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Propylthiouracil

Pronunciation

Pronunciation

(proe pil thye oh YOOR a sil)

Index Terms

  • PTU (error-prone abbreviation)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Generic: 50 mg

Pharmacologic Category

  • Antithyroid Agent
  • Thioamide

Pharmacology

Inhibits the synthesis of thyroid hormones by blocking the conversion of thyroxine to triiodothyronine in peripheral tissues (does not inactivate existing thyroxine and triiodothyronine stores in circulating blood and the thyroid and does not interfere with replacement thyroid hormones).

Distribution

Concentrated in the thyroid gland (Clark 2006)

Metabolism

Hepatic

Excretion

Urine (35%; primarily as metabolites)

Onset of Action

For significant therapeutic effects 24 to 36 hours are required; remission of hyperthyroidism usually does not occur before 4 months of continued therapy

Time to Peak

1 to 2 hours (Clark 2006)

Duration of Action

12 to 24 hours (Clark 2006)

Half-Life Elimination

~1 hour (Clark 2006)

Protein Binding

80% to 85% (Clark 2006)

Use: Labeled Indications

Hyperthyroidism: Treatment of hyperthyroidism in patients with Graves' disease or toxic multinodular goiter who are intolerant of methimazole and for whom surgery or radioactive iodine therapy is not an appropriate treatment regimen; amelioration of hyperthyroid symptoms in preparation for thyroidectomy or radioactive iodine therapy (in patients who are intolerant of methimazole).

Off Label Uses

Thyroid storm or thyrotoxicosis

Based on the American Thyroid Association guidelines for the management of Hyperthyroidism and Other Causes of Thyrotoxicosis, treatment with propylthiouracil is recommended in thyroid storm or thyrotoxicosis to reduce thyroid hormone production and to block T4 to T3 conversion. Propylthiouracil is preferred over methimazole in thyroid storm due to inhibition of peripheral conversion of T4 to T3 as well as thyroid hormone synthesis [Ross 2016].

Contraindications

Hypersensitivity to propylthiouracil or any component of the formulation

Canadian labeling: Additional contraindications (not in US labeling): Breastfeeding

Dosing: Adult

Hyperthyroidism: Oral: Initial: 300 mg daily in 3 equally divided doses (~8-hour intervals); 400 mg daily in patients with severe hyperthyroidism and/or very large goiters; an occasional patient will require 600 to 900 mg daily; usual maintenance: 100 to 150 mg daily in 3 equally divided doses

Adjust dosage as required to achieve and maintain serum T3, T4, and TSH levels in the normal range. An elevated T3 may be the sole indicator of inadequate treatment. An elevated TSH indicates excessive antithyroid treatment.

Hyperthyroidism associated with Graves’ disease (off-label) (Ross 2016): Oral: Initial: 50 to 150 mg (depending on severity) 3 times daily to restore euthyroidism; as clinical condition improves, may reduce dosage to usual maintenance dose of 50 mg 2 to 3 times daily for a total of ~12 to 18 months then discontinue if thyroid function tests (eg, TSH, thyrotropin receptor antibody [TRAb]) are normal at that time.

Thyrotoxic crisis/thyroid storm (off-label use): Oral: Note: Recommendations vary widely and have not been evaluated in comparative trials. The American Thyroid Association recommends a loading dose of 500 to 1,000 mg followed by 250 mg every 4 hours (Ross 2016). As thyrotoxicosis improves, a gradual dose reduction to a dose within the standard maintenance ranges is recommended (Goldberg 2003).

Dosing: Geriatric

Refer to adult dosing; use with caution.

Dosing: Pediatric

Hyperthyroidism: Oral: Note: Due to reports of severe liver toxicity, use in pediatric patients is not recommended unless alternative therapies are not appropriate. If used, limit duration to short course of therapy (Ross 2016).

Manufacturer's labeling: Children ≥6 years and Adolescents: Initial: 50 mg/day in 3 equally divided doses (~8-hour intervals); titrate carefully based upon clinical response and evaluation of TSH and free T4 levels

Alternatively, the following dosing recommendations have been made (Propyl-thyracil Canadian product labeling 2013):

Initial dose guideline: 150 mg/m2/day

Children 6 to 10 years: 50 to 150 mg/day in 3 equally divided doses (~8-hour intervals)

Children ≥10 years and Adolescents: 150 to 300 mg/day in 3 equally divided doses (~8-hour intervals)

Maintenance dose (general): 50 mg twice daily (when euthyroid)

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling.

Extemporaneously Prepared

A 5 mg/mL oral suspension may be made with tablets and a 1:1 mixture of Ora-Plus and Ora-Sweet. Crush twenty 50 mg propylthiouracil tablets in a mortar and reduce to a fine powder. Add small portions of vehicle and mix to a uniform paste; mix while adding vehicle in incremental proportions to almost 200 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 200 mL. Label "shake well" and "refrigerate". Stable for 91 days refrigerated (preferred) and 70 days at room temperature.

Nahata MC, Pai VB, and Hipple TF, Pediatric Drug Formulations, 5th ed, Cincinnati, OH: Harvey Whitney Books Co, 2004.

Administration

Oral: Administer in 3 equally divided doses at approximately 8-hour intervals.

Storage

Store at 15°C to 30°C (59°F to 86°F).

Drug Interactions

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Cardiac Glycosides: Antithyroid Agents may increase the serum concentration of Cardiac Glycosides. Monitor therapy

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Sodium Iodide I131: Antithyroid Agents may diminish the therapeutic effect of Sodium Iodide I131. Management: Discontinue antithyroid therapy 3-4 days prior to sodium iodide I-131 administration. Avoid combination

Theophylline Derivatives: Antithyroid Agents may increase the serum concentration of Theophylline Derivatives. Exceptions: Dyphylline. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Antithyroid Agents may diminish the anticoagulant effect of Vitamin K Antagonists. Consider therapy modification

Adverse Reactions

Frequency not defined.

Cardiovascular: Edema, periarteritis, vasculitis (ANCA-positive, cutaneous, leukocytoclastic)

Central nervous system: Drowsiness, drug fever, headache, neuritis, paresthesia, vertigo

Dermatologic: Alopecia, dermal ulcer, erythema nodosum, exfoliative dermatitis, pruritus, skin pigmentation, skin rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria

Gastrointestinal: Ageusia, dysgeusia, nausea, salivary gland disease, stomach pain, vomiting

Hematologic & oncologic: Agranulocytosis, aplastic anemia, granulocytopenia, hemorrhage, hypoprothrombinemia, leukopenia, lymphadenopathy, splenomegaly, thrombocytopenia

Hepatic: Acute hepatic failure, hepatitis, hepatotoxicity (idiosyncratic) (Chalasani 2014), jaundice

Neuromuscular & skeletal: Arthralgia, lupus-like syndrome, myalgia

Renal: Acute renal failure, glomerulonephritis, nephritis

Respiratory: Interstitial pneumonitis, pulmonary alveolar hemorrhage

Miscellaneous: Fever

ALERT: U.S. Boxed Warning

Hepatotoxicity:

Severe liver injury and acute liver failure, in some cases fatal, have been reported in patients treated with propylthiouracil. These reports of hepatic reactions include cases requiring liver transplantation in adults and pediatric patients.

Reserve propylthiouracil for patients who cannot tolerate methimazole and in whom radioactive iodine therapy or surgery are not appropriate treatments for the management of hyperthyroidism.

Pregnancy:

Because of the risk of fetal abnormalities associated with methimazole, propylthiouracil may be the treatment of choice when an antithyroid drug is indicated during or just prior to the first trimester of pregnancy.

Warnings/Precautions

Concerns related to adverse effects:

• Bleeding: May cause hypoprothrombinemia and bleeding. Monitoring is recommended, especially before surgical procedures.

• Bone marrow suppression: May cause significant bone marrow depression; the most severe manifestation is agranulocytosis (usually occurs within first 3 months of therapy). Aplastic anemia, thrombocytopenia, and leukopenia may also occur. Use with caution in patients receiving other drugs known to cause myelosuppression (particularly agranulocytosis); discontinue if significant bone marrow suppression occurs, particularly agranulocytosis or aplastic anemia.

• Dermatologic toxicity: May occur; discontinue in the presence of exfoliative dermatitis.

• Fever: Discontinue in the presence of unexplained fever.

• Hepatotoxicity: [US Boxed Warning]: Severe liver injury and acute liver failure (some fatal) have been reported and have included cases requiring liver transplantation in adult and pediatric patients, including pregnant women. Reserve propylthiouracil for patients who cannot tolerate methimazole and in whom radioactive iodine therapy or surgery are not appropriate treatments for the management of hyperthyroidism. Routine liver function test monitoring may not reduce risk due to unpredictable and rapid onset. Patients should be counseled to recognize and report symptoms suggestive of hepatic dysfunction (eg, anorexia, pruritus, right upper quadrant pain), especially in first 6 months of treatment, which should prompt immediate discontinuation. Discontinue therapy if transaminases are >3 times the upper limit of normal or if levels elevated at the onset of therapy increase further (Ross 2016).

• Hypothyroidism: May cause hypothyroidism; routinely monitor TSH and free T4 levels, adjust dose to maintain euthyroid state.

• Lupus-like syndrome: A lupus-like syndrome (including splenomegaly and vasculitis) may occur.

• Nephritis: Has been associated with nephritis and glomerulonephritis, sometimes leading to acute renal failure.

• Pneumonitis: Interstitial pneumonitis has been reported; discontinue if this reaction occurs.

• Vasculitis: ANCA-positive vasculitis or leukocytoclastic vasculitis may occur; discontinue in patients who develop vasculitis during therapy.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pregnancy: [US Boxed Warning]: Due to the risk of fetal abnormalities associated with methimazole, propylthiouracil may be the treatment of choice when an antithyroid drug is indicated during or just prior to the first trimester of pregnancy.

Monitoring Parameters

Signs and symptoms of illness (ie fever, sore throat, skin eruptions, general malaise)

CBC with differential (baseline and if development of febrile illness or pharyngitis occurs); prothrombin time (especially before surgical procedures), liver function tests (bilirubin, alkaline phosphatase, ALT, AST at baseline and if symptoms of liver injury occur [Ross 2016])

Thyroid function tests:

TSH (periodically throughout treatment, may remain suppressed for several months after starting therapy) (Ross 2016)

Serum free T4 and total T3 2 to 6 weeks after initiation, repeat in 4 to 6 weeks if dose is adjusted and then every 2 to 3 months once euthyroid levels are achieved; [with long term therapy (ie, >18 months) may extend interval to every 4 to 6 months]; if TRAb is negative, thyroid function tests should be monitored every 2 to 3 months for the first 6 months after discontinuing therapy, then at 4- to 6-month intervals for the next 6 months, then every 6 to 12 months thereafter (Ross 2016)

TRAb (prior to stopping medication, elevation at the end of therapy decreases likelihood of remission) (Ross 2016)

Pregnancy Risk Factor

D

Pregnancy Considerations

Propylthiouracil has been found to readily cross the placenta. Teratogenic effects have not been observed; however, nonteratogenic adverse effects, including fetal and neonatal hypothyroidism, goiter, and hyperthyroidism, have been reported following maternal propylthiouracil use. The transfer of thyroid-stimulating immunoglobulins can stimulate the fetal thyroid in utero and transiently after delivery and may increase the risk of fetal or neonatal hyperthyroidism (De Groot 2012; Peleg 2002).

Antithyroid treatment is recommended for the control of hyperthyroidism during pregnancy (Casey 2006; De Groot 2012). Uncontrolled maternal hyperthyroidism may result in adverse neonatal outcomes (eg, prematurity, low birth weight) and adverse maternal outcomes (eg, preeclampsia, congestive heart failure, stillbirth, and abortion). To prevent adverse fetal and maternal events, normal maternal thyroid function should be maintained prior to conception and throughout pregnancy (De Groot 2012).

[US Boxed Warning]: Because of the risk of fetal abnormalities associated with methimazole, propylthiouracil may be the treatment of choice when an antithyroid drug is indicated during or just prior to the first trimester of pregnancy. Due to an increased risk of liver toxicity with propylthiouracil, the use of methimazole may be preferred during the second and third trimesters. If drug therapy is changed, maternal thyroid function should be monitored after 2 weeks and then every 2 to 4 weeks (De Groot 2012). Propylthiouracil, along with other medications, is used for the treatment of thyroid storm in pregnant women (ACOG 2015).

The pharmacokinetics of propylthiouracil are not changed significantly during pregnancy; however, the severity of hyperthyroidism may fluctuate throughout pregnancy (DeGroot 2012; Sitar 1979; Sitar 1982). Doses of propylthiouracil may be decreased as pregnancy progresses and discontinued weeks to months prior to delivery.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, abdominal pain, hair loss, muscle pain, or change in taste. Have patient report immediately to prescriber bruising, bleeding, joint pain, joint edema, severe headache, severe dizziness, passing out, urinary retention, change in amount of urine passed, burning or numbness feeling, loss of strength and energy, coughing up blood, pale stools, signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), or signs of infection (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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