Dosage and AdministrationThe elimination half-life is prolonged in proportion to the degree of impairment. No dose adjustment is needed in patients with liver disease although clearance may be decreased.
| Indication | Initial Dose | Maintenance Dose | Maximum Dose | Clinical Comment | | Hyperthyroidism | 0.4 mg/kg/day given daily | 0.2 mg/kg/day given daily | Maximum
30 mg/24 h
| Consider dividing doses (i.e., Q8H) initially to minimize or prevent gastrointestinal adverse effects. |
| Indication | Initial Dose | Maintenance Dose | Duration of Therapy | Clinical Comment | | Mild hyperthyroidism | 15 mg daily | 5–15 mg daily | 12–18 months of treatment with methimazole is associated with a higher rate of remission compared to 6 months; no additional benefit seen in patients receiving 42 months of therapy. | A latent period of a few days to two weeks may be observed before thyroid hormone stores are depleted and for clinical effect to become evident.
Obtain baseline differential white cell count before initiation of therapy.
Consider dividing doses (i.e., Q8H) initially to minimize or prevent gastrointestinal adverse effects.
Consider dose increase if no improvement in TSH and T4 levels in 4–6 weeks.
Monitor thyroid indices monthly until euthyroid state is achieved. The goal is normalizing TSH and tapering the dose of methimazole to 5–15 mg/day. However, it is important to note that the recovery of TSH is slow so initial titration should target normalizing free T3 and free T4 levels. Monitor thyroid indices every 3 months during maintenance therapy.
Adjust dose as required to achieve and maintain serum free T3, free T4 and TSH.
Inadequate treatment is indicated by elevated free T3.
Excessive antithyroid treatment is indicated by elevated TSH.
| | Moderately severe hyperthyroidism | 30–40 mg daily | 5–15 mg daily | | Severe hyperthyroidism or large goitres | 60 mg daily | 5–15 mg daily |
No dose adjustment needed in renal impairment. Methimazole can be taken with or without food. Gastrointestinal side effects may be minimized if taken with food. Consider even spacing the dose throughout the day when given in multidose regimens.
Adverse Reactionscholestatic hepatitis (see Warnings and Precautions), immunoallergic hepatitis, jaundice, fulminant hepatitis (rare), hepatic necrosis, encephalopathy (rare). vomiting, loss of taste (rare), sialadenopathy (rare), neutropenic colitis with cecal perforation. agranulocytosis (see Warnings and Precautions), granulocytopenia, leukopenia, aplastic anemia, thrombocytopenia. lymphadenopathy (rare), anti-neutrophil cytoplasmic antibody (ANCA)-positive vasculitis (rare; discontinue methimazole), lupus-like syndrome. The most serious but rare adverse events include agranulocytosis and cholestatic jaundice. The toxic effects generally resolve upon discontinuation of drug therapy. The most commonly reported reactions include skin rash and gastrointestinal upset. Hypersensitivity reactions can also occur; some resolve with continued therapy, while others may require a short course of corticosteroids.
| Body System | Effect | Clinical Comment | | Musculoskeletal | Arthralgias, polyarthritis | May resolve within 4 weeks of stopping therapy.
Arthralgias may be a harbinger of severe transient migratory polyarthritis known as the “antithyroid arthritis syndrome” which may occur within 2 months of starting methimazole. | | Dermatologic | Skin rash | Incidence of 3–5%, usually a maculopapular eruption. May also be urticarial or macular.
If maculopapular pruritic rash, it may resolve with concomitant antihistamine and/or topical corticosteroid use. Consider switching to propylthiouracil.
If rash is urticarial or associated with fever or arthralgias, consider radioiodine therapy as cross-reactivity can be as high as 50%. | | Gastrointestinal | Dyspepsia, gastric distress, nausea | Of concern only if persists or becomes bothersome. Dose-dependent; consider dividing the dose. |
hypothyroidism (due to prolonged therapy), pancreatitis, hypoglycemia.
| Test | Effect | Clinical Comment | | WBC count | Leukopenia | Observed in 10% of patients with untreated hyperthyroidism.
Transient, not an indication to discontinue methimazole therapy. | | 123I,131I, 99mTc | ↓ uptake | Antithyroid drug should be stopped at least 5 days before the diagnostic test. | | ALT, AST, bilirubin, LDH, INR | ↑ concentration/time | May indicate an adverse event. | Legend WBC=white blood cell; ALT=alanine aminotransferase; AST=aspartate aminotransferase; LDH=lactate dehydrogenase; INR=international normalized ratio.
urticaria, pruritus, skin pigmentation.
Indications and Clinical UseMethimazole is used in children and adolescents to treat hyperthyroidism, usually in an attempt to delay ablative therapy. If immunologic remission does not occur, surgery or RAI therapy may be considered specifically in older children and adolescents. Maintenance high dose methimazole therapy to achieve euthyroidism may be predictive of no remission.
OverdosageFor management of a suspected drug overdose, CPhA recommends that you contact your regional Poison Control Centre. See the eCPS Directories section for a list of Poison Control Centres. Warnings and PrecautionsMethimazole readily crosses the placenta. Case reports of aplasia cutis congenita suggest a weak association with methimazole use during gestation. “Methimazole embryopathy,” which is characterized by choanal and esophageal atresia, scalp defects, minor facial anomalies and psychomotor delay, is also associated with methimazole use during the first trimester. It is not clear, however, whether the reported congenital abnormalities are associated with in utero exposure to methimazole or to maternal hyperthyroid state. Poorly controlled hyperthyroidism is associated with the following sequelae: spontaneous abortion, premature labor, low birth weight, stillbirth, preeclampsia and heart failure. Good fetal and maternal outcome is dependent on control of maternal hyperthyroidism. If methimazole is to be used in pregnancy, the lowest possible dose should be used to prevent fetal hypothyroidism or goiter. The risk of fetal hypothyroidism or goiter is negligible if the maternal free thyroxine level is maintained at slightly above the upper limit of normal. Methimazole may be discontinued in the last few weeks of pregnancy in some women with Graves' disease because thyroid function diminishes as pregnancy proceeds. Methimazole is excreted into breast milk. In a study that involved administration of 2.5 mg of methimazole Q12H, the mean milk: plasma ratio was 16 to 39 μg in the daily milk supply. This is equivalent to 3 mg/day of methimazole in breast milk when extrapolated to the usual daily dose of 20 mg. Methimazole 30 mg/day or less does not appear to pose a major risk to the nursing infant. Closely monitor thyroid function of the infant. Methimazole is considered compatible with breastfeeding by the American Academy of Pediatrics.
Storage and StabilityStore between 15 and 30°C in a closed, light-resistant container. Action and Clinical PharmacologyWidely distributed; actively concentrated in the thyroid gland. No significant protein binding is observed. Methimazole is readily absorbed from the gastrointestinal tract with an absolute bioavailability of 93%. The effect of food on absorption is unpredictable. Methimazole is actively transported into the thyroid gland. It inhibits the formation of thyroid hormones by blocking the incorporation of iodine into tyrosine residues of thyroglobulin. It also inhibits the coupling reaction of these residues to form iodothyronines. Methimazole is believed to interfere with the oxidation of iodide ion and iodotyrosyl groups via inhibition of the peroxidase enzyme. Methimazole does not inactivate stored or circulating T3 and T4 hormones, nor the exogenous thyroxine administered as part of therapy. Unlike propylthiouracil, methimazole does not inhibit the peripheral conversion of T4 to T3. The metabolites and about 11% of unchanged drug are excreted in the urine.
| Cmax | Duration of Action | Elimination t½ | Clearance | Volume of Distribution | | 0.5–1 h | 6–8 h | ~ 4–6 h | 10 L/h | 0.6 L/kg |
Rapidly metabolized in the liver by the flavin-containing monooxygenase to sulfenic and sulfinic acids, the latter is converted to N-methylimidazole and sulfite anion upon the reaction with water. Cytochrome P450 metabolism also produces N-methylimidazole. No active metabolites have been found. FMO-mediated metabolism seems to suppress cytochrome P450-catalyzed N-hydroxylation, as well as the content of cytochrome P450 itself.
ContraindicationsPatients who are hypersensitive to methimazole or to any ingredient in the formulation or component of the container.
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