Tapazole

DESCRIPTION

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 administeredantithyroid 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:

INDICATIONS

TAPAZOLE is indicated:

• In patients withGraves' diseasewith hyperthyroidism ortoxic multinodular goiterfor whom surgery orradioactive iodinetherapy is not an appropriate treatment option.
• To ameliorate symptoms of hyperthyroidism in preparation forthyroidectomyor radioactiveiodinetherapy.

DOSAGE AND ADMINISTRATION

TAPAZOLE 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

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 100NDC60793-104-01

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 100NDC60793-105-01

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

SIDE EFFECTS

Major adverse reactions (which occur with much less frequency than the minor adverse reactions) include inhibition of myelopoieses (agranulocytosis,granulocytopenia,thrombocytopenia, and aplasticanemia), drug fever, alupus-like syndrome,insulinautoimmunesyndrome (which can result inhypoglycemiccoma),hepatitis(jaundicemay persist for several weeks after discontinuation of the drug), periarteritis, and hypoprothrombinemia.Nephritisoccurs very rarely.

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, skinpigmentation, jaundice, sialadenopathy, andlymphadenopathy.

DRUG INTERACTIONS

Anticoagulants (Oral)

Due to potential inhibition ofvitamin Kactivity 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 ahyperthyroidpatient becomeseuthyroid.

Digitalis Glycosides

当超级血清洋地黄水平可能增加thyroid 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.

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 ofcongenitaldefects, includingaplasiacutis, craniofacial malformations (facial dysmorphism;choanal atresia),gastrointestinalmalformations (esophagealatresiawith or without tracheoesophagealfistula),omphaloceleand abnormalities of the omphalomesentericducthave 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 orsore throat.Leukopenia, thrombocytopenia, andaplastic anemia(pancytopenia) may also occur. The drug should be discontinued in the presence of agranulocytosis, aplastic anemia (pancytopenia), ANCA-positivevasculitis, hepatitis, or exfoliativedermatitisand the patient'sbone marrowindices should be monitored.

Liver Toxicity

Although there have been reports of hepatotoxicity (including acuteliver failure) associated with TAPAZOLE, the risk of hepatotoxicity appears to be less with methimazole than withpropylthiouracil, especially in the pediatric population. Symptoms suggestive of hepatic dysfunction (anorexia, pruritis, right upperquadrantpain, 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 causehypothyroidismnecessitating 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 fetalgoiterandcretinismwhen administered to a pregnant woman. For this reason, it is important that a sufficient, but not excessive, dose be given during pregnancy (seePRECAUTIONS,Pregnancy).

PRECAUTIONS

General

患者应该在收到甲巯基咪唑close surveillance and should be cautioned to report immediately any evidence of illness, particularlysorethroat, skin eruptions, fever, headache, or generalmalaise. 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 timeshould be monitored during therapy with the drug, especially before surgical procedures.Thyroid功能测试应该定期监控during therapy. Once clinical evidence of hyperthyroidism has resolved, the finding of a rising serum TSH indicates that a lower maintenance dose of TAPAZOLE should be employed.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

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). Thyroidhyperplasia,adenoma, andcarcinomadeveloped in rats at the two higher doses. The clinical significance of these findings is unclear.

Pregnancy

Pregnancy Category D

SeeWARNINGS

如果使用TAPAZOLE在妊娠前三个月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 maternalheart failure,spontaneous abortion, preterm birth, stillbirth and fetal orneonatalhyperthyroidism.

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 during organogenesis.

Given the potential maternal adverse effects of propylthiouracil (e.g., hepatotoxicity), it may be preferable to switch from propylthiouracil to TAPAZOLE 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. 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. 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, TAPAZOLE is the preferred choice when an antithyroid drug is required for a pediatric patient (seeDOSAGE AND ADMINISTRATION).

OVERDOSE

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 medianlethaldose 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, a good resource is your certified Regional Poison Control Center. In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drugkineticsin the patient.

In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient's medical status.

CONTRAINDICATIONS

TAPAZOLE is contraindicated in the presence of hypersensitivity to the drug or any of the other product components.

CLINICAL PHARMACOLOGY

Methimazole inhibits the synthesis ofthyroid hormonesand thus is effective in the treatment of hyperthyroidism. The drug does not inactivate existingthyroxineand tri-iodothyronine 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 thegastrointestinal tract, metabolized in the liver, and excreted in the urine.

PATIENT INFORMATION

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.