Methimazole

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

TAPAZOLE® (Methimazole Tablets, USP) (1-methylimidazole-2-thiol) is a white, crystalline substance that is freely soluble in water. It differs chemically from the drugs of the thiouracil series primarily because it has a 5- instead of a 6-membered ring.

Each tablet contains 5 or 10 mg (43.8 or 87.6 μmol) methimazole, an orally administered antithyroid drug.

Each tablet also contains lactose monohydrate, magnesium stearate, starch (corn), pregelatinized starch and talc.

The molecular weight is 114.16, and the molecular formula is C4H6N2S. The structural formula is as follows:

TAPAZOLE Tablets are available in:

The 5-mg tablets are round, white to off-white, scored on one side and the other side debossed with "J94".

They are available as follows:

Bottles of 100 NDC 60793-104-01

The 10-mg tablets are round, white to off-white, scored on one side and the other side debossed with "J95".

They are available as follows:

Bottles of 100 NDC 60793-105-01

Store at controlled room temperature, 15° to 30°C (59° to 86°F).

Manufactured by: AAI Pharma, 1726 North 23rd St., Wilmington, NC 28405. Revised: Dec 2015

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 TAPAZOLE in the first trimester of pregnancy. If TAPAZOLE is 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 TAPAZOLE in the first trimester of pregnancy, it may be appropriate to use other agents in pregnant women requiring treatment for hyperthyroidism. If TAPAZOLE is used, the lowest possible dose to control the maternal disease should be given.

Agranulocytosis

Agranulocytosis is potentially a life-threatening adverse reaction of TAPAZOLE 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, aplastic anemia (pancytopenia), ANCA-positive vasculitis, hepatitis, or exfoliative dermatitis 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 TAPAZOLE, 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 hepatocellur 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

TAPAZOLE 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).

Before taking methimazole, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to methimazole
• have liver disease
• have a bleeding disorder
• are pregnant or breastfeeding

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Your pharmacist can provide more information about methimazole.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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Methimazole prevents the thyroid gland from producing too much thyroid hormone.

Methimazole is used to treat hyperthyroidism (overactive thyroid). It is also used before thyroid surgery or radioactive iodine treatment.

Methimazole may also be used for purposes not listed in this medication guide.

You should not breast-feed while using this medicine.

Follow all directions on your prescription label. Your doctor may occasionally change your dose. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Methimazole is usually taken every 8 hours. Take your doses at regular intervals to keep a steady amount of the drug in your body at all times.

If a child is using this medicine, tell your doctor if the child has any changes in weight. Methimazole doses are based on weight in children, and any changes may affect your child's dose.

Methimazole can lower blood cells that help your body fight infections and help your blood to clot. This can make it easier for you to bleed from an injury or get sick from being around others who are ill. Your blood may need to be tested often.

Use methimazole regularly to get the most benefit, even if you feel fine or have no symptoms of hyperthyroidism. Get your prescription refilled before you run out of medicine completely.

If you need surgery, tell the surgeon ahead of time that you are using methimazole.

Store at room temperature away from moisture and heat.

Storage

Oral

15–30°C.101

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.

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 should be employed.

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.

ß−adrenergic blocking agents:

Hyperthyroidism may cause an increased clearance of beta-blockers with a high extraction ratio. A reduced dose 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.

In a 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 Category D

Due to the rare occurrence of congenital malformations associated with Methimazole use, it may be appropriate to use other agents in pregnant women requiring treatment for hyperthyroidism, particularly in the first trimester of pregnancy (during organogenesis).

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.

In many pregnant women, the thyroid dysfunction diminishes as the pregnancy proceeds; consequently, a reduction in dosage of anti-thyroid therapy may be possible. In some instances, use of anti-thyroid therapy can be discontinued 2 or 3 weeks before delivery. 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 WARNINGS)

Nursing Mothers

Methimazole is excreted into breast milk. However, several studies found no effect on clinical status in nursing infants of mothers taking Methimazole, particularly if thyroid function is monitored at frequent (weekly or biweekly) intervals. A 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.

Pediatric Use

Because of postmarketing reports of severe liver injury in pediatric patients treated with propylthiouracil, Methimazole is the preferred choice when an anti-thyroid drug is required for a pediatric patient.  (See DOSAGE AND ADMINISTRATION.)

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.

ß−adrenergic blocking agents:

Hyperthyroidism may cause an increased clearance of beta-blockers with a high extraction ratio. A reduced dose 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.

In a 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 Category D

Due to the rare occurrence of congenital malformations associated with Methimazole use, it may be appropriate to use other agents in pregnant women requiring treatment for hyperthyroidism, particularly in the first trimester of pregnancy (during organogenesis).

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.

In many pregnant women, the thyroid dysfunction diminishes as the pregnancy proceeds; consequently, a reduction in dosage of anti-thyroid therapy may be possible. In some instances, use of anti-thyroid therapy can be discontinued 2 or 3 weeks before delivery. 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 WARNINGS)

Nursing Mothers

Methimazole is excreted into breast milk. However, several studies found no effect on clinical status in nursing infants of mothers taking Methimazole, particularly if thyroid function is monitored at frequent (weekly or biweekly) intervals. A 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.

Pediatric Use

Because of postmarketing reports of severe liver injury in pediatric patients treated with propylthiouracil, Methimazole is the preferred choice when an anti-thyroid drug is required for a pediatric patient.  (See DOSAGE AND ADMINISTRATION.)

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.

To obtain up-to-date information about the treatment of overdose, a good resource is the 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 patient’s medical status.

DOSAGE AND ADMINISTRATION

Methimazole is administered orally. The total daily dosage is usually given in 3 divided doses at approximately 8-hour intervals.

Adult-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 3 doses at 8-hour intervals. The maintenance dosage is 5 to 15 mg daily.

Pediatric-Initially, the daily dosage is 0.4 mg/kg of body weight divided into 3 doses and given at 8-hour intervals. The maintenance dosage is approximately 1/2 of the initial dose.

HOW SUPPLIED

Methimazole Tablets, USP 5 mg white, round, flat-faced, beveled-edged tablets with “VM” on one side and scored on the other.

They are available in: Bottles of 100 NDC 42808-405-01

Methimazole Tablets, USP 10 mg white, round, flat-faced, beveled-edged tablets with “XM” on one side and scored on the other.

They are available in: Bottles of 100 NDC 42808-410-01

Store at controlled room temperature, 20°- 25° C (68°- 77°F).

Dispense in a tight, light-resistant container.

Prescribing Information as of January 2012.

Manufactured for: Exact-Rx, Inc., Melville, NY 11747

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Tapazole: 5 mg, 10 mg [scored]

Generic: 5 mg, 10 mg

• Tapazole

• Antithyroid Agent
• Thioamide

Iodine-induced thyrotoxicosis

Based on the American Thyroid Association guidelines for the management of Hyperthyroidism and Other Causes of Thyrotoxicosis, treatment with methimazole is recommended in iodine-induced thyrotoxicosis to reduce thyroid hormone production [Ross 2016].

Thyroid storm or thyrotoxicosis

Based on the American Thyroid Association guidelines for the management of Hyperthyroidism and Other Causes of Thyrotoxicosis, treatment with methimazole is recommended in thyroid storm or thyrotoxicosis to reduce thyroid hormone production [Ross 2016].

Thyrotoxicosis (type 1 amiodarone-induced)

Based on the American Thyroid Association guidelines for the management of Hyperthyroidism and Other Causes of Thyrotoxicosis, treatment with methimazole is recommended in overt thyrotoxicosis (type 1 amiodarone-induced) to reduce thyroid hormone production [Ross 2016]. Use in combination with a corticosteroid if etiology of thyrotoxicosis (eg type 1 or type 2) cannot be unequivocally determined or if patient is too clinically unstable to allow a trial of monotherapy.

Refer to adult dosing.

Hyperthyroidism: Children and Adolescents: Oral: Initial: 0.4 mg/kg/day; maintenance: 0.2 mg/kg/day Note: The manufacturer suggests dividing the daily dose into 3 equal administrations; however, administration as a single daily dose or in 2 divided doses (for doses >30 mg/day) may be preferred (Ross 2016)

Hyperthyroidism associated with Graves disease (off-label) (Ross 2016): Infants, Children, and Adolescents: Oral:

Initial: Weight-based dosing: 0.2 to 0.5 mg/kg once daily (range: 0.1 to 1 mg/kg/day); in severe cases, initial doses that are 50% to 100% higher may be used; once patient is euthyroid, reduce dose by 50% or more and continue for a total duration of therapy of 1 to 2 years; may then discontinue or reduce dose to assess if patient is in remission.

The following fixed dosing approach may also be considered (using one-quarter, one-half, or whole tablets) (Ross 2016):

Infants: 1.25 mg/day

Children 1 to 5 years: 2.5 to 5 mg/day

Children 5 to 10 years: 5 to 10 mg/day

Children and Adolescents 10 to 18 years: 10 to 20 mg/day