of hyperthyroid symptoms in preparation for thyroidectomy or radioactive iodine therapy.

Off Label Uses

Iodine-induced thyrotoxicosis

Based on the American Thyroid Association guidelines for the management of Hyperthyroidism and Other Causes of Thyrotoxicosis, treatment with methimazole is recommended in iodine-induced thyrotoxicosis to reduce thyroid hormone production [Ross 2016].

Thyroid storm or thyrotoxicosis

Based on the American Thyroid Association guidelines for the management of Hyperthyroidism and Other Causes of Thyrotoxicosis, treatment with methimazole is recommended in thyroid storm or thyrotoxicosis to reduce thyroid hormone production [Ross 2016].

Thyrotoxicosis (type 1 amiodarone-induced)

Based on the American Thyroid Association guidelines for the management of Hyperthyroidism and Other Causes of Thyrotoxicosis, treatment with methimazole is recommended in overt thyrotoxicosis (type 1 amiodarone-induced) to reduce thyroid hormone production [Ross 2016]. Use in combination with a corticosteroid if etiology of thyrotoxicosis (eg type 1 or type 2) cannot be unequivocally determined or if patient is too clinically unstable to allow a trial of monotherapy.

Contraindications

Hypersensitivity to methimazole or any component of the formulation

Dosing: Adult

Hyperthyroidism: Oral: Initial: 15 to 60 mg/day depending on severity of disease; usual maintenance dose: 5 to 15 mg/day. Note: The manufacturer suggests dividing the daily dose into 3 equal administrations; however, administration as a single daily dose or in 2 divided doses (for doses >30 mg/day) may be preferred (Ross 2016).

Adjust dosage as required to achieve and maintain serum T3, T4, and TSH levels in the normal range. An elevated T3 may be the sole indicator of inadequate treatment. An elevated TSH indicates excessive antithyroid treatment.

Hyperthyroidism associated with Graves disease (off label) (Ross 2016): Oral: Note: Individualize dose based on serum free T4 and T3 levels and clinical status to restore euthyroidism and minimize adverse effects. Adjunctive therapy with potassium iodide may be beneficial in controlling hyperthyroidism and may allow lower initial dosages of methimazole to be used (Sato 2015).

Initial: 10 to 30 mg once daily; based on free T4 levels, lower doses (eg, 5 mg/day) or higher doses (eg, 40 mg/day) may be considered however initial doses >30 mg/day are associated with increased adverse effects. In patients with severe disease, administering the daily dose in 2 divided doses (eg, 15 to 20 mg twice daily) may increase efficacy (methimazole duration of action may be less than 24 hours).

The following recommendations may be considered to guide initial dosing based on free T4 levels:

1 to 1.5 times ULN: 5 to 10 mg/day

>1.5 to 2 times ULN: 10 to 20 mg/day

>2 times ULN: 30 to 40 mg/day

Usual maintenance: 5 to 10 mg once daily for a total of 12 to 18 months, then discontinue if thyroid function tests (eg, TSH, thyrotropin receptor antibody [TRAb]) are normal at that time.

Iodine-induced thyrotoxicosis (off-label use): Oral: 20 to 40 mg daily given either once or twice daily (Ross 2016)

Thyrotoxicosis or thyroid storm (off-label use): Oral: Note: Recommendations vary; use in combination with other specific agents. Dosages of 20 to 25 mg every 6 hours have been used; once stable, dosing frequency may be reduced to once or twice daily (Nayak 2006). The American Thyroid Association recommends 60 to 80 mg/day (Ross 2016). Rectal administration has also been described (Nabil 1982).

Thyrotoxicosis, type 1 amiodarone-induced (off-label use): Oral: 40 mg once daily to restore euthyroidism (generally 3 to 6 months). If high doses continue to be required, dividing the dose may be more effective. Note: Use in combination with a corticosteroid if etiology of thyrotoxicosis (eg, type 1 or type 2) cannot be unequivocally determined or if patient is too clinically unstable to allow a trial of monotherapy (Ross 2016).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Hyperthyroidism: Children and Adolescents: Oral: Initial: 0.4 mg/kg/day; maintenance: 0.2 mg/kg/day Note: The manufacturer suggests dividing the daily dose into 3 equal administrations; however, administration as a single daily dose or in 2 divided doses (for doses >30 mg/day) may be preferred (Ross 2016)

Hyperthyroidism associated with Graves disease (off-label) (Ross 2016): Infants, Children, and Adolescents: Oral:

Initial: Weight-based dosing: 0.2 to 0.5 mg/kg once daily (range: 0.1 to 1 mg/kg/day); in severe cases, initial doses that are 50% to 100% higher may be used; once patient is euthyroid, reduce dose by 50% or more and continue for a total duration of therapy of 1 to 2 years; may then discontinue or reduce dose to assess if patient is in remission.

The following fixed dosing approach may also be considered (using one-quarter, one-half, or whole tablets) (Ross 2016):

Infants: 1.25 mg/day

Children 1 to 5 years: 2.5 to 5 mg/day

Children 5 to 10 years: 5 to 10 mg/day

Children and Adolescents 10 to 18 years: 10 to 20 mg/day

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling.

Extemporaneously Prepared

Suppositories can be made from methimazole tablets; dissolve 1200 mg methimazole in 12 mL of water and add to 52 mL cocoa butter containing 2 drops of Span 80. Stir the resulting mixture to form a water-oil emulsion and pour into 2.6 mL suppository molds to cool.

Nabil N, Miner DJ, and Amatruda JM, "Methimazole: An Alternative Route of Administration," J Clin Endo Metab, 1982, 54(1):180-1.7054215

Administration

Rectal: In thyrotoxic crisis, rectal administration has been described (Nabil 1982).

Storage

Store at 15°C to 30°C (59°F to 86°F).

Drug Interactions

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Cardiac Glycosides: Antithyroid Agents may increase the serum concentration of Cardiac Glycosides. Monitor therapy

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

PrednisoLONE (Systemic): MethIMAzole may decrease the serum concentration of PrednisoLONE (Systemic). Monitor therapy

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Sodium Iodide I131: Antithyroid Agents may diminish the therapeutic effect of Sodium Iodide I131. Management: Discontinue antithyroid therapy 3-4 days prior to sodium iodide I-131 administration. Avoid combination

Theophylline Derivatives: Antithyroid Agents may increase the serum concentration of Theophylline Derivatives. Exceptions: Dyphylline. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Antithyroid Agents may diminish the anticoagulant effect of Vitamin K Antagonists. Consider therapy modification

Adverse Reactions

Frequency not defined.

Cardiovascular: Edema, hypersensitivity angiitis (including ANCA-positive), periarteritis

Central nervous system: Drowsiness, headache, neuritis, paresthesia, vertigo

Dermatologic: Alopecia, exfoliative dermatitis, pruritus, skin pigmentation, skin rash, urticaria

Endocrine & metabolic: Goiter, hypoglycemic coma, insulin autoimmune syndrome, weight gain

Gastrointestinal: Ageusia, constipation, enlargement of salivary glands, epigastric distress, nausea, vomiting

Hematologic & oncologic: Agranulocytosis, aplastic anemia, granulocytopenia, hypoprothrombinemia, leukopenia, lymphadenopathy, thrombocytopenia

Hepatic: Hepatic necrosis, hepatitis, jaundice

Neuromuscular & skeletal: Arthralgia, lupus-like syndrome, myalgia

Renal: Nephritis

Miscellaneous: Fever

Warnings/Precautions

Concerns related to adverse effects:

• Bleeding: May cause hypoprothrombinemia and bleeding. Monitoring is recommended, especially before surgical procedures.

• Bone marrow suppression: May cause significant bone marrow depression; the most severe manifestation is agranulocytosis. Aplastic anemia, thrombocytopenia, and leukopenia may also occur. Use with caution with concomitant use of other drugs known to cause myelosuppression (particularly agranulocytosis). Monitor patients closely; discontinue if significant bone marrow suppression occurs, particularly agranulocytosis or aplastic anemia.

• Dermatitis: Antithyroid agents have been associated with rare but severe dermatologic reactions. Discontinue in the presence of exfoliative dermatitis.

• Fever: Discontinue in the presence of unexplained fever.

• Hepatic effects: Hepatotoxicity (including acute liver failure) may occur. Symptoms suggestive of hepatic dysfunction (eg, anorexia, pruritus, right upper quadrant pain) should prompt evaluation. Discontinue in the presence of hepatitis and clinically significant hepatic abnormality, including transaminase >3 times upper limit of normal.

• Hypothyroidism: May cause hypothyroidism; routinely monitor TSH and free T4 levels, adjust dose to maintain euthyroid state.

• Lupus-like syndrome: A lupus-like syndrome may occur.

• Vasculitis: ANCA-positive vasculitis may develop during therapy; discontinue use in the presence of vasculitis.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Monitoring Parameters

Signs and symptoms of illness (ie fever, sore throat, skin eruptions, general malaise)

CBC with differential (baseline and if development of febrile illness or pharyngitis occurs); prothrombin time (especially before surgical procedures), liver function tests (bilirubin, alkaline phosphatase, ALT, AST at baseline and if symptoms of liver injury occur (Ross 2016)

Thyroid function tests:

TSH (periodically throughout treatment, may remain suppressed for several months after starting therapy) (Ross 2016)

Serum free T4 and total T3 2 to 6 weeks after initiation, repeat in 4 to 6 weeks if dose is adjusted and then every 2 to 3 months once euthyroid levels are achieved (with long term therapy [ie, >18 months] may extend interval to every 4 to 6 months); if TRAb is negative, thyroid function tests should be monitored every 2 to 3 months for the first 6 months after discontinuing therapy, then at 4- to 6-month intervals for the next 6 months, then every 6 to 12 months thereafter (Ross 2016)

TRAb (prior to stopping medication, elevation at the end of therapy decreases likelihood of remission) (Ross 2016)

Pregnancy Risk Factor

D

Pregnancy Considerations

Methimazole crosses the placenta. Birth defects have been observed in neonates exposed to maternal methimazole in the first trimester of pregnancy and include anomalies of the upper gastrointestinal tract (esophageal atresia or tracheoesophageal fistula), respiratory tract (choanal atresia), skin (aplasia cutis), and facial dysmorphism. Additional abdominal wall defects (umbilicocele), ventricular septal defects, and defects of the eye and urinary system have also been reported (Alexander 2017). Hypothyroidism may occur in the newborn.

Uncontrolled maternal hyperthyroidism may result in adverse neonatal and maternal outcomes. Antithyroid drugs are the treatment of choice for the control of hyperthyroidism during pregnancy, although recommendations for specific agents vary by guideline (ACOG 2015; Alexander 2017; De Groot 2012). Dose requirements of methimazole may be decreased as pregnancy progresses. To prevent adverse pregnancy outcomes, maternal TT4/FT4 should be at or just above the pregnancy specific upper limit of normal (Alexander 2017).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience itching, change in taste, dizziness, fatigue, muscle pain, joint pain, hair loss, numbness or tingling, skin discoloration, vomiting, or nausea. Have patient report immediately to prescriber signs of infection, signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of lupus (rash on the cheeks or other body parts, sunburn easy, muscle or joint pain, chest pain or shortness of breath, or swelling in the arms or legs), signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating), severe headache, bruising, bleeding, severe loss of strength and energy, or edema (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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