ATC Class:H03BA02
VA Class:HS852
Propylthiouracil is a thiourea-derivative antithyroid agent.
Propylthiouracil is used in patients with Graves' disease with hyperthyroidism or toxic multinodular goiter who are intolerant of methimazole and for whom surgery or radioactive iodine therapy is not an appropriate treatment option.109 The drug also is used to ameliorate symptoms of hyperthyroidism in preparation for thyroidectomy or radioactive iodine therapy in patients who are intolerant of methimazole.109
Because use of propylthiouracil is associated with a higher risk of clinically serious or fatal liver injury in adult and pediatric patients compared with methimazole, propylthiouracil should be reserved for patients who cannot tolerate methimazole and for whom radioactive iodine therapy or surgery are not appropriate for the management of hyperthyroidism.100, 103, 107, 109, 112, 118 (See Cautions: Hepatic Effects and also see Cautions: Precautions and Contraindications.) Propylthiouracil is not recommended for use in pediatric patients except in rare instances in which methimazole is not well tolerated and surgery or radioactive iodine therapy are not appropriate therapies.100, 103, 106, 109, 112 (See Cautions: Hepatic Effects and also see Cautions: Pediatric Precautions.)
Because of the risk of fetal abnormalities associated with methimazole, propylthiouracil is the preferred agent when an antithyroid drug is indicated during or just prior to the first trimester of pregnancy (during organogenesis).100, 103, 107, 108, 109, 112, 118, 119 However, it may be preferable to switch from propylthiouracil to methimazole for the second and third trimesters (i.e., after the first trimester) because of the risk of maternal adverse effects associated with propylthiouracil (e.g., hepatotoxicity).108, 109, 118, 119 (See Pregnancy under Cautions: Pregnancy and Lactation.)
Thioamide antithyroid agents (e.g., propylthiouracil, methimazole) are used to control the symptoms of hyperthyroidism associated with Graves' disease and maintain the patient in a euthyroid state for a period of several years (generally 1-2 years) until a spontaneous remission occurs.118 Thioamide antithyroid agents do not affect the underlying cause of hyperthyroidism. Spontaneous remission does not occur in all patients receiving therapy with thioamide antithyroid agents, and most patients eventually require ablative therapy (i.e., surgery, radioactive iodine). The minimum duration of thioamide therapy necessary before assessing whether spontaneous remission has occurred is not clearly established. However, some clinicians suggest that the optimum duration of antithyroid drug therapy in patients with Graves' disease generally is 12-18 months.122, 123, 124, 125
Propylthiouracil returns the hyperthyroid patient to a normal metabolic state prior to thyroidectomy and controls the thyrotoxic crisis that may accompany thyroidectomy. (See Thyrotoxic Crisis under Uses: Hyperthyroidism.)
Propylthiouracil also controls symptoms of hyperthyroidism prior to and after administration of radioactive iodine until the ablative effects of the iodine occur.123, 129, 130, 131 However, the beneficial and detrimental effects and optimal sequencing of antithyroid drugs before or after radioactive iodine therapy have not been clearly established.129 In addition, pretreatment with propylthiouracil may increase the radioresistance of the thyroid and the risk of radioactive iodine treatment failure.118, 123, 129, 130
Antithyroid agents do not induce remission in patients with nodular thyroid disease (i.e., toxic adenoma†, toxic multinodular goiter), and discontinuance of therapy results in relapse.118 Therefore, some clinicians suggest that adults with overt toxic adenoma or toxic multinodular goiter be treated with either radioactive iodine therapy or thyroidectomy.118
In the management of thyrotoxic crisis, thioamide antithyroid agents are used to inhibit thyroid hormone synthesis. Because propylthiouracil also blocks the peripheral conversion of thyroxine to triiodothyronine, it theoretically may be more useful than methimazole or carbimazole (not commercially available in the US) in the management of thyrotoxic crisis.103, 109 Iodides (e.g., potassium iodide, strong iodine solution) are given to inhibit the release of thyroid hormone from the gland but may subsequently be used as a substrate for thyroid hormone synthesis; therefore, treatment with a thioamide antithyroid agent is usually initiated before iodide therapy. A β-adrenergic blocking agent (e.g., propranolol) is also usually given concomitantly to manage peripheral signs and symptoms of hyperthyroidism, particularly cardiovascular effects (e.g., tachycardia).
Propylthiouracil has been studied in patients with alcoholic liver disease†.116 However, analysis of data from 6 randomized clinical trials with propylthiouracil found that no substantial benefit has been demonstrated on any clinically important outcomes of alcoholic liver disease (e.g., all-cause mortality, liver-related mortality, complications associated with the liver disease, liver histology) and that the currently available evidence does not support its use outside of randomized clinical studies.116 Additional research (e.g., large clinical trials with adequate methodology, several years of treatment, independent and close monitoring of efficacy and safety) is needed to determine the safety and efficacy of propylthiouracil in patients with alcoholic liver disease.116
Propylthiouracil is administered orally; daily dosage is usually given in 3 equally divided doses at approximately 8-hour intervals. In some cases, more frequent administration (e.g., at 4- or 6-hour intervals) may be necessary.
For the treatment of hyperthyroidism, the manufacturer states that the usual initial adult dosage of propylthiouracil is 300 mg daily, usually given in 3 equally divided doses at approximately 8-hour intervals.109 The manufacturer also states that in patients with severe hyperthyroidism and/or very large goiters, the initial dosage may be increased to 400 mg daily; however, initial dosages of 600-900 mg daily occasionally may be required.109 Alternatively, for the treatment of Graves' disease, some clinicians recommend an initial adult dosage of 50-150 mg 3 times daily, depending on the severity of the hyperthyroidism.118 In general, most patients improve considerably or achieve normal thyroid function following 4-12 weeks of therapy, after which dosage may be decreased while maintaining normal thyroid function.118, 122, 123, 124 Subsequent dosage should be carefully adjusted according to the patient's tolerance and therapeutic response. The manufacturer states that the usual adult maintenance dosage is 100-150 mg daily, given in 3 equally divided doses at approximately 8-hour intervals.109 Alternatively, as the clinical findings and thyroid function tests return to normal, some clinicians state that reducing the maintenance dosage to 50 mg 2 or 3 times daily is usually possible for treatment of Graves' disease.118 (See Cautions: Precautions and Contraindications and also see Cautions: Adverse Effects.) The optimum duration of antithyroid therapy remains to be clearly established. However, some clinicians suggest that the optimum duration of antithyroid drug therapy in patients with Graves' disease generally is 12-18 months.122, 123, 124, 125
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.109 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.109 (See Pregnancy under Cautions: Pregnancy and Lactation.)
Dosage of propylthiouracil should be selected with caution in geriatric patients because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy.109 (See Cautions: Geriatric Precautions.)
For the treatment of thyrotoxic crisis (i.e., thyroid storm) in adults, some clinicians recommend a propylthiouracil loading dose of 500 mg to 1 g, followed by 250 mg every 4 hours.118
If propylthiouracil is used prior to thyroidectomy to render adults euthyroid, propylthiouracil should be discontinued at the time of the procedure.118
If propylthiouracil is used as pretreatment prior to radioactive iodine therapy in adults, some clinicians recommend that propylthiouracil be discontinued 2-7 days before administration of radioactive iodine, restarted 3-7 days after radioactive iodine, and discontinued once thyroid function has normalized.122, 123, 130
Propylthiouracil generally is not recommended for use in pediatric patients except in rare instances in which alternative therapies are not appropriate options.109 The manufacturer states that studies evaluating appropriate dosage regimens have not been conducted in the pediatric population, although general practice would suggest initiation of therapy in children 6 years of age or older at a dosage of 50 mg daily with careful upward titration based on clinical response and evaluation of thyrotropin (thyroid stimulating hormone, TSH) and free thyroxine (T4) concentrations.109 Although cases of severe liver injury have been reported with dosages as low as 50 mg daily, most cases were associated with dosages of 300 mg daily and higher.109 (See Cautions: Pediatric Precautions and also see Cautions: Hepatic Effects.)
Minor adverse effects of propylthiouracil include rash, urticaria, pruritus, abnormal hair loss, skin pigmentation, edema, nausea, vomiting, epigastric distress, loss of taste, taste perversion,109 arthralgia, myalgia, paresthesia, and headache.109 Drowsiness, neuritis, vertigo, sialadenopathy, lymphadenopathy, and jaundice also have occurred in patients receiving the drug.109 (See Cautions: Hepatic Effects.)
Although reported much less frequently, severe adverse effects of propylthiouracil include liver injury (resulting in hepatitis, liver failure, a need for liver transplantation, or death [see Cautions: Hepatic Effects]);100, 109 inhibition of myelopoiesis with resultant agranulocytosis (see Cautions: Agranulocytosis), granulocytopenia, and thrombocytopenia; aplastic anemia; drug fever; lupus-like syndrome (including splenomegaly and vasculitis); hepatitis; periarteritis; and hypoprothrombinemia and bleeding.109 Nephritis, glomerulonephritis, interstitial pneumonitis, exfoliative dermatitis, and erythema nodosum also have been reported.109
A vasculitic syndrome associated with the presence of antineutrophil cytoplasmic antibodies (ANCA) has been reported.109 Manifestations of ANCA-positive vasculitis may include rapidly progressive glomerulonephritis (crescentic and pauci-immune necrotizing glomerulonephritis), sometimes resulting in acute renal failure; pulmonary infiltrates or alveolar hemorrha skin ulcers; and leukocytoclastic vasculitis.109 Cutaneous vasculitis, which may manifest as purpuric and/or bullous hemorrhagic lesions or erythema nodosum, and possibly may progress to necrotic ulcerations, and polymyositis also have occurred.
Liver injury (including severe liver injury) resulting in hepatitis, liver failure (including acute liver failure), liver transplantation, or death has been reported with propylthiouracil therapy in adult and pediatric patients.109, 112, 117 An analysis of adverse event reports received by the US Food and Drug Administration (FDA) found that, while severe propylthiouracil-associated hepatotoxicity has been reported among patients in all age groups, the reports and signals of hepatotoxicity were highest among those younger than 17 years of age.117 No cases of liver failure have been reported with the use of methimazole, another antithyroid drug, in pediatric patients.109, 117 For this reason, propylthiouracil is not recommended for use in pediatric patients except in rare instances in which methimazole is not well tolerated and surgery or radioactive iodine therapy are not appropriate therapies.109 (See Cautions: Pediatric Precautions.)
Cases of liver injury, including liver failure and death, have been reported in women receiving propylthiouracil during pregnancy.109 Two cases of in utero exposure to the drug with liver failure and death of a newborn have been reported.109 The use of an alternative antithyroid drug (e.g., methimazole) may be advisable after the first trimester of pregnancy.109 (See Pregnancy under Cautions: Pregnancy and Lactation.)
The extent of propylthiouracil-induced hepatitis and the true incidence of severe liver injury in patients receiving propylthiouracil is not known.104, 107, 117 The total annual number of cases of propylthiouracil-induced hepatitis in the United States has been estimated to be approximately 40-50 (31 adults, 4-8 pregnant women, 4 children) based on a 0.1% incidence of severe hepatitis; the total number of annual cases could range from 20-100 depending on the frequency of propylthiouracil-induced hepatitis and the prevalence of propylthiouracil use.104 In addition, propylthiouracil-induced acute liver failure has been estimated to occur in approximately 0.01% of adults and 0.025-0.05% of children receiving the drug.103, 104 Between 1969 and June 2009, a total of 34 cases (23 adult and 11 pediatric) of serious liver injury associated with propylthiouracil use was reported to the FDA Adverse Event Reporting System (AERS).100, 101, 112 Among the 23 adult cases, 13 resulted in death and 5 resulted in liver transplantation; among the 11 pediatric cases, 2 resulted in death and 7 resulted in liver transplantation (one patient died while awaiting transplantation).100, 112 In contrast, 5 AERS cases of serious liver injury were identified for methimazole; all cases were in adults and 3 resulted in death.100, 112 Based on these results and a review of the medical literature, FDA has concluded that use of propylthiouracil is associated with a higher risk for clinically serious or fatal liver injury compared with methimazole in both adult and pediatric patients.112 According to the United Network for Organ Sharing (UNOS) and the Organ Procurement and Transplantation Network (OPTN), liver transplantation was performed in 16 adults and 7 children between 1990 and 2007 as a result of propylthiouracil-induced liver failure;102, 106, 107 no liver transplantation attributed to methimazole toxicity occurred during this same time period.107
Propylthiouracil-induced liver failure may occur at any time during therapy with a sudden onset, rapid progression, and a low chance of reversibility.103, 104 According to data from the AERS database, liver failure occurred after 6-450 days of propylthiouracil therapy (median: 120 days).107 Although the effect of dosage on the risk of hepatotoxicity has not been clearly elucidated,104 the reported average daily dosage of propylthiouracil associated with liver failure in the AERS database was approximately 300 mg in both children and adults.107 Biochemical monitoring of liver function (bilirubin, alkaline phosphatase) and hepatocellular integrity (ALT, AST) is not expected to attenuate the risk of severe liver injury due to its rapid and unpredictable onset.109 (See Cautions: Precautions and Contraindications.)
Agranulocytosis occurs in approximately 0.2-0.5% of patients receiving propylthiouracil and is a potentially life-threatening adverse effect of the drug.109 Agranulocytosis typically occurs within the first 3 months of therapy,109 but rarely may occur after 4 months of therapy. Agranulocytosis may occur irrespective of dosage, length of treatment, or previous exposure to the antithyroid drug, and may occur more frequently in geriatric patients.122, 123 Although the mechanism(s) of propylthiouracil-induced agranulocytosis has not been determined, antigranulocyte antibodies have been reported in some patients with thioamide-induced agranulocytosis; a direct toxic effect of these drugs on bone marrow has not been excluded as an additional possible cause.
Propylthiouracil may cause hypothyroidism necessitating routine monitoring of thyrotropin (thyroid stimulating hormone, TSH) and free thyroxine (T4) concentrations; dosage should be adjusted to maintain a euthyroid state.109 (See Cautions: Precautions and Contraindications.) Because propylthiouracil readily crosses the placenta, the drug can cause fetal goiter and cretinism when administered to a pregnant woman.109 (See Pregnancy under Cautions: Pregnancy and Lactation.)
Precautions and Contraindications
Some clinicians suggest that liver function tests, including alkaline phosphatase, aminotransferase, and bilirubin, be performed prior to initiating antithyroid drug therapy in patients with Graves' disease.118 Patients receiving propylthiouracil should be closely monitored for signs and symptoms of liver injury, particularly during the first 6 months following initiation of therapy.100 (See Cautions: Hepatic Effects.) Routine biochemical monitoring of liver function (bilirubin, alkaline phosphatase) and hepatocellular integrity (ALT, AST) may not be effective in identifying patients at risk of developing propylthiouracil-induced liver failure and is not expected to attenuate the risk of severe liver injury because of its rapid and unpredictable onset; however, such tests should be performed in symptomatic patients.103, 104, 107, 109, 118 Patients should be informed of the risk of liver failure associated with propylthiouracil and advised to immediately discontinue the drug and promptly contact their clinician if signs and symptoms of liver injury or hepatic dysfunction (e.g., fatigue, weakness, vague abdominal pain, right upper quadrant pain, anorexia, pruritus, easy bruising, jaundice, pruritic rash, light-colored stool, dark urine, joint pain, bloating, nausea) occur, particularly in the first 6 months of therapy.100, 103, 109, 112, 118 Propylthiouracil should be discontinued immediately if a patient develops these symptoms, and the patient should be promptly evaluated for evidence of liver injury, including evaluation of liver function (bilirubin, alkaline phosphatase) and hepatocellular integrity (ALT, AST), and should be provided supportive care.100, 109, 118 Some clinicians state that propylthiouracil should be discontinued if aminotransferase concentrations (whether elevated at initiation of therapy, found incidentally, or measured as clinically indicated) increase to 2-3 times the upper limit of normal and fail to improve within 1 week with repeat testing.118 Following discontinuance of the drug, liver function (i.e., alkaline phosphatase, bilirubin, transaminases) should be monitored weekly until there is evidence of resolution.118 If resolution is not evident, prompt referral to a gastroenterologist or hepatologist is warranted.118
Some clinicians suggest that a baseline complete blood count, including white count with differential, should be performed prior to initiating antithyroid drug therapy in patients with Graves' disease.118 Patients receiving propylthiouracil should be closely monitored and should be instructed to contact their clinician immediately if signs or symptoms of illness, particularly sore throat, skin eruptions, fever, chills, headache, or general malaise, occur; it is particularly important to carefully monitor for these signs and symptoms during the early stages of propylthiouracil therapy since propylthiouracil-induced agranulocytosis usually occurs during the first several months of therapy. Leukopenia, thrombocytopenia, and/or aplastic anemia (pancytopenia) also may occur. Leukocyte and differential counts should be performed in patients who develop fever or sore throat or other signs or symptoms of illness while receiving the drug.109 Leukopenia (i.e., leukocyte count less than 4000/mm3) occurs in 10% of untreated hyperthyroid patients and often is associated with relative granulocytopenia; this should be considered when evaluating the patient's myelopoietic response to the drug. Propylthiouracil should be used with extreme caution in patients receiving concomitant drugs known to be associated with agranulocytosis.109 The manufacturer states that propylthiouracil should be discontinued if agranulocytosis, aplastic anemia (pancytopenia), ANCA-positive vasculitis, hepatitis, interstitial pneumonitis, fever, or exfoliative dermatitis is suspected, and the patient's bone marrow indices should be obtained.109 Some clinicians state that patients should be informed of the adverse effects associated with propylthiouracil (e.g., agranulocytosis) and advised to immediately discontinue the drug and promptly contact their clinician if fever or pharyngitis occurs.118 In a patient who develops agranulocytosis or other serious adverse effects while receiving either methimazole or propylthiouracil, some clinicians state that use of the other drug also is contraindicated because of the risk of cross-sensitivity between the two drugs.118
Because propylthiouracil may cause hypoprothrombinemia and bleeding, monitoring of prothrombin time should be considered during therapy with the drug, particularly prior to surgery (see Drug Interactions: Anticoagulants).109
Thyroid function should be monitored periodically in patients receiving propylthiouracil.109 In patients with Graves' disease, some clinicians state that thyroid function (e.g., serum free T4, serum free or total triiodothyronine [T3], TSH) should be monitored before initiating therapy and then every 4-8 weeks thereafter (with subsequent dosage adjustments as needed) until thyroid function is stable or the patient is euthyroid; once the patient is euthyroid, thyroid function may be monitored every 2-3 months.118, 122, 123, 124 Early in the course of antithyroid therapy, serum TSH concentration is not a reliable parameter to monitor because it may remain suppressed for several months after initiation of therapy despite normalization of free T4 concentrations.118, 122, 123, 124 The finding of a suppressed TSH concentration during this period, therefore, does not indicate a need for a dosage increase.123 However, once clinical evidence of resolution of hyperthyroidism occurs, the finding of an elevated serum TSH concentration indicates that a lower maintenance dosage of propylthiouracil should be employed.109, 123 Monitoring serum T3 concentrations may sometimes be useful for dosage adjustment; in patients in whom total or free T3 concentrations remain elevated despite low, normal, or reduced free T4 concentrations, an increase in antithyroid dosage may be necessary.122, 123, 124
Patients should inform clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.109, 112 Patients also should be advised not to discontinue propylthiouracil therapy unless instructed to do so by their clinician.112
Propylthiouracil is contraindicated in patients who are hypersensitive to the drug or any ingredient in the formulation.109 Cross-sensitivity between thioamides may occur118, 121 (i.e., in approximately 50% of patients switched from one thioamide agent to the other).122 In patients who develop agranulocytosis or other serious adverse effects while receiving either propylthiouracil or methimazole, some clinicians state that use of the other drug also is contraindicated because of the risk of cross-sensitivity between the two drugs.118 In patients experiencing serious allergic reactions to propylthiouracil, some clinicians state that using the alternative antithyroid drug (i.e., methimazole) is not recommended.118
During postmarketing experience, cases of severe liver injury, including hepatic failure requiring liver transplantation or resulting in death, have been reported in pediatric patients receiving propylthiouracil; however, no such cases have been reported in pediatric patients treated with methimazole.109, 117 Therefore, propylthiouracil is not recommended for use in pediatric patients except in rare instances in which methimazole is not well tolerated and surgery or radioactive iodine therapy are not appropriate therapies.100, 103, 106, 109 In addition, some experts state that alternative therapy should be considered for children who are currently receiving propylthiouracil and that it is reasonable and prudent to discontinue propylthiouracil use in children receiving this drug for the treatment of Graves' disease.105, 106 When propylthiouracil is used in children, parents and patients should be informed of the risk of liver failure.109 If patients receiving propylthiouracil develop tiredness, nausea, anorexia, fever, pharyngitis, or malaise, propylthiouracil should be discontinued immediately, a clinician should be contacted, and a leukocyte count, liver function tests, and transaminase concentrations obtained.109 (See Cautions: Hepatic Effects and also see Cautions: Precautions and Contraindications.)
Clinical studies of propylthiouracil did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.109 Other reported clinical experience has not identified differences in responses between geriatric and younger patients.109 Dosage of propylthiouracil generally should be selected with caution in geriatric patients because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy.109
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.109, 113 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.112 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).112 In addition, there was a distinct and consistent pattern of congenital malformations associated with the use of methimazole that was not found with propylthiouracil.112 Approximately 90% of the congenital malformations with methimazole were craniofacial malformations (e.g., scalp epidermal aplasia [aplasia cutis], facial dysmorphism, choanal atresia).112 In most of the cases, there were multiple malformations that frequently included a combination of craniofacial defects and GI atresia or aplasia.112 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.112 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.112
Despite the potential fetal hazard, antithyroid agents are still considered the therapy of choice for the management of hyperthyroidism during pregnancy.108, 118, 119, 122 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.100, 103, 106, 107, 108, 109, 118, 119 Patients receiving methimazole should be switched to propylthiouracil if pregnancy is confirmed in the first trimester.119 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).108, 109, 118, 119 If the patient is switching from propylthiouracil to methimazole, thyroid function should be assessed after 2 weeks and then every 2-4 weeks thereafter.108 It is not known if the risk of methimazole-induced aplasia cutis or embryopathy outweighs the risk of propylthiouracil-induced hepatotoxicity.104
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.109 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.108, 119 In women receiving antithyroid drugs during pregnancy, free T4 and TSH concentrations should be monitored approximately every 2-6 weeks.119 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.109
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.109, 112 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.104, 106, 109 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.108 (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.109, 110 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.109, 110
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.119, 120, 121, 122 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.118, 119 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.119
Propylthiouracil should be used with extreme caution in patients receiving concomitant treatment with drugs known to be associated with agranulocytosis.109 (See Cautions: Agranulocytosis and also see Cautions: Precautions and Contraindications.)
Because of the potential inhibition of vitamin K activity by propylthiouracil, the activity of oral anticoagulants (e.g., warfarin) may be increased.109 However, propylthiouracil also may decrease the anticoagulant effect of warfarin.122 Additional monitoring of prothrombin time (PT)/international normalized ratio (INR) should be considered, particularly prior to surgery.109 Adjustment of warfarin dosage may be necessary.122
Beta-Adrenergic Blocking Agents
Hyperthyroidism may cause an increased clearance of β-adrenergic blocking agents with a high extraction ratio.109 Dosage reduction of the β-adrenergic blocking agent may be needed when a hyperthyroid patient becomes euthyroid.109
Serum digitalis concentrations may be increased when hyperthyroid patients receiving a stable digitalis glycoside regimen become euthyroid; dosage reduction of the digitalis glycoside may be needed.109
Theophylline clearance may decrease when hyperthyroid patients receiving a stable theophylline regimen become euthyroid; dosage reduction of theophylline may be needed.109
In general, overdosage of propylthiouracil may be expected to produce effects that are extensions of common adverse reactions. Nausea, vomiting, epigastric distress, headache, fever, arthralgia, pruritus, edema, and pancytopenia have been reported. Agranulocytosis is the most serious adverse effect associated with propylthiouracil overdosage. Exfoliative dermatitis, hepatitis, neuropathies, or CNS stimulation or depression may occur rarely.109
Treatment of propylthiouracil overdosage generally involves appropriate supportive care as dictated by the patient's medical status.109 Clinicians should consider consulting a poison control center for the most current information on the management of propylthiouracil overdosage.109
Propylthiouracil inhibits the synthesis of thyroid hormones by interfering with the incorporation of iodine into tyrosyl residues of thyroglobulin; the drug also inhibits the coupling of these iodotyrosyl residues to form iodothyronine. Although the exact mechanism(s) has not been fully elucidated, propylthiouracil may interfere with the oxidation of iodide ion and iodotyrosyl groups. Based on limited evidence it appears that the coupling reaction is more sensitive to antithyroid agents than the iodination reaction. Propylthiouracil does not inhibit the action of thyroid hormones already formed and present in the thyroid gland or circulation nor does the drug interfere with the effectiveness of exogenously administered thyroid hormones. Patients whose thyroid gland contains relatively high concentration of iodine (e.g., from prior ingestion or from administration during diagnostic radiologic procedures) may respond relatively slowly to antithyroid agents. Unlike methimazole, propylthiouracil inhibits the peripheral deiodination of thyroxine to triiodothyronine. Although the importance of this inhibition has not been established, propylthiouracil has a theoretical advantage compared with methimazole or carbimazole in patients with thyrotoxic crisis, since a decreased rate of conversion of circulating thyroxine to triiodothyronine may be clinically beneficial in these patients.
Propylthiouracil is rapidly and readily absorbed from the GI tract following oral administration with peak plasma concentrations of about 6-9 mcg/mL occurring within 1-1.5 hours after a single dose of 200-400 mg. In one study in which the drug was administered orally and IV, about 75% of the oral dose was absorbed. Plasma concentrations of the drug do not appear to correlate with the therapeutic effects.
Although distribution of propylthiouracil into human body tissues and fluids has not been fully characterized, the drug appears to be concentrated in the thyroid gland. Propylthiouracil readily crosses the placenta. The manufacturer states that propylthiouracil is distributed into milk to a small extent; one study indicated that the extent of distribution is about 0.007-0.077% of a single dose.109, 110, 111 (See Cautions: Pregnancy and Lactation.)
The elimination half-life of propylthiouracil has generally been reported to be about 1-2 hours.
Although the exact metabolic fate of propylthiouracil has not been fully established, the drug is extensively metabolized to its glucuronide conjugate and other minor metabolites. The drug and its metabolites are excreted in urine, with about 35% of a dose excreted within 24 hours.109
Propylthiouracil is a thiourea-derivative antithyroid agent. The drug differs chemically and structurally from methimazole in that propylthiouracil has a 6-membered ring instead of a 5-membered ring. Although presence of a thioamide group appears to be sufficient for antithyroid activity, propylthiouracil, like methimazole and carbimazole, contains the thioureylene moiety.
Propylthiouracil is a white, crystalline substance with a bitter taste.109 The drug is very slightly soluble in water.109
Commercially available propylthiouracil tablets should be stored in well-closed containers at 25°C but may be exposed to temperatures ranging from 15-30°C.109
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 50 mg* |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
100. Food and Drug Administration. FDA Alert: Propylthiouracil-induced liver failure. Rockville, MD; 2009 Jun 4. From FDA website. Accessed 2009 Oct 28. [Web]
101. Food and Drug Administration. FDA News Release: FDA warns about serious liver injury associated with anti-thyroid drug. Rockville, MD; 2009 Jun 3. From FDA website. Accessed 2009 Oct 30. [Web]
102. Russo MW, Galanko JA, Shrestha R et al. Liver transplantation for acute liver failure from drug induced liver injury in the United States. Liver Transpl . 2004; 10:1018-23. [PubMed 15390328]
103. Bahn RS, Burch HS, Cooper DS et al. The Role of Propylthiouracil in the Management of Graves' Disease in Adults: report of a meeting jointly sponsored by the American Thyroid Association and the Food and Drug Administration. Thyroid . 2009; 19:673-4. [PubMed 19583480]
104. Eunice Kennedy Shriver National Institute of Child Health and Human Development. Hepatic toxicity following treatment for pediatric Graves' disease meeting: October 28, 2008. Conference proceeding. Available from website. Accessed 2009 Oct 30. [Web]
105. Rivkees SA, Mattison DR. Ending propylthiouracil-induced liver failure in children. N Engl J Med . 2009; 360:1574-5. [PubMed 19357418]
106. Rivkees SA, Mattison DR. Propylthiouracil (PTU) hepatotoxicity in children and recommendations for discontinuation of use. Int J Pediatr Endocrinol . 2009. Article ID 132041. DOI:10.1155/2009/132041.
107. Cooper DS, Rivkees SA. Putting propylthiouracil in perspective. J Clin Endocrinol Metab . 2009; 94:1881-2. [PubMed 19401361]
108. De Groot L, Abalovich M, Alexander EK et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab . 2012; 97:2543-65. [PubMed 22869843]
109. Actavis Elizabeth LLC. Propylthiouracil tablets prescribing information. Elizabeth, NJ; 2012 Jul.
110. Kampmann JP, Johansen K, Hansen JM et al. Propylthiouracil in human milk. Revision of a dogma. Lancet . 1980; 1:736-7. [PubMed 6103158]
111. Low LC, Lang J, Alexander WD. Excretion of carbimazole and propylthiouracil in breast milk. Lancet . 1979; 2:1011. [PubMed 91730]
112. Food and Drug Administration. FDA drug safety communication: New boxed warning on severe liver injury with propylthiouracil. Rockville, MD; 2010 Apr 21. Available from FDA website. Accessed 2010 Sep 8. [Web]
113. Actavis Elizabeth LLC. Propylthiouracil tablets medication guide. Elizabeth, NJ; 2012 Jul.
116. Fede G, Germani G, Gluud C et al. Propylthiouracil for alcoholic liver disease. Cochrane Database Syst Rev . 2011; :CD002800.
117. Rivkees SA, Szarfman A. Dissimilar hepatotoxicity profiles of propylthiouracil and methimazole in children. J Clin Endocrinol Metab . 2010; 95:3260-7. [PubMed 20427502]
118. Bahn Chair RS, Burch HB, Cooper DS et al. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid . 2011; 21:593-646. [PubMed 21510801]
119. Stagnaro-Green A, Abalovich M, Alexander E et al. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid . 2011; 21:1081-125. [PubMedCentral][PubMed 21787128]
120. Methimazole. In: Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011:920-5.
121. American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists, number 37, August 2002: Thyroid disease in pregnancy. Obstet Gynecol . 2002; 100:387-96. [PubMed 12166417]
122. . Drugs for thyroid disorders. Treat Guidel Med Lett . 2009; 7:57-64; quiz 2p following 64. [PubMed 19636287]
123. Franklyn JA, Boelaert K. Thyrotoxicosis. Lancet . 2012; 379:1155-66. [PubMed 22394559]
124. Cooper DS. Antithyroid drugs. N Engl J Med . 2005; 352:905-17. [PubMed 15745981]
125. Abraham P, Avenell A, McGeoch SC et al. Antithyroid drug regimen for treating Graves' hyperthyroidism. Cochrane Database Syst Rev . 2010; :CD003420. [PubMed 20091544]
129. Walter MA, Briel M, Christ-Crain M et al. Effects of antithyroid drugs on radioiodine treatment: systematic review and meta-analysis of randomised controlled trials. BMJ . 2007; 334:514. [PubMedCentral][PubMed 17309884]
130. Ross DS. Radioiodine therapy for hyperthyroidism. N Engl J Med . 2011; 364:542-50. [PubMed 21306240]
131. Seigel SC, Hodak SP. Thyrotoxicosis. Med Clin North Am . 2012; 96:175-201. [PubMed 22443970]