Methimazole inhibits the synthesis of thyroid hormones and thus is effective in the treatment of hyperthyroidism. The drug does not inactivate existing thyroxine and triiodo-thyronine 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. The actions and use of methimazole are similar to those of propylthiouracil. On a weight basis, the drug is at least ten times as potent as propylthiouracil, but methimazole may be less consistent in action. Methimazole is readily absorbed from the gastrointestinal tract. It is metabolized rapidly and requires frequent administration. Methimazole is excreted in the urine.

A comparative bioavailability study was performed on healthy human volunteers under fasting conditions. The rate and extent of absorption of methimazole was measured and compared following a single oral dose (2 x 5 mg) of APO-METHIMAZOLE (methimazole) or Tapazole tablets. The results from measured data are summarized as follows:

APO-METHIMAZOLE (methimazole) is indicated in the medical treatment of hyperthyroidism. Long-term therapy may lead to remission of the disease. APO-METHIMAZOLE may be used to ameliorate hyperthyroidism in preparation for subtotal thyroidectomy or radioactive iodine therapy. APO-METHIMAZOLE is also used when thyroidectomy is contraindicated or not advisable.

CONTRAINDICATIONS

APO-METHIMAZOLE (methimazole) is contraindicated in the presence of hypersensitivity to the drug and in nursing mothers because the drug is excreted in breast milk.

WARNINGS

Agranulocytosis is potentially the most serious side effect of therapy with APO- METHIMAZOLE (methimazole). Patients should be instructed to report to their physicians any symptoms 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), hepatitis, or exfoliative dermatitis. The patient's bone marrow function should be monitored.

Due to the similar hepatic toxicity profiles of methimazole and propylthiouracil, attention is drawn to the severe hepatic reactions which have occurred with both drugs. There have been rare reports of fulminant hepatitis, hepatic necrosis, encephalopathy, and death. Symptoms suggestive of hepatic dysfunction (anorexia, pruritis, right upper quadrant pain, etc) should prompt evaluation of liver function. 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.

Methimazole can cause fetal harm when administered to a pregnant woman. Methimazole readily crosses the placental membranes and can induce goiter and even cretinism in the developing fetus. In addition, rare instances of aplasia cutis, as manifested by scalp defects have occurred in infants born to mothers who received methimazole during pregnancy. If methimazole 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. Since scalp defects have not been reported in offspring of patients treated with propylthiouracil, the agent may be preferable to methimazole in pregnant women requiring treatment with antithyroid drugs.

PRECAUTIONS

Patients who receive APO-METHIMAZOLE (methimazole) should be under close surveillance and should be impressed with the necessity of reporting 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 made to determine whether agranulocytosis has developed. Particular care should be exercised with patients who are receiving additional drugs known to cause agranulocytosis.

Because methimazole may cause hypoprothrombinemia and bleeding, prothrombin time should be monitored during therapy with the drug, especially before surgical procedures. Periodic monitoring of thyroid function is warranted, and the finding of an elevated TSH warrants a decrease in the dosage of APO-METHIMAZOLE.

The activity of anticoagulants may be potentiated by anti-vitamin-K activity attributed to methimazole.

Rats treated for 2 years with methimazole demonstrated thyroid hyperplasia and thyroid adenoma and carcinoma formation. Such findings are seen with continuous suppression of thyroid function by sufficient doses of a variety of antithyroid agents. Pituitary adenomas have also been observed.

APO-METHIMAZOLE used judiciously is an effective drug in hyperthyroidism complicated by pregnancy. In many pregnant women, the thyroid dysfunction diminishes as the pregnancy proceeds; consequently, a reduction in dosage may be possible. In some instances, use of methimazole can be discontinued 2 or 3 weeks before delivery. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

The drug appears in human breast milk and its use is contraindicated in nursing mothers.

ADVERSE REACTIONS

Adverse reactions probably occur in less than 1 percent of patients. 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. Major adverse reactions (which occur with much less frequency than the minor adverse reactions) include inhibition of myelopoiesis (agranulocytosis, granulocytopenia, and thrombocytopenia), aplastic anemia, drug fever, a lupuslike 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. It should be noted that about 10% of patients with untreated hyperthyroidism have leukopenia (white-blood-cell count of less than 4,000/mm3), often with relative granulopenia.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

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. Although not well studied, methimazole-induced agranulocytosis is generally associated with doses of 40 mg or more in patients older than 40 years of age. 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.

In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient. Protect the patient's airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient's vital signs, blood gases, serum electrolytes, etc. The patient's bone marrow function should be monitored. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient's airway when employing gastric emptying or charcoal. Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion have not been established as beneficial for an overdose of methimazole.

DOSAGE AND ADMINISTRATION

APO-METHIMAZOLE (methimazole) is administered orally. It is usually given in three equal doses at approximately eight-hour intervals.

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 three doses at eight-hour intervals. The maintenance dosage is 5 to 15 mg daily.

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

Proper/Common Name: methimazole Chemical Name(s): 1) 2H-Imidazole-2-thione, 1,3-dihydro-1-methyl;

Structural Formula: Molecular Formula: C4H6N2S Molecular Weight: 114.17 Description: A white to slightly cream coloured powder. Solubility: Freely soluble in water, alcohol and chloroform, slightly soluble in ether, petroleum ether and benzene. pH: 7.8 (1% solution in water at 25oC) pKa: 11.9 Melting Range: between 143o and 146oC

In addition to the active ingredient methimazole, each tablet contains the non-medicinal ingredients crospovidone, magnesium stearate and anhydrous lactose.

Store between 15EC and 30EC. Preserve in well-closed, light-resistant containers.

APO-METHIMAZOLE Tablets 5 mg: Each white, round, flat-faced bevelled edged tablet, engraved "APO" on one side, scored and engraved "MET" over "5" on the other, contains 5 mg methimazole. Available in bottles of 100 tablets.

This leaflet has been developed to help patients understand the importance of using APO- METHIMAZOLE properly. Please read the entire leaflet very carefully before you start taking this medicine. If there is anything that you do not understand or if you have any additional questions, please ask your doctor or your pharmacist. You should keep this leaflet, as you may need to read it again.

Before you start taking APO-METHIMAZOLE, be sure to tell your doctor about all medicines you are taking or have taken recently including any that you bought without a prescription or any natural products. This is because the effects of APO-METHIMAZOLE or the other medicines may be changed or you might get side effects. Furthermore, do not start any new medicine, whether prescription, non-prescription or natural products without first checking with your doctor. It is especially important that your doctor knows if you are taking anticoagulants (blood thinners) as the use of antithyroid agents many affect the way anticoagulants work in your body.

if you have ever had any unusual or allergic reaction to methimazole. Also tell your doctor if you are allergic to any other substances, such as foods, preservatives, or dyes. if you are nursing your baby, as APO-METHIMAZOLE passes into breast milk and its effects on the nursing infant are not known; if you suspect that you may be pregnant. You must inform your doctor and you must not start taking APO-METHIMAZOLE. APO-METHIMAZOLE may increase the risk of having a baby with a birth defect. if you have any blood disorders. Otherwise, your symptoms may get worse; if you have a disease of the liver. Otherwise, your disease may get worse.

The active ingredient in APO-METHIMAZOLE tablets is called methimazole and it belongs to the class of medications called antithyroid medications. It is used to treat hyperthyroidism (overactive thyroid gland). APO-METHIMAZOLE may also be used to improve the symptoms of hyperthyroidism before a thyroidectomy (removal of part of the thyroid gland) or radioactive iodine therapy. APO-METHIMAZOLE prevents the thyroid gland from over-producing thyroid hormone, but does not interfere with the actions of thyroid hormone. It may take weeks to months before methimazole has its full effect on the symptoms of overactive thyroid (e.g., palpitations, sweating). During this time period, other medications may be used to control these symptoms.

APO-METHIMAZOLE is supplied as tablets of 5 mg. Your doctor will usually want you to build up the amount of methimazole in your body and dosage amounts can vary depending on the severity of your hyperthyroidism. For adults, the following are possible initial doses: Mild hyperthyroidism - 5 mg taken 3 times a day (i.e. every 8 hours) Moderately Severe Hyperthyroidism - 10 mg taken 3 times a day (i.e. every 8 hours) Severe Hyperthyroidism - 20 mg taken 3 times a day (i.e. every 8 hours) Thereafter, your doctor may reduce the dose to between 5 and 15 mg taken once a day. For children, the initial daily dosage is 0.4 mg per kg of body weight. This amount is divided into 3 doses so that the drug is taken 3 times a day (i.e. every 8 hours). The maintenance dosage is 5 to 15 mg daily. You should always follow your doctor's instructions. Do not take any more or any less than what your doctor says. You may be taking APO-METHIMAZOLE over long periods of time. However, your doctor will advise you if and when you need to stop taking APO- METHIMAZOLE. You can take APO-METHIMAZOLE during meals or at any time between meals. However, to make sure that you always get the same effects, try to take APO-METHIMAZOLE at the same time in relation to meals every day. That is, always take it with meals or always take it on an empty stomach. Swallow the tablet whole with a glass of water or another fluid.

If you forget to take a tablet of APO-METHIMAZOLE take it as soon as you remember. If it is almost time for your next dose, take both doses together. Then go back to your regular dosing schedule. If you miss more than one dose or if you have any questions about this, check with your doctor.

If you accidentally take one tablet too many, nothing is likely to happen. If you accidentally take several tablets too many, contact your doctor or get other medical advice. If possible, take your tablets with you to show the doctor. In general, an overdose may lead to increased symptoms as described under "What are the side effects of APO-METHIMAZOLE". Should this happen, it is possible that medicine may be administered by your doctor in order to speed up the elimination of APO-METHIMAZOLE from your body.

WHAT ARE THE SIDE EFFECTS OF APO-METHIMAZOLE AND WHAT SHOULD I DO IF THEY OCCUR?

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Cough; fever or chills (continuing or severe); general feeling of tiredness, illness or weakness; sore throat; skin eruptions or headache; dizziness; loss of taste; nausea; stomach pain; vomiting; joint pain; muscle pain; or abnormal loss of hair

Yellow eyes or skin; backache; black, tarry stools; blood in urine or stools; shortness of breath; increase in bleeding or bruising; increase or decrease in urination; numbness or tingling of fingers, toes, or face; pinpoint red spots on skin; swelling of feet or lower legs; swollen lymph nodes; swollen salivary glands; loss of appetite; pain in the right side of the upper body

Changes in menstrual periods; coldness; constipation; dry, puffy skin; headache; listlessness or sleepiness; muscle aches; swelling in the front of the neck; unusual tiredness or weakness; weight gain (unusual)

to make sure that this medicine is working properly and to check for unwanted effects.

It may take several days or weeks for this medicine to work. However, do not stop taking this medicine without first checking with your doctor. Some medical problems may require several years of continuous treatments. Before having any kind of surgery (including dental surgery) or emergency treatment, tell the medical doctor or dentist in charge that you are taking this medicine. Before you have any medical tests, tell the doctor in charge that you are taking this medicine. The results of some tests may be affected by this medicine.

The tablets contain the active drug, methimazole. In addition, they contain the following non- medicinal ingredients: crospovidone, magnesium stearate and anhydrous lactose.

Do not expose APO-METHIMAZOLE tablets to light. Store this medicine at temperatures between 15 degC and 30 degC. As with all medicines, you should keep APO-METHIMAZOLE tablets out of the reach of children. Do not use the tablets in this package after the expiry date shown on the container label.

PHARMACOLOGY

Pharmacokinetics Based on urinary radio-iodine excretion/PBI ration after a single oral dose of 30 mg in euthyroid or thyrotoxic human subjects, the peak response of methimazole is 12 to 18 hours and the duration is 36 to 72 hours. Methimazole is widely distributed throughout the body; it crosses the placental barrier. Areas with the high concentrations in humans are bone marrow, adrenal gland, blood, liver and spleen. In healthy subjects, methimazole is primarily metabolized in the liver and 80% is excreted through the kidneys with 11% as unchanged methimazole and the remainder as metabolites. The elimination half-life of the parent compound is 2 to 28 hours, being slightly longer in hyperthyroid patients (6 hours) as compared to euthyroid (2 to 3 hours) patients.

The mechanism of action of methimazole is not completely understood. In human patients, therapy begins with 30 mg of methimazole and serum methimazole levels of less than 0.2 ug per milliliter almost totally inhibit thyroid iodide organification. Virtually all patients can be made euthyroid with methimazole. The time to euthyroidism after starting treatment is usually two to four months, depending on the severity of the underlying disease, the size of the thyroid (reflecting the amount of stored hormone), and the drug dose and its timing.

A four year study was conducted on the treatment of hyperthyroidism with methimazole. There were 184 patients, 141 were women and 40 were men and in 3 the sex was not recorded. Of the 37 patients who were treated preoperatively only, 35 had a nodular goiter and 2 a hyperplastic goiter. Seventeen of these patients received 15 mg daily and preparation for surgery required a range of less than five to thirteen weeks. The remaining 20 patients received from 30 to 60 mg daily and preparation for surgery required less than five weeks in all patients. Complete control of the thyrotoxic state was attained as readily in those patients with nodular goiter as in those with a hyperplastic gland. Extremely toxic patients were often the first to note improvement and returned to a euthyroid state more quickly that the less toxic patients. The time required for the patient to improve after receiving methimazole was also established. An improvement was determined to include any of the following: amelioration of tremors, hyper-reactivity, sweating, tachycardia, disturbances of appetite and bowel, or altered sleep. From 150 patients recorded, 77 had an improvement in 1 week, 62 in two weeks, 8 in three to four weeks and 5 in five to eight weeks. It was also determined how much time was required to induce a euthyroid state. This was established to be when clinical finding of hyperthyroidism had disappeared and the basal metabolic rate and serum cholesterol level were within normal limits. Observations were made in 137 of the 184 patients; 3 were never satisfactorily controlled with methimazole, 40 became euthyroid between day 12 and 21 of treatment, 51 between day 21 and 28 days, 22 during the fifth week, 8 during the sixth week, and the remaining 13 between the seventh and twenty-sixth weeks. The 3 patients in whom the drug was ineffectual in controlling the thyrotoxicosis showed a granulocytopenic response. The size of the thyroid gland was reported in the records of 90 patients; in 12 cases (7 controlled hyperthyroidism) there was an increase; in 45 (all well controlled), a decrease; and in 33 (27 well controlled), no change. In 20 of these subjects, an early slight increase in the size of the gland was followed by a definite decrease, as full control of the thyrotoxic state was attained. In the final disposition of 133 of the 184 cases, 29 had relapses, 8 had recurrences, 34 had recovered completely and 44 had operations. Of the 96 cases available for long-range therapy with methimazole, 41 were still taking the drug after 4 years. Very few patients who recovered completely were treated for less than six months.

TOXICOLOGY

In the rat, the oral LD50 is 2250 mg/kg and in the mouse, the oral LD50 is 860 mg/kg. A bolus dose of methimazole was administered IV over 1 minute to 5 healthy adult dogs at a dosage of 40 mg/kg of body weight, a dosage higher than that routinely used in various species for long-term suppression of thyroid hormone concentrations. Dog 1 vomited once, 6 hours after receiving the methimazole dose. Otherwise, changes were not observed in physical finding, attitude, appetite, urination, or defecation in any of the subjects. A slight, but statistically significant, increase in total WBC count was detected on days 5 and 10 after methimazole administration. Only dog 3 had any change in serum biochemistry profile, which consisted of mild transient increase in ALP, ALT, and AST activities on day 1 after methimazole administration; values normalized by the fifth day after methimazole administration. At this dosage, methimazole appears to be safe and well tolerated in dogs. In addition, methimazole did not alter serum thyroid hormone concentrations.

Effects of chronic dosing have been studied in the rat, given oral or intravenous (IV) doses of methimazole.

In an in vitro cytogenetic study performed in cultured human lymphocytes, methimazole significantly decreases the mitotic activity (23% decrease at a concentration of 2.5 mcg/mL and 41% decrease at a concentration of 5.0 mcg/mL). There was no significant difference in the number of polyploid mitoses and there were no numeric or morphologic changes in the chromosomes. In another study, the inhibitory effect of methimazole on mouse T lymphocytes was investigated. Fifty inbred C57BL/6 male mice were divided into three groups with each group having a different duration of dosing. Methimazole was given at 0.1% in the drinking water ad libitum for 2, 4 or 6 weeks and the in vitro responses of the lymphocytes were studied. Proliferative responses of T lymphocytes from the spleen of methimazole treated mice significantly decreased and the inhibitory effect became prominent with the increased duration of methimazole treatment. A concomitant increase in the frequency of induced sister- chromatid exchanges was also observed in these T lymphocytes. Methimazole interfered with the normal proliferation of T lymphocytes by suppressing the production of IL-2, a cytokine also known as T cell growth factor, as well as inducing a higher incidence of sister- chromatid exchange during cell division. In a third study, inducibility of chromosome aberrations of cultured mouse mammary carcinoma FM3A cells was examined on methimazole. The concentrations of methimazole used on the cells were 10 mM and 3.2 mM and the effects were severe chromosome aberrations including chromatid gaps, isochromatid gaps, breaks and exchanges. Even though this test is used to predict carcinogenic or mutagenic toxic substances, the ratio of the effective concentration of methimazole in the chromosome test compared to the maximum blood concentration in clinical use in humans was very high (1,200).

One study looked at the effects of long-term ingestion of methimazole on the thyroids of rats. Harlan rats (initial body weight 86-136 g) were fed methimazole in the diet at levels of 0, 5, 30 and 180 ppm for 2 years. The control group consisted of 50 males and 50 females and each dosing group consisted of 25 males and 25 females. The survival was poor in the rats of the 180 ppm group, with a 50% mortality during the first year compared with less than 10% for the other groups. Only 6% survived the 2 year study, whereas 16-20% of the other groups survived. Also in this group, the rat's growth was greatly inhibited and after reaching maturity they became obese. Hypertrophy and hyperplasia of the thyroid occurred in rats of the 30 and 180 ppm groups but not in those of the 5 ppm group. In rats of the 30 and 180 ppm groups there was a high incidence of thyroid follicular adenoma and a lower incidence of follicular adenocarcinoma. The incidences of thyroid adenomas and adenocarcinomas are provided in the following table. The incidence of adenomas was similar in the 30 and 180 ppm methimazole groups, whereas that for adenocarcinomas was greater for the 180 ppm group (21 compared to 12%). The tumour incidence for the 180 ppm group was based on a much smaller group of surviving rats than that for the 30 ppm group.

Table 1. Incidence of thyroid neoplasia in rats given 0-180 ppm methimazole in the diet in a 2-year toxicity study

Expressed as no. of rats with tumour/no. surviving when first tumour was detected in the group. There was no indication of any sex difference in the incidence of either type of tumour.

The incidence, induction time and/or severity of neoplasias other than of the thyroid and of naturally occurring disease processes were similar in the treated and control groups. The incidences of pituitary and mammary gland neoplasia were greatly reduced in rats on the 180 ppm methimazole regimen because of the high mortality in this group during the first year of the test, at an age prior to the usual onset of these lesions. In a second study the tumourgenic effect of methimazole was studied in mice. A total of 475 animals (236 male and 239 female) were nontreated controls on an iodine-rich diet, and 100 mice (50 male and 50 female) were nontreated controls on an iodine-poor diet. A total of 188 animals (108 female and 80 male) on an iodine-rich diet received methimazole in their drinking water from the age of 2 months. The starting dose was 35 mg in 1 litre of water and was increased gradually over a period of 26 months to 500 mg per litre. A total of 75 mice (35 female and 40 male) on iodine-poor diet received 250 mg of methimazole per 1 litre of water from the age of 2 months and at the age of 4 months the dose was increased to 500 mg per litre. Thyroid weight as well as the occurrence of thyroid adenomas, pulmonary metastases and hepatomas were determined in all groups with the duration of treatment varying from 6-9, 9-12, 12-18 or 18-22 months. The iodine-poor diet alone did not have any effect on the weight of the thyroid gland but the weight did increase considerably with methimazole treatment and both the iodine-poor or iodine rich diet. Methimazole also caused a significant increase in the incidence of thyroid adenomas in mice on the iodine-poor diet, however there were no to minimal changes in the occurrence of both pulmonary nodules and hepatomas. The maximal effect on thyroid weight, and on the occurrence of thyroid adenomas, pulmonary nodules and hepatomas was seen after 12-18 months of methimazole treatment.

Charles C Thomas, Springfield, IL, 1976. Brock N & Lorenz D: Pharmacology of 1-methyl-2-mercaptoimidazole. Arzneimittelforschung 1954; 4: 20-26. Chevalley, J, McGavack, TH, Kenigsberg, S, Pearson S: A four-year study of the treatment of hyperthyroidism with methimazole. J Clin Endocrinol Metab 1954; 14: 948- 960. Comer CP, Norton S: Effects of perinatal methimazole exposure on a developmental test battery neurobehavioral toxicity in rats. Toxicol Appl Pharmacol 1982; 63: 133-141. Cooper DS: Antithyroid drugs. N Engl J Med 1984: 311:1353-1362. Dailey GE III, Beschi RG, Smitherman TC et al: Absorption and excretion of methimazole in man. Ala J Med Sci 1971; 8: 220-222. Hengstmann JH & Hohn H: Pharmacokinetics of methimazole in humans. Klin Wochenschr 1985; 63:1212-1217. Hood A, Liu YP, Gattone VH 2nd, Klassen CD: Sensitivity of thyroid gland growth to thyroid stimulating hormone (TSH) in treated with antithyroid drugs. Toxicol Sci 1999; 49: 263- 271. Jansson R, Lindstrom B & Dahlberg PA: Pharmacokinetic properties and bioavailability of methimazole. Clin Pharmacokinet 1985; 10:443-450. Jemec B: Studies of the tumorigenic effect of two goitrogens. Cancer 1977; 40: 2188- 2202. Karg E, Bereg E, Gaspar L, Katona M, Turi S: Aplasia cutis congenita after methimazole exposure in utero. Pediatr Dermatol 2004; 21: 491-4. Kodama F, Fukushima K, Umeda M: Chromosome aberrations induced by clinical medicines. J Toxicol Sci 1980; 5: 141-150. Liu WK, Tsui KW, Lai KW, Xie Y: Sister-chromatid exchanges in lymphocytes from methimazole-induced hypothyroid mice. Mutat Res 1995; 326: 193-197. Owen NV, Worth HM, Kiplinger GF: The effect of long-term ingestion of methimazole on the thyroid of rats. Food Cosmet Toxicol 1973; 11: 649-653. Pittman JA, Beschi RJ, Smitherman TC: Methimazole: its absorption and excretion in man and tissue distribution in rats. J Clin Endocrinol Metab 1971; 33: 182-185. Rice SA, Millan, DP, West JA: The behavioral effect of perinatal methimazole exposure in Swiss Webster mice. The Fourth Annual Meeting of The Behavioral Teratology Society. Teratology 1983; 27: 71A. Rice SA, Millan DP: Validation of a developmental swimming test using Swiss Webster mice perinatally treated with methimazole. Neurobehav Toxicol Teratol 1986; 8: 69-75. Rice SA, Millan DP, West JA: The behavioral effects of perinatal methimazole administration in Swiss Webster mice. Fundam Appl Toxicol 1987; 8: 531-540. Schneider, BF & Golden WL: Perinatal hypothyroidism and neurologic development in rats - a dose-response study with methimazole. The Teratology Society, twenty-fifth annual meeting. Teratology 1985; 31: 64A. Sosenko IR, Frank L: Thyroid inhibition and developmental increases in fetal rat lung antioxidant enzymes. Am J Physiol 1989; 257: L94-99. Szakacs, NA and Halladay SC: Behavioral assessment of rats treated prenatally with methimazole - industrial application of the test battery. The Fourth Annual Meeting of The Behavioral Teratology Society. Teratology 1983; 27: 79A. Vail DM, Elfarra AA, Panciera DL, Hutson PR: Pharmacokinetics and short-term clinicopathologic changes after intravenous administration of a high dose of methimazole in dogs. Am J Vet Res 1994; 55: 1597-1601. Todd GC: Induction and reversibility of thyroid proliferative changes in rats given an antithyroid compound. Vet Pathol 1986; 23: 110-117. Wartofsky L & Ingbar SH: A method for assessing the latency, potency, and duration of action for antithyroid agents in man. Clin Res 1969; 17:295. Zamrazil V, Nemec J, Hronova J, Seidlova L: The effect of a thyrostatic drug on mitotic activity of human lymphocytes in vitro. Humangenetik 1975; 26: 155-156. Prescribing Information for Tapazole(r), Paladin Labs Inc. (Prepared 01/18/2001)

Summary Table of the Comparative Bioavailability Data Methimazole (Dose: 2 x 5 mg) From Measured Data - Under Fasting Conditions Based on Methimazole
Parameter	Geometric Mean Arithmetic Mean (CV%)		Ratio of Geometric Means (%) * *
Parameter	Apo-Methimazole	Tapazole (r) +
AUC T	1465	1489	98.4
(ng.h/mL)	1497 (21)	1512 (18)	98.4
AUC I	1511	1531	98.6
(ng.h/mL)	1544 (22)	1556 (19)	98.6
C MAX	202	198	102.3
(ng/mL)	210 (30)	204 (28)	102.3
T M AX * (h)	0.773 (46)	0.714 (55)
T 1/2 * (h)	6.81 (13)	6.87 (15)
* Arithmetic means (CV%). * * Based on the least squares estimate. + Tapazole (r) is marketed by Paladin Laboratories Inc., and was purchased in Canada .

Species	No. per group		Dose Levels	Route	Duration	Effects
	M	F
Rat	4		26.3 umoles/120 g	I.V.	4 days	Mostly excreted in the urine (70%), and some was found in all organs examined. Thyroid and adrenal glands had the highest organ/plasma ratios.
Rat	Not provided		3, 10, 30, 100, 300 or 1000 ppm /225-250 g	Oral	21 days	Examined the effect of increasing serum thyroid- stimulating hormone (TSH) concentration on thyroid growth by measuring thyroid gland weight and thyroid follicular cell proliferation. TSH, thyroid follicular cell proliferation and thyroid weight were increased 560%, 1400% and 200% respectively.
Rat	50	50	90 ppm;	Oral	1, 3 and 6	Treated animals had no physical signs of toxicity.

	Incidence * in groups of rats fed methimazole (ppm )
Thyroid neoplasia	0	5	30	180

Follicular adenoma	1/55	1/8	31/55 (56%)	17/32 (53%)
Follicular adenocarcinoma	1/17	0	5/42 (12%)	5/24 (21%)

Species	No. per group	Dose Levels	Route	Duration	Effects
Rat	Not provided	0.1 or 0.05 mg/ml	Oral	17 days preg - 10 days post	Pups were tested for neurologic development from postnatal (PN) day 2 to 14. Delay in acquisition of auditory startle reflex (delays of 3 and 6 days, respectively) and reduction in body weight (7% and 13% reductions on PN 14); measure of reflex suspension and surface righting were more variable and not as responsive to dose.
Rat	Not provided	0.1 mg/ml	Oral	17 days preg - 10 days post	Pups were tested beginning on PN 3. Body weights were significantly reduced on PN days 7, 14 and 21, eye opening and incisor eruption were delayed 2 to 3 days, surface righting was delayed in some instances by several days, pivoting locomotion was delayed by one test day, significant changes in swimming development were observed in the direction of swim and angle of head in the water, auditory startle was delayed up to 6 days, residential maze activity was greater in the treated pups at 60 days of age but the rearing activity was decreased at 21 and 60 days of age.
Rat	8 experimental; 8 control female mothers	Approx. 31 mg/kg	Oral	17 days preg -10 days post	Pups had delayed acquisition of a righting response by 7 days, the appearance of the auditory startle response was delayed 6 days, the time of eye opening was delayed 2 days. A deficit, rather than a delay, was observed in body weight gain and in a reflex-suspension test of motor development. Treated rats showed decreased exploratory activity in an open field.
Species	No. per group	Dose Levels	Route	Duration	Effects
Rat	Not provided	0.5 mg/kg	Subcuta- neous	17-20 days preg	Pups were studied at 20, 21 or 22 days of gestation. They had no significant differences in body weight, lung wet weight, or lung weight-to- body weight ratios compared to control. Significant increases in pulmonary superoxide dismutase activity at 20 and 21 days of gestation and in catalase and glutathione peroxidase activities at 21 days compared with control offspring. Surfactant was not different in the methimazole group compared to control.
Mouse	10 experimental; 12 control litters	0.1 mg/ml	Oral	16 days preg - 10 days post	No differences in the days of pinna detachment, incisor eruption, eye- opening, vaginal patency and testis decent. Treated mice weighed less than control through PN 98 and 119. Surface righting time was longer and swimming ability was delayed (PN 4-20) for treated pups. Rotating rod times and brain weights were not different.
Mouse	15	4.1	Oral	16-21	There were no identifiable growth rate differences between the offspring of
	experimental;	mg/ml		days	control and methimazole-treated mothers.
	15 control	or		preg - 10
	female	1.8		days post	Methimazole pups exhibited a statistically significant delay in swimming
	mothers	mg/day			ability on PN 9 through 16.
	10
	experimental;
	12 control
	litters

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ACTIONS AND CLINICAL PHARMACOLOGY