Side effects of stopping methimazole

Antithyroid Medications for Hyperthyroidism

Antithyroid medications—sometimes written as anti-thyroid medications—are a common treatment for hyperthyroidism, particularly if you have an ongoing form of hyperthyroidism caused by Graves’ disease or a goiter. The goal of antithyroid medications is to prevent the thyroid from producing excess amounts of hormone.

In the US, there are two antithyroid medications available—propylthiouracil (PTU) and methimazole (also known as Tapazole). The medications are similar, as they both stop the thyroid from producing T3 and T4 hormones.

Though the medications work essentially the same way, they each have their own unique merits and drawbacks.

Propylthiouracil is an oral medication prescribed to help manage an overactive thyroid. (Photo:123rf)

Propylthiouracil (PTU)
One of the advantages of PTU is that it has a lower risk of birth defects and therefore it is the first line treatment for pregnant women.

A disadvantage is that PTU is only available in 50-milligram units. You need to take it in three equal doses, approximately 8 hours apart, each day. According to the American Thyroid Association clinical guidelines, daily dosage varies from 100 to 600 milligrams, depending on the seriousness of your condition and your age. This information is general, as dosing varies from patient to patient. Always follow your doctor’s specific dosing instructions.

Methimazole (Tapazole)
The main benefit of Tapazole is that it can be taken one, two, or three times a day (depending on your dosage). Pills are available in 5 or 10 milligrams. It also has fewer side effects and often reverses hyperthyroidism quickly.

Tapazole is more concentrated than PTU. According to the American Thyroid Association clinical guidelines, daily dosage varies from 10 to 40 milligrams, depending on the seriousness of your condition and your age. Again, this information is general, as dosing varies from patient to patient. Always follow your doctor’s specific dosing instructions.

Side Effects of Antithyroid Medications
Adverse reactions to antithyroid medications are uncommon (affecting only 1-3% of patients), but they do occur. These side effects include rash, itching, abnormal hair loss, and fever. Less common side effects include nausea, swelling, heartburn, muscle and joint aches, numbness, and headache.

In very rare instances, both drugs can cause liver damage. In the most severe of cases, this can result in death. Regular follow-up visits with your doctor will greatly reduce the risk of this severe complication.

Agranulocytosis: A Rare but Serious Complication
Another extremely rare, but serious, complication of antithyroid medications is known as agranulocytosis. Researchers have yet to discover what exactly causes agranulocytosis, but they do know that is a reaction characterized by attacking immune cells, called granulocytes. These cells protect the body from outside “invaders,” such as bacteria. Without granulocytes, the body is defenseless against bacteria and infection.

Agranulocytosis occurs more in patients taking PTU than Tapazole—twice as often, in fact. Regardless of their dosage, patients taking PTU have the same risk of developing the condition. With Tapazole, on the other hand, the risk is likely dependent on the dosage. The lower the dose, the lower the risk.

If you notice any infection—even if it’s as ordinary as a sore throat—seek immediate medical treatment. Again, agranulocytosis is an extremely rare complication of antithyroid medications, but it’s important to understand all the risks. You should have regular follow-up with your doctor while you are on these medications.

Long-term Effectiveness
One of the main drawbacks of antithyroid drugs is that some patients experience a relapse of their symptoms upon decreasing the dose of the antithyroid medicine. Antithyroid medications usually alleviate your hyperthyroid symptoms in six to 12 weeks. While there is no standard for how long you will take the medication, you will most likely continue with it for 12 to 18 months. That time period, combined with a gradual, controlled decrease in your dosage, lessens your chance of developing hyperthyroidism again.

Your doctor may suggest that you not use antithyroid medications as a life-long treatment, as your risk for adverse effects increases the longer you continue with the medication. While some patients may experience a permanent end to their symptoms, these medications do not guarantee life-long prevention of hyperthyroidism.

Updated on: 05/07/19 Continue Reading Radioactive Iodine for Hyperthyroidism View Sources

  • Mayo Clinic Hypothyroidism Treatments and drugs page. Mayo Clinic Health Information Web site. Available at: Accessed June 29, 2009.
  • Skugor, M. Treating Hyperthyroidism. In: The Cleveland Clinic Guide to Thyroid Disorders. New York: Kaplan Publishing; 2009:70-74.
  • Treatment Guidelines for Patients with Hyperthyroidism and Hypothyroidism. American Thyroid Association Web site. Available at: Accessed June 29, 2009.


How does this medication work? What will it do for me?

Methimazole belongs to the class of medications called antithyroid medications. It is used to treat hyperthyroidism (overactive thyroid gland). It 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.

Your doctor may have suggested this medication for conditions other than those listed in these drug information articles. As well, some forms of this medication may not be used for all of the conditions discussed here. If you have not discussed this with your doctor or are not sure why you are taking this medication, speak to your doctor. Do not stop taking this medication without consulting your doctor.

Do not give this medication to anyone else, even if they have the same symptoms as you do. It can be harmful for people to take this medication if their doctor has not prescribed it.

What form(s) does this medication come in?

5 mg
Each round, white, scored tablet, marked with “J94” on one side and plain on the other, contains methimazole 5 mg. Nonmedicinal ingredients: corn starch, lactose monohydrate, magnesium stearate, and talc.

10 mg
Each round, white tablet, marked with “10” on one side and plain on the other side, contains 10 mg methimazole. Nonmedicinal ingredients: corn starch, lactose monohydrate, magnesium stearate, and talc.

How should I use this medication?

Adults: Methimazole is taken 3 times daily, every 8 hours. The recommended starting total dose of methimazole is 15 mg daily for mild hyperthyroidism, 30 mg to 40 mg daily for moderately severe hyperthyroidism, and 60 mg daily for severe hyperthyroidism. The eventual maintenance dose is normally 5 mg to 15 mg daily.

Children: For children, the daily dose is initially 0.4 mg per kilogram of body weight, divided into 3 doses and given every 8 hours. The eventual maintenance dose is usually one-half the initial dose.

Methimazole can be taken with or without food.

Many things can affect the dose of medication that a person needs, such as body weight, other medical conditions, and other medications. If your doctor has recommended a dose different from the ones listed here, do not change the way that you are taking the medication without consulting your doctor or pharmacist.

It is important to take this medication exactly as prescribed by your doctor. The 3 daily doses should be taken as close to every 8 hours as possible so that blood levels are kept as constant as possible. If you miss a dose of this medication, take it as soon as possible and check with your doctor or pharmacist.

Store this medication at room temperature, protect it from light and moisture, and keep it out of the reach of children.

Do not dispose of medications in wastewater (e.g. down the sink or in the toilet) or in household garbage. Ask your pharmacist how to dispose of medications that are no longer needed or have expired.

Who should NOT take this medication?

Methimazole should not be taken by anyone who:

  • is allergic to methimazole or to any of the ingredients of the medication
  • is breast-feeding

What side effects are possible with this medication?

Many medications can cause side effects. A side effect is an unwanted response to a medication when it is taken in normal doses. Side effects can be mild or severe, temporary or permanent. The side effects listed below are not experienced by everyone who takes this medication. If you are concerned about side effects, discuss the risks and benefits of this medication with your doctor.

The following side effects have been reported by at least 1% of people taking this medication. Many of these side effects can be managed, and some may go away on their own over time.

Contact your doctor if you experience these side effects and they are severe or bothersome. Your pharmacist may be able to advise you on managing side effects.

  • dizziness
  • loss of taste sensation
  • nausea
  • stomach pain
  • vomiting

Although most of these side effects listed below don’t happen very often, they could lead to serious problems if you do not check with your doctor or seek medical attention.

Check with your doctor as soon as possible if any of the following side effects occur:

  • backache
  • black, tarry stools
  • blood in urine or stools
  • increase in bleeding or bruising
  • increase or decrease in urination
  • numbness or tingling of fingers, toes, or face
  • pinpoint-sized red spots on skin
  • shortness of breath
  • swelling of feet or lower legs
  • swollen lymph nodes
  • swollen salivary glands
  • symptoms of liver damage (e.g., yellow skin or eyes, abdominal pain, dark urine, clay-coloured stools, loss of appetite, nausea and vomiting, or itching)

Stop taking the medication and seek immediate medical attention if any of the following occur:

  • cough
  • fever or chills
  • general feeling of discomfort, illness, or weakness
  • headache
  • hoarseness
  • mouth sores
  • pain, swelling, or redness in joints
  • skin rash
  • sore throat

Some people may experience side effects other than those listed. Check with your doctor if you notice any symptom that worries you while you are taking this medication.

Are there any other precautions or warnings for this medication?

Before you begin using a medication, be sure to inform your doctor of any medical conditions or allergies you may have, any medications you are taking, whether you are pregnant or breast-feeding, and any other significant facts about your health. These factors may affect how you should use this medication.

Blood tests: Your doctor will likely want you to have laboratory tests done on a regular basis because in rare cases, methimazole can cause the levels of white blood cells to decrease. Low white blood cell levels can increase the risk of infection. If you have a sore throat, skin rash, fever, headache, or a general feeling of being unwell, tell your doctor immediately.

Pregnancy: This medication should not be used during pregnancy unless the benefits outweigh the risks. If you become pregnant while taking this medication, contact your doctor immediately.

Breast-feeding: Women using methimazole should not breast-feed.

What other drugs could interact with this medication?

There may be an interaction between methimazole and any of the following:

If you are taking any of these medications, speak with your doctor or pharmacist. Depending on your specific circumstances, your doctor may want you to:

  • stop taking one of the medications,
  • change one of the medications to another,
  • change how you are taking one or both of the medications, or
  • leave everything as is.

An interaction between two medications does not always mean that you must stop taking one of them. Speak to your doctor about how any drug interactions are being managed or should be managed.

Medications other than those listed above may interact with this medication. Tell your doctor or prescriber about all prescription, over-the-counter (non-prescription), and herbal medications you are taking. Also tell them about any supplements you take. Since caffeine, alcohol, the nicotine from cigarettes, or street drugs can affect the action of many medications, you should let your prescriber know if you use them.

All material copyright MediResource Inc. 1996 – 2020. Terms and conditions of use. The contents herein are for informational purposes only. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Source:


Medical Therapy

Methimazole blocks thyroid hormone synthesis by inhibiting thyroid peroxidase, an enzyme involved in the oxidation of iodide to iodine, incorporation of iodine into thyroglobulin, and coupling of tyrosine residues to form T4 and T3. Methimazole does not block the release of preformed thyroid hormone, so there is a delay of 2 to 4 weeks before serum T4 concentrations return to normal after initializing therapy.99 Methimazole does not decrease goiter size, and because hyperplasia or adenomatous growth continues, goiters may become larger over time despite therapy. In most cats 2.5 mg twice daily is an appropriate dose to manage clinical signs. In one study of 40 hyperthyroid cats, 5 mg once daily was less effective than 2.5 mg twice daily, with only 54% of cats euthyroid after 2 weeks of once-daily treatment, compared with 87% of cats treated with divided daily dosing.129 Doses can be titrated upward if the cat does not respond to the initial dose.

Carbimazole is a derivative of methimazole that is converted to methimazole in vivo.90 It is available in Australia and Europe. Because a 5-mg carbimazole dose is equivalent to a 3-mg methimazole dose, 5 mg twice daily is an appropriate dose to manage hyperthyroidism in most cats.73 For initial control 5 mg three times daily has been advocated,73 but 5 mg twice daily is adequate in most cats, and if the dose needs to be titrated upward, 7.5 mg twice daily achieves the same result as 5 mg three times daily.

Adverse effects can be seen with both methimazole and carbimazole, although these may be less common and less severe with carbimazole.63 Transient, self-limiting anorexia, vomiting, and lethargy are the most common side effects, occurring in approximately 10% of cats treated with methimazole.99 Halving the dose and titrating to the lowest effective dose may be helpful to reduce these side effects.130 More serious side effects include blood dyscrasias such as neutropenia and thrombocytopenia in 3% to 9% of treated cats; hepatopathy in approximately 2% of cats99,111; and excoriations of the face and neck in 2% to 3% of cats.99 All these adverse effects are reversible on discontinuation of the medication.130

Methimazole or carbimazole is adequate to manage 99% of hyperthyroid cats.99 Some cats, however, will not tolerate the dose of methimazole or carbimazole necessary to control their hyperthyroidism. In these cases a permanent therapy is recommended. For cats that are not good candidates for permanent therapy (e.g., moderate to severe azotemia, advanced age with other debilitating problems), lower doses of methimazole or carbimazole can be used, and adjunctive medical therapy can be used to manage other problems—for example, a beta blocker such as atenolol to control tachycardia or amlodipine for hypertension. These cats need to be monitored for changes in renal function or continued weight loss.130

Transdermal preparations of methimazole48,49,111 and, more recently, carbimazole15 have proved to be effective alternatives to the oral versions of these medications. Transdermal preparations must be prepared by a compounding pharmacy and, to ensure drug stability, should be dispensed in quantities lasting for no more than 1 month. They may be used when the owner has difficulty medicating the cat and may result in reduced gastrointestinal side effects.111

Recent studies have indicated that diets with restricted iodine levels (Hill’s Prescription Diet y/d Feline–Thyroid Health) can result in normalization of T4 levels in hyperthyroid cats.67b,150 In one study, cats were fed diets with sequentially reduced iodine contents; an iodine restricted food with 0.28 ppm iodine resulted in euthyroidism in 8 of 9 cats and a diet with an iodine content of 0.17 ppm resulted in euthyroidism in all cats tested.67b The one cat that required the lower iodine level for euthyroidism had a notably higher total T4 than the other cats tested, suggesting this therapy may be more appropriate for cats with only moderate elevations of T4. Another study by the same investigators found that a dietary iodine level of 0.32 ppm also resulted in euthyroidism in cats with moderate elevations of T4 (up to 84 nmol/L ).150 Continued control of total T4 levels was not possible when iodine content was increased to 0.39 ppm.67a,67b These interesting findings may change management of hyperthyroidism in the future. Ironically, a recent publication showed varying levels of available iodine in commercially available foods and suggested that hyperthyroidism in cats may be reduced by providing diets that are adequately supplemented with iodine.26b In humans, it is recognized that both high-iodine115a and low-iodine60a diets can contribute to hyperthyroidism; similar associations in cats are unproven but, if so, restricted dietary iodine therapy would not be expected to be helpful in all hyperthyroid cats. Further, cats with very high total T4 levels may not be manageable with dietary therapy alone. Additionally, low-iodine diets may increase the percentage uptake of I131; some authors believe that low-iodine diets in humans can increase radioiodine uptake in thyroid tissue as much as twofold.52a The reduced total I131 dose required would shorten the necessary hospitalization time after such therapy.

Once euthyroidism has been achieved, it is ideal for the cat to undergo permanent therapy. Thyroidectomy can be performed immediately. Antithyroid drugs appear to interfere with the thyroid’s ability to uptake and concentrate radioactive iodine.10 This is controversial: One study did not find such an association,18 and another indicated that uptake can be enhanced,75 which may create a risk of subsequent hypothyroidism. One recommendation is to discontinue methimazole or carbimazole for at least 1 week before treatment with radioiodine.89 This solution is inappropriate for cats with serious consequences of their hyperthyroidism (e.g., congestive heart failure). These circumstances must be addressed on a case-by-case basis. Cats in these circumstances can continue with medical therapy, undergo thyroidectomy, or proceed with radioiodine therapy (perhaps with less predictable results but without apparent problems in many cases).

Those cats whose owners choose to continue with medical therapy should have ongoing monitoring; every 3 months is an appropriate interval. It is important to assess the cat for clinical signs of hyperthyroidism, but also, ideally, serum total T4 should be checked. If renal parameters are normal, these need to be checked only every 6 months.

A publication of the American Thyroid Association

Summaries for the Public from Clinical Thyroidology (from recent articles in Clinical Thyroidology)
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Does a break in antithyroid drug treatment of hyperthyroidism lead to an increased risk of agranulocytosis?


Hyperthyroidism: a condition where the thyroid gland is overactive and produces too much thyroid hormone. Hyperthyroidism may be treated with antithyroid meds (Methimazole, Propylthiouracil), radioactive iodine or surgery.

Methimazole (MMI): an antithyroid medication that blocks the thyroid from making thyroid hormone. Methimazole is used to treat hyperthyroidism, especially when it is caused by Graves’ disease.

Propylthiouracil (PTU): an antithyroid medication that blocks the thyroid from making thyroid hormone. Propylthiouracil is used to treat hyperthyroidism, especially in women during pregnancy.

Agranulocytosis: a marked decrease in the white blood cell count that causes a patient to be more likely to develop an infection. This is commonly associated with a fever and/or a sore throat.

White blood cells: the infection-fighting cells of the blood.

The antithyroid drugs methimazole (MMI) and propylthiouracil (PTU) are used as one option to treat patients with hyperthyroidism, especially those with Graves’ disease. The goal of antithyroid drug treatment is to treat for a defined period of time then stop to determine if the Graves’ disease has gone into remission. If the hyperthyroidism returns, the antithyroid drugs are re-started. Agranulocytosis, a marked decrease in white blood cells which increases the risk for infection, is a rare complication of treatment with the antithyroid drugs. Most cases of agranulocytosis occur within 3 months of beginning therapy with these drugs. There has been speculation that re-starting therapy with these drugs in patients who have relapsed after the first course of antithyroid drug treatment may increase the risk or accelerate the onset of agranulocytosis. This study was designed to exam whether agranulocytosis is likely to occur faster in a patient who stops antithyroid drug therapy and then resumes at a later time in contrast to a patient who stays on the drug continuously.

Kobayashi S et al. Characteristics of Agranulocytosis as an Adverse Effect of Antithyroid Drugs in the Second or Later Course of Treatment. Thyroid. December 16, 2013 . Available at

A total of 87 patients seen at the Ito Hospital in Tokyo between 1983 and 2012 were found to have agranulocytosis. After excluding patients with other possible causes, 67 patients were identified as having MMI or PTU-induced agranulocytosis. Of these, 35 developed it while on a continuous course of the drug, while 22 had gaps in therapy that ranged from 5 months to 22 years. On closer inspection, several of the latter patients were excluded because they did not fit the criteria for the study, leaving 14 patients with interrupted treatment.

There was no significant difference in the time to onset of agranulocytosis between the continuous or the interrupted groups. No agranulocytosis occurred in patients with 1-5 months of a “gap”. None of the patients in the continuous treatment group who were exposed to the other drug developed side effects, whereas 9 of 10 patients in the “gap” group exposed to the other drug developed minor side effects. Thus, short term gaps (<5 months) did not appear to increase the rapidity of occurrence of agranulocytosis.

After re-starting MMI or PTU therapy following a 5 or month gap, patients should be observed for agranulocytosis for the first 3 months, similarly to those who start these drugs for the first time. Patients should be aware of the signs and symptoms of agranulocytosis which include fever, fatigue or sore throat. If these occur they should notify their physician and have a white blood cell count measured before resuming MMI or PTU.

—Glenn Braunstein, MD



Graves’ disease:

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Generic Name: methimazole (me THIM a zole)
Brand Name: Tapazole, Northyx

Medically reviewed by on Feb 20, 2019 – Written by Cerner Multum

  • Overview
  • Side Effects
  • Dosage
  • Professional
  • Interactions
  • More

What is methimazole?

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.

Important Information

You should not breast-feed while using methimazole.

Before taking this medicine

You should not use methimazole if you are allergic to it, or:

  • if you are pregnant or breast-feeding.

To make sure methimazole is safe for you, tell your doctor if you have:

  • liver disease;

  • a blood cell disorder; or

  • a weak immune system.

Using methimazole during pregnancy could harm the unborn baby. Tell your doctor if you are pregnant or if you become pregnant while using this medicine.

Methimazole can pass into breast milk and may harm a nursing baby. You should not breast-feed while using this medicine.

Do not give this medicine to a child without medical advice.

How should I take methimazole?

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

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

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

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

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

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

Store at room temperature away from moisture and heat.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include nausea, vomiting, upset stomach, headache, joint pain, fever, itching, swelling, or pale skin and easy bruising or bleeding.

What should I avoid while taking methimazole?

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.

Methimazole side effects

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 methimazole 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.

Methimazole dosing information

Usual Adult Dose for Hyperthyroidism:

Initial dose:
Mild hyperthyroidism: 15 mg orally per day
Moderately severe hyperthyroidism: 30 to 40 mg orally per day
Severe hyperthyroidism: 60 mg orally per day
Maintenance dose:
5 to 15 mg orally per day
Comments: Daily doses are usually given in 3 divided doses at approximately 8 hour intervals
-For the treatment of Graves’ disease with hyperthyroidism or toxic multinodular goiter in whom surgery or radioactive iodine therapy is not an appropriate treatment option.
-To ameliorate symptoms of hyperthyroidism in preparation for thyroidectomy or radioactive iodine therapy.

Usual Pediatric Dose for Hyperthyroidism:

Initial dose: 0.4 mg/kg orally per day
Maintenance dose: 0.2 mg/kg orally per day (approximately half the initial dose)
Comments: Daily doses are usually given in 3 divided doses at approximately 8 hour intervals

What other drugs will affect methimazole?

Tell your doctor about all your current medicines and any you start or stop using, especially:

This list is not complete. Other drugs may interact with methimazole, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Further information

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

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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  • Hyperthyroidism

Long-term, Low-Dose Methimazole Reduces Hyperthyroidism Relapses

VICTORIA, BC — Graves’ disease patients treated with long-term, low-dose methimazole therapy show significantly lower rates of relapse compared with short-term exposure, with no serious side effects linked to the longer-term treatment, according to new results from a randomized study.

“Our findings show that long-term, low-dose methimazole treatment for 60 to 120 months is a safe and effective method for treatment of Graves’ hyperthyroidism,” said senior author Fereidoun Azizi, MD, of the Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran, in presenting the findings here at the 2017 Annual Meeting of the American Thyroid Association.

Those assigned to the longer-term treatment arm with methimazole took it for a median of 96 months (8 years).

In commenting on the study, Catherine A Dinauer, MD, a pediatric endocrinologist and clinician at the Yale Pediatric Thyroid Center, in New Haven, Connecticut, said the study sheds important light on an issue that often challenges decision-making.

“There’s a lot of debate about how long we can treat these patients, with the general thought that maybe we should stop treatment after about 1 year, or 2 at the most, and then if the patient is not in remission we should to move to definitive treatment,” Dr Dinauer told Medscape Medical News.

“But there are increasing data coming out in adults, as well as some in pediatrics now, indicating it may be safe to continue these patients longer term and, for our younger patients, in particular, that might be advantageous to buy ourselves time,” she noted.

“So these data are reassuring, suggesting that as long as patients are consistent with taking the methimazole and don’t show signs of toxicity, longer-term treatment is a reasonable strategy.”

Daily Dose of Methimazole That Was Effective Declined to < 5 mg in Long Term

While most previous studies have not shown a reduction in the rate of remission in Graves’ disease with antithyroid drug treatment when administered for an optimal period of 12 to 18 months, Dr Azizi and colleagues published a meta-analysis of six articles this year that did indicate a higher remission with long-term therapy (> 24 months) compared with shorter-term therapy (Thyroid. 2017;27:1223-1231).

In conducting their own randomized trial, the Iranian researchers enrolled a group of 302 patients with a first episode of Graves’ hyperthyroidism who were initially all treated with 18.8 ± 2.2 months of methimazole.

After the 18 months, 258 of the patients were randomized to either continue treatment with the drug (n = 130) or to discontinue it (n = 128).

In the long-term group, 115 patients continued methimazole treatment for at least 60 months and discontinued use of the drug after a median of 96 months.

All patients in the short- and long-term groups were followed for 48 months after discontinuation.

Among patients in the short-term group, 29% had a relapse of hyperthyroidism within 12 months of withdrawal from the drug, compared with only 3.3% of those in the long-term group.

At 48 months after methimazole withdrawal, 51% in the short-term group had a relapse compared with 16% in the long-term treatment group (P < .001).

The median time to relapse after discontinuation was 6.0 months in the short-term group and 11.5 months in the long-term group.

Leading risk factors associated with relapse in the short-term group included male gender, thyroid volume, serum thyroid-stimulating hormone (TSH) receptor antibody (TRAb), and HLA polymorphism. In the long-term group, only free-T4 levels were significantly associated with relapse.

Dr Azizi noted that the daily dose of methimazole needed to maintain TSH levels in the normal range in the long-term group declined to less than 5 mg.

“The majority in the long-term group were taking less than 5 mg of methimazole, and some only needed two or three pills per week, so it is interesting to see that as you continue there appears to be more of a response to methimazole,” he commented.

Side effects associated with the treatment in the first 18 months included cutaneous reactions in 14 patients and increased liver enzymes in two patients; however, no further side effects were reported in the long-term group for up to 120 months of therapy.

“It is very reassuring that after 18 months we did not see any major complications” afterward, for up to 10 years of treatment, Dr Azizi concluded.

Dr Azizi and Dr Dinauer had no relevant financial relationships.

2017 Annual Meeting of the American Thyroid Association. October 19, 2017; Victoria, British Columbia.

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Bobbi – I may not have a recent blood test, but I have the blood pressure tests and the history of the blood pressure/irregular heartbeat tests and the blood tests that were taken during the same periods. My endo has seen my records. It’s really clear that my irregular heartbeat is an indicator that I’ve gone hypothyroid.
When I was hypo last summer, it was really bad. I had terrible pains – muscle cramps, backaches, headaches, and I was so tired that I spent a lot of days in bed sleeping. So when, 10 days before I was to leave on vacation, I saw that familiar irregular heartbeat indicator, I became concerned. This vacation was a cruise with my siblings; a gift from our mother and an occasion to remember our father who had passed away in April and our sister who had passed away 3 years before him. I had been working really hard learning about the various ports, and I needed every ounce of energy I had to explore them. Wasting the days away in the cabin was not an option.
When I had stopped taking methimazole last summer (on doctors’ orders), the ihb went away immediately, so I figured I could try something less drastic this time and just cut my 10 mg dose in half. That may sound like a lot, but I’ve changed doses in much larger increments before – from 20 to 40 to 60 to 40 to 20 to none. There wasn’t time to consult the doctor this time. She’s only in 3 days a week, and I was so busy getting ready for my trip. I waited a couple of days to make sure the ihb’s weren’t random and then a week before the trip I started halving the pills. The ihb indicator finally stopped triggering the day before the trip, and it never triggered during the entire 10-day trip. (I took the monitor with me to keep track.) After coming home and resuming my regular 10 mg dose, it took 5-6 days for the ihb to be consistent again.
I think I’ll get my labs done on Wednesday. I fully expect a call from the nurse next week telling me that I’m hypo and that the doctor is reducing my dosage to 5 mg. Then I’ll tell the nurse to tell the doctor that I took a 2 1/2 week detour. I’d tell the doctor myself, but I know she’s busy. We’ll go over everything at my next appointment in January. She’ll tell me I could have called her, but what’s done is done. She’s a really good doctor. I can tell her anything, and I’d always planned to.

Long-term methimazole therapy improves Graves disease remission rate

VICTORIA, B.C. – In the debate over the optimal duration of methimazole therapy for Graves disease, findings of a new randomized, controlled trial reported at the annual meeting of the American Thyroid Association tip the balance in favor of long-term therapy.

The relapse rate among patients who stayed on the drug long term, for a median of 96 months, was about one-third that among patients who stopped after 18 months, reported lead investigator Fereidoun Azizi, MD, of the Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran. Patients staying on the drug long term did not experience any adverse effects during that time, although only those able to tolerate the drug initially were randomized.

Susan London/Frontline Medical News

Dr. Fereidoun Azizi

“Long-term, low-dose methimazole treatment for 60-120 months is a safe and effective treatment for Graves hyperthyroidism and is accompanied by much higher remission rates than the usual 18-24 months of methimazole treatment,” he summarized.

There may be two explanations for this benefit of long-term therapy, according to Dr. Azizi. Long-term therapy may alter immune-related molecular signaling and cell subsets in both the thymus and periphery, ultimately shifting disease course. On the other hand, establishing and maintaining euthyroidism for a prolonged period of time may quell the autoimmune response.

“We are looking at this in depth and also at some of the in order to elucidate the mechanism behind our striking findings,” he said.

One of the session cochairs, Yaron Tomer, MD, chair of the department of medicine and the Anita and Jack Saltz Chair in Diabetes Research at the Montefiore Medical Center, New York, commented, “There is a move today away from radioactive iodine – many patients do not want radioactive iodine, and we do more surgery now because of that. So this opens up a new option that we didn’t have before.”

Dr. Yaron Tomer

At the same time, the potential for rare but serious toxicity of methimazole must be taken into account, especially for certain patients, such as those who travel frequently. “That’s sometimes a consideration when somebody is long term, because even if they don’t develop agranulocytosis, they may develop symptoms that suggest it, creating unnecessary anxiety. In those cases where this is not an issue, long-term treatment could be another new option that we didn’t have before.”

The other session cochair, Catherine A. Dinauer, MD, a pediatric endocrinologist and clinician at the Yale Pediatric Thyroid Center, New Haven, Conn., noted that duration of therapy frequently comes up in her practice.

Susan London/Frontline Medical News

Dr. Catherine A. Dinauer

“It’s similar that there is sort of a move, if we can, to keep kids on treatment potentially longer because sometimes the kids are too young or we’d rather not do definitive therapy when they are less than 10 years of age, and we want to buy ourselves some time. So this is somewhat reassuring that it’s probably safe to do that as long as they are compliant, they don’t have toxicity, those sorts of things. And there is the chance that perhaps more of them will enter remission over a long period of time,” she said. “I think it just tells us we have to be more patient, perhaps, with how long we treat these patients.”

Study details

Relapse of hyperthyroidism after discontinuation of antithyroid drugs remains problematic, Dr. Azizi pointed out when introducing the study.

“Many of the major papers have noted that longer antithyroid drug treatment does not really influence remission rate of Graves, and therefore most of us treat for between 12 and 24 months with antithyroid drugs, and then we stop the medication,” he said. However, recent studies and in particular a meta-analysis (Thyroid. 2017;27:1223-31) suggest there may be an advantage of long-term therapy.

Dr. Azizi and coinvestigators recruited to their trial 302 consecutive patients from a single clinic who had untreated Graves disease and were started on methimazole (Tapazole) therapy.

The 258 patients completing 18 months of therapy were randomized to stop the drug or continue on a maintenance dose long term, for 60-120 months, on a single-blind basis. (The other 44 patients withdrew mainly because of side effects, relapse, and loss to follow-up.)

Patients in the long-term therapy group stayed on the drug for a median of 96 months. The decision about specifically when to stop in this group was guided by thyroid function test results and patients’ clinical status and preferences, according to Dr. Azizi.

The rate of relapse at 48 months after stopping methimazole was 51% among patients in the short-term therapy group but just 16% among patients in the long-term therapy group (P less than or equal to .001). “Definitely, this looks like a cure of the disease if we consider this very low incidence of relapse,” he commented.

Within the group treated long term, patients who did and did not experience relapse were statistically indistinguishable with respect to temporal trends in levels of triiodothyronine (T3), free thyroxine (T4), thyroid-stimulating hormone (TSH), and thyroid-stimulating hormone receptor antibody (TRAb).

Additionally, the daily dose of methimazole therapy required to maintain TSH levels in the normal range fell similarly over time, to about half the initial dose, regardless of whether patients had a relapse or not.

“At the end of treatment, the majority of patients were taking less than 5 mg/day of methimazole,” Dr. Azizi reported. “Some patients needed only two or three pills of 5-mg methimazole per week, and this is very interesting to know, that after you continue, you have definitely more response to methimazole.”

Multivariate analyses showed that in the short-term therapy group, risk factors for relapse were age, sex, and end-of-therapy levels of T3, TSH, and TRAb. In the long-term therapy group, risk factors were end-of-therapy levels of free T4 and TSH.

“We are currently performing more in-depth analysis of genetic markers, including both SNPs and HLA subtyping on these samples to assess any potential association between relapse rates and genetic background,” Dr. Azizi noted. “However, the problem is the low number of patients who have had a relapse long term.”

During the first 18 months of methimazole therapy, 16 patients had adverse effects in the first 2 months (14 had cutaneous reactions and 2 had elevation of liver enzymes). However, there were no serious complications, such as agranulocytosis.

“It’s very reassuring that after 18 months, in those who had long-term treatment, we did not see any minor or major complications throughout, up to the 120 months of treatment we have had in some of our patients,” Dr. Azizi commented.

Dr. Azizi disclosed that he had no relevant conflicts of interest.

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