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    Anti-thyroid Agents

    BOXED WARNING

    Hepatic disease, hepatitis, hepatotoxicity, jaundice

    Hepatotoxicity is a potential complication of propylthiouracil, PTU. Propylthiouracil can cause hepatic complications such as jaundice, fatal hepatic necrosis, and death. Severe hepatic injury and acute hepatic failure, in some cases fatal, have been reported; these events include cases requiring liver transplantation. Pediatric patients appear especially at risk. Patients with preexisting hepatic disease should receive propylthiouracil with caution, although there is no evidence that pre-existing hepatic disease increases the risk for severe hepatic reactions to PTU. When compared to methimazole, PTU has an increased risk of hepatotoxicity; however, the decision to initiate either therapy in patients with liver dysfunction with a new diagnosis of Grave's disease should be carefully considered. Experts do suggest that prescribers to reconsider whether to initiate PTU therapy in patients with baseline liver transaminase levels more than 5 times the upper level of normal (ULN). Biochemical routine monitoring of hepatocellular integrity/liver function tests (LFTs such as bilirubin, alkaline phosphatase, ALT, AST) is not expected to attenuate the risk of severe liver injury due to its rapid and unpredictable onset. Inform patients of the risk of liver failure. Patients on PTU therapy should be monitored for signs and symptoms of hepatic injury, especially during the first 6 months after drug initiation; discontinue PTU if clinical evidence of hepatic dysfunction (e.g., abdominal pain, anorexia, pruritus, light-colored stools, or LFT elevation, hepatitis) occurs. When these symptoms occur, discontinue PTU immediately and monitor LFTs.[45237]

    Neonates, pregnancy

    Female patients of childbearing potential should contact their physician immediately if pregnancy occurs or is desired; close monitoring of the thyroid condition and fetal health is needed. Because of the risk of fetal abnormalities associated with methimazole, propylthiouracil (PTU) may be the treatment of choice when an antithyroid drug is indicated during or just prior to the first trimester of pregnancy. Methimazole should be used when antithyroid drug therapy is started after the first trimester unless the patient is allergic or intolerant, as PTU does present health risks to the mother and the exposed fetus. PTU is transferred across the placenta. Antithyroid drugs, including PTU, have been shown to cause goiter and hypothyroidism in the developing fetus. There is also a risk for maternal or fetal hepatotoxicity from PTU. Hepatic injury, including hepatic failure and death, have been reported in women treated with PTU during pregnancy, and cases of in utero exposure with liver failure and death have been reported in neonates. PTU is considered to have less risk of birth defects than methimazole, a drug for which teratogenic effects are well documented. Population studies note an increase in the rate of birth defects (2.3% above the background rate) observed after PTU exposure in early pregnancy, but these defects tended to be less severe than with methimazole. The dosage of any antithyroid drug used during pregnancy should be closely monitored so that sufficient, but not excessive, dosage is used to produce the desired clinical results. Because thyroid dysfunction may improve as pregnancy proceeds in some patients, it may be possible to discontinue PTU in the 2 to 3 months prior to delivery after careful clinical evaluation of thyroid function; hyperthyroidism may recur following delivery. 

    DEA CLASS

    Rx

    DESCRIPTION

    Oral thio-urea derivative antithyroid agent
    Used for various hyperthyroid conditions including Graves disease
    Due to hepatotoxicity risk reserved for patients intolerant of methimazole or in whom radioiodine therapy or surgery are not appropriate, except during the first trimester of pregnancy, when PTU is preferred over methimazole

    HOW SUPPLIED

    Propylthiouracil Oral Tab: 50mg

    DOSAGE & INDICATIONS

    For the treatment of hyperthyroidism (due to Graves' disease or toxic multinodular goiter) or to ameliorate symptoms of hyperthyroidism prior to thyroidectomy or radioactive iodine therapy.
    Oral dosage
    Adults

    Initially, 300 mg/day PO divided every 8 hours. May increase to 400 mg/day PO in patients with severe hyperthyroidism and/or very large goiters. Doses of 600 to 900 mg/day PO are sometimes needed initially. Maintenance doses range from 100 to 150 mg/day PO divided every 8 hours. In general, use caution when selecting or titrating a dose for a geriatric patient. PTU is considered a second line therapy, for patients intolerant of or allergic to methimazole or other therapies.

    Children and Adolescents 6 years and older

    FDA recommends the use of PTU in children only when the patient is allergic to or intolerant of methimazole, and no other treatment options are available. Initially, give 50 mg/day PO divided every 8 hours; titrate dose upward based on clinical response and TSH and free T4 levels. Usual dosage range is 5 to 7 mg/kg/day, given in divided doses. Severe liver injury in children is usually associated with doses of 300 mg/day or more; however, cases have been reported with doses as low as 50 mg/day.

    Neonates†

    Usual dose range for neonatal Graves' disease is 5 mg to 10 mg/kg/day PO, in divided doses given every 8 hours.

    For the treatment of thyrotoxicosis† (thyroid storm†).
    Oral dosage
    Adults

    500 to 1,000 mg PO loading dose, then 250 mg PO every 4 hours. Once full control of symptoms achieved, dosage is gradually decreased to usual maintenance dosage.

    †Indicates off-label use

    MAXIMUM DOSAGE

    PTU has a narrow therapeutic window; individualize dosage. General max. doses for routine treatment of hyperthyroidism are listed. Higher doses in the treatment of thyrotoxicosis are typically necessary.

    Adults

    900 mg/day PO; 1.2 grams/day PO in severe disease.

    Geriatric

    900 mg/day PO; 1.2 grams/day PO in severe disease.

    Adolescents

    300 mg/day PO or maximum based on weight: 7 mg/kg/day PO. If growth is complete, doses used may be similar to adult dosing.

    Children

    11 years and older: 300 mg/day PO. Usual weight based maximum: 7 mg/kg/day PO.
    6 to 10 years: 150 mg/day PO. Usual weight based maximum: 7 mg/kg/day PO.
    Less than 6 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    10 mg/kg/day PO has been used off-label for neonatal Graves' disease.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    While there is no evidence that pre-existing hepatic disease increases the risk of complications from propylthiouracil, PTU, experts suggest that a prescriber reconsider the use of PTU in a patient with liver transaminase (AST and/or ALT) levels more than 5-fold above the upper limit of normal (ULN). Discontinue PTU and evaluate the patient if evidence of hepatic dysfunction occurs during PTU use.

    Renal Impairment

    No dosage adjustment is needed; less than 10% of PTU is excreted unchanged in the urine.

    ADMINISTRATION

    Oral Administration

    Propylthiouracil, PTU is administered orally. The daily dose is generally divided into 3 equal parts and administered at regular intervals (generally every 8 hours).

    Rectal Administration

    NOTE: Rectal administration is usually reserved for thyrotoxic emergencies in patients unable to tolerate oral therapy.
     
    Rectal Enema†:
    Dissolve eight 50-mg propylthiouracil tablets in 60 ml aqueous sodium phosphates solution (e.g., Fleet's Phospho-Soda).
     
    Rectal Suppository†:
    Using eight 50-mg propylthiouracil tablets and sufficient hardfat (Withepsol H15), compound 4 suppositories containing 100 mg of propylthiouracil each.
    Moisten the suppository with water prior to insertion. If suppository is too soft because of storage in a warm place, chill in the refrigerator for 30 minutes or run cold water over it before removing the wrapper.

    STORAGE

    Generic:
    - Store at room temperature (between 59 to 86 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Antithyroid agents, such as PTU, should be discontinued at least 3 to 4 days prior to treatment with radioiodine (sodium iodide, I-131). Typically, antithyroid agents are not reintroduced until 1 week after the radioiodine treatment.

    Agranulocytosis, bone marrow suppression, fever, neutropenia, vasculitis

    Propylthiouracil (PTU) is contraindicated in patients with a history of hypersensitivity to the drug. Cross-hypersensitivity occurs in roughly 50% of patients who have previously exhibited a significant hypersensitivity to an antithyroid thioimidazole medication (i.e., methimazole). PTU has been associated with severe side effects. Agranulocytosis (severe neutropenia) occurs in approximately 0.2% to 0.5% of patients and is a potentially life-threatening side effect of PTU therapy. Agranulocytosis typically occurs within the first 3 months of therapy. Leukopenia, thrombocytopenia, and aplastic anemia (pancytopenia) may also occur. PTU should be discontinued if agranulocytosis, aplastic anemia (pancytopenia) is suspected, and the patient's bone marrow indices should be obtained. Use the drug with caution in patients with risk factors for bone marrow suppression and with extreme caution in combination with other drugs known to cause agranulocytosis. Baseline leukopenia occurs in 10% of untreated hyperthyroid patients and is not a contraindication for the use of PTU; however, a CBC and differential should be monitored periodically during PTU treatment. Propylthiouracil (PTU)-associated vasculitis may be severe and is normally associated with fever, sore throat, arthralgia, and skin lesions but may also involve multiple organ systems. Some cases have resulted in nephritis, interstitial pneumonitis, cerebral angiitis, other serious conditions, or death. Drug discontinuation may improve or resolve some cases of vasculitis; however, more severe cases require treatment with corticosteroids, immunosuppressant therapy, and plasmapheresis. If vasculitis is suspected, discontinue therapy and initiate appropriate intervention. Instruct patients taking PTU to immediately report any symptoms suggestive of hypersensitivity, vasculitis, or agranulocytosis, including fever or a sore throat, headache, skin eruptions, hematuria, decreased urine output, dyspnea, or hemoptysis to their prescriber.[45237]

    Hepatic disease, hepatitis, hepatotoxicity, jaundice

    Hepatotoxicity is a potential complication of propylthiouracil, PTU. Propylthiouracil can cause hepatic complications such as jaundice, fatal hepatic necrosis, and death. Severe hepatic injury and acute hepatic failure, in some cases fatal, have been reported; these events include cases requiring liver transplantation. Pediatric patients appear especially at risk. Patients with preexisting hepatic disease should receive propylthiouracil with caution, although there is no evidence that pre-existing hepatic disease increases the risk for severe hepatic reactions to PTU. When compared to methimazole, PTU has an increased risk of hepatotoxicity; however, the decision to initiate either therapy in patients with liver dysfunction with a new diagnosis of Grave's disease should be carefully considered. Experts do suggest that prescribers to reconsider whether to initiate PTU therapy in patients with baseline liver transaminase levels more than 5 times the upper level of normal (ULN). Biochemical routine monitoring of hepatocellular integrity/liver function tests (LFTs such as bilirubin, alkaline phosphatase, ALT, AST) is not expected to attenuate the risk of severe liver injury due to its rapid and unpredictable onset. Inform patients of the risk of liver failure. Patients on PTU therapy should be monitored for signs and symptoms of hepatic injury, especially during the first 6 months after drug initiation; discontinue PTU if clinical evidence of hepatic dysfunction (e.g., abdominal pain, anorexia, pruritus, light-colored stools, or LFT elevation, hepatitis) occurs. When these symptoms occur, discontinue PTU immediately and monitor LFTs.[45237]

    Children, infants

    Propylthiouracil (PTU) is associated with an unacceptable risk of hepatotoxicity in pediatric patients, with a risk of liver failure of 1 in 2,000 to 4,000 children and adolescents taking the medication. FDA Medwatch data indicate that pediatric patients are more susceptible to hepatotoxic reactions from PTU than are adults. For this reason, PTU propylthiouracil is not recommended for use in the pediatric population except in rare instances in which methimazole is not well-tolerated and surgery or radioactive iodine therapy are not appropriate. In children, there have been postmarketing reports of severe hepatic injury with doses as low as 50 mg/day; most cases, however, were associated with doses of 300 mg/day and higher. Reports include hepatic failure requiring liver transplantation or resulting in death in pediatric patients taking PTU. If PTU is used in children or adolescents, warn the patients and caregivers of the hepatic risk, and monitor for signs and symptoms of liver failure, including tiredness, nausea, anorexia, fever, pharyngitis, or malaise. Tell patients to contact their health care prescriber immediately. Discontinue PTU immediately if symptoms suggestive of liver injury develop, and obtain a white blood cell count, liver function tests, and transaminase levels. The safety and effectiveness of propylthiouracil, PTU in infants have not been established.

    Neonates, pregnancy

    Female patients of childbearing potential should contact their physician immediately if pregnancy occurs or is desired; close monitoring of the thyroid condition and fetal health is needed. Because of the risk of fetal abnormalities associated with methimazole, propylthiouracil (PTU) may be the treatment of choice when an antithyroid drug is indicated during or just prior to the first trimester of pregnancy. Methimazole should be used when antithyroid drug therapy is started after the first trimester unless the patient is allergic or intolerant, as PTU does present health risks to the mother and the exposed fetus. PTU is transferred across the placenta. Antithyroid drugs, including PTU, have been shown to cause goiter and hypothyroidism in the developing fetus. There is also a risk for maternal or fetal hepatotoxicity from PTU. Hepatic injury, including hepatic failure and death, have been reported in women treated with PTU during pregnancy, and cases of in utero exposure with liver failure and death have been reported in neonates. PTU is considered to have less risk of birth defects than methimazole, a drug for which teratogenic effects are well documented. Population studies note an increase in the rate of birth defects (2.3% above the background rate) observed after PTU exposure in early pregnancy, but these defects tended to be less severe than with methimazole. The dosage of any antithyroid drug used during pregnancy should be closely monitored so that sufficient, but not excessive, dosage is used to produce the desired clinical results. Because thyroid dysfunction may improve as pregnancy proceeds in some patients, it may be possible to discontinue PTU in the 2 to 3 months prior to delivery after careful clinical evaluation of thyroid function; hyperthyroidism may recur following delivery. 

    Breast-feeding

    According to the American Thyroid Association (ATA) guidelines, either propylthiouracil (PTU) or methimazole may be used in breast-feeding women when necessary; low to moderate doses are recommended (PTU less than 300 mg/day or methimazole 20 to 30 mg/day). However, due to hepatotoxicity concerns, PTU is generally reserved for the treatment of lactating women intolerant of or allergic to methimazole, due to the potential for liver toxicity. Propylthiouracil is present in breast milk to a small extent but likely results in clinically insignificant doses to the nursing infant. The high protein binding and significant ionization at physiologic pH limits PTU distribution into breast milk versus other antithyroid agents (e.g., methimazole). In one study, lactating women (n = 9) were administered 400 mg of PTU by mouth. The mean amount of PTU excreted into the breast milk during the 4 hours after drug administration was 0.025% of the administered dose. The ATA recommends the mother's and the infant's thyroid function be monitored regularly during use of antithyroid agents; treated mothers should take their antithyroid medication in divided doses, with doses administered immediately following an infant feeding.[47186] [47187] [61515] [62890]

    ADVERSE REACTIONS

    Severe

    agranulocytosis / Delayed / 0.2-0.5
    aplastic anemia / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    hepatotoxicity / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    erythema nodosum / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    ischemic colitis / Early / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known

    Moderate

    leukopenia / Delayed / 15.0-25.0
    lymphadenopathy / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    hypothyroidism / Delayed / Incidence not known
    bleeding / Early / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    hypoprothrombinemia / Delayed / Incidence not known
    peripheral neuropathy / Delayed / Incidence not known
    neuritis / Delayed / Incidence not known

    Mild

    arthralgia / Delayed / 0-5.0
    pruritus / Rapid / 0-1.0
    rash / Early / 0-1.0
    urticaria / Rapid / 0-1.0
    alopecia / Delayed / 0-1.0
    skin hyperpigmentation / Delayed / 0-1.0
    fever / Early / Incidence not known
    malaise / Early / Incidence not known
    nausea / Early / Incidence not known
    vomiting / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    myalgia / Early / Incidence not known
    headache / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    dysgeusia / Early / Incidence not known
    vertigo / Early / Incidence not known
    drowsiness / Early / Incidence not known

    DRUG INTERACTIONS

    Acebutolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Amiodarone: (Moderate) Amiodarone contains iodine and excess intake of iodine/iodide can decrease the efficacy of propylthiouracil. Clinicians should consider the possibility of reduced response to propylthiouracil if amiodarone is used concomitantly.
    Atenolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Atenolol; Chlorthalidone: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Bendroflumethiazide; Nadolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Beta-blockers: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Betaxolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Bisoprolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Brimonidine; Timolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Carteolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Carvedilol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Deferiprone: (Major) Avoid concomitant use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis, such as propylthiouracil, PTU; however, if this is not possible, closely monitor the absolute neutrophil count and interrupt deferiprone therapy if neutropenia develops.
    Digoxin: (Minor) Serum concentrations of digoxin can increase as hyperthyroidism is corrected. In patients receiving antithyroid therapy, the dosage of digoxin may need to be reduced as the patient becomes euthyroid.
    Dorzolamide; Timolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Esmolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Hydrochlorothiazide, HCTZ; Propranolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Iodine; Potassium Iodide, KI: (Severe) Potassium iodide should not be used concurrently with other antithyroid agents. Agents such as methimazole and propylthiouracil, PTU can increase the likelihood of hypothyroidism when used in combination with potassium iodide.
    Iodoquinol: (Moderate) Iodoquinol should be used with caution in patients treated with thyroid agents. Iodine-containing compounds like iodoquinol may result in overt thyroid disease.
    Labetalol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Levobetaxolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Levobunolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Macimorelin: (Major) Avoid use of macimorelin with drugs that may blunt the growth hormone response to macimorelin, such as antithyroid agents. Healthcare providers are advised to discontinue antithyroid therapy at least 1 week before administering macimorelin. Use of these medications together may impact the accuracy of the macimorelin growth hormone test.
    Methylprednisolone: (Moderate) The metabolism of corticosteroids is increased in hyperthyroidism and decreased in hypothyroidism. Dosage adjustments may be necessary when initiating, changing or discontinuing thyroid hormones or antithyroid agents.
    Metoprolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Nadolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Nebivolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Nebivolol; Valsartan: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Penbutolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Pexidartinib: (Moderate) Monitor for evidence of hepatotoxicity if pexidartinib is coadministered with propylthiouracil. Avoid concurrent use in patients with increased serum transaminases, total bilirubin, or direct bilirubin (more than ULN) or active liver or biliary tract disease.
    Pindolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Potassium Iodide, KI: (Severe) Potassium iodide should not be used concurrently with other antithyroid agents. Agents such as methimazole and propylthiouracil, PTU can increase the likelihood of hypothyroidism when used in combination with potassium iodide.
    Prednisone: (Moderate) The metabolism of corticosteroids is increased in hyperthyroidism and decreased in hypothyroidism. Dosage adjustments may be necessary when initiating, changing or discontinuing thyroid hormones or antithyroid agents.
    Propranolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Riluzole: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and propylthiouracil. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Sodium Iodide: (Severe) The recent intake of antithyroid agents will affect the uptake of radioiodide from sodium iodide, I-131; patients must discontinue all medications and supplements that may interfere with iodide uptake into thyroid tissue prior to therapy with sodium iodide I-131. Various protocols are used. Many manufacturers state that concurrent antithyroid agents should be discontinued at least 3 to 4 days before administration of radioiodide. The following withdrawal timing recommendations were set forth in a procedure guideline published by the Society of Nuclear Medicine in February 2002. Antithyroid agents may affect iodide protein binding for an average of 5 days after administration; allow a 3 day wash out period for the antithyroid agent (e.g., PTU, methimazole) prior to sodium iodide I-131 administration. The antithyroid agent may be resumed 2 to 3 days after treatment.
    Sotalol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Theophylline, Aminophylline: (Minor) Patients with hyperthyroidism may exhibit accelerated clearance of theophylline. Correction of hyperthyroidism can lead to a decrease in theophylline clearance. Theophylline serum concentrations should be monitored closely during the initial stages of treatment for hyperthyroidism.
    Thyroid hormones: (Major) Antithyroid agents should generally not be administered with the thyroid hormones due to their opposing effects. However, in selected cases some clinicians co-administer T4 (e.g., levothyroxine) to circumvent drug-induced hypothyroidism when large suppressive doses of antithyroid agents are administered for long periods of time. However, clinical and biochemical euthyroid status may usually be maintained with careful titration of the antithyroid agent dosage alone.
    Timolol: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Warfarin: (Moderate) The interaction between thioamine antithyroid agents and warfarin is variable. Administration of propylthiouracil, PTU can reduce the effectiveness of warfarin. Conversely, the effects of warfarin can be enhanced due to the anti-vitamin K properties of propylthiouracil, PTU. Prothrombin times should be monitored closely. Warfarin dosage should be adjusted accordingly based on the INR and the clinical goals for the patient.

    PREGNANCY AND LACTATION

    Pregnancy

    According to the American Thyroid Association (ATA) guidelines, either propylthiouracil (PTU) or methimazole may be used in breast-feeding women when necessary; low to moderate doses are recommended (PTU less than 300 mg/day or methimazole 20 to 30 mg/day). However, due to hepatotoxicity concerns, PTU is generally reserved for the treatment of lactating women intolerant of or allergic to methimazole, due to the potential for liver toxicity. Propylthiouracil is present in breast milk to a small extent but likely results in clinically insignificant doses to the nursing infant. The high protein binding and significant ionization at physiologic pH limits PTU distribution into breast milk versus other antithyroid agents (e.g., methimazole). In one study, lactating women (n = 9) were administered 400 mg of PTU by mouth. The mean amount of PTU excreted into the breast milk during the 4 hours after drug administration was 0.025% of the administered dose. The ATA recommends the mother's and the infant's thyroid function be monitored regularly during use of antithyroid agents; treated mothers should take their antithyroid medication in divided doses, with doses administered immediately following an infant feeding.[47186] [47187] [61515] [62890]

    MECHANISM OF ACTION

    Propylthiouracil (PTU) directly interferes with the first step in thyroid hormone biosynthesis in the thyroid gland. By acting as a substrate for the catalyst thyroid peroxidase, propylthiouracil inhibits the incorporation of iodide into the thyroid hormone precursor, thyroglobulin. Consequently, the drug is iodinated and degraded within the thyroid gland. Oxidized iodine is diverted away from thyroglobulin, which effectively diminishes the biosynthesis of thyroid hormone. An additional mechanism is the inhibition of iodotyrosyl residues coupling to form thyroglobulin. Propylthiouracil may interfere with the oxidation of the iodide ion and iodotyrosyl groups. Eventually, thyroglobulin is depleted and circulating thyroid hormone levels diminish. Unlike methimazole, propylthiouracil inhibits the conversion of peripheral thyroxine (T4) to triiodothyronine (3). This action may be an advantage in the treatment of severe hyperthyroidism. Propylthiouracil does not, however, alter the action of existing thyroxine (T4) and triiodothyronine (T3) in the circulation or in the thyroid gland. Similarly, no alterations in the effectiveness of exogenously administered thyroid hormones have been observed.

    PHARMACOKINETICS

    Propylthiouracil (PTU) is administered orally.  Propylthiouracil is actively concentrated by the thyroid gland following absorption. The drug is 60—80% protein-bound and is significantly ionized at physiologic pH. Because of higher protein binding and ionization, propylthiouracil has less placental transfer and distribution into breast milk than methimazole, and is often preferred over methimazole when treatment is needed in pregnant or lactating females.
     
    The metabolism of PTU is complex due to the concentration of the drug in the thyroid gland. Extensive hepatic metabolism occurs via glucuronidation. The plasma elimination half-life of propylthiouracil is approximately 1 hour and is not appreciably altered by the patient's thyroid status. The drug persists in the thyroid gland despite the short plasma half life, thereby allowing an 8-hour or longer dosing interval. The drug and its metabolites are excreted partially via the kidney (35%); but only 10% or less of PTU is excreted as unchanged drug.

    Oral Route

    Following administration, propylthiouracil is rapidly absorbed from the gastrointestinal tract with peak serum concentrations occurring in 1 hour. However, it usually takes 2—4 months of treatment to achieve initial euthyroid status; response rates are dependent on several pharmacodynamic and patient variables.