Side effects of methimazole

Tapazole

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.

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 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). Thyroid hyperplasia, adenoma, and carcinoma developed in rats at the two higher doses. The clinical significance of these findings is unclear.

Pregnancy

Pregnancy Category D

See WARNINGS

If TAPAZOLE is 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 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 (see DOSAGE AND ADMINISTRATION).

Medical Editor: John P. Cunha, DO, FACOEP

Last reviewed on RxList 2/01/2019

Tapazole (methimazole) is an anti-thyroid drug used to treat hyperthyroidism (overactive thyroid). Tapazole is also used before thyroid surgery or radioactive iodine treatment. Tapazole is available in generic form. Common side effects of Tapazole include

Tell your doctor if you experience rare but serious side effects of Tapazole including

  • yellowing eyes/skin (jaundice),
  • dark urine,
  • severe stomach or abdominal pain,
  • persistent nausea or vomiting, or
  • changes in the amount of urine.

The initial adult dose of Tapazole is between 15-60 mg/day, depending on the severity of the hyperthyroidism, divided into three doses taken 8 hours apart. Some products that may interact with Tapazole include blood thinners (such as warfarin), digoxin, and theophylline. Tapazole is not recommended for use during the first 3 months of pregnancy and should be used only when prescribed during the last 6 months of pregnancy. Discuss the risks and benefits with your doctor. This medication passes into breast milk. Consult your doctor before breast-feeding.

Our Tapazole Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Tapazole Side Effects

Incidence not known

Black, tarry stools

bleeding gums

bleeding under the skin

bloody or cloudy urine

burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feelings

chest pain

chills

cough

dark urine

difficulty in breathing

dizziness or lightheadedness

drowsiness

feeling of constant movement of self or surroundings

fever

general feeling of discomfort, illness, or weakness

headache

hoarseness

itching, skin rash

light-colored stools

loss of appetite and weight

loss of consciousness

lower back or side pain

nausea

painful or difficult urination

pinpoint red spots on the skin

redness, soreness, or itching skin

sensation of spinning

sore throat

soreness of the muscles

sores, ulcers, or white spots on the lips or in the mouth

sores, welts, or blisters

stomach pain

swelling of the face, feet, or lower legs

swollen or painful glands

swollen salivary glands

swollen, painful, or tender lymph glands in the neck, armpit, or groin

tightness in the chest

unusual bleeding or bruising

unusual tiredness or weakness

unusual weight gain

upper right abdominal pain

yellow eyes or skin

Can Hyperthyroidism Cause Weight Gain?

Some people with hyperthyroidism might experience weight gain instead of the more common weight loss. Some reasons why that might happen include:

Increased appetite

Hyperthyroidism usually increases your appetite. If you’re taking in a lot more calories, you can gain weight even if your body is burning more energy. Make sure you eat healthy foods, get regular exercise, and work with a doctor on a nutrition plan. These steps can all help combat weight gain from an increased appetite.

Hyperthyroidism treatment

Hyperthyroidism is an abnormal state for your body. Treatment brings your body back to its normal state. Because of this, when you lose weight from hyperthyroidism, you might gain some weight back after you start treatment. Your body starts making less thyroid hormone than it was before.

Some weight gain from treatment is usually fine, especially if you lost a lot of weight before treatment. If you’re concerned, talk to your doctor. You may need to readjust your calorie intake as your treatment takes effect. If the side effects of treatment, including weight gain, are intolerable to you, your doctor can help you find a new treatment.

Thyroiditis

Thyroiditis is an inflammation of the thyroid. This can cause either too high or too low levels of thyroid hormone. The most common type of thyroiditis is Hashimoto disease. It’s also the most common cause of hypothyroidism.

In some rare cases, the immune response to Graves disease — the most common type of hyperthyroidism — can continue long enough to attack the thyroid and lead to inflammation. Therefore, it can cause Hashimoto disease, which can in turn cause weight gain.

Other symptoms of Hashimoto disease are:

  • fatigue
  • dry skin
  • constipation
  • depression

If you start experiencing any of these symptoms, see your doctor. They can help make a correct diagnosis and find the right treatment for you. Treatment for Hashimoto disease is generally thyroid hormone replacement pills.

Last week, actress Jenny Mollen shared a naked photo of herself on Instagram that quickly went viral. Mollen’s post isn’t popular because she’s baring it all, but because it shows off her protruding ribs with a warning that unexpected weight loss can be a sign of a serious illness.

“Not anorexia, it’s a thyroid issue … My doc thinks it’s Graves’,” she wrote, stressing that she is still waiting on blood work for confirmation.

Mollen, 38, is referring to Graves’ disease, an autoimmune disorder that occurs because of an over-active thyroid gland. It’s the most common cause of hyperthyroidism in the U.S. that causes people to lose weight even when they may be eating more.

“The weight loss is pretty dramatic, and it is usually unintentional,” Dr. Mayumi Endo, an assistant professor of endocrinology at The Ohio State University, told TODAY.

Mollen, who had her second baby with husband Jason Biggs six months ago, went to the doctor because she noticed a bulge on her neck. The thyroid, a butterfly-shaped organ nestled in the front of the neck, sometimes becomes swollen in those with Graves’ disease.

Symptoms of Graves’ disease

Trending stories,celebrity news and all the best of TODAY.

Mollen shared her dramatic photo to encourage others to pay attention to changes in their bodies.

“If you just had a baby and have lost an inordinate amount of weight … are suddenly heat intolerant, can’t stop losing hair, and think your husband is being a d–k it might just be your thyroid!! Get checked ASAP,” Mollen wrote.

According to the American Thyroid Association, common signs of hyperthyroidism include:

  • Muscle weakness and pain
  • Bulging eyes
  • Racing heart or palpitations
  • Sweating
  • Hand tremors
  • Nervousness or anxiety
  • Oily skin
  • Changes in bowel movements
  • Difficulty sleeping

Doctors often see women develop thyroid problems after giving birth. While some patients experience postpartum thyroiditis — a short-term form of hyperthyroidism that resolves itself — others experience overactive thyroids because of Graves’ disease.

“Graves’ disease is commonly diagnosed in the postpartum period,” said Dr. Elise Brett, an associate clinical professor at the Icahn School of Medicine at Mount Sinai in New York City. “The immune system is quiet in the pregnancy and then can rev up again after delivery.”

While it’s unclear whether pregnancy can trigger Graves’ disease, Brett stresses that men and women of all ages can develop the condition, though it’s more common in women.

Treatment is necessary

While some forms of hyperthyroidism resolve on their own, Graves’ disease does not. “This type of overactive thyroid needs to be treated,” Brett said. Left untreated, Graves’ disease can lead to irregular heartbeat and stroke.

Doctors often prescribe antithyroid drugs (like methimazole) for 12 to 18 months to regulate the thyroid. In about 30 percent of cases, Graves’ goes into remission. Another treatment option is a radioactive iodine drink that “knocks out” the thyroid disease. In some cases, surgical removal of their thyroid is necessary. These latter two options cause hypothyroidism, or an underactive thyroid, which requires patients take synthetic thyroid hormones.

Experts agree that patients should consult a doctor immediately if they have any signs of hyperthyroidism.

“Graves’ disease can be very serious,” said Brett.

Identification

Are you a new drug developer? Contact us to learn more about our customized products and solutions. Stay in the know! As part of our commitment to providing the most up-to-date drug information, we will be releasing #DrugBankUpdates with our newly added curated drug pages. #DrugBankUpdates Name Methimazole Accession Number DB00763 (APRD00002) Type Small Molecule Groups Approved Description

Methimazole is a thionamide antithyroid agent that inhibits the synthesis of thyroid hormones.6,14,12 It was first introduced as an antithyroid agent in 19492 and is now commonly used in the management of hyperthyroidism, particularly in those for whom more aggressive options such as surgery or radioactive iodine therapy are inappropriate.18,19

On a weight basis, methimazole is 10 times more potent than the other major antithyroid thionamide used in North America, propylthiouracil,19 and is the active metabolite of the pro-drug carbimazole, which is an antithyroid medication used in the United Kingdom and parts of the former British Commonwealth.14 Traditionally, methimazole has been preferentially used over propylthiouracil due to the risk of fulminant hepatotoxicity carried by the latter,15 with propylthiouracil being preferred in pregnancy due to a perceived lower risk of teratogenic effects. Despite documented teratogenic effects in its published labels,18,19 the true teratogenicity of methimazole appears to be unclear11,15,16 and its place in therapy may change in the future.

Structure 3D Download Similar Structures

Structure for Methimazole (DB00763)

× Close Synonyms

  • 1-Methylimidazole-2(3H)-thione
  • Methimazole
  • Thiamazol
  • Thiamazole
  • Thiamazolum
  • Tiamazol

External IDs NSC 38608 / USAF el-30 Product Images Prescription Products

Name Dosage Strength Route Labeller Marketing Start Marketing End
Unlock Additional Data
Methimazole Tablet 10 mg/1 Oral United Research Laboratories, Inc. 2006-04-19 Not applicable US
Methimazole Tablet 5 mg/1 Oral United Research Laboratories, Inc. 2006-04-19 Not applicable US
Methimazole Tablets USP Tablet Oral Endo Ventures Ltd Not applicable Not applicable Canada
Methimazole Tablets USP Tablet Oral Endo Ventures Ltd Not applicable Not applicable Canada
Methimazole Tablets USP Tablet Oral Endo Ventures Ltd Not applicable Not applicable Canada
Tapazole Tablet 10 mg Oral Paladin Labs Inc 2008-01-07 Not applicable Canada
Tapazole Tablet 20 mg Oral Paladin Labs Inc Not applicable Not applicable Canada
Tapazole 5mg Tablet Tablet Oral Paladin Labs Inc 1951-12-31 Not applicable Canada

Additional Data Available

  • Application Number Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

    Learn more

  • Product Code Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

    Learn more

Generic Prescription Products

Name Dosage Strength Route Labeller Marketing Start Marketing End
Unlock Additional Data
Apo-methimazole Tablet Oral Apotex Corporation 2005-03-18 Not applicable Canada
Dom-methimazole Tablet Oral Dominion Pharmacal Not applicable Not applicable Canada
Jamp Methimazole Tablet Oral Jamp Pharma Corporation Not applicable Not applicable Canada
Jamp Methimazole Tablet Oral Jamp Pharma Corporation Not applicable Not applicable Canada
Mar-methimazole Tablet Oral Marcan Pharmaceuticals Inc 2018-10-19 Not applicable Canada
Mar-methimazole Tablet Oral Marcan Pharmaceuticals Inc 2018-10-19 Not applicable Canada
Methimazole Tablet 10 mg/1 Oral State of Florida DOH Central Pharmacy 2013-01-01 Not applicable US
Methimazole Tablet 5 mg/1 Oral American Health Packaging 2010-03-02 2019-11-30 US
Methimazole Tablet 10 mg/1 Oral Nucare Pharmaceuticals,inc. 2012-01-15 Not applicable US
Methimazole Tablet 5 mg/1 Oral A-S Medication Solutions 2015-09-28 Not applicable US

Additional Data Available

  • Application Number Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

    Learn more

  • Product Code Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

    Learn more

International/Other Brands Danantizol (Gador S.A.) / Favistan (Temmler) / Metizol (ICN) / Strumazol (Organon) / Strumazole / Thacapzol (Recip) / Thycapzol (Sandoz) / Thyrozol (Merck) / Tirozol (Merck) Categories UNII 554Z48XN5E CAS number 60-56-0 Weight Average: 114.169
Monoisotopic: 114.025168892 Chemical Formula C4H6N2S InChI Key PMRYVIKBURPHAH-UHFFFAOYSA-N InChI InChI=1S/C4H6N2S/c1-6-3-2-5-4(6)7/h2-3H,1H3,(H,5,7) IUPAC Name 1-methyl-2,3-dihydro-1H-imidazole-2-thione SMILES CN1C=CNC1=S

Pharmacology

Indication

In the United States, methimazole is indicated for the treatment of hyperthyroidism in patients with Graves’ disease or toxic multinodular goiter for whom thyroidectomy or radioactive iodine therapy are not appropriate treatment options. Methimazole is also indicated for the amelioration of hyperthyroid symptoms in preparation for thyroidectomy or radioactive iodine therapy.18

In Canada, methimazole carries the above indications and is also indicated for the medical treatment of hyperthyroidism regardless of other available treatment options.19

Associated Conditions

  • Graves’ Disease
  • Hyperthyroidism
  • Toxic multinodular goiter

Pharmacodynamics

Methimazole inhibits the synthesis of thyroid hormones resulting in an alleviation of hyperthyroidism.18,19 Onset of action occurs within 12 to 18 hours, and its duration of action is 36 to 72 hours, likely due to concentration of methimazole and some metabolites within the thyroid gland after administration.11

The most serious potential side effect of methimazole therapy is agranulocytosis, and patients should be instructed to monitor for, and report, any signs or symptoms of agranulocytosis such as fever or sore throat. Other cytopenias may also occur during methimazole therapy. There also exists the potential for severe hepatic toxicity with the use of methimazole, and monitoring for signs and symptoms of hepatic dysfunction, such as jaundice, anorexia, pruritus, and elevation in liver transaminases, is prudent in patients using this therapy.18,19

Mechanism of action

Methimazole’s primary mechanism of action appears to be interference in an early step in thyroid hormone synthesis involving thyroid peroxidase (TPO), however the exact method through which methimazole inhibits this step is unclear.6 TPO, along with hydrogen peroxide, normally catalyzes the conversion of iodide to iodine and then further catalyzes the incorporation of this iodine onto the 3 and/or 5 positions of the phenol rings of tyrosine residues in thyroglobulin. These thyroglobulin molecules then degrade within thyroid follicular cells to form either thyroxine (T4) or tri-iodothyronine (T3), which are the main hormones produced by the thyroid gland.13

Methimazole may directly inhibit TPO, but has been shown in vivo to instead act as a competitive substrate for TPO, thus becoming iodinated itself and interfering with the iodination of thyroglobulin.6 Another proposed theory is that methimazole’s sulfur moiety may interact directly with the iron atom at the centre of TPO’s heme molecule, thus inhibiting its ability to iodinate tyrosine residues.12 Other proposed mechanisms with weaker evidence include methimazole binding directly to thyroglobulin or direct inhibition of thyroglobulin itself.6

Target Actions Organism
AThyroid peroxidase substrate inhibitor Humans

Unlock Additional Data Additional Data Available Adverse Effects

Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.

Learn more Additional Data Available Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

Learn more Additional Data Available Blackbox Warnings

Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.

Learn more Absorption

Absorption of methimazole after oral administration is rapid and extensive,3,5,1 with an absolute bioavailability of approximately 0.931 and a Tmax ranging from 0.25 to 4.0 hours.3,1 Cmax is slightly, but not significantly, higher in hyperthyroid patients, and both Cmax and AUC are significantly affected by the oral dose administered.3

Volume of distribution

The apparent volume of distribution of methimazole has been reported as roughly 20 L.5 Following oral administration, methimazole is highly concentrated in the thyroid gland – intrathyroidal methimazole levels are approximately 2 to 5 times higher than peak plasma levels, and remain high for 20 hours after ingestion.6

Protein binding

Methimazole exhibits little-to-no protein binding, existing primarily as free drug in the serum.4,5,11

Metabolism

Methimazole is rapidly and extensively metabolized by the liver, mainly via the CYP450 and FMO enzyme systems.7,8 Several metabolites have been identified, though the specific enzyme isoforms responsible for their formation are not entirely clear. One of the first methimazole metabolites identified, 3-methyl-2-thiohydantoin, may contribute to antithyroid activity – its antithyroid activity has been demonstrated in rats and may explain the prolonged duration of iodination inhibition following administration despite methimazole’s relatively short half-life.5

A number of metabolites have been investigated as being the culprits behind methimazole-induced hepatotoxicity. Both glyoxal and N-methylthiourea have established cytotoxicity and are known metabolic products of methimazole’s dihydrodiol intermediate. Sulfenic and sulfinic acid derivatives of methimazole are thought to be the ultimate toxicants responsible for hepatotoxicity, though their origin is unclear – they may arise from direct oxidation of methimazole via FMO, or from oxidation of N-methylthiourea further downstream in the metabolic process.7,8

  • Methimazole Methimazole Epoxide Metabolite
    • Methimazole Epoxide Metabolite Methimazole Dihydrodiol Metabolite
      • Methimazole Dihydrodiol Metabolite Methimazole Glyoxal Metabolite
      • Methimazole Dihydrodiol Metabolite Methimazole N-methyl Thiourea Metabolite
        • Methimazole N-methyl Thiourea Metabolite Methimazole Sulfenic Acid Metabolite (Open)
          • Methimazole Sulfenic Acid Metabolite (Open) Methimazole Sulfinic Acid Metabolite (Open)
  • Methimazole Methimazole Sulfenic Acid Metabolite (Ring)
    • Methimazole Sulfenic Acid Metabolite (Ring) Methimazole Sulfinic Acid Metabolite (Ring)
  • Methimazole 3-methyl-2-thiohydantoin

Route of elimination

Urinary excretion of unchanged methimazole has been reported to be between 7% and 12%. Elimination via feces appears to be limited, with a cumulative fecal excretion of 3% after administration of methimazole.3 Enterohepatic circulation also appears to play a role in the elimination of methimazole and its metabolites, as significant amounts of these substances are found in the bile post-administration.11

Half life

Following a single intravenous bolus injection of 10mg of methimazole, the t1/2 of the distribution phase was 0.17 hours and the t1/2 of the elimination phase was 5.3 hours.1 Methimazole’s primary active metabolite, 3-methyl-2-thiohydantoin, has a half-life approximately 3 times longer than its parent drug.5 Renal impairment does not appear to alter the half-life of methimazole, but patients with hepatic impairment showed an increase in half-life roughly proportional to the severity of their impairment – moderate insufficiency resulted in a elimination t1/2 of 7.1 hours, while severe insufficiency resulted in an elimination t1/2 of 22.1 hours.1

There does not appear to be any significant differences in half-life based on thyroid status (i.e. no difference between euthyroid and hyperthyroid patients).1,2,3

Clearance

Following a single intravenous bolus injection of 10mg of methimazole, clearance was found to be 5.70 L/h.1 Renal impairment does not appear to alter clearance of methimazole, but patients with hepatic impairment showed a reduction in clearance roughly proportional to the severity of their impairment – moderate insufficiency resulted in a clearance of 3.49 L/h, while severe insufficiency resulted in a clearance of 0.83 L/h.1

There does not appear to be any significant differences in clearance based on thyroid status (i.e. no difference between euthyroid and hyperthyroid patients).1,2,3

Toxicity

The oral LD50 of methimazole in rats is 2250 mg/kg.17 Signs and symptoms of methimazole overdose may include gastrointestinal distress, headache, fever, joint pain, pruritus, and edema. More serious adverse effects, such as aplastic anemia or agranulocytosis, may manifest within hours to days.18,19 Hepatitis, nephrotic syndrome, exfoliative dermatitis, and CNS effects such as neuropathy or CNS depression/stimulation are also potential, albeit less frequent, results of overdose.18,19

Management of overdose involves supportive treatment as dictated by the patient’s status.18,19 This may involve monitoring of the patient’s vital signs, blood gases, serum electrolytes, or bone marrow function as indicated.19

Affected organisms

  • Humans and other mammals

Pathways Not Available Pharmacogenomic Effects/ADRs Not Available

Interactions

Drug Interactions This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

  • All Drugs
  • Approved
  • Vet approved
  • Nutraceutical
  • Illicit
  • Withdrawn
  • Investigational
  • Experimental
Drug Interaction
Unlock Additional Data
(R)-warfarin Methimazole may decrease the anticoagulant activities of (R)-warfarin.
(S)-Warfarin Methimazole may decrease the anticoagulant activities of (S)-Warfarin.
2-Methoxyethanol The risk or severity of adverse effects can be increased when Methimazole is combined with 2-Methoxyethanol.
2,5-Dimethoxy-4-ethylamphetamine The risk or severity of adverse effects can be increased when 2,5-Dimethoxy-4-ethylamphetamine is combined with Methimazole.
2,5-Dimethoxy-4-ethylthioamphetamine The risk or severity of adverse effects can be increased when 2,5-Dimethoxy-4-ethylthioamphetamine is combined with Methimazole.
3–2-indolinone The therapeutic efficacy of Methimazole can be decreased when used in combination with 3–2-indolinone.
3-isobutyl-1-methyl-7H-xanthine Methimazole may decrease the excretion rate of 3-isobutyl-1-methyl-7H-xanthine which could result in a higher serum level.
4-Bromo-2,5-dimethoxyamphetamine The risk or severity of adverse effects can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Methimazole.
4-hydroxycoumarin Methimazole may decrease the anticoagulant activities of 4-hydroxycoumarin.
4-Methoxyamphetamine The metabolism of 4-Methoxyamphetamine can be decreased when combined with Methimazole.

Additional Data Available

  • Extended Description Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

    Learn more

  • Severity Severity

    A severity rating for each drug interaction, from minor to major.

    Learn more

  • Evidence Level Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

    Learn more

  • Action Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

    Learn more

Food Interactions

  • Always take at the same moment in regard to meals, food may affect absorption unpredictably.

Synthesis Reference

李光文李剑平倪国成, “Methimazole synthesizing and purifying method.” Chinese Patent CN107162983A, published September, 2017.

General References External Links Human Metabolome Database HMDB0014901 KEGG Drug D00401 KEGG Compound C07190 PubChem Compound 1349907 PubChem Substance 46506536 ChemSpider 1131173 BindingDB 50241361 ChEBI 50673 ChEMBL CHEMBL1515 Therapeutic Targets Database DNC001429 PharmGKB PA450422 HET MMZ RxList RxList Drug Page Drugs.com Drugs.com Drug Page Wikipedia Methimazole ATC Codes H03BB52 — Thiamazole, combinations

  • H03BB — Sulfur-containing imidazole derivatives
  • H03B — ANTITHYROID PREPARATIONS
  • H03 — THYROID THERAPY
  • H — SYSTEMIC HORMONAL PREPARATIONS, EXCL. SEX HORMONES AND INSULINS

H03BB02 — Thiamazole

  • H03BB — Sulfur-containing imidazole derivatives
  • H03B — ANTITHYROID PREPARATIONS
  • H03 — THYROID THERAPY
  • H — SYSTEMIC HORMONAL PREPARATIONS, EXCL. SEX HORMONES AND INSULINS

AHFS Codes

  • 68:36.08 — Antithyroid Agents

PDB Entries 2gvc / 5ff1 / 5gsn

Clinical Trials

Clinical Trials

Phase Status Purpose Conditions Count
1, 2 Completed Treatment Graves´ Disease / Thyroid Associated Ophthalmopathy 1
2 Completed Treatment Dermatomyositis / Polymyositis 1
2 Terminated Supportive Care Glioblastoma Multiforme (GBM) 1
3 Recruiting Treatment Graves Diseases / Graves’ Ophthalmopathy Worsened / Thyroid Eye Disease 1
4 Completed Prevention Graves´ Disease 1
4 Completed Treatment Graves Diseases / Toxic Nodular Goitre 1
4 Completed Treatment Graves’ Disease 1
4 Completed Treatment Graves’ Disease / Toxic Nodular Goitre 1
4 Unknown Status Diagnostic Healthy Volunteers 1
Not Available Active Not Recruiting Not Available Hyperthyroidism 1
Not Available Completed Not Available Graves Diseases 1
Not Available Completed Treatment Graves Diseases 1
Not Available Completed Treatment Graves’ Disease 1
Not Available Recruiting Not Available Gut Microbiota 1
Not Available Recruiting Not Available Hyperthyroidism 1
Not Available Recruiting Not Available Microbiota 2
Not Available Terminated Treatment Thyroid Eye Disease 1

Pharmacoeconomics

Manufacturers

  • Actavis totowa llc
  • Caraco pharmaceutical laboratories ltd
  • Cedar pharmaceuticals llc
  • Mylan pharmaceuticals inc
  • Sandoz inc
  • King pharmaceuticals inc
  • King pharmaceuticals research and development inc sub king pharmaceuticals inc

Packagers

  • AAIPharma Inc.
  • Actavis Group
  • Amerisource Health Services Corp.
  • Caraco Pharmaceutical Labs
  • Cedar Pharmaceuticals LLC
  • Centrix Pharmaceuticals
  • Dispensing Solutions
  • Eon Labs
  • Heartland Repack Services LLC
  • Kaiser Foundation Hospital
  • King Pharmaceuticals Inc.
  • Medisca Inc.
  • Mikart Inc.
  • Murfreesboro Pharmaceutical Nursing Supply
  • Mylan
  • Nucare Pharmaceuticals Inc.
  • Par Pharmaceuticals
  • Philopharm GmbH
  • Physicians Total Care Inc.
  • Remedy Repack
  • Resource Optimization and Innovation LLC
  • Southwood Pharmaceuticals
  • United Research Laboratories Inc.
  • Vangard Labs Inc.

Dosage forms

Form Route Strength
Tablet Oral 10 mg/1
Tablet Oral 5 mg/1
Tablet Oral 10 mg
Tablet Oral 20 mg
Tablet Oral

Prices

Unit description Cost Unit
Methimazole powder 9.49USD g
Methimazole 20 mg tablet 1.9USD tablet
Tapazole 10 mg tablet 1.45USD tablet
Northyx 20 mg tablet 0.94USD tablet
Northyx 15 mg tablet 0.82USD tablet
Methimazole 10 mg tablet 0.78USD tablet
Tapazole 5 mg tablet 0.66USD tablet
Northyx 10 mg tablet 0.47USD tablet
Methimazole 5 mg tablet 0.45USD tablet
Northyx 5 mg tablet 0.29USD tablet

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only. Patents Not Available

Properties

State Solid Experimental Properties

Property Value Source
melting point (°C) 143-146 °C DPD Label (Canada)
water solubility Freely soluble DPD Label (Canada)

Predicted Properties

Property Value Source
Water Solubility 11.3 mg/mL ALOGPS
logP -0.38 ALOGPS
logP 0.75 ChemAxon
logS -1 ALOGPS
pKa (Strongest Acidic) 10.41 ChemAxon
pKa (Strongest Basic) -3 ChemAxon
Physiological Charge 0 ChemAxon
Hydrogen Acceptor Count 0 ChemAxon
Hydrogen Donor Count 1 ChemAxon
Polar Surface Area 15.27 Å2 ChemAxon
Rotatable Bond Count 0 ChemAxon
Refractivity 33.23 m3·mol-1 ChemAxon
Polarizability 11.64 Å3 ChemAxon
Number of Rings 1 ChemAxon
Bioavailability 1 ChemAxon
Rule of Five Yes ChemAxon
Ghose Filter No ChemAxon
Veber’s Rule Yes ChemAxon
MDDR-like Rule No ChemAxon

Predicted ADMET features

Property Value Probability
Human Intestinal Absorption + 0.9156
Blood Brain Barrier + 0.9731
Caco-2 permeable + 0.6156
P-glycoprotein substrate Non-substrate 0.8213
P-glycoprotein inhibitor I Non-inhibitor 0.7552
P-glycoprotein inhibitor II Non-inhibitor 0.944
Renal organic cation transporter Non-inhibitor 0.7662
CYP450 2C9 substrate Non-substrate 0.7919
CYP450 2D6 substrate Non-substrate 0.8985
CYP450 3A4 substrate Non-substrate 0.7849
CYP450 1A2 substrate Non-inhibitor 0.9045
CYP450 2C9 inhibitor Non-inhibitor 0.9071
CYP450 2D6 inhibitor Non-inhibitor 0.9232
CYP450 2C19 inhibitor Non-inhibitor 0.9025
CYP450 3A4 inhibitor Non-inhibitor 0.8309
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.7105
Ames test Non AMES toxic 0.8582
Carcinogenicity Non-carcinogens 0.9348
Biodegradation Not ready biodegradable 0.9815
Rat acute toxicity 1.8215 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9401
hERG inhibition (predictor II) Non-inhibitor 0.8416

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST) (8.12 KB) Spectra

Taxonomy

Description This compound belongs to the class of organic compounds known as imidazolethiones. These are aromatic compounds containing an imidazole ring which bears a thioketone group. Kingdom Organic compounds Super Class Organoheterocyclic compounds Class Azolines Sub Class Imidazolines Direct Parent Imidazolethiones Alternative Parents N-substituted imidazoles / Heteroaromatic compounds / Thioureas / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Hydrocarbon derivatives Substituents N-substituted imidazole / Imidazole-2-thione / Heteroaromatic compound / Imidazole / Azole / Thiourea / Azacycle / Organic nitrogen compound / Organopnictogen compound / Hydrocarbon derivative Molecular Framework Aromatic heteromonocyclic compounds External Descriptors imidazoles, thioureas (CHEBI:50673) / a small molecule (CPD-11282)

Targets

Kind Protein Organism Humans Pharmacological action Yes Actions Substrate Inhibitor General Function Peroxidase activity Specific Function Iodination and coupling of the hormonogenic tyrosines in thyroglobulin to yield the thyroid hormones T(3) and T(4). Gene Name TPO Uniprot ID P07202 Uniprot Name Thyroid peroxidase Molecular Weight 102961.63 Da

Enzymes

Kind Protein Organism Humans Pharmacological action Unknown Actions Inhibitor Curator comments Supporting data are limited to in vitro studies. General Function Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen Specific Function Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un… Gene Name CYP1A2 Uniprot ID P05177 Uniprot Name Cytochrome P450 1A2 Molecular Weight 58293.76 Da

  1. Guo Z, Raeissi S, White RB, Stevens JC: Orphenadrine and methimazole inhibit multiple cytochrome P450 enzymes in human liver microsomes. Drug Metab Dispos. 1997 Mar;25(3):390-3.

Kind Protein Organism Humans Pharmacological action Unknown Actions Inhibitor General Function Steroid hydroxylase activity Specific Function Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Const… Gene Name CYP2A6 Uniprot ID P11509 Uniprot Name Cytochrome P450 2A6 Molecular Weight 56501.005 Da Kind Protein Organism Humans Pharmacological action Unknown Actions Inhibitor General Function Steroid hydroxylase activity Specific Function Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un… Gene Name CYP2B6 Uniprot ID P20813 Uniprot Name Cytochrome P450 2B6 Molecular Weight 56277.81 Da Kind Protein Organism Humans Pharmacological action Unknown Actions Inhibitor Curator comments Current data supporting this enzyme inhibition is limited to one in vitro study. General Function Steroid hydroxylase activity Specific Function Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im… Gene Name CYP2C19 Uniprot ID P33261 Uniprot Name Cytochrome P450 2C19 Molecular Weight 55930.545 Da

  1. Guo Z, Raeissi S, White RB, Stevens JC: Orphenadrine and methimazole inhibit multiple cytochrome P450 enzymes in human liver microsomes. Drug Metab Dispos. 1997 Mar;25(3):390-3.

Kind Protein Organism Humans Pharmacological action Unknown Actions Inhibitor Curator comments Data supporting this enzyme action are limited to the findings of 1 in vitro study. General Function Steroid hydroxylase activity Specific Function Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un… Gene Name CYP2C9 Uniprot ID P11712 Uniprot Name Cytochrome P450 2C9 Molecular Weight 55627.365 Da

  1. Guo Z, Raeissi S, White RB, Stevens JC: Orphenadrine and methimazole inhibit multiple cytochrome P450 enzymes in human liver microsomes. Drug Metab Dispos. 1997 Mar;25(3):390-3.

Kind Protein Organism Humans Pharmacological action Unknown Actions Inhibitor General Function Steroid hydroxylase activity Specific Function Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic… Gene Name CYP2D6 Uniprot ID P10635 Uniprot Name Cytochrome P450 2D6 Molecular Weight 55768.94 Da

  1. Guo Z, Raeissi S, White RB, Stevens JC: Orphenadrine and methimazole inhibit multiple cytochrome P450 enzymes in human liver microsomes. Drug Metab Dispos. 1997 Mar;25(3):390-3.

Kind Protein Organism Humans Pharmacological action Unknown Actions Inhibitor General Function Steroid hydroxylase activity Specific Function Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic … Gene Name CYP2E1 Uniprot ID P05181 Uniprot Name Cytochrome P450 2E1 Molecular Weight 56848.42 Da Kind Protein Organism Humans Pharmacological action Unknown Actions Inhibitor General Function Vitamin d3 25-hydroxylase activity Specific Function Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react… Gene Name CYP3A4 Uniprot ID P08684 Uniprot Name Cytochrome P450 3A4 Molecular Weight 57342.67 Da

  1. Guo Z, Raeissi S, White RB, Stevens JC: Orphenadrine and methimazole inhibit multiple cytochrome P450 enzymes in human liver microsomes. Drug Metab Dispos. 1997 Mar;25(3):390-3.

Kind Protein Organism Humans Pharmacological action Unknown Actions Substrate General Function Trimethylamine monooxygenase activity Specific Function Involved in the oxidative metabolism of a variety of xenobiotics such as drugs and pesticides. It N-oxygenates primary aliphatic alkylamines as well as secondary and tertiary amines. Plays an impor… Gene Name FMO3 Uniprot ID P31513 Uniprot Name Dimethylaniline monooxygenase 3 Molecular Weight 60032.975 Da ×

Unlock Data

There is additional data available for commercial users including Adverse Effects, Contraindications, and Blackbox Warnings. Contact us to learn more about these and other features.

Learn more

Drug created on June 13, 2005 07:24 / Updated on February 02, 2020 00:19

Comparison of Methimazole and Propylthiouracil in Patients with Hyperthyroidism Caused by Graves’ Disease

Abstract

Context: Although methimazole (MMI) and propylthiouracil (PTU) have long been used to treat hyperthyroidism caused by Graves’ disease (GD), there is still no clear conclusion about the choice of drug or appropriate initial doses.

Objective: The aim of the study was to compare the MMI 30 mg/d treatment with the PTU 300 mg/d and MMI 15 mg/d treatment in terms of efficacy and adverse reactions.

Design, Setting, and Participants: Patients newly diagnosed with GD were randomly assigned to one of the three treatment regimens in a prospective study at four Japanese hospitals.

Main Outcome Measures: Percentages of patients with normal serum free T4 (FT4) or free T3 (FT3) and frequency of adverse effects were measured at 4, 8, and 12 wk.

Results: MMI 30 mg/d normalized FT4 in more patients than PTU 300 mg/d and MMI 15 mg/d for the whole group (240 patients) at 12 wk (96.5 vs. 78.3%; P = 0.001; and 86.2%, P = 0.023, respectively). When patients were divided into two groups by initial FT4, in the group of the patients with severe hyperthyroidism (FT4, 7 ng/dl or more, 64 patients) MMI 30 mg/d normalized FT4 more effectively than PTU 300 mg/d at 8 and 12 wk and MMI 15 mg/d at 8 wk, respectively (P < 0.05). No remarkable difference between the treatments was observed in patients with initial FT4 less than 7 ng/dl. Adverse effects, especially mild hepatotoxicity, were higher with PTU and significantly lower with MMI 15 mg/d compared with MMI 30 mg/d.

Conclusions: MMI 15 mg/d is suitable for mild and moderate GD, whereas MMI 30 mg/d is advisable for severe cases. PTU is not recommended for initial use.

DESPITE METHIMAZOLE (MMI) and propylthiouracil (PTU) having been used for more than half a century to treat hyperthyroidism caused by Graves’ disease (GD), controversy still exists in antithyroid drug (ATD) therapy. For example, according to a survey reported in 1991, MMI was selected as the drug for initial treatment in Japan and Europe, whereas PTU was preferred in the United States (1). Which is more suitable, MMI or PTU, in terms of drug efficacy or adverse effects? In Japan, treatment with MMI 30 mg daily has been “a standard regimen” for GD for a long time, but some reports have insisted that a smaller dosage such as 15 mg daily of MMI is as effective as the standard of 30 mg (2–4). How much should the initial ATD dosage be, a moderate dosage such as 30 mg daily of MMI or a smaller dosage of 15 mg?

The Japan Thyroid Association has been formulating a guideline for the treatment of hyperthyroidism caused by GD, but the data collected on ATD therapy over time were indeterminate on drug selection or suitable starting dosage. Therefore, we undertook this prospective randomized clinical study on initial treatments for thyrotoxic GD to decide the most suitable regimen by comparing the standard treatment of MMI 30 mg/d with PTU 300 mg/d and MMI 15 mg/d in terms of the short-term efficacy and adverse effects.

Patients and Methods

Patients

Only patients with untreated hyperthyroidism due to GD were recruited. GD was diagnosed according to Japan Thyroid Association’s diagnosis guidelines (http://thyroid.umin.ac.jp/en/frame.html), defined by clinical findings and the determination of serum free T4 (FT4), free T3 (FT3), TSH, TSH receptor antibody (TRAb), and 123I- or 99mTc-uptake. The following conditions excluded patients from the study: age younger than 16 yr old; pregnancy; relapsed patients after subtotal thyroidectomy or radioiodine therapy; previous treatment with ATD; severe complications, such as heart failure; and patients on glucocorticoid steroids or drugs that may influence thyroid functions.

Study design

This study was conducted as an open prospective randomized trial, with an observation period of 12 wk. Four hospitals in Japan, Ito Hospital in Tokyo, Kuma Hospital in Kobe, Sumire Hospital in Osaka, and Hamamatsu University Hospital in Hamamatsu, participated in the study. The Ethical Committee of Hamamatsu University School of Medicine and each hospital involved in the study approved the protocol. All eligible patients with untreated GD seen by the four participating hospitals from October 2003 to July 2004 were registered for the trial after obtaining informed consent. To compare the efficiency between MMI 30 mg/d and PTU 300 mg/d or MMI 15 mg/d, patients were distributed at random to the group with MMI 30 mg/d in two divided doses, PTU 300 mg/d in three divided doses or MMI 15 mg/d in a single dose. The necessary sample size was estimated by statistical calculation. For example, when type I error is 0.05, power is 0.8, and efficacy is 60% vs. 40%, 82 patients in each group are required. The method of assigning patients to groups was by their admission order at the outpatient clinic in Sumire Hospital and Hamamatsu University Hospital, and by the day of the week when patients first visited the outpatient clinic in Ito Hospital and Kuma Hospital.

A total of 396 patients with untreated GD were initially recruited for the study, with 93 patients excluded from the final analysis of the ATD treatment due to the reasons in Table 1. The percentage of withdrawal was less in the MMI 15-mg group than for other groups due to the significantly less occurrence of early adverse effects. Finally, 303 patients (134 patients at Ito Hospital, 92 at Kuma Hospital, 62 at Hamamatsu University Hospital and 15 at Sumire Hospital) were evaluated. For the adverse event analysis, 371 patients (excluding 25 dropout patients) were examined.

TABLE 1.

Patient groupings and data

A total of 396 patients with untreated GD were initially recruited for the study, with 93 patients excluded from the final evaluation for short-term efficacy of the ATD treatments due to side effects within 4 wk, not visiting a hospital regularly, or dropout. Finally, 303 patients (134 patients at Ito Hospital, 92 at Kuma Hospital, 62 at Hamamatsu University Hospital, and 15 at Sumire Hospital) were analyzed. For the adverse event analysis, 371 patients excluding 25 dropout patients were examined.

TABLE 1.

Patient groupings and data

A total of 396 patients with untreated GD were initially recruited for the study, with 93 patients excluded from the final evaluation for short-term efficacy of the ATD treatments due to side effects within 4 wk, not visiting a hospital regularly, or dropout. Finally, 303 patients (134 patients at Ito Hospital, 92 at Kuma Hospital, 62 at Hamamatsu University Hospital, and 15 at Sumire Hospital) were analyzed. For the adverse event analysis, 371 patients excluding 25 dropout patients were examined.

Patients were scheduled to visit the hospitals at 2, 4, 8, and 12 wk after initiation of their treatment. Adverse effects of the drugs were looked for systematically by careful health interview and clinical examinations. Aspirate aminotransferase (AST), alanine aminotransferase (ALT), γ glutamyl transpeptidase, and hematological values were measured for evaluation every visit to the outpatient clinic. Serum FT4 and FT3 with or without TSH were assayed at 4, 8, and 12 wk. When serum FT4 and FT3 were both within normal ranges (FT4, 0.8–1.6 ng/dl; FT3, 3.1–4.9 pg/ml), the dosages of ATD were lessened as follows: MMI from 30 to 15 mg; from 15 to 10 mg; and PTU from 300 to 150 mg. After that, patients were given suitable doses of ATD to maintain normal thyroid hormone (TH) concentrations. When necessary, β-blocker was given concomitantly. The initial dose of ATD was continued without increasing for 12 wk, even if TH did not fall into the normal range. Each of the four hospitals obtained the values for serum FT4 and FT3 within 60 min after taking blood samples at outpatient clinics, and doctors could decide the dose of ATD after checking hormone values.

The number of patients finally analyzed for ATD effectiveness was 98 in the MMI 30-mg, 81 in the PTU 300-mg, and 124 in the MMI 15-mg groups, respectively. The ratio of sex, values for age, and initial TRAb before treatment did not differ between groups (Table 1). Before ATD treatment, all patients had elevated FT4 levels more than 2 ng/dl.

Methods

Serum FT4, FT3, and TSH were measured with a Roche ECLusys kit (Roche, Basel, Switzerland) in Ito Hospital, Sumire Hospital, and Hamamatsu University Hospital, or Architect kits (Abbott Japan Co., Ltd, Osaka 540-0001 Japan) in Kuma Hospital. Although values for the hormones obtained by these two assay kits differed slightly, the data were combined for the analyses because the difference was small (data not shown). The normal values and measurable ranges are as follows: FT4 0.8–1.6 ng/dl (measurable range up to 7 ng/dl), FT3 3.1–4.9 pg/ml (measurable range up to 30 pg/ml). TRAb (normal range 0–10%) was assayed with TRAb-CT (Cosmic Corporation, Tokyo, Japan).

Statistical analysis

Data were analyzed statistically using the χ2 test for independence and comparison of frequencies. When expected values less than 5 are included in the table of the data, Fisher’s exact probability test was used instead of the χ2 test. For comparison of age and TRAb values among the three groups, ANOVA was used. Calculations were performed using StatView, version 5.0 (SAS Institute Inc., Cary, NC). Statistical significance was defined as P < 0.05.

Results

Comparisons of the efficiency of the MMI 30 mg/d treatment with that of the PTU 300 mg/d and MMI 15 mg/d treatment

Fig. 1.

Comparison of the efficiency of treatment with MMI 30 mg/d and PTU 300 mg/d or MMI 15 mg/d in whole patients with GD in terms of normalizing serum FT4 levels . The numbers in the columns show patients with normal FT4/total patients. The numbers above the columns are P values of χ2 analyses between MMI 30 mg/d and PTU 300 mg/d or MMI 15 mg/d. #, Significantly different among three treatment groups. *, Statistically significant between MMI 30 mg/d and PTU 300 mg/d or MMI 15 mg/d. W, Weeks.

Fig. 1.

Comparison of the efficiency of treatment with MMI 30 mg/d and PTU 300 mg/d or MMI 15 mg/d in whole patients with GD in terms of normalizing serum FT4 levels . The numbers in the columns show patients with normal FT4/total patients. The numbers above the columns are P values of χ2 analyses between MMI 30 mg/d and PTU 300 mg/d or MMI 15 mg/d. #, Significantly different among three treatment groups. *, Statistically significant between MMI 30 mg/d and PTU 300 mg/d or MMI 15 mg/d. W, Weeks.

Because the severity of hyperthyroidism varied among the patients, we divided the patients into two groups according to their pretreatment serum FT4 values; group A included patients with initial FT4 less than 7 ng/dl and group B with 7 ng/dl or more. There was no difference in the pretreatment FT4 and FT3 values in group A (data not shown), and almost all patients in group B had FT4 above the measurable range. In group A, no difference was found between the treatments at 4 and 8 wk, but at 12 wk, MMI 30 mg/d achieved normal FT4 in every patient, while PTU 300 mg/d and MMI 15 mg/d induced normal FT4 in 87.5% and 92%, respectively, with a statistically significant difference (Fig. 2, upper). In group B, MMI 30 mg/d is clearly more effective than PTU 300 mg/d and MMI 15 mg/d in normalizing FT4. At 4 wk after beginning treatment, 38.5% of the patients achieved normal FT4 with MMI 30 mg/d, but only 13.0% with PTU 300 mg/d and 14.3% with MMI 15 mg/d, with both about 35–40% efficiency of MMI 30 mg/d in normalizing FT4. The same tendency was observed at 8 and 12 wk also (Fig. 2, lower).

Fig. 2.

Comparison of the efficiency of treatment with MMI 30 mg/d and PTU 300 mg/d or MMI 15 mg/d in patients with GD in terms of normalizing serum FT4 levels . The patients were divided into two groups according to their pretreatment serum FT4 values: group A with initial FT4 less than 7 ng/dl (90 pmol/l) (upper) and group B with 7 ng/dl or more (lower). The numbers in the columns show patients with normal FT4/total patients. The numbers above the columns are P values of χ2 analyses between MMI 30 mg/d and PTU 300 mg/d or MMI 15 mg/d. #, Significantly different among three treatment groups. *, Statistically significant between MMI 30 mg/d and PTU 300 mg/d or MMI 15 mg/d. W, Weeks.

Fig. 2.

Comparison of the efficiency of treatment with MMI 30 mg/d and PTU 300 mg/d or MMI 15 mg/d in patients with GD in terms of normalizing serum FT4 levels . The patients were divided into two groups according to their pretreatment serum FT4 values: group A with initial FT4 less than 7 ng/dl (90 pmol/l) (upper) and group B with 7 ng/dl or more (lower). The numbers in the columns show patients with normal FT4/total patients. The numbers above the columns are P values of χ2 analyses between MMI 30 mg/d and PTU 300 mg/d or MMI 15 mg/d. #, Significantly different among three treatment groups. *, Statistically significant between MMI 30 mg/d and PTU 300 mg/d or MMI 15 mg/d. W, Weeks.

When the efficiency of these ATD regimens was analyzed in terms of achieving normal FT3 levels (<5 pg/ml), a similar tendency was found, although the difference was less evident (Table 2). For whole patients, MMI 30 mg/d induced normal FT3 more efficiently than PTU 300 mg/d at 8 wk (75.6% vs. 57.4%, respectively; P = 0.021) and 12 wk (90.0% vs. 62.9%, respectively; P < 0.001). When the patients in groups A and B were analyzed, there was no difference between the treatments at 4 and 8 wk, but at 12 wk, MMI 30 mg/d was more effective than PTU 300 mg/d and MMI 15 mg/d. The efficiency to achieve normal FT3 level was almost half with PTU 300 mg/d compared with MMI 30 mg/d (66.7 vs. 35.0%, respectively; P = 0.043) in group B. No relation was found between the efficacy of ATD to normalize TH and age, sex, initial TRAb values, or goiter size (data not shown).

TABLE 2.

Comparison of the efficiency of treatment with MMI 30 mg/d and PTU 300 mg/d or MMI 15 mg/d in patients with GD in terms of normalizing serum FT3

FT3 was considered normalized when it became less than 5 pg/ml (7.68 pmol/liter). Group A patients are those with pretreatment serum FT4 less than 7 ng/dl (90 pmol/liter) and group B with 7 ng/dl or more.

a

Statistically significant compared with MMI 30-mg group.

b

Statistically significant among the three groups.

TABLE 2.

Comparison of the efficiency of treatment with MMI 30 mg/d and PTU 300 mg/d or MMI 15 mg/d in patients with GD in terms of normalizing serum FT3

FT3 was considered normalized when it became less than 5 pg/ml (7.68 pmol/liter). Group A patients are those with pretreatment serum FT4 less than 7 ng/dl (90 pmol/liter) and group B with 7 ng/dl or more.

a

Statistically significant compared with MMI 30-mg group.

b

Statistically significant among the three groups.

Comparison of adverse events between MMI 30 mg/d and PTU 300 mg/d or MMI 15 mg/d

Table 3 summarizes the incidence of adverse effects in the ATD regimen groups. The incidence was surprisingly high in the PTU group, in which more than half the patients (54 of 104) had some adverse effects. PTU was stopped or changed to MMI for 39 patients. In the MMI 30-mg group, adverse effects occurred in 39 of 130 patients (30%), and the drug was stopped or changed for 28 patients. The difference was statistically significant between the PTU group and the MMI 30-mg group. We found a very high incidence of elevation of transaminase values with PTU. The percentage of patients who showed AST and ALT higher than double the upper range of the normal standard was 26.9% on PTU 300 mg/d, compared with only 6.6% on MMI 30 mg/d (P < 0.001). Skin eruption or urticaria similarly occurred in about 22% in either group, but leukocytopenia (less than 1000/μl) was observed in five patients in the PTU group only. One patient treated with MMI 30 mg/d had arthralgia, and the drug was discontinued. Fortunately, no patient experienced serious side effects, such as agranulocytosis.

TABLE 3.

Comparison of the incidence of side effects between the MMI 30 mg/d regimen and the PTU 300 mg/d or MMI 15 mg/d regimen

a

Elevation of AST and ALT more than double the upper range of the normal standard.

b

Less than 1000/μl.

c

Arthralgia.

d

Statistically significant.

TABLE 3.

Comparison of the incidence of side effects between the MMI 30 mg/d regimen and the PTU 300 mg/d or MMI 15 mg/d regimen

a

Elevation of AST and ALT more than double the upper range of the normal standard.

b

Less than 1000/μl.

c

Arthralgia.

d

Statistically significant.

On the contrary, MMI 15 mg/d caused significantly fewer adverse events than MMI 30 mg/d. The total incidence in the MMI 15 mg group was about half that of the MMI 30-mg group. Although the frequency of mild hepatotoxicity was similar, skin eruption/urticaria induced by MMI 15 mg was only about one third that of MMI 30 mg.

Discussion

There have been only limited studies that compared the effectiveness of MMI and PTU to treat hyperthyroidism caused by GD. Okamura et al. (5) reported that MMI 30 mg/d normalized more rapidly TH than PTU 300 mg/d. The mean time required to normalize TH was 6.7 ± 4.6 wk by MMI and 16.8 ± 13.7 wk by PTU (P < 0.05). However, their study was retrospective, and it was unclear whether the patients in each group were truly equivalent (5). In fact, only 17 patients were treated with PTU, one fourth that of MMI. There were four prospective randomized controlled trials (RCTs) to compare MMI and PTU (6–9), and the results of these studies indicated the tendency that MMI is somewhat more effective. However, the conclusion should be cautious because of the small number of patients in each group (6, 7, 9). In addition, in one study, both ATDs were given in a single daily usage (8). Because the half-life of PTU is much shorter than that of MMI and a single daily dose regimen is known to be less effective than a divided dose regimen for PTU administration (10), comparison between MMI and PTU in a single daily usage may be unsuitable.

As for the initial dosage of ATD, Benker et al. (11) reported that 42.2% of patients became euthyroid within 3 wk on MMI 10 mg/d and 64.8% on 40 mg/d after 3 wk in the European Multicenter Trial Study. At 6 wk, 77.5% and 92.6% of patients became euthyroidism on 10 mg and 40 mg MMI, respectively. In an RCT comparing the effects of 20, 30, 40 mg/d MMI, and 200, 300, 400 mg/d PTU, Kallner et al. (7) showed that almost all patients had a normal FT4 level within 12 wk except those who received 20 mg MMI or 200 mg PTU. They concluded that these small doses of ATD were unsuitable due to an unacceptably high incidence of failure to attain euthyroidism within 12 wk. In contrast, Shiroozu et al. (2) reported similar effectiveness between MMI 15 mg/d and 30 mg/d, showing that the percentage of patients who became euthyroid and the mean times to achieve it were similar among the groups. Following this report, Mashio et al. (3) performed a similar study and confirmed the conclusion of Shiroozu et al. (2). The results of both studies are clear, but there were some limitations. In the RCT by Shiroozu et al. (2), a significant number of patients were considered to be mild because 20–35% of the patients had TRAb values less than 15%. In addition, the dropout ratio was as high as 20%, and a retrospective control group was included. In the study by Mashio et al. (3, 4), no information was given about the ratio of dropout patients. Both studies did not pay any attention to the baseline severity of the disease before treatment. Analysis based on the baseline severity of hyperthyroidism is important because it is quite conceivable that a small amount of ATD may be suitable for mild GD but unsuitable for very severe hyperthyroid patients. There has been only one study reporting such an analysis (12), which observed that 20 mg/d carbimazole, a precursor of MMI, was too low for severe Graves’ patients (initial T4 > 20 μg/dl) but adequate for less severely hyperthyroid patients. The data are interesting and suggestive, but the number of patients in each group was very small (just seven to nine subjects). Our RCT showed that the MMI 30 mg/d treatment is clearly superior in the effectiveness to achieve normal TH than PTU 300 mg/d and MMI 15 mg/d, especially for patients with severe hyperthyroidism.

Regarding adverse effects, minor ones occurred in as high as 52% of patients treated with PTU 300 mg/d, while 30% and 13.9% with MMI 30 mg/d and MMI 15 mg/d, respectively, in our study. The frequency of minor side effects was reported not to differ between MMI and PTU (13), but this is the first RCT that demonstrated the significantly higher frequency of adverse effects in PTU than MMI. Notably PTU induced mild liver damages four times higher than MMI 30 mg/d. Liaw et al. (14) reported that although PTU commonly induces subclinical and asymptomatic liver injury, liver damage is usually transient, and PTU may be continued with caution. However, we stopped the initial medication when AST or ALT elevated more than double the normal level because of the risk of PTU-induced severe hepatotoxicity. Williams et al. (15) collected two of their own and 28 cases in the literature of PTU-induced severe hepatic toxicity and reported that seven patients died. MMI 15 mg/d is evidently advantageous over MMI 30 mg/d, with a total incidence less than half and the frequency of skin eruption one third of MMI 30 mg/d. This result was compatible with that of Shiroozu et al. (2) and Benker (11) et al.

In conclusion, we recommend MMI 15 mg/d for patients with mild and moderate GD. MMI of this dosage can induce euthyroidism as effectively as MMI 30 mg/d, and the frequency of adverse reaction is significantly lower. For severe Graves’ patients, MMI 30 mg/d may be advisable to induce euthyroidism within 3 months. PTU is not recommended as an initial ATD because of its high frequency of adverse reactions and rather poor efficacy to decrease TH levels.

Acknowledgments

The members of the Working Group of the Japan Thyroid Association for the Guideline of the Treatment of Graves’ Disease are Yoshifumi Abe, Nobuyuki Amino, Koichi Ito, Makoto Iitaka, Ken Okamura, Yasunori Ozawa, Keiichi Kamijo, Jun Sasaki, Yoshimasa Shishiba, Yuji Tanaka, Junichi Tajiri, Toshio Tsushima, Hirotoshi Nakamura (chairman), Noboru Hamada, You Hidaka, Shuji Fukata, Tomoaki Mitsuhashi, Akira Niyauchi, Naoko Momotani, and Jaeduk Yoshimura Noh.

Disclosure Statement: The authors have nothing to disclose.

* See Acknowledgments for members of the Working Group of the Japan Thyroid Association for the Guideline of the Treatment of Graves’ Disease.

Abbreviations:

  • ALT,

    Alanine aminotransferase;

  • AST,

    aspirate aminotransferase;

  • ATD,

    antithyroid drug;

  • GD,

    Graves’ disease;

  • MMI,

    methimazole;

  • PTU,

    propylthiouracil;

  • RCT,

    randomized controlled trial;

  • TH,

    thyroid hormone;

  • TRAb,

    thyroid stimulating hormone receptor antibody.

1 Wartofsky L , Glinoer D , Solomon B , Nagataki S , Lagasse R , Nagayama Y , Izumi M 1991 Differences and similarities in the diagnosis and treatment of Graves’ disease in Europe, Japan, and the United States. Thyroid 1:129–135 2 Shiroozu A , Okamura K , Ikenoue H , Sato K , Nakashima T , Yoshinari M , Fujishima M , Yoshizumi T 1986 Treatment of hyperthyroidism with a small single daily dose of methimazole. J Clin Endocrinol Metab 63:125–128 3 Mashio Y , Beniko M , Ikota A , Mizumoto H , Kunita H 1988 Treatment of hyperthyroidism with a small single daily dose of methimazole. Acta Endocrinol (Copenh) 119:139–144 4 Mashio Y , Beniko M , Matsuda A , Koizumi S , Matsuya K , Mizumoto H , Ikota A , Kunita H 1997 Treatment of hyperthyroidism with a small single daily dose of methimazole: a prospective long-term follow-up study. Endocr J 44:553–558 5 Okamura K , Ikenoue H , Shiroozu A , Sato K , Yoshinari M , Fujishima M 1987 Reevaluation of the effects of methylmercaptoimidazole and propylthiouracil in patients with Graves’ hyperthyroidism. J Clin Endocrinol Metab 65:719–723 6 Nicholas WC , Fischer RG , Stevenson RA , Bass JD 1995 Single daily dose of methimazole compared to every 8 hours propylthiouracil in the treatment of hyperthyroidism. South Med J 88:973–976 7 Kallner G , Vitols S , Ljunggren JG 1996 Comparison of standardized initial doses of two antithyroid drugs in the treatment of Graves’ disease. J Intern Med 239:525–529 8 Homsanit M , Sriussadaporn S , Vannasaeng S , Peerapatdit T , Nitiyanant W , Vichayanrat A 2001 Efficacy of single daily dosage of methimazole vs. propylthiouracil in the induction of euthyroidism. Clin Endocrinol (Oxf) 54:385–390 9 He CT , Hsieh AT , Pei D , Hung YJ , Wu LY , Yang TC , Lian WC , Huang WS , Kuo SW 2004 Comparison of single daily dose of methimazole and propylthiouracil in the treatment of Graves’ hyperthyroidism. Clin Endocrinol (Oxf) 60:676–681 10 Gwinup G 1978 Prospective randomized comparison of propylthiouracil. JAMA 239:2457–2459 11 Benker G , Vitti P , Kahaly G , Raue F , Tegler L , Hirche H , Reinwein D 1995 Response to methimazole in Graves’ disease. The European Multicenter Study Group. Clin Endocrinol (Oxf) 43:257–263 12 Page SR , Sheard CE , Herbert M , Hopton M , Jeffcoate WJ 1996 A comparison of 20 or 40 mg per day of carbimazole in the initial treatment of hyperthyroidism. Clin Endocrinol (Oxf) 45:511–516 13 Werner MC , Romaldini JH , Bromberg N , Werner RS , Farah CS 1989 Adverse effects related to thionamide drugs and their dose regimen. Am J Med Sci 297:216–219 14 Liaw YF , Huang MJ , Fan KD , Li KL , Wu SS , Chen TJ 1993 Hepatic injury during propylthiouracil therapy in patients with hyperthyroidism. A cohort study. Ann Intern Med 118:424–428 15 Williams KV , Nayak S , Becker D , Reyes J , Burmeister LA 1997 Fifty years of experience with propylthiouracil-associated hepatotoxicity: what have we learned? J Clin Endocrinol Metab 82:1727–1733 Copyright © 2007 by The Endocrine Society

Brand Names: Northyx, Tapazole

Generic Name: methimazole

  • What is methimazole (Northyx, Tapazole)?
  • What are the possible side effects of methimazole (Northyx, Tapazole)?
  • What is the most important information I should know about methimazole (Northyx, Tapazole)?
  • What should I discuss with my healthcare provider before taking methimazole (Northyx, Tapazole)?
  • How should I take methimazole (Northyx, Tapazole)?
  • What happens if I miss a dose (Northyx, Tapazole)?
  • What happens if I overdose (Northyx, Tapazole)?
  • What should I avoid while taking methimazole (Northyx, Tapazole)?
  • What other drugs will affect methimazole (Northyx, Tapazole)?
  • Where can I get more information (Northyx, Tapazole)?

What is methimazole (Northyx, Tapazole)?

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.

What are the possible side effects of methimazole (Northyx, Tapazole)?

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Serious and sometimes fatal infections may occur during treatment with methimazole. Stop using this medicine and call your doctor right away if you have signs of infection such as:

  • sudden weakness or ill feeling, fever, chills, sore throat, cold or flu symptoms;
  • painful mouth sores, pain when swallowing, red or swollen gums; or
  • pale skin, easy bruising, unusual bleeding.

Call your doctor at once if you have:

  • swollen glands in your neck or jaw; or
  • liver problems–nausea, upper stomach pain, itching, tiredness, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Common side effects may include:

  • nausea, vomiting, upset stomach;
  • headache, dizziness, drowsiness;
  • numbness or tingly feeling;
  • rash, itching, skin discoloration;
  • muscle or joint pain;
  • hair loss; or
  • decreased sense of taste.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What is the most important information I should know about methimazole (Northyx, Tapazole)?

You should not breast-feed while using this medicine.

About the author

Leave a Reply

Your email address will not be published. Required fields are marked *