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  • CLASSES

    Anti-thyroid Preparations

    DEA CLASS

    Rx

    DESCRIPTION

    Oral thioimidazole antithyroid agent used for various hyperthyroid conditions including Graves disease; ammenable to once-daily dosing; may exhibit a lower risk of hepatotoxicity or agranulocytosis as compared to PTU.

    COMMON BRAND NAMES

    Northyx, Tapazole

    HOW SUPPLIED

    Methimazole/Northyx/Tapazole Oral Tab: 5mg, 10mg

    DOSAGE & INDICATIONS

    For the treatment of hyperthyroidism, including hyperthyroidism due to Graves' disease.
    NOTE: Ablative therapy with radioiodine or surgery is typically preferred for toxic nodular goiters or a single autonomically functioning nodule since these conditions do not undergo a spontaneous remission.
    NOTE: Antithyroid drugs are not helpful for the treatment of hyperthyroidism associated with subacute or lymphocytic thyroiditis, since these condition are due to the release, not the overproduction, of thyroid hormones.
    NOTE: In general, the initial methimazole dose is continued for 2 months after full control of symptoms is achieved, then reduced to the maintenance dose. Dosages greater than 40 mg/day may increase the risk for agranulocytosis.
    For initial treatment of mild hyperthyroidism.
    Oral dosage
    Adults

    Initially, 15 mg/day PO given in 1—3 divided doses. Doses are usually given in 3 equally divided doses at 8-hour intervals.

    For initial treatment of moderately severe hyperthyroidism.
    Oral dosage
    Adults

    Initially, 30—40 mg/day PO given in 1—3 divided doses. Doses are usually given in 3 equally divided doses at 8-hour intervals.

    For initial treatment of severe hyperthyroidism.
    Oral dosage
    Adults

    Initially, 60 mg/day PO given in 1—3 divided doses. Doses are usually given in 3 equally divided doses at 8-hour intervals.

    For initial treatment of hyperthyroidism in children.
    Oral dosage
    Children

    Initially, 0.4 mg/kg/day (range: 0.5—0.7 mg/kg/day) PO given in 1—3 divided doses. Doses are usually given in 3 equally divided doses at 8-hour intervals.

    For maintenance therapy of hyperthyroidism.
    Oral dosage
    Adults

    5—30 mg/day PO in 1—3 divided doses. Doses are usually given in 3 equally divided doses at 8-hour intervals.

    Children

    0.2 mg/kg/day PO in 1—3 divided doses. Doses are usually given in 3 equally divided doses at 8-hour intervals. Maximum recommended dose is 30 mg/day.

    For the treatment of thyrotoxicosis.
    Oral dosage
    Adults

    15—20 mg PO every 4 hours during the first day as an adjunct to other measures. Adjust subsequent doses based on patient response.

    Children and Infants

    Initially 0.5 mg/kg/day (range: 0.5—1 mg/kg/day) PO given in 3 equally divided doses at 8-hour intervals. Adjust subsequent doses and duration of treatment based on patient response.

    MAXIMUM DOSAGE

    Methimazole has a narrow therapeutic window; individualize dosage. General maximum doses for routine treatment of hyperthyroidism are listed.

    Adults

    40 mg/day PO; 60 mg/day in severe disease.

    Elderly

    40 mg/day PO; 60 mg/day in severe disease.

    Adolescents

    With complete growth and puberty: 40 mg/day PO; 60 mg/day in severe disease.

    Children

    30 mg/day PO.

    Infants

    0.7 mg/kg/day PO.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No specific recommendations for dosage adjustments are available. Discontinue if clinically important evidence of hepatic dysfunction (e.g., LFT elevation) occurs during use.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration

    Administer orally at the same time(s) each day in relation to meals.

    STORAGE

    Northyx:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Tapazole:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Antithyroid agents should be discontinued at least 3—4 days prior to treatment with radioiodine (sodium iodide, I-131). Typically, antithyroid agents are not reintroduced until 1 week after the radioiodine treatment.

    Agranulocytosis, bone marrow suppression, fever, geriatric

    Methimazole is contraindicated in patients with a history of hypersensitivity to the drug, including a history of serious skin eruption, drug-induced liver disease, or drug-induced agranulocytosis. Cross-hypersensitivity occurs in roughly 50% of patients who have previously exhibited a major hypersensitivity to an antithyroid thioamide medication (like propylthiouracil). Agranulocytosis is the most serious adverse reaction of methimazole, and is most likely immune-mediated. Patients should report symptoms of sore throat, fever, and general malaise promptly to their prescriber during the use of this drug. Should agranulocytosis occur during treatment, the drug should be discontinued and not re-introduced. Methimazole should be used cautiously in other patients with bone marrow suppression. Leukopenia occurs in 10% of untreated hyperthyroid patients and is not a contraindication for use of methimazole, however, CBCs and differentials should be monitored closely. Use with caution in geriatric adults and adults >= 40 years of age. Doses of greater than 40 mg/day should generally be avoided, if possible, due to the increased risk of agranulocytosis. Use methimazole with extreme caution in combination with other drugs known to cause agranulocytosis.

    Pregnancy

    Methimazole is classified as FDA pregnancy risk category D; use during pregnancy should generally be avoided due to the possibility of inducing fetal goiter, hypothyroidism, or fetal death. Females of childbearing potential should inform their prescriber if they desire to become pregnant or think they may be pregnant, in order to have close monitoring of their thyroid condition and fetal health. Rare instances of congenital defects such as aplasia cutis, as manifested by scalp defects; esophageal atresia with tracheoesophageal fistula; and choanal atresia with absent/hypoplastic nipples, have occurred in infants born to mothers who received methimazole during pregnancy. Since the above congenital defects have been reported with the maternal use of methimazole, it may be appropriate to use other agents in pregnant women requiring treatment for hyperthyroidism. Propylthiouracil (PTU) is usually the preferred agent during organogenesis, in the first trimester; it less readily crosses the placenta (see Propylthiouracil, PTU  monograph). However, because PTU has been associated with hepatotoxicity, it may be preferable to switch from PTU to methimazole after the first trimester. Because thyroid dysfunction may improve as pregnancy proceeds in some patients, it may be possible to discontinue the antithyroid agent 2 to 3 months prior to delivery after careful clinical evaluation of thyroid function. Hyperthyroidism may recur following delivery.

    Breast-feeding

    According to the manufacturer, methimazole is contraindicated during breast-feeding because it has been shown to be excreted in breast milk. However, the American Academy of Pediatrics (AAP) considers methimazole to be generally compatible with breast-feeding. Propylthiouracil (PTU) has traditionally been recommended as the preferred antithyroid agent for use during breast-feeding due to low passage to breast milk, but due to concerns of hepatotoxicity some prescribers may prefer methimazole over PTU in this population (see Propylthiouracil, PTU monograph). According to the American Thyroid Association guidelines, either drug is appropriate in lactating women with caution; however, moderate doses are recommended (PTU < 300 mg/d or methimazole 20—30 mg/d). The Association also recommends that the infant's thyroid function be monitored regularly and that the mothers take their thyroid medication in divided doses, with doses taken immediately following a feeding.

    Hepatic disease, jaundice

    Use methimazole with caution in patients with pre-existing hepatic disease; the elimination half-life of methimazole can be prolonged in such patients. In addition, methimazole may contribute to hepatic complications such as cholestatic jaundice or rarely, hepatotoxicity. This drug should be discontinued if clinically important evidence of hepatic dysfunction (e.g., abdominal pain, anorexia, pruritus, or LFT elevation) develops.

    ADVERSE REACTIONS

    Severe

    pancytopenia / Delayed / 0-1.0
    agranulocytosis / Delayed / 0-1.0
    aplastic anemia / Delayed / 0-1.0
    hepatic necrosis / Delayed / 0-1.0
    hepatic encephalopathy / Delayed / 0-1.0
    exfoliative dermatitis / Delayed / Incidence not known
    periarteritis / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    nephrotic syndrome / Delayed / Incidence not known
    teratogenesis / Delayed / Incidence not known

    Moderate

    leukopenia / Delayed / 0-25.0
    neutropenia / Delayed / 0-10.0
    thrombocytopenia / Delayed / 0-1.0
    peripheral neuropathy / Delayed / 0-1.0
    hepatitis / Delayed / 0-1.0
    jaundice / Delayed / 0-1.0
    bleeding / Early / Incidence not known
    hypoprothrombinemia / Delayed / Incidence not known
    hypothyroidism / Delayed / Incidence not known
    lymphadenopathy / Delayed / Incidence not known
    edema / Delayed / Incidence not known
    hypoglycemia / Early / Incidence not known
    sialadenitis / Delayed / Incidence not known
    neuritis / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known

    Mild

    nausea / Early / 1.0-10.0
    pruritus / Rapid / 3.0-5.0
    rash (unspecified) / Early / 3.0-5.0
    alopecia / Delayed / 3.0-5.0
    skin hyperpigmentation / Delayed / 3.0-5.0
    urticaria / Rapid / 3.0-5.0
    dysgeusia / Early / 0-1.0
    fever / Early / Incidence not known
    arthralgia / Delayed / Incidence not known
    myalgia / Early / Incidence not known
    headache / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    vertigo / Early / Incidence not known
    drowsiness / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    vomiting / Early / Incidence not known

    DRUG INTERACTIONS

    Acebutolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Amiodarone: (Moderate) In hyperthyroid patients, the combination of amiodarone and methimazole has been associated with a greater decrease in serum triiodothyronine and thyroxine levels, as compared to the administration of methimazole alone. This may be due to increased iodide release associated with amiodarone. Monitor serum T3 and T4 levels in patients receiving combination therapy.
    Atenolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Atenolol; Chlorthalidone: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Bendroflumethiazide; Nadolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Beta-blockers: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Betaxolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Bisoprolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Brimonidine; Timolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Carteolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Carvedilol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Deferiprone: (Major) Avoid concomitant use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis, such as methimazole; however, if this is not possible, closely monitor the absolute neutrophil count and interrupt deferiprone therapy if neutropenia develops.
    Digoxin: (Minor) Serum concentrations of digoxin can increase as hyperthyroidism is corrected. In patients receiving antithyroid therapy, the dosage of digoxin may need to be reduced as the patient becomes euthyroid.
    Dorzolamide; Timolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Esmolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Hydrochlorothiazide, HCTZ; Propranolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Iodine; Potassium Iodide, KI: (Moderate) Potassium iodide should not be used concurrently with other antithyroid agents. Agents such as methimazole and propylthiouracil, PTU can increase the likelihood of hypothyroidism when used in combination with potassium iodide.
    Iodoquinol: (Moderate) Iodoquinol should be used with caution in patients treated with thyroid agents. Iodine-containing compounds like iodoquinol may result in overt thyroid disease.
    Labetalol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Levobetaxolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Levobunolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Metoprolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Nadolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Nebivolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Nebivolol; Valsartan: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Penbutolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Pindolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Potassium Iodide, KI: (Moderate) Potassium iodide should not be used concurrently with other antithyroid agents. Agents such as methimazole and propylthiouracil, PTU can increase the likelihood of hypothyroidism when used in combination with potassium iodide.
    Propranolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Sodium Iodide: (Severe) The recent intake of antithyroid agents will affect the uptake of radioiodide from sodium iodide, I-131; patients must discontinue all medications and supplements that may interfere with iodide uptake into thyroid tissue prior to therapy with sodium iodide I-131. Various protocols are used. Many manufacturers state that concurrent antithyroid agents should be discontinued at least 3 to 4 days before administration of radioiodide. The following withdrawal timing recommendations were set forth in a procedure guideline published by the Society of Nuclear Medicine in February 2002. Antithyroid agents may affect iodide protein binding for an average of 5 days after administration; allow a 3 day wash out period for the antithyroid agent (e.g., PTU, methimazole) prior to sodium iodide I-131 administration. The antithyroid agent may be resumed 2 to 3 days after treatment. When patients are taking sodium iodide (non-radioiodide) for supplementation in TPN, the effect of the iodide on antithyroid therapy should be considered.
    Sotalol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Theophylline, Aminophylline: (Minor) Patients with hyperthyroidism may exhibit accelerated clearance of theophylline. Correction of hyperthyroidism can lead to a decrease in theophylline clearance. Theophylline serum concentrations should be monitored closely during the initial stages of treatment for hyperthyroidism.
    Thyroid hormones: (Major) Antithyroid agents should generally not be administered with the thyroid hormones due to their opposing effects. However, in selected cases some clinicians coadminister T4 (e.g., levothyroxine) to circumvent drug-induced hypothyroidism when large suppressive doses of antithyroid agents are administered for long periods of time. However, clinical and biochemical euthyroid status may usually be maintained with careful titration of the antithyroid agent dosage alone.
    Timolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Warfarin: (Moderate) The interaction between thioamine antithyroid agents and warfarin is variable. The effects of warfarin can be enhanced due to the vitamin K antagonistic properties of methimazole or propylthiouracil, PTU. Isolated cases have reported hypoprothrombinemia due to methimazole or propylthiouracil, which may be additive with warfarin. In addition, as hyperthyroidism is corrected, the anticoagulant effect of warfarin can diminish due to a change in the clearance rate of endogenous clotting factors. Thus, administration of antithyroid agents such as methimazole or PTU can also reduce the effectiveness of warfarin. INRs should be monitored closely whenever methimazole is added or discontinued during warfarin therapy or when the thyroid status of a patient is expected to change. Warfarin dosage should be adjusted accordingly based on the INR and the clinical goals for the patient.

    PREGNANCY AND LACTATION

    Pregnancy

    Methimazole is classified as FDA pregnancy risk category D; use during pregnancy should generally be avoided due to the possibility of inducing fetal goiter, hypothyroidism, or fetal death. Females of childbearing potential should inform their prescriber if they desire to become pregnant or think they may be pregnant, in order to have close monitoring of their thyroid condition and fetal health. Rare instances of congenital defects such as aplasia cutis, as manifested by scalp defects; esophageal atresia with tracheoesophageal fistula; and choanal atresia with absent/hypoplastic nipples, have occurred in infants born to mothers who received methimazole during pregnancy. Since the above congenital defects have been reported with the maternal use of methimazole, it may be appropriate to use other agents in pregnant women requiring treatment for hyperthyroidism. Propylthiouracil (PTU) is usually the preferred agent during organogenesis, in the first trimester; it less readily crosses the placenta (see Propylthiouracil, PTU  monograph). However, because PTU has been associated with hepatotoxicity, it may be preferable to switch from PTU to methimazole after the first trimester. Because thyroid dysfunction may improve as pregnancy proceeds in some patients, it may be possible to discontinue the antithyroid agent 2 to 3 months prior to delivery after careful clinical evaluation of thyroid function. Hyperthyroidism may recur following delivery.

    According to the manufacturer, methimazole is contraindicated during breast-feeding because it has been shown to be excreted in breast milk. However, the American Academy of Pediatrics (AAP) considers methimazole to be generally compatible with breast-feeding. Propylthiouracil (PTU) has traditionally been recommended as the preferred antithyroid agent for use during breast-feeding due to low passage to breast milk, but due to concerns of hepatotoxicity some prescribers may prefer methimazole over PTU in this population (see Propylthiouracil, PTU monograph). According to the American Thyroid Association guidelines, either drug is appropriate in lactating women with caution; however, moderate doses are recommended (PTU < 300 mg/d or methimazole 20—30 mg/d). The Association also recommends that the infant's thyroid function be monitored regularly and that the mothers take their thyroid medication in divided doses, with doses taken immediately following a feeding.

    MECHANISM OF ACTION

    Mechanism of Action: Methimazole directly interferes with the first step in thyroid hormone biosynthesis in the thyroid gland. By acting as a substrate for the catalyst thyroid peroxidase, methimazole inhibits the incorporation of iodide into the thyroid hormone precursor, thyroglobulin. Consequently, the drug is iodinated and degraded within the thyroid gland. Oxidized iodine is diverted away from thyroglobulin, which effectively diminishes the biosynthesis of thyroid hormone. An additional mechanism is the inhibition of iodotyrosyl residues coupling to form thyroglobulin. Methimazole may interfere with the oxidation of the iodide ion and iodotyrosyl groups. Eventually, thyroglobulin is depleted and circulating thyroid hormone levels diminish. Methimazole does not alter the action of existing thyroxine (T4) and triiodothyronine (T3) in the circulation or stored in the thyroid gland. Similarly, no alterations in the effectiveness of exogenously administered thyroid hormones have been observed.

    PHARMACOKINETICS

    Methimazole is administered orally. Once absorbed, methimazole is actively concentrated by the thyroid gland. Protein binding is insignificant, as a result, methimazole is excreted more readily into breast milk than other drugs in its class. The drug also readily crosses the placenta.
     
    Methimazole undergoes hepatic metabolism with no active metabolites. Renal excretion is < 10%. The elimination half-life is approximately 5—9 hours. However, the intrathyroidal residence of methimazole is roughly 20 hours, and the duration of action 40 hours, which allows once-daily dosing some patients. The plasma elimination half-life of methimazole is not appreciably altered by the patient's thyroid status.

    Oral Route

    Methimazole is rapidly absorbed from the gastrointestinal tract, reaching peak serum concentrations within 1—2 hours after administration. However, it usually takes 2—4 months of treatment to achieve initial euthyroid status; response rates are dependent on several pharmacodynamic and patient variables.