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.
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.
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.
Internal contamination with radioactive iodine (I-131) (off-label use): Use may be considered if potassium iodide is unavailable, contraindicated, or unlikely to be effective (eg, too late for potassium iodide to be effective). In patients >40 years of age, treatment for inhalational exposure to radioactive iodine is not recommended unless the projected thyroid dose is >5 sievert (Sv) (REMM 2022b).
Oral: 100 mg 3 times daily for 8 days (REMM 2022a).
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).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling.
(For additional information see "Propylthiouracil: Pediatric drug information")
Note: Due to reports of severe liver toxicity, propylthiouracil is not recommended for use in pediatric patients; use should be limited to patients who have developed minor toxic reactions to methimazole and who are not candidates for surgery or radioactive iodine treatment. If use deemed necessary, patients and parents should be informed of risks and propylthiouracil therapy limited to a short course with close patient monitoring (eg, baseline CBC, liver profile including LFTs, bilirubin, and alkaline phosphatase recommended). Discontinue therapy at first sign of hepatotoxicity and initiate hepatic assessment (see "Dosing: Hepatic Impairment: Pediatric") (ATA [Ross 2016]).
Hyperthyroidism, alternate therapy: Note: Adjust dosage to maintain T3, T4, and thyroid stimulating hormone (TSH) in normal range; elevated T3 may be sole indicator of inadequate treatment. Elevated TSH indicates excessive antithyroid treatment.
Children: ≥6 years and Adolescents: Limited data available (Propyl-Thyracil Canadian product monograph):
Initial:
BSA-directed dosing: Oral: 150 mg/m2/day in divided doses every 8 hours.
Age-directed fixed dosing:
6 to 10 years: Oral: 50 to 150 mg/day divided every 8 hours.
≥10 years: Oral: 150 to 300 mg/day divided every 8 hours.
Maintenance (once euthyroid): Dose should be individualized based on patient response: Oral: Usual dose: 50 mg twice daily.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Dosage adjustment for toxicity: Discontinue use for signs of infection (fever, arthralgias, mouth sores, pharyngitis, or malaise); assess WBC count (ATA [Ross 2016]).
There are no dosage adjustments provided in the manufacturer's labeling.
Due to reports of severe liver toxicity, propylthiouracil is not recommended for use in pediatric patients. If used, limit duration to short course of therapy.
Baseline hepatic impairment: ALT or AST >5 x ULN: Reconsider initiation of therapy (ATA [Ross 2016]).
Hepatotoxicity during treatment: Discontinue therapy at first sign of liver injury (eg, anorexia, pruritus, rash, jaundice, light stool, dark urine, joint pain, right upper quadrant pain, abdominal bloating, nausea, malaise) and assess LFTs. Permanently discontinue if AST or ALT 2 to 3 times ULN fails to resolve within a week of repeat testing (ATA [Ross 2016]).
Refer to adult dosing; use with caution.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Generic: 50 mg
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet, Oral:
Propyl-Thyracil: 50 mg [DSC], 100 mg [DSC]
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/006188s026lbl.pdf#page=7, must be dispensed with this medication.
Oral: Administer in 3 equally divided doses at approximately 8-hour intervals.
Oral: Administer in 3 equally divided doses at approximately 8-hour intervals.
Hazardous agent (NIOSH 2016 [group 2]).
Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage.
NIOSH recommends single gloving for administration of intact tablets or capsules. If manipulating tablets/capsules (eg, to prepare an oral suspension), NIOSH recommends double gloving, a protective gown, and preparation in a controlled device; if not prepared in a controlled device, respiratory and eye/face protection as well as ventilated engineering controls are recommended. NIOSH recommends double gloving, a protective gown, and (if there is a potential for vomit or spit up) eye/face protection for administration of an oral liquid/feeding tube administration (NIOSH 2016). Assess risk to determine appropriate containment strategy (USP-NF 2017).
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).
Internal contamination with radioactive iodine (I-131); Thyroid storm or thyrotoxicosis
Propylthiouracil may be confused with Purinethol [DSC]
PTU is an error-prone abbreviation (mistaken as mercaptopurine [Purinethol; 6-MP])
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
<1%: Hematologic: Agranulocytosis
Frequency not defined:
Cardiovascular: Edema
Dermatologic: Alopecia, pruritus, skin pigmentation, skin rash, urticaria
Gastrointestinal: Ageusia, dysgeusia, epigastric discomfort, nausea, salivary gland disease, vomiting
Hematologic & oncologic: Leukopenia, lymphadenopathy
Hepatic: Jaundice
Nervous system: Drowsiness, headache, neuritis, paresthesia, vertigo
Neuromuscular & skeletal: Arthralgia, myalgia
Postmarketing:
Cardiovascular: Hypersensitivity angiitis, periarteritis, vasculitis (ANCA-positive and cerebral)
Dermatologic: Erythema nodosum, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis
Gastrointestinal: Ischemic colitis
Hematologic & oncologic: Aplastic anemia, granulocytopenia, hemorrhage, hypoprothrombinemia, splenomegaly, thrombocytopenia
Hepatic: Hepatic failure (including acute hepatic failure), hepatic injury (severe), hepatitis, hepatotoxicity (idiosyncratic) (Chalasani 2014)
Hypersensitivity: Hypersensitivity reaction
Nervous system: Drug fever
Neuromuscular & skeletal: Lupus-like syndrome
Renal: Glomerulonephritis, nephritis
Respiratory: Interstitial pneumonitis, pulmonary alveolar hemorrhage
Hypersensitivity to propylthiouracil or any component of the formulation
Canadian labeling: Additional contraindications (not in US labeling): Breastfeeding
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 (Shaikh 2019), 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: Cases of vasculitis resulting in severe complications and death have been reported. Most cases were ANCA-positive and included alveolar/pulmonary hemorrhage, cerebral angiitis, glomerulonephritis, ischemic colitis, and leukocytoclastic cutaneous vasculitis. Discontinue use for confirmed or suspected vasculitis. Some cases resolve/improve with drug discontinuation; severe cases may require further treatment (eg, corticosteroids, immunosuppressant therapy, plasmapheresis).
Dosage form specific issues:
• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates; the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP 1997; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.
In pediatric patients, severe liver injury including hepatic failure requiring transplantation or resulting in death have been reported with propylthiouracil (most cases with doses ≥300 mg, but has also been reported with the lower 50 mg dose). Routine liver function test monitoring may not reduce risk due to unpredictable and rapid onset. Use is not recommended and should be limited to patients who have developed minor toxic reactions to methimazole and who are not candidates for surgery or radioactive iodine treatment. If use necessary, patients and parents should be informed of risks and propylthiouracil therapy limited to a short course with close patient monitoring (baseline CBC, liver profile including LFTs, bilirubin, and alkaline phosphatase recommended). Discontinue use, contact prescriber, and obtain CBC (WBC) and LFTs (transaminases) if any of the following occur: Tiredness, nausea, anorexia, fever, pharyngitis, malaise, pruritus, rash, jaundice, light-colored stool or dark urine, joint pain, right upper quadrant pain, abdominal bloating (ATA [Ross 2016]).
None known.
5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
Cardiac Glycosides: Antithyroid Agents may increase the serum concentration of Cardiac Glycosides. Risk C: Monitor therapy
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination
Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination
Macimorelin: Propylthiouracil may diminish the diagnostic effect of Macimorelin. Risk X: Avoid combination
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification
Sodium Iodide I131: Antithyroid Agents may diminish the therapeutic effect of Sodium Iodide I131. Management: Discontinue antithyroid medications at least 3 days before sodium iodide I-131 administration, and avoid concurrent use. Risk X: Avoid combination
Theophylline Derivatives: Antithyroid Agents may increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Antithyroid Agents may diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Patients taking propylthiouracil should use effective contraception and postpone becoming pregnant until a stable euthyroid state is achieved. Unless otherwise contraindicated, propylthiouracil may be the preferred treatment when an antithyroid drug is indicated just prior to the first trimester of pregnancy. Patients taking propylthiouracil should notify their health care provider immediately once pregnancy is suspected. The decision to continue antithyroid medications during pregnancy should be individualized (ATA [Alexander 2017]).
Propylthiouracil crosses the placenta.
Adverse events associated with propylthiouracil use during pregnancy include liver damage in the mother and fetus and hypothyroidism in the fetus/neonate. Face and neck cysts and urinary tract abnormalities in male offspring have also been reported (ATA [Alexander 2017]).
Uncontrolled maternal hyperthyroidism may result in adverse neonatal and maternal outcomes. Adverse outcomes associated with poorly controlled thyrotoxicosis include pregnancy loss, pregnancy-induced hypertension, maternal congestive heart failure, and thyroid storm, as well as prematurity, low birth weight, intrauterine growth restriction, and stillbirth (ATA [Alexander 2017]).
The pharmacokinetic properties of propylthiouracil are not significantly changed by pregnancy; however, the severity of hyperthyroidism may fluctuate throughout pregnancy (ES [De Groot 2012]; Sitar 1979; Sitar 1982). If a euthyroid state is maintained, doses of propylthiouracil may be decreased as pregnancy progresses and discontinued weeks to months prior to delivery.
To avoid potential adverse effects, antithyroid drugs may be discontinued as soon as pregnancy is detected in select patients with well-controlled Graves disease at low risk for relapse; close monitoring of maternal and fetal thyroid function is recommended (ATA [Alexander 2017]). When treatment is necessary, antithyroid drugs are the treatment of choice for the control of hyperthyroidism during pregnancy (ACOG 2020; ATA [Alexander 2017]; ES [De Groot 2012]). Propylthiouracil may be the treatment of choice when an antithyroid drug is indicated during the first 16 weeks of pregnancy. Due to the potential for hepatic toxicity, other antithyroid medications could be considered after 16 weeks' gestation (ATA [Alexander 2017]). To prevent adverse outcomes, the lowest effective dose should be used to keep the maternal TT4/FT4 at or just above the pregnancy-specific ULN. Propylthiouracil may be used for the treatment of thyroid storm in pregnant patients (ACOG 2020; ATA [Alexander 2017]).
Propylthiouracil is present in breast milk.
Information related to the presence of propylthiouracil in breast milk is available from 9 euthyroid breastfeeding women (2 with Graves disease) at 1 to 8 months postpartum. Propylthiouracil 400 mg was administered as a single dose and drug concentrations in maternal serum and breast milk were measured every 30 minutes for 4 hours. The mean maternal serum concentration at 90 minutes was 7.7 ± 1 mcg/mL and decreased to 3.9 ± 0.5 mcg/mL after 4 hours. The mean propylthiouracil concentration in milk at 90 minutes was 0.7 ± 0.2 mcg/mL and decreased to 0.5 ± 0.1 mcg/mL after 4 hours. The mean volume of milk collected in 4 hours contained propylthiouracil equivalent to 0.025% of the ingested dose. The authors calculated that a 3.5 kg infant would receive a dose equivalent to 3 mg (range: 0.8 to 9.2 mg) for a 70 kg adult and it is unlikely to affect infant thyroid hormone metabolism (Kampmann 1980). Using a mean milk concentration of 0.7 mcg/mL, the estimated exposure to the breastfeeding infant would be 0.11 mg/kg/day (relative infant dose <2% based on a weight adjusted maternal dose of 400 mg/day). In general, breastfeeding is considered acceptable when the radial immunodiffusion of a medication is <10% (Anderson 2016; Ito 2000).
Based on available data, thyroid function is normal in infants exposed to propylthiouracil via breast milk. The treatment of hyperthyroidism in breastfeeding patients is the same as non-breastfeeding patients. Maternal use of propylthiouracil is considered acceptable while breastfeeding (ATA [Alexander 2017]; WHO 2002) although it may not be preferred due to the potential risk of maternal hepatic toxicity (Amino 2020). The lowest effective dose should be used; maternal doses of propylthiouracil ≤450 mg/day are advised in breastfeeding patients. Infants exposed to antithyroid medications via breast milk should be monitored for adequate growth and development; routine tests of thyroid function are not recommended (ATA [Alexander 2017]). Taking the dose of propylthiouracil after breastfeeding may help decrease potential infant exposure by providing a 3- to 4-hour interval before the next feed (Amino 2020).
Signs and symptoms of illness (ie fever, sore throat, skin eruptions, general malaise) or vasculitis.
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:
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]; in patients with Graves’ disease, if thyrotropin receptor autoantibody (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).
Thyroid stimulating hormone (TSH) (periodically throughout treatment; TSH is not an adequate parameter to assess initial response as levels may remain suppressed for several months after starting therapy) (Ross 2016).
TRAb in patients with Graves disease (prior to stopping medication, elevation at the end of therapy decreases likelihood of remission) (Ross 2016).
Pregnant patients: Free T4 and total T3 every 2 to 4 weeks until stabilized (ACOG 2020). Free T4, total T4, and TSH ~ every 4 weeks throughout pregnancy. TRAb once pregnancy is confirmed, at 18 to 22 weeks' gestation, and 30 to 34 weeks' gestation (ATA [Alexander 2017]).
Normal laboratory values:
Total T4: 5 to 12 mcg/dL
Serum T3: 90 to 185 ng/dL
Free thyroxine index (FT4 I): 6 to 10.5
TSH: 0.5 to 4.0 microunits/mL
TRAb: <1.75 int. units/L
Inhibits the synthesis of thyroid hormones by interfering with thyroid peroxidase (TPO) which oxidizes iodide, subsequently catalyzes formation of mono- and di-iodotyrosines (MIT and DIT) on thyroglobulin, and catalyzes coupling reactions between MIT and DIT to form thyroxine (T4) and triiodothyronine (T3) (Burch 2015); also blocks conversion of T4 to T3 in peripheral tissues (does not inactivate existing T4 and T3 stores in circulating blood and the thyroid and does not interfere with replacement thyroid hormones). Propylthiouracil also acts as a thyroid blocker to decrease the retention of radioactive iodine (I-131) into the thyroid (REMM 2022b).
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
Duration: 12 to 24 hours (Clark 2006)
Distribution: Concentrated in the thyroid gland (Clark 2006)
Protein binding: 80% to 85% (Clark 2006)
Metabolism: Hepatic
Bioavailability: 53% to 88% (Clark 2006)
Half-life elimination: ~1 hour (Clark 2006)
Time to peak, serum: 1 to 2 hours (Clark 2006)
Excretion: Urine (35%; primarily as metabolites)
Tablets (Propylthiouracil Oral)
50 mg (per each): $0.90
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.