Propylthiouracil (propylthiouracil)

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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)

Agents 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: Many compounds can affect iodide protein binding and alter iodide pharmacokinetics and pharmacodynamics.(1,2)

CLINICAL EFFECTS: 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: Discuss the use of agents that affect iodide pharmacokinetics and pharmacodynamics with the patient's oncologist.(1,2) 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.(3) 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.(4)

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 (1,2)

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.

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• Acute hepatic failure
• Drug-induced hepatitis
• Pancytopenia

• Bone marrow depression
• Hyperbilirubinemia
• Leukopenia
• Pregnancy
• Thrombocytopenic disorder

• Hypothyroidism

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More Frequent

• Pruritus of skin
• Skin rash

Less Frequent

• Acute abdominal pain
• Arthralgia
• Lupus-like syndrome
• Vasculitis

Rare or Very Rare

• Agranulocytosis
• Alveolar hemorrhage
• Aplastic anemia
• Cerebral vasculitis
• Erythema nodosum
• Exfoliative dermatitis
• Fever
• Glomerulonephritis
• Hepatic failure
• Hepatic necrosis
• Hepatitis
• Hypersensitivity angiitis
• Hypoprothrombinemia
• Interstitial pneumonitis
• Ischemic colitis
• Jaundice
• Leukopenia
• Lymphadenopathy
• Nephritis
• Peripheral neuropathy
• Polyarteritis nodosa
• Pulmonary infiltrates
• Renal vasculitis
• Skin ulcer
• Stevens-johnson syndrome
• Thrombocytopenic disorder
• Toxic epidermal necrolysis
• Urticaria

Less Frequent

• Nausea
• Vomiting

Rare or Very Rare

• Alopecia
• Drowsy
• Dysgeusia
• Edema
• Headache disorder
• Hypothyroidism
• Loss of taste
• Myalgia
• Paresthesia
• Salivary secretion disorder
• Skin pigmentation enhancement
• Vertigo

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Propylthiouracil crosses the placenta and may cause fetal harm when administered to pregnant women; the drug can induce goiter and hypothyroidism (cretinism) in the developing fetus. In April 2010, 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 and choanal atresia, 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 propylthiouracil is used during pregnancy for the management of hyperthyroidism, the manufacturer states that a sufficient, but not excessive, dosage of propylthiouracil is necessary. 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 may be possible, and, in some patients, propylthiouracil can be discontinued several weeks or months 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 propylthiouracil is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be advised of the rare potential hazard of liver damage in the mother and fetus; in addition, when considering antithyroid drug use during pregnancy, the patient should be informed of this potential risk, as well as the risks of methimazole-associated fetal malformations. Although liver toxicity may appear abruptly, some clinicians state that it is reasonable to monitor liver function every 3-4 weeks in pregnant women receiving propylthiouracil and to encourage patients to promptly report any new symptoms. (See Cautions: Hepatic Effects and also see Cautions: Precautions and Contraindications.)

The manufacturer and some clinicians state that propylthiouracil is distributed into milk to a small extent and, therefore, is unlikely to result in clinically important doses in the nursing infant. In one study in 9 lactating women who received a single 400-mg dose of propylthiouracil orally, the mean amount of propylthiouracil distributed into milk during 4 hours following drug administration was 0.025% (range: 0.007-0.077%) of the administered dose.

Propylthiouracil generally is compatible with breast-feeding, and moderate dosages of the drug (i.e., less than 300 mg daily) appear to be safe during breast-feeding. However, some clinicians consider propylthiouracil to be a second-line agent in nursing women because of concerns regarding severe hepatotoxicity (i.e., hepatic necrosis in either woman or child) following maternal use of the drug; these clinicians state that methimazole is 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.

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