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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).

Use: Unlabeled

Graves' disease (management); Thyrotoxic crisis (management); Thyroid storm (management)

Contraindications

Hypersensitivity to propylthiouracil or any component of the formulation

Canadian labeling: Additional contraindications (not in US labeling): Breast-feeding

Dosing: Adult

Hyperthyroidism: Oral:

US labeling: 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

Canadian labeling: Initial: 50 to 100 mg every 8 hours; may increase up to a maximum of 500 mg daily; some patients may require initial doses up to 900 mg daily. May reduce dose (euthyroid usually occurs after 6 to 8 weeks) by 1/3 every 4 to 6 weeks to a maintenance dose of 50 mg 2 or 3 times daily. Note: Administer doses >300 mg daily every 4 to 6 hours.

Graves’ disease (off-label dosing): Oral: Initial: 50 to 150 mg (depending on severity) 3 times daily to restore euthyroidism; maintenance: 50 mg 2 to 3 times daily for a total of 12 to 18 months, then tapered or discontinued if TSH is normal at that time (Bahn 2011)

Thyrotoxic crisis/thyroid storm (off-label dosing): Oral: Note: Recommendations vary widely and have not been evaluated in comparative trials. Typical dosing is 800 to 1,200 mg/day given as 200 to 300 mg every 4 to 6 hours; some clinicians advocate an initial loading dose of 600 to 1,000 mg. After initial response, dose may be reduced gradually to a maintenance dosage (100 to 600 mg/day in divided doses) (Goldberg 2003; Nayak 2006). The American Thyroid Association and the American Association of Clinical Endocrinologists recommend 500 to 1,000 mg loading dose followed by 250 mg every 4 hours (Bahn 2011).

Duration of therapy: Clinical improvement generally occurs in 1 to 3 months, after which dosage reduction may be employed (to prevent hypothyroidism), with discontinuation considered after 12 to 18 months of therapy. Thyroid function should be monitored every 2 months thereafter for 6 months until remission is confirmed, followed by annual evaluations (Cooper 2005).

Dosing: Pediatric

Hyperthyroidism: Canadian labeling: Oral: (generally not recommended for use in children unless alternative therapies are not appropriate):

Initial dose guideline: 150 mg/m2/day

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

Children >10 years and Adolescents: 150 to 300 mg daily 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

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]). When manipulating tablets, NIOSH recommends double gloving, a protective gown, and preparation in a controlled device; if not prepared in a controlled device, respiratory and eye protection as well as ventilated engineering controls are recommended (NIOSH 2014).

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

Administer orally in 3 equally divided doses at approximately 8 hour intervals. Administer doses >300 mg/day divided every 4 to 6 hours (Canadian labeling).

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]). Avoid exposure to crushed or broken tablets; if it is necessary to manipulate the tablets (eg, to prepare an oral solution), it is recommended to double glove, wear a protective gown, and prepare in a controlled device. Disposable gloves should be worn when handling tablets or suspension for administration; health care providers should also wear a protective gown (NIOSH 2014).

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

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.

• 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.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Monitoring Parameters

CBC with differential, prothrombin time (especially before surgical procedures), liver function tests (bilirubin, alkaline phosphatase, ALT, AST), and thyroid function tests (TSH, T3, T4) every 4 to 6 weeks until euthyroid; periodic blood counts are recommended for chronic therapy

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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