Methimazole

114.17

114.17

108646

200-482-4

554Z48XN5E

757111|38608

DTXSID4020820

C641

LEAFLETS FROM ALCOHOL|WHITE TO PALE BUFF, CRYSTALLINE SUBSTANCE; STARCH-LIKE IN APPEARANCE & TO TOUCH

H03BB02|H - Systemic hormonal preparations, excl. sex hormones and insulins

29332990

47.4

-0.3

White to slightly cream or pale buff Crystalline Powder

1.35 g/cm³

146-148 °C

280 °C

280°C

1.633

H2O: soluble

Refrigerator

FAINT, CHARACTERISTIC

SOLN ARE PRACTICALLY NEUTRAL TO LITMUS

117.2 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]|117.1 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

NONH for all modes of transport

3

43-62-63-22

26-27-36-45-36/37

NI8615000

Xn

SENSITIVE TO LIGHT

P280

H317-H361

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

|Warning|H302 (17.86%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P261, P264, P270, P272, P280, P281, P301+P312, P302+P352, P308+P313, P321, P330, P333+P313, P363, P405, and P501|Aggregated GHS information provided by 57 companies from 10 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Rashes may follow high doses of methimazole (120 mg daily). Both major (agranulocytosis, hepatotoxicity) and minor (arthralgias, skin rash, gastric intolerance) adverse effects are not dose related.

The oral LD50 of methimazole in rats is 2250 mg/kg. Signs and symptoms of methimazole overdose may include gastrointestinal distress, headache, fever, joint pain, pruritus, and edema. More serious adverse effects, such as aplastic anemia or agranulocytosis, may manifest within hours to days. Hepatitis, nephrotic syndrome, exfoliative dermatitis, and CNS effects such as neuropathy or CNS depression/stimulation are also potential, albeit less frequent, results of overdose. Management of overdose involves supportive treatment as dictated by the patient's status. This may involve monitoring of the patient's vital signs, blood gases, serum electrolytes, or bone marrow function as indicated.

Methimazole has been associated with transient, asymptomatic elevations in serum aminotransferase levels, typically during the first 3 months after starting during high dose, induction therapy. These elevations are rarely clinically significant and usually resolve even with continuation of therapy. Methimazole is also capable of causing clinically apparent, idiosyncratic liver injury. The onset of hepatotoxicity is usually within 2 to 12 weeks of starting and the pattern of enzyme elevations is typically cholestatic or mixed, although hepatocellular patterns have also been described. The cholestatic hepatitis caused by methimazole can be prolonged, but fatalities are rare and symptoms and jaundice usually clear within 2 to 8 weeks of stopping therapy. Rare instances of prolonged cholestasis have been described, but no instance of vanishing bile duct syndrome.

...BILIARY EXCRETION WAS INCREASED BY PENTOBARBITAL. ADMIN OF BOTH PROPYLTHIOURACIL & METHIMAZOLE CAUSES INCR SERUM TRI-IODOTHYRONINE (T3):THYROXINE 1(T4) RATIO IN PT, OWING EITHER TO DIRECT ACTION ON THYROID GLAND OR TO INCR PERIPHERAL DEIODINATION OF T4 TO T3.|Hyperthyroid patients have exhibited increased metabolic clearance of aminophylline and theophyline, which returned to normal as the patients became euthyroid; decreased dose of aminophylline, oxtriphylline, or theophylline may be necessary as patients become euthyroid. /Antithyroid agents/|Iodide or iodine excess may decrease response to antithyroid agents, requiring an increase in dosage or longer duration of therapy with antithyroid agents; amiodarone contains 37% iodine by weight, and therefore its use significantly increases iodine intake; iodine deficiency may increase response to antithyroid agents requiring a decrease in dosage or shorter duration of therapy with antithyroid agents. /Antithyroid agents/|As thyroid and metabolic status of patient decreases toward normal, response to oral anticoagulants may decrease; however, if thioamide-induced hypoprothrombinemia occurs, anticoagulant effect may be enhanced; adjustment of oral anticoagulant dosage on the basis of prothrombin time is recommended. /Antithyroid agents/|For more Interactions (Complete) data for METHIMAZOLE (6 total), please visit the HSDB record page.

LD50 Rat oral 2250 mg/kg|LD50 Rat sc 1050 mg/kg|LD50 Mouse oral 860 mg/kg|LD50 Mouse ip 500 mg/kg|LD50 Mouse sc 345 mg/kg

Methimazole exhibits little-to-no protein binding, existing primarily as free drug in the serum.

Methimazole ... is distributed into milk in concentrations approximately equal to those in maternal serum.

In the United States, methimazole is indicated for the treatment of hyperthyroidism in patients with Graves' disease or toxic multinodular goiter for whom thyroidectomy or radioactive iodine therapy are not appropriate treatment options. Methimazole is also indicated for the amelioration of hyperthyroid symptoms in preparation for thyroidectomy or radioactive iodine therapy. In Canada, methimazole carries the above indications and is also indicated for the medical treatment of hyperthyroidism regardless of other available treatment options.

Methimazole is an antithyroid medication which is now considered the first line agent for medical therapy of hyperthyroidism and Graves disease. Methimazole has been linked to serum aminotransferase elevations during therapy as well as to a clinically apparent, idiosyncratic liver injury that is typically cholestatic and self-limited in course.

Antithyroid Agents

Antithyroid Agents|METHIMAZOLE IS APPROX 10 TIMES AS POTENT AS PROPYLTHIOURACIL & IS MORE PROMPT IN ELICITING ANTITHYROID RESPONSE. DRUG ALSO EXHIBITS MORE PROLONGED ACTION THAN PROPYLTHIOURACIL...|...USED IN TREATMENT OF HYPERTHYROIDISM...(1) AS DEFINITIVE TREATMENT, TO CONTROL DISORDER IN ANTICIPATION OF SPONTANEOUS REMISSION IN GRAVE'S DISEASE; (2) IN CONJUNCTION WITH RADIOIODINE, TO HASTEN RECOVERY WHILE AWAITING EFFECTS OF RADIATION; & (3) TO CONTROL DISORDER IN PREPN FOR SURGICAL TREATMENT. /ANTITHYROID DRUGS/|THERE ARE NO COMMERCIAL PREPN AVAIL FOR PARENTERAL USE IN RARE EVENT THAT TREATMENT CANNOT BE GIVEN BY MOUTH. FOR THIS EVENTUALITY & FOR EXPTL PURPOSES, FREELY WATER-SOL COMPD, METHIMAZOLE, CAN BE DISSOLVED IN SALINE SOLN & STERILIZED BY HEAT.|Methimazole /is/ indicated in the treatment of hyperthyroidism, including prior to surgery or radiotherapy, and as adjunct in the treatment of thyrotoxicosis or thyroid storm. Propylthiouracil may be preferred over methimazole for use in thyroid storm, since propylthiouracil inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3). /Included in US product labeling/

...WOMEN TAKING THESE AGENTS SHOULD NOT BREAST-FEED THEIR INFANTS. /ANTITHYROID DRUGS/|BECAUSE AGRANULOCYTOSIS CAN DEVELOP RAPIDLY, PERIODIC WHITE-CELL COUNTS ARE OF LITTLE HELP. PATIENTS SHOULD IMMEDIATELY REPORT DEVELOPMENT OF SORE THROAT OR FEVER, WHICH USUALLY HERALDS ONSET OF THIS REACTION.|MAIN DRAWBACK TO THERAPY WITH ANTITHYROID DRUGS IS HIGH INCIDENCE OF RELAPSE WHEN TREATMENT IS STOPPED. ... FREQUENT TAKING OF MEDICATION FOR LONG PERIODS OF TIME IS ANOTHER DISADVANTAGE &, ALTHOUGH UNTOWARD REACTIONS...ARE NOT FREQUENT & RARELY SERIOUS, THEY CONSTITUTE FURTHER DISADVANTAGE.|CROSS SENSITIVITY TO OTHER THIOAMIDE DERIVATIVES MAY OCCUR IN SUSCEPTIBLE PT.|For more Drug Warnings (Complete) data for METHIMAZOLE (13 total), please visit the HSDB record page.

Methimazole inhibits the synthesis of thyroid hormones resulting in an alleviation of hyperthyroidism. Onset of action occurs within 12 to 18 hours, and its duration of action is 36 to 72 hours, likely due to concentration of methimazole and some metabolites within the thyroid gland after administration. The most serious potential side effect of methimazole therapy is agranulocytosis, and patients should be instructed to monitor for, and report, any signs or symptoms of agranulocytosis such as fever or sore throat. Other cytopenias may also occur during methimazole therapy. There also exists the potential for severe hepatic toxicity with the use of methimazole, and monitoring for signs and symptoms of hepatic dysfunction, such as jaundice, anorexia, pruritus, and elevation in liver transaminases, is prudent in patients using this therapy.

Agents that are used to treat hyperthyroidism by reducing the excessive production of thyroid hormones. (See all compounds classified as Antithyroid Agents.)

Absorption of methimazole after oral administration is rapid and extensive, with an absolute bioavailability of approximately 0.93 and a T_max ranging from 0.25 to 4.0 hours. C_max is slightly, but not significantly, higher in hyperthyroid patients, and both C_max and AUC are significantly affected by the oral dose administered.|Urinary excretion of unchanged methimazole has been reported to be between 7% and 12%. Elimination via feces appears to be limited, with a cumulative fecal excretion of 3% after administration of methimazole. Enterohepatic circulation also appears to play a role in the elimination of methimazole and its metabolites, as significant amounts of these substances are found in the bile post-administration.|The apparent volume of distribution of methimazole has been reported as roughly 20 L. Following oral administration, methimazole is highly concentrated in the thyroid gland - intrathyroidal methimazole levels are approximately 2 to 5 times higher than peak plasma levels, and remain high for 20 hours after ingestion.|Following a single intravenous bolus injection of 10mg of methimazole, clearance was found to be 5.70 L/h. Renal impairment does not appear to alter clearance of methimazole, but patients with hepatic impairment showed a reduction in clearance roughly proportional to the severity of their impairment - moderate insufficiency resulted in a clearance of 3.49 L/h, while severe insufficiency resulted in a clearance of 0.83 L/h. There does not appear to be any significant differences in clearance based on thyroid status (i.e. no difference between euthyroid and hyperthyroid patients).|FOUR DAYS AFTER IV ADMIN OF (14)C-METHIMAZOLE TO RATS, RETENTION OF (14)C WAS GREATEST IN THYROID & ADRENALS; 76% OF DOSE HAD BEEN EXCRETED IN URINE & 6% IN FECES.|(14)C-METHIMAZOLE RADIOACTIVITY CONCENTRATES MORE IN THE THYROID THAN IN ANY OTHER TISSUE, WITH THYROID:PLASMA RATIO REACHING 62.5 AFTER 4 DAYS' CONTINUOUS DOSING.|COMPLETE ABSORPTION...FROM ORAL DOSES...DEMONSTRATED IN RATS. ...IS NEGLIGIBLY BOUND TO PLASMA PROTEINS &...EXHIBITS SINGLE-COMPARTMENT KINETICS EVEN AFTER IV DOSES. ...ATTRIBUTED TO FASTER TISSUE PENETRATION BY METHIMAZOLE DUE TO ITS HIGHER LIPID:WATER PARTITION COEFFICIENT.|BILIARY EXCRETION OF RADIOACTIVITY FROM...(35)S-METHIMAZOLE...AMOUNTED TO ONLY 21%...OF IV DOSES. BILIARY RADIOACTIVITY WAS ALMOST ENTIRELY DUE TO METABOLITES...|For more Absorption, Distribution and Excretion (Complete) data for METHIMAZOLE (9 total), please visit the HSDB record page.

Methimazole is rapidly and extensively metabolized by the liver, mainly via the CYP450 and FMO enzyme systems. Several metabolites have been identified, though the specific enzyme isoforms responsible for their formation are not entirely clear. One of the first methimazole metabolites identified, 3-methyl-2-thiohydantoin, may contribute to antithyroid activity - its antithyroid activity has been demonstrated in rats and may explain the prolonged duration of iodination inhibition following administration despite methimazole's relatively short half-life. A number of metabolites have been investigated as being the culprits behind methimazole-induced hepatotoxicity. Both glyoxal and N-methylthiourea have established cytotoxicity and are known metabolic products of methimazole's dihydrodiol intermediate. Sulfenic and sulfinic acid derivatives of methimazole are thought to be the ultimate toxicants responsible for hepatotoxicity, though their origin is unclear - they may arise from direct oxidation of methimazole via FMO, or from oxidation of N-methylthiourea further downstream in the metabolic process.|ADMIN...TO SPRAGUE-DAWLEY RATS...UP TO 21% OF DOSE...EXCRETED UNCHANGED IN 24-HR URINE, IN WHICH MAJOR METABOLITE WAS...GLUCURONIDE (36-48%); REMAINING URINARY METABOLITE HAS NOT BEEN IDENTIFIED.|INCUBATION OF METHIMAZOLE WITH RAT HEPATIC MICROSOMES LED TO FORMATION OF 3-METHYL-2-THIOHYDANTOIN & N-METHYLIMIDAZOLE.

Following a single intravenous bolus injection of 10mg of methimazole, the t_1/2 of the distribution phase was 0.17 hours and the t_1/2 of the elimination phase was 5.3 hours. Methimazole's primary active metabolite, 3-methyl-2-thiohydantoin, has a half-life approximately 3 times longer than its parent drug. Renal impairment does not appear to alter the half-life of methimazole, but patients with hepatic impairment showed an increase in half-life roughly proportional to the severity of their impairment - moderate insufficiency resulted in a elimination t_1/2 of 7.1 hours, while severe insufficiency resulted in an elimination t_1/2 of 22.1 hours. There does not appear to be any significant differences in half-life based on thyroid status (i.e. no difference between euthyroid and hyperthyroid patients).|Plasma half-life is 3-5 hr|The elimination half-life of methimazole reportedly ranges from about 5-13 hours.|T/2...IN PLASMA...FOR METHIMAZOLE IS ABOUT 4-6 HR. ...

Methimazole's primary mechanism of action appears to be interference in an early step in thyroid hormone synthesis involving thyroid peroxidase (TPO), however the exact method through which methimazole inhibits this step is unclear. TPO, along with hydrogen peroxide, normally catalyzes the conversion of iodide to iodine and then further catalyzes the incorporation of this iodine onto the 3 and/or 5 positions of the phenol rings of tyrosine residues in thyroglobulin. These thyroglobulin molecules then degrade within thyroid follicular cells to form either thyroxine (T₄) or tri-iodothyronine (T₃), which are the main hormones produced by the thyroid gland. Methimazole may directly inhibit TPO, but has been shown in vivo to instead act as a competitive substrate for TPO, thus becoming iodinated itself and interfering with the iodination of thyroglobulin. Another proposed theory is that methimazole’s sulfur moiety may interact directly with the iron atom at the centre of TPO’s heme molecule, thus inhibiting its ability to iodinate tyrosine residues. Other proposed mechanisms with weaker evidence include methimazole binding directly to thyroglobulin or direct inhibition of thyroglobulin itself.|ANTITHYROID DRUGS INHIBIT FORMATION OF THYROID HORMONE LARGELY BY INTERFERING WITH INCORPORATION OF IODINE INTO ORGANIC FORM. ...IMPLIES THAT THEY INTERFERE WITH OXIDATION OF IODIDE ION.../WHICH/ IS PROBABLY BROUGHT ABOUT BY PEROXIDASE. /ANTITHYROID DRUGS/|ANTITHYROID DRUGS INHIBIT THE FORMATION OF THYROID HORMONES BY ITERFERING WITH THE INCORPORATION OF IODINE INTO TYROSYL RESIDUES OF THYROGLOBULIN; THEY ALSO INHIBIT THE COUPLING OF THESE IODOTYROSYL RESIDUES TO FORM IODOTHYRONINES.|Methimazole inhibits the synthesis of thyroid hormones by interfering with the incorporation of iodine into tyrosyl residues of thyroglobulin; the drug also inhibits the coupling of these iodotyrosyl residues to form iodothyronine. Although the exact mechanism(s) has not been fully elucidated, methimazole may interfere with the oxidation of iodide ion and iodotyrosyl groups. Based on limited evidence, it appears that the coupling reaction is more sensitive to antithyroid agents than the iodination reaction. Methimazole does not inhibit the action of thyroid hormones already formed and present in the thyroid gland or circulation nor does the drug interfere with the effectiveness of exogenously administered thyroid hormones.

...AUTOIMMUNE PHENOMENA MAY OCCUR. ARTHRALGIAS, VASCULITIS, & "LUPUS-LIKE" SYNDROMES...MAY OR MAY NOT BE DOSE-DEPENDENT. HEPATITIS IS MORE COMMON WITH METHIMAZOLE, & MAY BE PROLONGED. ... HAS BEEN ASSOC WITH DEVELOPMENT OF SCALP LESIONS, INCLUDING APLASIA CUTIS, IN OFFSPRING OF MOTHERS TREATED IN PREGNANCY.|MATERNAL ANTI-THYROID MEDICATION WITH...METHIMAZOLE HAS RESULTED FREQUENTLY IN DEVELOPMENT OF FETAL GOITER, & OCCASIONALLY IN HYPOTHYROIDISM IN NEONATE LEADING TO MENTAL RETARDATION. ... JUST OCCASIONALLY, GOITER IN AFFECTED INFANTS MAY OBSTRUCT AIR PASSAGE, & CAUSE RESPIRATORY DISTRESS.|METHIMAZOLE STRONGLY INHIBITED THYROID PEROXIDASE. PROPYLTHIOURACIL HAD LESS PRONOUNCED EFFECT, & CARBIMAZOLE WAS ALMOST & PROPRANOLOL WAS ENTIRELY INACTIVE AT EQUIMOLAR CONCN (0.1, 0.33, & 1.0 MMOLAR) IN IN VITRO THYROID TISSUE SPECIMENS FROM EUTHYROID PATIENTS.|Nine cases of scalp defects (aplasia cutis) in newborns exposed in utero to methimazole or carbimazole (converted in vivo to methimazole) have been reported. In two of the nine infants, umbilical defects (patent urachus in one; patent vitelline duct in another) were also observed, suggesting ... because of the rarity of these defects, that the combination of anomalies represented a possible malformation syndrome.|For more Human Toxicity Excerpts (Complete) data for METHIMAZOLE (6 total), please visit the HSDB record page.

1 Methyl 2 mercaptoimidazole

...METHIMAZOLE, USP (1-METHYL-2-MERCAPTOIMIDAZOLE; TAPAZOLE), MARKETED IN 5- & 10-MG TABLETS.

2H-Imidazole-2-thione, 1,3-dihydro-1-methyl-: ACTIVE

A NMR SPECTROMETRIC ANALYSIS OF METHIMAZOLE IN PURE STATE & IN TABLETS IS DESCRIBED.|COLUMN CHROMATOGRAPHY; SPECTROPHOTOMETRY.|AOAC Method 967.32. Methimazole in Drugs. Infrared Spectrophotometric Method.

MEASUREMENT OF METHIMAZOLE IN HUMAN PLASMA USING GAS-LIQUID CHROMATOGRAPHY. LIMIT OF DETECTION WAS 30 NG/ML OF PLASMA.|DETERMINATION OF METHIMAZOLE IN PLASMA BY HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY. SENSITIVITY OF METHOD ALLOWED DETECTION OF A CONCN AS LOW AS 5 NG/ML OF PLASMA. NO INTERFERENCE WITH OTHER BIOLOGICAL PRODUCTS WAS DETECTED.|DETERMINATION OF METHIMAZOLE IN PLASMA USING GAS CHROMATOGRAPHY-MASS SPECTROMETRY AFTER EXTRACTIVE ALKYLATION. PRECISION OF METHOD AT LEVEL OF 5 NG METHIMAZOLE/ML OF PLASMA WAS 6%.

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