Methimazole (methimazole)

No dosing information is available for this tab.

No dosing information is available for this tab.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Agents Affecting Growth Hormone/Macimorelin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Agents affecting growth hormone may impact the accuracy of the macimorelin diagnostic test.(1)

CLINICAL EFFECTS: Concurrent use of agents affecting growth hormone may impact the accuracy of the macimorelin diagnostic test.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of macimorelin states concurrent use with agents affecting growth hormone may impact the accuracy of the macimorelin diagnostic test. Discontinue growth hormone products at least 1 week before administering the macimorelin diagnostic test. Sufficient washout time of drugs affecting growth hormone release prior to administration of macimorelin is recommended.(1) Agents affecting growth hormone include: - Drugs that directly affect the pituitary secretion of growth hormone (e.g. somatostatin, insulin, glucocorticoids, cyclooxygenase inhibitors) - Drugs that may transiently elevate growth hormone concentrations (e.g. clonidine, levodopa, insulin) - Drugs that may blunt the growth hormone response (e.g. muscarinic antagonists, anti-thyroid medications, growth hormone products)

DISCUSSION: Concurrent use of agents affecting growth hormone may impact the accuracy of the macimorelin diagnostic test.(1)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Agents That Affect Iodide/Radioactive Iodide

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Many compounds can affect iodide protein binding and alter iodide pharmacokinetics and pharmacodynamics.(1)

CLINICAL EFFECTS: Compounds that affect iodide pharmacokinetics and pharmacodynamics may impact the effectiveness of radioactive iodide.(1)

PREDISPOSING FACTORS: Compounds that affect iodide pharmacokinetics and pharmacodynamics are expected to have the most impact during therapy using radioactive iodide. Diagnostic procedures would be expected to be impacted less.

PATIENT MANAGEMENT: Discuss the use of agents that affect iodide pharmacokinetics and pharmacodynamics with the patient's oncologist.(1) Because indocyanine green contains sodium iodide, the iodine-binding capacity of thyroid tissue may be reduced for at least one week following administration. Do not perform radioactive iodine uptake studies for at least one week following administration of indocyanine green.(2) The manufacturer of iopamidol states administration may interfere with thyroid uptake of radioactive iodine and decrease therapeutic and diagnostic efficacy. Avoid thyroid therapy or testing for up to 6 weeks post administration of iopamidol.(3)

DISCUSSION: Many agents interact with radioactive iodine. The average duration of effect is: anticoagulants - 1 week antihistamines - 1 week anti-thyroid drugs, e.g: carbimazole, methimazole, propylthiouracil - 3-5 days corticosteroids - 1 week iodide-containing medications, e.g: amiodarone - 1-6 months expectorants - 2 weeks Lugol solution - 3 weeks saturated solution of potassium iodine - 3 weeks vitamins - 10-14 days iodide-containing X-ray contrast agents - up to 1 year lithium - 4 weeks phenylbutazone - 1-2 weeks sulfonamides - 1 week thyroid hormones (natural or synthetic), e.g.: thyroxine - 4 weeks tri-iodothyronine - 2 weeks tolbutamide - 1 week topical iodide - 1-9 months (1)

Myelosuppressives That Affect Iodide/Sodium Iodide I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1) Many compounds can affect iodide protein binding and alter iodide pharmacokinetics and pharmacodynamics.

CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1) Compounds that affect iodide pharmacokinetics and pharmacodynamics may impact the effectiveness of radioactive iodide.(1,2)

PREDISPOSING FACTORS: Compounds that affect iodide pharmacokinetics and pharmacodynamics are expected to have the most impact during therapy using radioactive iodide. Diagnostic procedures would be expected to be impacted less.

PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1) Discuss the use of agents that affect iodide pharmacokinetics and pharmacodynamics with the patient's oncologist.(1,2)

DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1) Many agents interact with radioactive iodine. The average duration of effect is: anticoagulants - 1 week antihistamines - 1 week anti-thyroid drugs, e.g: carbimazole, methimazole, propylthiouracil - 3-5 days corticosteroids - 1 week iodide-containing medications, e.g: amiodarone - 1-6 months expectorants - 2 weeks Lugol solution - 3 weeks saturated solution of potassium iodine - 3 weeks vitamins - 10-14 days iodide-containing X-ray contrast agents - up to 1 year lithium - 4 weeks phenylbutazone - 1-2 weeks sulfonamides - 1 week thyroid hormones (natural or synthetic), e.g.: thyroxine - 4 weeks tri-iodothyronine - 2 weeks tolbutamide - 1 week topical iodide - 1-9 months (1,2)

Selected Myelosuppressive Agents/Clozapine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clozapine and other myelosuppressive agents may be associated with neutropenia or agranulocytosis.(2)

CLINICAL EFFECTS: Moderate neutropenia, even if due to combination therapy, may require abrupt discontinuation of clozapine resulting in decompensation of the patient's psychiatric disorder (e.g. schizophrenia). The disease treated by the myelosuppressive agent may be compromised if myelosuppression requires dose reduction, delay, or discontinuation of the myelosuppressive agent. Undetected severe neutropenia or agranulocytosis may be fatal.

PREDISPOSING FACTORS: Low white blood counts prior to initiation of the myelosuppressive agent may increase risk for clinically significant neutropenia.

PATIENT MANAGEMENT: If a patient stabilized on clozapine therapy requires treatment with a myelosuppressive agent, the clozapine prescriber should consult with prescriber of the myelosuppressive agent (e.g. oncologist) to discuss treatment and monitoring options.(2) More frequent absolute neutrophil count (ANC) monitoring or treatment alternatives secondary to neutropenic episodes may need to be considered. The U.S. Food and Drug Administration (FDA) recommends that prescribers monitor patients' ANC according to the monitoring frequencies described in the prescribing information. Severe neutropenia remains a serious, potentially fatal risk that is greatest in the first several months of clozapine treatment. ANC monitoring can help identify neutropenia early to allow for timely intervention.(1-2) Australia, Canada, and U.K.: Clozapine is only available through a restricted distribution system which requires documentation of the ANC prior to dispensing. For most clozapine patients, clozapine treatment must be interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter. For patients with benign ethnic neutropenia (BEN), treatment must be interrupted for suspected clozapine-induced neutropenia < 500 cells/microliter.(2)

DISCUSSION: Concurrent use of clozapine and selected myelosuppressive agents may require more frequent ANC monitoring or consideration of treatment alternatives secondary to neutropenic episodes. Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(3-26)

Selected Myelosuppressive Agents/Deferiprone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1)

CLINICAL EFFECTS: Concurrent use of deferiprone and myelosuppressive agents may result in severe neutropenia or agranulocytosis, which may be fatal.

PREDISPOSING FACTORS: Agranulocytosis may be less common in patients receiving deferiprone for thalassemia, and more common in patients treated for other systemic iron overload conditions (e.g. myelodysplastic syndromes, sickle cell disease).(2,3) Inadequate monitoring appears to increase the risk for severe outcomes. Manufacturer post market surveillance found that in all fatal cases of agranulocytosis reported between 1999 and 2005, data on weekly white blood count (WBC) monitoring was missing. In three fatal cases, deferiprone was continued for two to seven days after the detection of neutropenia or agranulocytosis.(2)

PATIENT MANAGEMENT: If possible, discontinue one of the drugs associated with risk for neutropenia or agranulocytosis. If alternative therapy is not available, documentation and adherence to the deferiprone monitoring protocol is essential. Baseline absolute neutrophil count (ANC) must be at least 1,500/uL prior to starting deferiprone. Monitor ANC weekly during therapy. If infection develops, interrupt deferiprone therapy and monitor ANC more frequently. If ANC is less than 1,500/uL but greater than 500/uL, discontinue deferiprone and any other drugs possibly associated with neutropenia. Initiate ANC and platelet counts daily until recovery (i.e. ANC at least 1,500/uL). If ANC is less than 500/uL, discontinue deferiprone, evaluate patient and hospitalize if appropriate. Do not resume deferiprone unless potential benefits outweigh potential risks.(1)

DISCUSSION: Drugs linked to this monograph have an FDA Boxed Warning for risk of neutropenia, agranulocytosis, or pancytopenia, or have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(1-25) In pooled clinical studies submitted to the FDA, 6.1% of deferiprone patients met criteria for neutropenia and 1.7% of patients developed agranulocytosis.(1) The time to onset of agranulocytosis was highly variable with a range of 65 days to 9.2 years (median, 161 days).(3)

Selected Myelosuppressive Agents/Dipyrone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of dipyrone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1-29)

CLINICAL EFFECTS: Concurrent use of dipyrone with agents that cause bone marrow depression, including myelosuppressives, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding. Undetected severe neutropenia or agranulocytosis may be fatal.(1-29)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of dipyrone and myelosuppressive agents should be avoided. The European Medicines Agency states dipyrone is contraindicated in patients with a prior medical history of dipyrone-induced agranulocytosis (or from other pyrazolones/pyrazolidines), impaired bone marrow function or diseases of the hematopoietic system.(3) International labeling for dipyrone and methotrexate state that co-administration may increase the hematotoxicity of methotrexate, especially in elderly patients, and therefore should be avoided.(1-2) The European Medicines Agency advises if agranulocytosis is suspected with dipyrone, a complete blood count (including differential blood count) should be performed immediately, and treatment must be stopped while waiting for the results. If confirmed, treatment must not be reintroduced.(1-3)

DISCUSSION: A retrospective cohort study analyzed new users of dipyrone (n=444,972), non-steroidal anti-inflammatory drugs (n=3,814,367) which served as a reference cohort, and opioids-paracetamol (n=3,129,221) which was the negative control. During continuous treatment over a median of 37-40 days, 26 cases of hospitalized agranulocytosis occurred. With the assumption that agranulocytosis onset was 7 days prior to admission, the hazard ratio of agranulocytosis associated with dipyrone was 4.40 [0.90-21.57] compared to NSAIDs and 2.45 [0.68-8.83] compared to opioid-paracetamol. HR of neutropenia from dipyrone was 2.98 [1.57-5.65] compared to NSAIDs and not statistically significant compared to opioids-paracetamol. In a sensitivity analysis assuming that the onset of agranulocytosis was the date of hospitalization, the HR of dipyrone-induced agranulocytosis was 7.20 [95% confidence interval: 1.92-26.99] compared to NSAIDs and 3.31 [1.17-9.34] compared to opioids-paracetamol. Agranulocytosis was very rare but more than 4 times more common with dipyrone than other analgesics.(4) In a review of 1,448 reports of agranulocytosis attributed to dipyrone, patients with fatal outcomes were older and more often had also received methotrexate compared to those with non-fatal outcomes (odds ratio: 5.18; 95% confidence interval: 3.06-8.78).(5) Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(2,6-26)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Antithyroid Drugs/Selected Anticoagulants

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Antithyroid drugs may decrease breakdown of vitamin-K dependent clotting factors, thus increasing the amount of clotting factors available for use.

CLINICAL EFFECTS: Decreased clearance of vitamin K dependent clotting factors by antithyroid drugs may result in decreased therapeutic effects of anticoagulants. However, if thioamide-induced hypothrombinemia occurs, the activity of the anticoagulant may be increased.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If antithyroid treatment is started or discontinued in patients stabilized on anticoagulant therapy, INRs should be closely monitored and the anticoagulant dose should be adjusted as needed. Some patients may require alternative hyperthyroid medication in order to achieve therapeutic anticoagulation. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Caution should be used when this drug combination if given. In the clinically hyperthyroid patient, the breakdown of the vitamin k-dependent clotting factors is increased resulting in quicker and greater response to the anticoagulant. When antithyroid drugs are administered to correct this, the response to the anticoagulant may decrease. An increase in the anticoagulant dosage may be required. There are several reports of decreased anticoagulant effects in patients receiving antithyroid agents. There has been one case reported where the patient experienced an increased response to warfarin when propylthiouracil was added to the patient's drug regimen.

Carbimazole; Methimazole/Thyroid Preparations

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Methimazole can affect the therapeutic response to thyroid hormone therapy. It decreases thyroid hormone secretion. Thyroid hormone therapy can antagonize the pharmacologic effects of methimazole by supplying an exogenous source of thyroid hormone. Carbimazole is a prodrug of methimazole.(1)

CLINICAL EFFECTS: Concurrent use of carbimazole or methimazole and thyroid hormones may result in opposing effects.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of carbimazole or methimazole and thyroid hormones should be avoided.

DISCUSSION: The 2016 American Thyroid Association guidelines recommended avoiding the concurrent use of methimazole and thyroid preparations for "block and replace" therapy to make a patient euthyroid. Meta-analyses have shown that a higher prevalence of adverse events occurs with block-and-replace regimens than dose titration.(2) The 2018 European Thyroid Association guidelines state that methimazole (30 mg) may be given combined with levothyroxine supplement ion for block-and-replace therapy to avoid drug-induced hypothyroidism but methimazole dose titration is the preferred therapy.(3)

There is no enhanced messaging for this drug.

• Drug-induced hepatitis
• Pancytopenia

• Anemia
• Leukopenia
• Neutropenic disorder
• Pregnancy
• Thrombocytopenic disorder

• Hypoprothrombinemia
• Hypothyroidism

There is no enhanced messaging for this drug.

More Frequent

• Fever
• Leukopenia
• Pruritus of skin

Less Frequent

• Agranulocytosis
• Neutropenic disorder
• Peripheral neuropathy
• Skin rash

Rare or Very Rare

• Acute pancreatitis
• Aplastic anemia
• Granulocytopenic disorder
• Hepatitis
• Lymphadenopathy
• Nephritis
• Obstructive hyperbilirubinemia
• Parotitis
• Thrombocytopenic disorder
• Vasculitis

Less Frequent

• Dizziness
• Dysgeusia
• Nausea
• Vomiting

Rare or Very Rare

• Anorexia
• Edema
• Jaundice
• Lupus-like syndrome
• Paresthesia
• Sialoadenitis
• Skin pigmentation enhancement
• Vertigo

No enhanced messaging available.

No enhanced messaging available.

Methimazole readily crosses the placental membranes and may cause fetal harm, particularly when administered in the first trimester of pregnancy. The drug can also cause fetal goiter and hypothyroidism (cretinism) when administered to a pregnant woman.

In April 2010, the US Food and Drug Administration (FDA) reported a review of postmarketing data analyzing the potential for birth defects associated with use of propylthiouracil or methimazole during pregnancy. FDA found that congenital malformations were reported approximately 3 times more often with prenatal exposure to methimazole compared with propylthiouracil (29 cases with methimazole; 9 cases with propylthiouracil). In addition, there was a distinct and consistent pattern of congenital malformations associated with the use of methimazole that was not found with propylthiouracil. Approximately 90% of the congenital malformations with methimazole were craniofacial malformations (e.g., scalp epidermal aplasia (aplasia cutis), facial dysmorphism, choanal atresia). In most of the cases, there were multiple malformations that frequently included a combination of craniofacial defects and GI atresia or aplasia. These specific birth defects were associated with the use of methimazole during the first trimester of pregnancy but were not found when the drug was administered later in pregnancy. In contrast, FDA did not find a consistent pattern of birth defects associated with the use of propylthiouracil and concluded that there is no convincing evidence of an association between propylthiouracil use and congenital malformations, even with use during the first trimester.

Despite the potential fetal hazard, antithyroid agents are still considered the therapy of choice for the management of hyperthyroidism during pregnancy. Since methimazole may be associated with the rare development of fetal abnormalities, such as aplasia cutis, craniofacial malformations (facial dysmorphism, choanal atresia), and GI malformations (esophageal atresia with or without tracheoesophageal fistula, umbilical abnormalities), propylthiouracil is the preferred agent when an antithyroid drug is indicated during organogenesis in the first trimester of pregnancy or just prior to the first trimester of pregnancy. Patients receiving methimazole should be switched to propylthiouracil if pregnancy is confirmed in the first trimester. Because of the potential adverse maternal effects of propylthiouracil (e.g., hepatotoxicity), however, it may be preferable to switch from propylthiouracil to methimazole for the second and third trimesters (i.e., after the first trimester). If the patient is switching from propylthiouracil to methimazole, thyroid function should be assessed after 2 weeks and then every 2-4 weeks thereafter. It is not known if the risk of methimazole-induced aplasia cutis or embryopathy outweighs the risk of propylthiouracil-induced hepatotoxicity.

If methimazole is used during pregnancy for the management of hyperthyroidism, the manufacturer states that a sufficient, but not excessive, dosage of methimazole is necessary; the lowest possible dosage of methimazole to control the maternal disease should be used. Some clinicians state that antithyroid drug therapy should be initiated or adjusted to maintain maternal free thyroxine (T4) concentrations at or just above the upper limit of normal (ULN) of the nonpregnant reference range, or to maintain total T4 concentrations at 1.5 times the ULN or the free T4 index in the ULN, while using the lowest possible dosage of antithyroid drugs. In women receiving antithyroid drugs during pregnancy, free T4 and TSH concentrations should be monitored approximately every 2-6 weeks. The manufacturer states that because thyroid dysfunction diminishes in many women as pregnancy proceeds, a reduction in dosage of antithyroid therapy may be possible, and, in some patients, use of antithyroid therapy can be discontinued 2-3 weeks before delivery.

Patients should be advised to contact their clinician immediately about their therapy if they are or plan to become pregnant while receiving an antithyroid drug. If methimazole is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be advised of the potential hazard to the fetus; in addition, when considering antithyroid drug use during pregnancy, the patient should be informed of the risks of methimazole-associated fetal malformations, as well as the risks of propylthiouracil-associated hepatotoxicity.

Methimazole is distributed into milk. However, several studies found no effect on clinical status in nursing infants of women receiving methimazole, particularly if thyroid function is monitored at frequent (weekly or biweekly) intervals. A long-term study of 139 thyrotoxic lactating women and their infants failed to demonstrate toxicity in infants who are breast-fed by women receiving methimazole.

Methimazole generally is compatible with breast-feeding, and moderate dosages of the drug (i.e., 20-30 mg daily) appear to be safe during breast-feeding. Because of concerns regarding severe hepatotoxicity (i.e., hepatic necrosis in either woman or child) associated with maternal use of propylthiouracil, some clinicians consider methimazole to be the preferred antithyroid drug in nursing women. If an antithyroid drug is used in nursing women, some clinicians recommend that the drug be administered after a feeding and in divided doses, and that thyroid function be monitored in nursing infants.

No enhanced messaging available.