GENERAL PRECAUTIONS SECTION.

General. Patients who receive methimazole should be under close surveillance and should be cautioned to report immediately any evidence of illness, particularly sore throat, skin eruptions, fever, headache, or general malaise. In such cases, white-blood-cell and differential counts should be obtained to determine whether agranulocytosis has developed. Particular care should be exercised with patients who are receiving additional drugs known to cause agranulocytosis.

HOW SUPPLIED SECTION.

HOW SUPPLIED. Methimazole Tablets, USP mg white to off-white, round, flat-faced, bevelled-edged tablets, scored with EM/5 on one side and plain on the other. They are available in: Unit dose packages of 100 (10 10) NDC 60687-357-01 Methimazole Tablets, USP 10 mg white to off-white, round, flat-faced, bevelled-edged tablets, scored with EM/10 on one side and plain on the other. They are available in: Unit dose packages of 100 (10 10) NDC 60687-370-01 Store at controlled room temperature 15 to 30C (59 to 86F).FOR YOUR PROTECTION: Do not use if blister is torn or broken.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. Methimazole tablets are administered orally. The total daily dosage is usually given in divided doses at approximately 8-hour intervals.. Adults. The initial daily dosage is 15 mg for mild hyperthyroidism, 30 to 40 mg for moderately severe hyperthyroidism, and 60 mg for severe hyperthyroidism, divided into doses at 8-hour intervals. The maintenance dosage is to 15 mg daily.. Pediatric. Initially, the daily dosage is 0.4 mg/kg of body weight divided into doses and given at 8-hour intervals. The maintenance dosage is approximately 1/2 of the initial dose.

DRUG INTERACTIONS SECTION.

Drug Interactions. Anticoagulants (oral). Due to potential inhibition of vitamin activity by methimazole, the activity of oral anticoagulants (e.g., warfarin) may be increased; additional monitoring of PT/INR should be considered, especially before surgical procedures.. ss-adrenergic blocking agents. Hyperthyroidism may cause an increased clearance of beta blockers with high extraction ratio. dose reduction of beta-adrenergic blockers may be needed when hyperthyroid patient becomes euthyroid.. Digitalis glycosides. Serum digitalis levels may be increased when hyperthyroid patients on stable digitalis glycoside regimen become euthyroid; reduced dosage of digitalis glycosides may be needed.. Theophylline. Theophylline clearance may decrease when hyperthyroid patients on stable theophylline regimen become euthyroid; reduced dose of theophylline may be needed.

ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Major adverse reactions (which occur with much less frequency than the minor adverse reactions) include inhibition of myelopoiesis (agranulocytosis, granulocytopenia, thrombocytopenia, and aplastic anemia), drug fever, lupus-like syndrome, insulin autoimmune syndrome (which can result in hypoglycemic coma), hepatitis (jaundice may persist for several weeks after discontinuation of the drug), periarteritis, and hypoprothrombinemia. Nephritis occurs very rarely. There have been postmarketing case reports of acute pancreatitis.There are reports of vasculitis, often associated with the presence of anti-neutrophilic cytoplasmic antibodies (ANCA), resulting in severe complications (see WARNINGS). Minor adverse reactions include skin rash, urticaria, nausea, vomiting, epigastric distress, arthralgia, paresthesia, loss of taste, abnormal loss of hair, myalgia, headache, pruritus, drowsiness, neuritis, edema, vertigo, skin pigmentation, jaundice, sialadenopathy, and lymphadenopathy.To report SUSPECTED ADVERSE REACTIONS, contact Par Pharmaceutical at 1-866-828-9393 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis, Mutagenesis, Impairment of Fertility. In 2 year study, rats were given methimazole at doses of 0.5, 3, and 18 mg/kg/day. These doses were 0.3, 2, and 12 times the 15 mg/day maximum human maintenance dose (when calculated on the basis of surface area). Thyroid hyperplasia, adenoma, and carcinoma developed in rats at the two higher doses. The clinical significance of these findings is unclear.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Methimazole inhibits the synthesis of thyroid hormones and thus is effective in the treatment of hyperthyroidism. The drug does not inactivate existing thyroxine and triiodothyronine that are stored in the thyroid or circulating in the blood nor does it interfere with the effectiveness of thyroid hormones given by mouth or by injection.Methimazole is readily absorbed in the gastrointestinal tract, metabolized in the liver, and excreted in the urine.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. Methimazole tablets are contraindicated in the presence of hypersensitivity to the drug or any of the other product components.

DESCRIPTION SECTION.

DESCRIPTION. Methimazole (1-methylimidazole-2-thiol) is white, crystalline substance that is freely soluble in water. It differs chemically from the drugs of the thiouracil series primarily because it has 5- instead of 6-membered ring.Methimazole tablet, USP contains or 10 mg (43.8 or 87.6 umol) methimazole, an orally administered antithyroid drug.Each tablet also contains lactose monohydrate, magnesium stearate, corn starch, and talc.The molecular weight is 114.17, and the molecular formula is 4H 6N 2S. The structural formula is as follows: Structural Formula.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. Methimazole tablets are indicated:In patients with Graves disease with hyperthyroidism or toxic multinodular goiter for whom surgery or radioactive iodine therapy is not an appropriate treatment option. To ameliorate symptoms of hyperthyroidism in preparation for thyroidectomy or radioactive iodine therapy. In patients with Graves disease with hyperthyroidism or toxic multinodular goiter for whom surgery or radioactive iodine therapy is not an appropriate treatment option. To ameliorate symptoms of hyperthyroidism in preparation for thyroidectomy or radioactive iodine therapy.

INFORMATION FOR PATIENTS SECTION.

Information for Patients. Patients should be advised that if they become pregnant or intend to become pregnant while taking an antithyroid drug, they should contact their physician immediately about their therapy.Inform patients that cases of vasculitis resulting in severe complications have occurred with methimazole tablets. Inform patients to promptly report symptoms that may be associated with vasculitis including new rash, hematuria or decreased urine output, dyspnea or hemoptysis (see WARNINGS and ADVERSE REACTIONS).

LABORATORY TESTS SECTION.

Laboratory Tests. Because methimazole may cause hypoprothrombinemia and bleeding, prothrombin time should be monitored during therapy with the drug, especially before surgical procedures. Thyroid function tests should be monitored periodically during therapy. Once clinical evidence of hyperthyroidism has resolved, the finding of rising serum TSH indicates that lower maintenance dose of methimazole tablets should be employed.

NURSING MOTHERS SECTION.

Nursing Mothers. Methimazole is present in breast milk. However, several studies found no effect on clinical status in nursing infants of mothers taking methimazole. long-term study of 139 thyrotoxic lactating mothers and their infants failed to demonstrate toxicity in infants who are nursed by mothers receiving treatment with methimazole. Monitor thyroid function at frequent (weekly or biweekly) intervals.

OVERDOSAGE SECTION.

OVERDOSAGE. Signs and Symptoms. Symptoms may include nausea, vomiting, epigastric distress, headache, fever, joint pain, pruritus, and edema. Aplastic anemia (pancytopenia) or agranulocytosis may be manifested in hours to days. Less frequent events are hepatitis, nephrotic syndrome, exfoliative dermatitis, neuropathies, and CNS stimulation or depression. No information is available on the median lethal dose of the drug or the concentration of methimazole in biologic fluids associated with toxicity and/or death.. Treatment. To obtain up-to-date information about the treatment of overdose, good resource is your certified Regional Poison Control Center. In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in the patient.In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patients medical status.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Package/Label Display Panel Carton 5 mg. NDC 60687- 357-01 MethimazoleTablets, USP mg100 Tablets (10 10) Rx OnlyEach Tablet Contains: Methimazole ................................................................................ mg Usual Dosage: See package insert for full prescribing information. WARNING: This drug may cause toxic reactions. If such reactions occur, discontinue the drug. Constant supervision of patient is essential. Store at controlled room temperature 15 to 30C (59 to 86F). Keep this and all drugs out of reach of children.FOR YOUR PROTECTION: Do not use if blister is torn or broken. The drug product contained in this package is from NDC 49884-640, Par Pharmaceutical. Distributed by: American Health Packaging Columbus, Ohio 43217 735701 0435701/0619OS 5 mg Methimazole Tablets Carton.

PEDIATRIC USE SECTION.

Pediatric Use. Because of postmarketing reports of severe liver injury in pediatric patient treated with propylthiouracil, methimazole is the preferred choice when an antithyroid drug is required for pediatric patient. (see DOSAGE AND ADMINISTRATION).

PRECAUTIONS SECTION.

PRECAUTIONS. General. Patients who receive methimazole should be under close surveillance and should be cautioned to report immediately any evidence of illness, particularly sore throat, skin eruptions, fever, headache, or general malaise. In such cases, white-blood-cell and differential counts should be obtained to determine whether agranulocytosis has developed. Particular care should be exercised with patients who are receiving additional drugs known to cause agranulocytosis.. Information for Patients. Patients should be advised that if they become pregnant or intend to become pregnant while taking an antithyroid drug, they should contact their physician immediately about their therapy.Inform patients that cases of vasculitis resulting in severe complications have occurred with methimazole tablets. Inform patients to promptly report symptoms that may be associated with vasculitis including new rash, hematuria or decreased urine output, dyspnea or hemoptysis (see WARNINGS and ADVERSE REACTIONS). Laboratory Tests. Because methimazole may cause hypoprothrombinemia and bleeding, prothrombin time should be monitored during therapy with the drug, especially before surgical procedures. Thyroid function tests should be monitored periodically during therapy. Once clinical evidence of hyperthyroidism has resolved, the finding of rising serum TSH indicates that lower maintenance dose of methimazole tablets should be employed.. Drug Interactions. Anticoagulants (oral). Due to potential inhibition of vitamin activity by methimazole, the activity of oral anticoagulants (e.g., warfarin) may be increased; additional monitoring of PT/INR should be considered, especially before surgical procedures.. ss-adrenergic blocking agents. Hyperthyroidism may cause an increased clearance of beta blockers with high extraction ratio. dose reduction of beta-adrenergic blockers may be needed when hyperthyroid patient becomes euthyroid.. Digitalis glycosides. Serum digitalis levels may be increased when hyperthyroid patients on stable digitalis glycoside regimen become euthyroid; reduced dosage of digitalis glycosides may be needed.. Theophylline. Theophylline clearance may decrease when hyperthyroid patients on stable theophylline regimen become euthyroid; reduced dose of theophylline may be needed.. Carcinogenesis, Mutagenesis, Impairment of Fertility. In 2 year study, rats were given methimazole at doses of 0.5, 3, and 18 mg/kg/day. These doses were 0.3, 2, and 12 times the 15 mg/day maximum human maintenance dose (when calculated on the basis of surface area). Thyroid hyperplasia, adenoma, and carcinoma developed in rats at the two higher doses. The clinical significance of these findings is unclear.. Pregnancy. See WARNINGS If methimazole tablets are used during the first trimester of pregnancy or if the patient becomes pregnant while taking this drug, the patient should be warned of the potential hazard to the fetus. In pregnant women with untreated or inadequately treated Graves disease, there is an increased risk of adverse events of maternal heart failure, spontaneous abortion, preterm birth, stillbirth and fetal or neonatal hyperthyroidism.Because methimazole crosses placental membranes and can induce goiter and cretinism in the developing fetus, hyperthyroidism should be closely monitored in pregnant women and treatment adjusted such that sufficient, but not excessive, dose be given during pregnancy. In many pregnant women, the thyroid dysfunction diminishes as the pregnancy proceeds; consequently, reduction of dosage may be possible. In some instances, anti-thyroid therapy can be discontinued several weeks or months before delivery.Due to the rare occurrence of congenital malformations associated with methimazole use, it may be appropriate to use an alternative anti-thyroid medication in pregnant women requiring treatment for hyperthyroidism particularly in the first trimester of pregnancy during organogenesis.Given the potential maternal adverse effects of propylthiouracil (e.g., hepatotoxicity), it may be preferable to switch from propylthiouracil to methimazole for the second and third trimesters.. Nursing Mothers. Methimazole is present in breast milk. However, several studies found no effect on clinical status in nursing infants of mothers taking methimazole. long-term study of 139 thyrotoxic lactating mothers and their infants failed to demonstrate toxicity in infants who are nursed by mothers receiving treatment with methimazole. Monitor thyroid function at frequent (weekly or biweekly) intervals.. Pediatric Use. Because of postmarketing reports of severe liver injury in pediatric patient treated with propylthiouracil, methimazole is the preferred choice when an antithyroid drug is required for pediatric patient. (see DOSAGE AND ADMINISTRATION).

SPL UNCLASSIFIED SECTION.

First Trimester Use of Methimazole and Congenital Malformations. Methimazole crosses the placental membranes and can cause fetal harm, when administered in the first trimester of pregnancy. Rare instances of congenital defects, including aplasia cutis, craniofacial malformations (facial dysmorphism; choanal atresia), gastrointestinal malformations (esophageal atresia with or without tracheoesophageal fistula), omphalocele and abnormalities of the omphalomesenteric duct have occurred in infants born to mothers who received methimazole tablets in the first trimester of pregnancy. If methimazole tablets are used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be warned of the potential hazard to the fetus.Because of the risk for congenital malformations associated with use of methimazole tablets in the first trimester of pregnancy, it may be appropriate to use other agents in pregnant women requiring treatment for hyperthyroidism. If methimazole tablets are used, the lowest possible dose to control the maternal disease should be given.

WARNINGS SECTION.

WARNINGS. First Trimester Use of Methimazole and Congenital Malformations. Methimazole crosses the placental membranes and can cause fetal harm, when administered in the first trimester of pregnancy. Rare instances of congenital defects, including aplasia cutis, craniofacial malformations (facial dysmorphism; choanal atresia), gastrointestinal malformations (esophageal atresia with or without tracheoesophageal fistula), omphalocele and abnormalities of the omphalomesenteric duct have occurred in infants born to mothers who received methimazole tablets in the first trimester of pregnancy. If methimazole tablets are used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be warned of the potential hazard to the fetus.Because of the risk for congenital malformations associated with use of methimazole tablets in the first trimester of pregnancy, it may be appropriate to use other agents in pregnant women requiring treatment for hyperthyroidism. If methimazole tablets are used, the lowest possible dose to control the maternal disease should be given.. Agranulocytosis. Agranulocytosis is potentially life-threatening adverse reaction of methimazole therapy. Patients should be instructed to immediately report to their physicians any symptoms suggestive of agranulocytosis, such as fever or sore throat. Leukopenia, thrombocytopenia, and aplastic anemia (pancytopenia) may also occur. The drug should be discontinued in the presence of agranulocytosis, or aplastic anemia (pancytopenia), and the patients bone marrow indices should be monitored.. Liver Toxicity. Although there have been reports of hepatotoxicity (including acute liver failure) associated with methimazole, the risk of hepatotoxicity appears to be less with methimazole than with propylthiouracil, especially in the pediatric population. Symptoms suggestive of hepatic dysfunction (anorexia, pruritis, right upper quadrant pain, etc.) should prompt evaluation of liver function (bilirubin, alkaline phosphatase) and hepatocellular integrity (ALT, AST). Drug treatment should be discontinued promptly in the event of clinically significant evidence of liver abnormality including hepatic transaminase values exceeding times the upper limit of normal.. Hypothyroidism. Methimazole can cause hypothyroidism necessitating routine monitoring of TSH and free T4 levels with adjustments in dosing to maintain euthyroid state. Because the drug readily crosses placental membranes, methimazole can cause fetal goiter and cretinism when administered to pregnant woman. For this reason, it is important that sufficient, but not excessive, dose be given during pregnancy (see PRECAUTIONS, Pregnancy). Vasculitis. Cases of vasculitis resulting in severe complications have been reported in patients receiving methimazole therapy. These cases of vasculitis include: leukocytoclastic cutaneous vasculitis, acute kidney injury and glomerulonephritis, alveolar/pulmonary hemorrhage, CNS vasculitis, and neuropathy. Most cases were associated with anti-neutrophilic cytoplasmic antibodies (ANCA)-positive vasculitis. In some cases, vasculitis resolved/improved with drug discontinuation; however, more severe cases required treatment with additional measures including corticosteroids, immunosuppressant therapy, and plasmapheresis. If vasculitis is suspected, discontinue therapy and initiate appropriate intervention.