Methimazole 5 mg Tablet, 100-count — NDC 69452-328-20 (Billing 69452-0328-20)

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 a 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 patient’s 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, pruritus, 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 3 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 a euthyroid state. Because the drug readily crosses placental membranes, methimazole can cause fetal goiter and cretinism when administered to a pregnant woman.

For this reason, it is important that a 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.

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, a 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 a 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 Bionpharma Inc. at 1-888-235-BION or 1-888-235-2466 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions Anticoagulants (oral) : Due to potential inhibition of vitamin K 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. β-adrenergic blocking agents : Hyperthyroidism may cause an increased clearance of beta blockers with a high extraction ratio. A dose reduction of beta-adrenergic blockers may be needed when a hyperthyroid patient becomes euthyroid. Digitalis glycosides : Serum digitalis levels may be increased when hyperthyroid patients on a stable digitalis glycoside regimen become euthyroid; a reduced dosage of digitalis glycosides may be needed.

Theophylline : Theophylline clearance may decrease when hyperthyroid patients on a stable theophylline regimen become euthyroid; a reduced dose of theophylline may be needed.

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 a rising serum TSH indicates that a lower maintenance dose of methimazole tablets should be employed.

Drug Interactions Anticoagulants (oral) : Due to potential inhibition of vitamin K 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. β-adrenergic blocking agents : Hyperthyroidism may cause an increased clearance of beta blockers with a high extraction ratio. A dose reduction of beta-adrenergic blockers may be needed when a hyperthyroid patient becomes euthyroid. Digitalis glycosides : Serum digitalis levels may be increased when hyperthyroid patients on a stable digitalis glycoside regimen become euthyroid; a reduced dosage of digitalis glycosides may be needed.

Theophylline : Theophylline clearance may decrease when hyperthyroid patients on a stable theophylline regimen become euthyroid; a reduced dose of theophylline may be needed. Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year study, rats were given methimazole at doses of 0.5 mg/kg/day, 3 mg/kg/day, and 18 mg/kg/day. These doses were 0.3 time, 2 times, 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 a sufficient, but not excessive, dose be given during pregnancy. In many pregnant women, the thyroid dysfunction diminishes as the pregnancy proceeds; consequently, a 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 dur… [Excerpted — this section continues on DailyMed.]