Hyperthyroidism associated with Graves disease, toxic multinodular goiter, toxic adenoma (labeled uses), or iodine-induced thyrotoxicosis (off-label use) :
Note: May use in combination with beta-blockade to manage hyperthyroid symptoms prior to definitive therapy or as chronic low-dose treatment; for iodine-induced thyrotoxicosis, may be used as an adjunct to beta-blockade for severe or prolonged (eg, >1 month) symptoms or in patients with underlying heart disease (ATA [Ross 2016]; Surks 2021).
Oral: Initial: Individualize initial dose based on clinical status and gland size; free T4 levels may be used to guide initial therapy (ATA [Ross 2016]; Ross 2020a):
Free T4 levels 1 to 1.5 times ULN: 5 to 10 mg once daily.
Free T4 levels >1.5 to 2 times ULN (or iodine-induced thyrotoxicosis): 10 to 20 mg once daily.
Free T4 levels >2 times ULN: 20 to 40 mg/day. To achieve euthyroidism more quickly and reduce GI-related adverse effects, may give in 2 to 3 divided doses (especially with doses >30 mg/day) (ATA [Ross 2016]; Burch 2015; Ross 2020a).
Dose adjustment: Oral: Usual maintenance dose: 5 to 10 mg once daily. Assess free T4 and total T3 at 4- to 6-week intervals; when normal, reduce dose by 30% to 50% and repeat thyroid function tests in 4 to 6 weeks; continue to adjust dose to achieve euthyroidism (ATA [Ross 2016]; Ross 2020a; Ross 2022b).
Duration of therapy: Depends on etiology and plans for definitive therapy:
Patients undergoing definitive therapy: Prior to definitive therapy, continue until euthyroid (typically 4 to 6 weeks); discontinue 2 to 3 days before radioactive iodine therapy or on the day of thyroidectomy (ATA [Ross 2016]; Walter 2006).
Patients not undergoing definitive therapy: For Graves disease, continue for 12 to 18 months, then assess for remission; for toxic multinodular goiter/toxic adenoma, continue indefinitely (ATA [Ross 2016]).
Iodine-induced thyrotoxicosis: Taper and discontinue therapy as iodine load is cleared (Surks 2021).
Thyroid storm (alternative to propylthiouracil) (off-label use): Note: Use in combination with other appropriate agents; if iodine is administered, delay iodine administration by ≥1 hour after methimazole (ATA [Ross 2016]).
Oral: Initial: 20 mg every 4 to 6 hours (ATA [Ross 2016]; Ross 2021c); once clinically stable, dose may be given less frequently (eg, 20 mg once or twice daily) (Nayak 2006). In patients who cannot take methimazole by mouth, alternative administration routes (eg, nasogastric, rectal) may be considered (Nabil 1982; Ross 2021c).
Thyrotoxicosis, type I amiodarone-induced (off-label use):
Oral: Initial: 30 to 40 mg once daily; adjust dose to achieve euthyroidism (eg, free T4, total T3, TSH levels in the normal range); if high doses (eg, >30 mg/day) are required after 3 to 6 months, it may be more effective to administer in 2 to 3 divided doses (ATA [Ross 2016]; Burch 2015; Ross 2020d). Note: If etiology of amiodarone-induced thyrotoxicosis (eg, type I or type II) cannot be determined or if patient is clinically unstable, use in combination with a glucocorticoid (ATA [Ross 2016]; Ross 2020d).
Duration of therapy: Depends on whether amiodarone therapy will be continued:
Continuing amiodarone: Continue methimazole indefinitely (ATA [Ross 2016]; Ross 2020d).
Discontinuing amiodarone: Taper methimazole slowly (eg, over months) to avoid recurrence of thyrotoxicosis (ATA [Ross 2016]; Ross 2020d).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling.
(For additional information see "Methimazole: Pediatric drug information")
Hyperthyroidism: Infants, Children, and Adolescents: Oral: Initial: 0.4 mg/kg/day in 3 divided doses (approximately every 8 hours); maintenance 0.2 mg/kg/day in 3 divided doses (50% of initial)
Graves disease (ATA [Ross 2016]): Note: In severe cases, higher doses may be required (50% to 100% higher); once patient euthyroid, reduce dose by ≥50% to maintain euthyroid; duration of therapy usually 1 to 2 years
Weight-based dosing: Infants, Children, and Adolescents: Oral: Initial: 0.2 to 0.5 mg/kg/dose once daily (range: 0.1 to 1 mg/kg/dose)
Fixed dosing (using 1/4, 1/2, or whole tablets): Oral:
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 ≥10 years and Adolescents: 10 to 20 mg/day
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer’s labeling.
There are no dosage adjustments provided in the manufacturer’s labeling.
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet, Oral:
Tapazole: 5 mg [DSC], 10 mg [DSC] [scored]
Generic: 5 mg, 10 mg
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet, Oral:
Tapazole: 5 mg [contains corn starch]
Tapazole: 10 mg, 20 mg [DSC]
Generic: 5 mg, 10 mg
Rectal: In thyrotoxic crisis, rectal administration has been described (Nabil 1982).
Oral: May administer without regard to food.
Hazardous agent (NIOSH 2016 [group 2]).
Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage.
NIOSH recommends single gloving for administration of intact tablets or capsules. NIOSH recommends double gloving, a protective gown, and preparation in a controlled device or use of ventilated engineering controls (a class II biological safety cabinet or a compounding aseptic containment isolator) for compounding; if not prepared in a controlled device, respiratory and eye/face protection are recommended (NIOSH 2016). Assess risk to determine appropriate containment strategy (USP-NF 2017).
Hyperthyroidism: Treatment of hyperthyroidism in patients with Graves disease or toxic multinodular goiter for whom surgery or radioactive iodine therapy is not appropriate; amelioration of hyperthyroid symptoms in preparation for thyroidectomy or radioactive iodine therapy.
Iodine-induced thyrotoxicosis; Thyroid storm; Thyrotoxicosis, type I amiodarone-induced
MethIMAzole may be confused with methazolAMIDE, metOLazone
Methimazole may cause agranulocytosis, a rare but potentially life-threatening adverse reaction that is reversible upon discontinuation. Patients should report immediately any sign/symptoms of infection (eg, fever, flu-like symptoms, pharyngitis) so a WBC can be assessed (Ref).
Mechanism: May be through direct toxicity, but more recent evidence supports an immune-mediated mechanism (Ref).
Onset: Varied; most cases occur within the first 3 months of treatment (mean 42 days) but can occur later (Ref).
Risk factors:
• Doses >30 mg/day (possible risk factor) (Ref)
• Age >40 years (possible risk factor) (Ref)
• Genetic variants: HLA-B*27:05 (Europeans) (Ref); HLA‐B*38:02 (Han Chinese) (Ref); HLA‐DRB1*08:03 (Han Chinese) (Ref); Nox3 variants (encodes NADPH oxidase) (Ref).
Methimazole may rarely cause potentially life-threatening hepatotoxicity, including acute hepatic failure and hepatitis (usually cholestatic or mixed) (Ref). Reported incidence is 0.04% to 0.09% (Ref). Hepatotoxicity is reversible with discontinuation. Patients with hepatotoxicity due to methimazole may be at increased risk for hepatotoxicity with propylthiouracil (Ref).
Mechanism: Dose-related; Exact mechanism unknown; hypothesized mechanisms are reactive metabolite formation and an immune-mediated reaction (Ref).
Onset: Varied; hepatotoxicity typically occurs within 2 weeks to 3 months of initiation (Ref).
Risk factors:
• Higher doses (Ref)
• Older age (Ref)
• Polymorphism in SLCO1B1*1a and SLCO1B1*1b (Ref)
• Carriers of the HLA-C*03:02 allele (Ref)
Methimazole may cause a lupus-like syndrome, a rare but potentially life-threatening adverse reaction that is reversible with discontinuation and additional treatment (Ref). Manifestations may range from cutaneous involvement to lupus nephritis (Ref).
Mechanism: Not clearly established; hypothesized to be an autoimmune response in genetically predisposed individuals (Ref).
Onset: Varied; typically manifesting weeks to months after initiation (Ref).
Risk factors:
• IgA deficiency (Ref)
Acute pancreatitis is a rare, but potentially life-threatening adverse effect of methimazole (Ref). Pancreatitis is typically reversible upon discontinuation but has resulted in death (Ref).
Mechanism: Non–dose-related. While the exact mechanism is unknown, it follows a pattern of a hypersensitivity-type reaction with rechallenge reactions occurring at a shorter latency (Ref).
Onset: Varied; typically occurs within the first 90 days of therapy (Ref).
Risk factors:
• Older age (Ref)
Although this adverse reaction is more common with propylthiouracil, cases of vasculitis with methimazole have been discussed in the literature (Ref), most notably involving the kidneys, lungs, and skin. Many of these cases involve a positive antineutrophil cytoplasmic antibody (ANCA). ANCA-positive cases involve an inflammatory and necrotic process impacting small vessels. Pulmonary capillaritis and diffuse pulmonary alveolar hemorrhage has been described (Ref). This adverse reaction is potentially life-threatening without intervention but is reversible with discontinuation and supportive care. A review of ANCA-positive vasculitis cases possibly associated with methimazole reported a prevalence range of 0% to 16% with a median prevalence of 6% (Ref).
Onset: Delayed; the median time to vasculitis presentation was 42 months (Ref).
Risk factors:
• Younger age (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
Frequency not defined:
Cardiovascular: Edema, periarteritis
Dermatologic: Alopecia, pruritus, skin pigmentation, skin rash
Endocrine & metabolic: Hypothyroidism
Gastrointestinal: Enlargement of salivary glands, epigastric distress, nausea, vomiting
Hematologic & oncologic: Granulocytopenia, lymphadenopathy
Nervous system: Drowsiness, drug fever, headache, paresthesia, vertigo
Neuromuscular & skeletal: Arthralgia, myalgia
Postmarketing:
Cardiovascular: Cerebral vasculitis (Tripodi 2008), hypersensitivity angiitis (Ribeiro 2013), vasculitis (Balavoine 2015)
Dermatologic: Urticaria (Kubota 2016)
Endocrine & metabolic: Insulin autoimmune syndrome (Chen 2018, Gomez 2012)
Gastrointestinal: Acute pancreatitis (Brix 2020), ageusia (Hallman 1953), gastrointestinal hemorrhage (Minkley 2011)
Hematologic & oncologic: Agranulocytosis (Cooper 2005), aplastic anemia (Josol 2010), hypoprothrombinemia (Minkley 2011)
Hepatic: Acute hepatic failure (Wang 2014), hepatitis (Wang 2014), hepatotoxicity (Wang 2014), jaundice (Wang 2014)
Nervous system: Neuritis (Roldan 1972), neuropathy
Neuromuscular & skeletal: Lupus-like syndrome (Beernaert 2020)
Renal: Acute kidney injury (Shell 2020), glomerulonephritis (Hori 1996), nephritis (Reynolds 1979)
Respiratory: Pulmonary alveolar hemorrhage (Arai 2018)
Hypersensitivity to methimazole or any component of the formulation.
Canadian labeling: Additional contraindications (not in US labeling): Breastfeeding, history of acute pancreatitis after administration of methimazole.
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. Monitor patients closely; use with caution with concomitant use of other drugs known to cause myelosuppression (particularly agranulocytosis). Instruct patients to report immediately any signs/symptoms of infection (eg, fever, sore throat, pharyngitis, flu-like symptoms) and to discontinue therapy immediately if symptoms suggestive of agranulocytosis are present. A CBC with differential should be performed prior to initiation of therapy, during febrile illness, and at the onset of pharyngitis in all patients during therapy (Ross 2016).
• Dermatologic effects: Antithyroid agents have been associated with dermatologic reactions. Discontinue in the presence of a severe reaction.
• 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: Cases of vasculitis resulting in severe complications have been reported. Most cases were ANCA-positive and included leukocytoclastic cutaneous vasculitis, acute kidney injury and glomerulonephritis, alveolar/pulmonary hemorrhage, CNS vasculitis and neuropathy. Discontinue use for confirmed or suspected vasculitis. Some cases resolve/improve with drug discontinuation; severe cases may require further treatment (eg, corticosteroids, plasmapheresis).
None known.
5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
Cardiac Glycosides: Antithyroid Agents may increase the serum concentration of Cardiac Glycosides. Risk C: Monitor therapy
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination
Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination
PrednisoLONE (Systemic): MethIMAzole may decrease the serum concentration of PrednisoLONE (Systemic). Risk C: Monitor therapy
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification
Sodium Iodide I131: Antithyroid Agents may diminish the therapeutic effect of Sodium Iodide I131. Management: Discontinue antithyroid medications at least 3 days before sodium iodide I-131 administration, and avoid concurrent use. Risk X: Avoid combination
Theophylline Derivatives: Antithyroid Agents may increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Antithyroid Agents may diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Patients taking methimazole should use effective contraception and postpone becoming pregnant until a stable euthyroid state is achieved. Patients taking methimazole should notify their health care provider immediately once pregnancy is suspected. The decision to continue antithyroid medications during pregnancy should be individualized (ATA [Alexander 2017]).
Methimazole crosses the placenta.
Congenital anomalies have been observed in neonates exposed in utero to methimazole in the first trimester and include anomalies of the upper GI tract (esophageal atresia with or without 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 (ATA [Alexander 2017]). Hypothyroidism may occur in the newborn.
Uncontrolled maternal hyperthyroidism may result in adverse neonatal and maternal outcomes. Adverse outcomes associated with poorly controlled thyrotoxicosis include pregnancy loss, pregnancy induced hypertension, maternal congestive heart failure, and thyroid storm, as well as prematurity, low birth weight, intrauterine growth restriction, and stillbirth (ATA [Alexander 2017]).
To avoid potential teratogenic effects, antithyroid drugs may be discontinued as soon as pregnancy is detected in select patients with well-controlled Graves disease at low risk for relapse; close monitoring of maternal and fetal thyroid function recommended (ATA [Alexander 2017]). When treatment is necessary, antithyroid drugs are the treatment of choice for the control of hyperthyroidism during pregnancy, although recommendations for specific agents vary by guideline. Methimazole is generally avoided during the first trimester but may be used later in pregnancy (ACOG 2020; ATA [Alexander 2017]; ES [De Groot 2012]). Dose requirements of methimazole may be decreased as pregnancy progresses. To prevent adverse pregnancy outcomes, the lowest effective dose should be used to keep the maternal TT4/FT4 at or just above the pregnancy specific upper limit of normal (ACOG 2020; ATA [Alexander 2017]).
Methimazole is present in breast milk.
Information related to the presence of methimazole in breast milk is available from 6 lactating women with Graves disease following a single dose of methimazole 15 mg. Peak methimazole concentrations were 0.32 ± 0.10 mcg/mL (breast milk) and 0.31 ± 0.09 mcg/mL (maternal plasma) 2 hours after administration. The half-life of methimazole was calculated to be 4.2 ± 0.8 hours in breast milk. Twelve hours after the dose, breast milk concentrations of methimazole had decreased to 0.03 ± 0.01 mcg/mL (Abe 1995).
Based on available data, thyroid function is normal in infants exposed to lower doses of methimazole via breast milk. In addition, IQ and physical development up to 74 months of age were not impaired in a long-term study of breastfed infants whose mothers were receiving treatment with methimazole. The treatment of hyperthyroidism in breastfeeding patients is the same as non-breastfeeding females. The lowest effective dose should be used; maternal doses of methimazole ≤20 mg/day are advised in breastfeeding patients. Infants exposed to antithyroid medications via breast milk should be monitored for adequate growth and development; routine tests of thyroid function are not recommended (ATA [Alexander 2017]). Taking the dose of methimazole after breastfeeding may help decrease potential infant exposure by providing a 3- to 4-hour interval before the next feed (Amino 2020).
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); LFTs (bilirubin, alkaline phosphatase, ALT, AST) at baseline and if symptoms of liver injury occur (Ross 2016).
Thyroid function tests:
Serum free T4 and total T3 at 4- to 6-week intervals during dose titration, 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); in patients with Graves disease, if thyrotropin receptor antibodies (TRAbs) are 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 (ATA [Ross 2016]).
Thyroid-stimulating hormone (TSH) periodically throughout treatment; TSH is not an adequate parameter to assess initial response as levels may remain suppressed for several months after starting therapy (ATA [Ross 2016]).
TRAb in patients with Graves disease prior to stopping medication; elevation at the end of therapy decreases likelihood of remission (ATA [Ross 2016]).
Pregnant patients: Free T4 and total T3 every 2 to 4 weeks until stabilized (ACOG 2020). Free T4, total T4, and TSH approximately every 4 weeks throughout pregnancy. TRAb once pregnancy is confirmed, at 18 to 22 weeks gestation, and 30 to 34 weeks gestation (ATA [Alexander 2017]).
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
Onset of action: Antithyroid: 12 to 18 hours (Clark 2006)
Duration: 36 to 72 hours (Clark 2006)
Absorption: Almost complete (Clark 2006)
Distribution: Concentrated in thyroid gland
Protein binding, plasma: None (Cooper 2005)
Metabolism: Hepatic
Bioavailability: ~93% (Clark 2006)
Half-life elimination: 4 to 6 hours (Clark 2006)
Time to peak, serum: 1 to 2 hours (Clark 2006)
Excretion: Urine
Tablets (methIMAzole Oral)
5 mg (per each): $0.44
10 mg (per each): $0.77
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