Propylthiouracil

PTU may increase the effect of oral blood thinners, for example warfarin (Coumadin). Therefore, warfarin dose changes and monitoring for the effects of warfarin on blood clotting are necessary.

Hyperthyroidism may cause increased elimination of beta blockers (for example, propranolol [Inderal, Inderal LA, Innopran XL)). Once hyperthyroidism is reversed the excretion of beta-blockers may return to normal and less beta-blocker will be needed to provide the same effect.

Digoxin (Lanoxin) blood levels may be increased when hyperthyroidism is reversed in patients on a stable digoxin dose. A smaller dose of digoxin may be needed in order to avoid toxicity of digoxin. Similarly, theophylline elimination may decrease when hyperthyroidism is reversed in patients on a stable theophylline dose. A reduced dose of theophylline may be needed in order to avoid toxicity of theophylline.

Serious side effects have been reported with propylthiouracil. See the "Drug Precautions" section.

The most common side effects of propylthiouracil include:

• skin rash or hives
• nausea
• vomiting
• upper stomach pain or tenderness
• joint pain
• itching or tingling
• loss or change in taste
• loss of hair
• muscle pain
• headache
• sleepiness
• nerve pain
• swelling (edema)
• dizziness
• enlarged salivary glands or enlarged lymph nodes

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effects of propylthiouracil. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

If you take too much propylthiouracil, call your local Poison Control Center or go to the nearest hospital emergency room right away.

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.

Tell your doctor about all your current medicines and any you start or stop using, especially:

• digoxin (digitalis);

• theophylline;

• heart or blood pressure medicine--atenolol, carvedilol, labetalol, metoprolol, propranolol, sotalol, and others; or

• a blood thinner--warfarin, Coumadin, Jantoven.

This list is not complete. Other drugs may interact with propylthiouracil, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Contraindications

• Known hypersensitivity to propylthiouracil or any ingredient in the formulation.109

Warnings/Precautions

Warnings

Liver injury (including severe liver injury) resulting in hepatitis, liver failure (including acute liver failure), liver transplantation, or death reported in adult and pediatric patients.100 101 102 103 104 106 107 109 112 (See Boxed Warning.) 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

No cases of liver failure reported with use of methimazole in pediatric patients; therefore, propylthiouracil 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 Pediatric Use under Cautions.)

Cases of liver injury, including liver failure and death, reported in women receiving propylthiouracil during pregnancy.109 Two cases of in utero exposure with liver failure and death of a newborn also reported.109 Use of an alternative antithyroid drug (e.g., methimazole) may be advisable after the first trimester of pregnancy.109 (See Fetal/Neonatal Morbidity and also see Pregnancy under Cautions.)

Extent of propylthiouracil-induced hepatitis and true incidence of severe liver injury not known.104 107

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 liver failure has been observed after 6–450 days of propylthiouracil therapy (median: 120 days).107

Effect of dosage on risk of hepatotoxicity not clearly elucidated;104 however, reported average daily dosage associated with liver failure was approximately 300 mg in both children and adults.107

Perform liver function tests (e.g., alkaline phosphatase, aminotransferase, bilirubin) prior to initiating therapy in patients with Graves’ disease.118

Routine biochemical monitoring of liver function (bilirubin, alkaline phosphatase) and hepatocellular integrity (ALT, AST) may not be effective in identifying patients at risk of liver failure and is not expected to attenuate risk of severe liver injury due to its rapid and unpredictable onset; however, should be performed in symptomatic patients.103 104 107 109 118

Closely monitor patients for signs and symptoms of liver injury (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), particularly during the first 6 months following initiation of therapy.100 109 112 118 If such symptoms occur, immediately discontinue the drug, evaluate the patient for evidence of liver injury (including evaluation of liver function [bilirubin, alkaline phosphatase] and hepatocellular integrity [ALT, AST]), and provide supportive care.100 109 118

Some clinicians recommend discontinuing propylthiouracil if aminotransferase concentrations (whether elevated at initiation of therapy, found incidentally, or measured as clinically indicated) increase to 2–3 times the ULN and fail to improve within 1 week with repeat testing.118 After discontinuing the drug, monitor liver function (i.e., alkaline phosphatase, bilirubin, transaminases) weekly until there is evidence of resolution.118 If resolution is not evident, promptly refer patient to a gastroenterologist or hepatologist.118

Risk of agranulocytosis;109 usually occurs within first 3 months of therapy,109 but rarely may occur after 4 months of therapy.b May occur irrespective of dosage, length of treatment, or previous exposure to antithyroid drug, and may occur more frequently in geriatric patients.122 123

Leukopenia, thrombocytopenia, and aplastic anemia (pancytopenia) may occur.109 Hypoprothrombinemia and bleeding also may occur.109 (See Laboratory Monitoring under Cautions.)

Perform baseline CBC, including white count with differential, prior to initiating therapy in patients with Graves’ disease.118

Monitor patient carefully for signs or symptoms of illness (e.g., sore throat, skin eruptions, fever, chills, headache, general malaise), particularly during the early stages of therapy.b If fever, sore throat, or other signs or symptoms of illness occur, determine leukocyte and differential counts to assess whether agranulocytosis has developed.109 b When evaluating myelopoietic response to propylthiouracil, consider that leukopenia (i.e., WBC <4000/mm3) occurs in 10% of untreated hyperthyroid patients and is often associated with relative granulocytopenia.109 b

If agranulocytosis, aplastic anemia (pancytopenia), or fever is suspected, discontinue propylthiouracil and obtain bone marrow indices.109 In patients who develop agranulocytosis or other serious adverse effects while receiving propylthiouracil or methimazole, use of the other drug is contraindicated because of risk of cross-sensitivity between the two drugs.118

May cause hypothyroidism necessitating routine monitoring of TSH and free T4 concentrations with dosage adjustments to maintain a euthyroid state.109

May cause fetal goiter and cretinism when administered to a pregnant woman, because the drug readily crosses the placenta.109 (See Fetal/Neonatal Morbidity and also see Pregnancy under Cautions.)

May cause fetal harm (i.e., induction of goiter, hypothyroidism, or cretinism).109 113

Congenital malformations reported approximately 3 times more often with prenatal exposure to methimazole compared with propylthiouracil.112 Distinct and consistent pattern of congenital malformations associated with the use of methimazole, but not with propylthiouracil, particularly craniofacial malformations (e.g., scalp epidermal aplasia [aplasia cutis], facial dysmorphism, choanal atresia).112 Specific birth defects were associated with use of methimazole during the first trimester of pregnancy and not found when the drug was administered later in pregnancy.112 FDA has not found a consistent pattern of birth defects associated with use of propylthiouracil and has concluded there is no convincing evidence of an association between propylthiouracil use and congenital malformations, even with use during the first trimester.112 (See Pregnancy under Cautions and also see Distribution under Pharmacokinetics.)

If used during pregnancy or if pregnancy occurs during therapy, apprise of rare potential hazard to the mother and fetus of liver damage; inform the patient of these potential risks and risks of methimazole-associated fetal malformations when considering antithyroid drug use during pregnancy.104 106 109 (See Hepatotoxicity under Cautions.)

Sensitivity Reactions

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 serious adverse effects (e.g., agranulocytosis) while receiving either propylthiouracil or methimazole, use of other drug also is contraindicated, because of risk of cross-sensitivity between the two drugs.118 In patients experiencing serious allergic reactions to propylthiouracil, use of the alternative antithyroid drug (i.e., methimazole) not recommended.118

General Precautions

Before initiating thioamide therapy in patients with Graves’ disease, some clinicians recommend obtaining baseline free T4 and TSH concentrations; CBC, including white count and differential; and liver function tests (e.g., alkaline phosphatase, aminotransferase, bilirubin).118 Routine biochemical monitoring of liver function (bilirubin, alkaline phosphatase) and hepatocellular integrity (ALT, AST) not expected to attenuate risk of severe liver injury, but should be performed in symptomatic patients.103 104 107 109 118 (See Hepatotoxicity under Cautions.)

Monitor thyroid function (e.g., serum free T4, serum free or total T3, TSH) periodically (e.g., every 4–8 weeks [with subsequent dosage adjustments as needed] until thyroid function is stable or patient is euthyroid); once euthyroidism is achieved, monitor thyroid function every 2–3 months.109 118 122 123 124 Serum TSH not a reliable parameter to monitor early in therapy because it may remain suppressed for several months after initiation of therapy despite normalization of free T4 concentrations.118 122 123 124 A suppressed TSH concentration during this period does not indicate a need for dosage increase.123 However, once hyperthyroidism resolves, decrease maintenance dosage if serum TSH is elevated.109 123 Monitoring serum T3 concentrations may sometimes be useful for dosage adjustment; if total or free T3 concentrations remain elevated despite low, normal, or reduced free T4 concentrations, may need to increase antithyroid dosage.122 123 124

Determine leukocyte and differential counts in patients who develop any signs or symptoms of illness (e.g., fever, sore throat) during therapy.109 b

Consider monitoring PT during therapy, particularly before surgical procedures, because of possible risk of hypoprothrombinemia and bleeding.109

Exfoliative dermatitis reported.109 If exfoliative dermatitis is suspected, discontinue propylthiouracil.109

Vasculitic syndrome associated with the presence of antineutrophil cytoplasmic antibody (ANCA) reported.109 Manifestations of ANCA-positive vasculitis may include rapidly progressive glomerulonephritis (crescentic and pauci-immune necrotizing glomerulonephritis) sometimes leading to acute renal failure, pulmonary infiltrates or alveolar hemorrhage, skin ulcers, and leukocytoclastic vasculitis.109 If ANCA-positive vasculitis is suspected, discontinue propylthiouracil.109

Interstitial pneumonitis reported.109 If interstitial pneumonitis is suspected, discontinue propylthiouracil.109

Specific Populations

Category D.109 (See Fetal/Neonatal Morbidity under Cautions and also see Distribution under Pharmacokinetics.)

Despite potential fetal hazard, antithyroid agents still considered therapy of choice for management of hyperthyroidism during pregnancy.108 118 119 122 Since methimazole may be associated with the rare development of fetal abnormalities (e.g., aplasia cutis, choanal atresia), propylthiouracil is preferred 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 (See Boxed Warning and also see Fetal/Neonatal Morbidity under Cautions.) Switch patients receiving methimazole to propylthiouracil if pregnancy is confirmed in first trimester.119 May be preferable to switch from propylthiouracil to methimazole for the second and third trimesters (i.e., after the first trimester), because of potential adverse maternal effects of propylthiouracil (e.g., hepatotoxicity).108 109 118 119 (See Hepatotoxicity under Cautions.) If switching from propylthiouracil to methimazole, assess thyroid function after 2 weeks and then every 2–4 weeks thereafter.108 Not known if risk of methimazole-induced aplasia cutis or embryopathy outweighs risk of propylthiouracil-induced hepatotoxicity.104

If used during pregnancy, a sufficient, but not excessive, dosage is necessary.109 Initiate or adjust antithyroid drug therapy to maintain maternal free T4 concentrations at or just above the ULN of 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 lowest possible dosage.108 119 As thyroid dysfunction diminishes in many women as pregnancy proceeds, may be possible to reduce propylthiouracil dosage; in some patients, may discontinue propylthiouracil several weeks or months before delivery.109

If used during pregnancy or if patient becomes pregnant while receiving the drug, apprise of rare potential hazard to the mother and fetus of liver damage; inform the patient of these potential risks and risks of methimazole-associated fetal malformations when considering antithyroid drug use during pregnancy.104 106 109 Although liver toxicity may appear abruptly, 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

Distributed into milk to a small extent and, therefore, likely does not result in clinically important doses to the nursing infant.109 110 Mean amount of propylthiouracil distributed into milk during 4 hours following single oral 400-mg dose in 9 lactating women was 0.025% (range: 0.007–0.077%) of the administered dose.109 110

Generally compatible with breast-feeding; moderate dosages (i.e., <300 mg daily) appear to be safe.119 120 121 122 However, considered by some clinicians to be a second-line agent in nursing women because of concerns regarding severe hepatotoxicity (i.e., hepatic necrosis in either woman or child); methimazole is the preferred antithyroid drug in nursing women.118 119 If antithyroid drug is used in nursing women, some clinicians recommend administering drug after a feeding and in divided doses, and monitoring thyroid function of nursing infants.119

Postmarketing cases of severe liver injury, including hepatic failure requiring liver transplantation or resulting in death, reported in pediatric patients; however, no such reports observed with methimazole.109 117 Propylthiouracil 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, inform parents and patients of risk of liver failure.109 If patients develop tiredness, nausea, anorexia, fever, pharyngitis, or malaise, immediately discontinue the drug, contact a clinician, and obtain WBC count, liver function tests, and transaminase concentrations.109 (See Hepatotoxicity under Cautions.)

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.109 Select dosage with caution due to greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy.109

Common Adverse Effects

Rash,109 urticaria,109 pruritus,109 abnormal hair loss,109 skin pigmentation,109 edema,109 nausea,109 vomiting,109 epigastric distress,109 loss of taste,109 taste perversion,109 arthralgia,109 myalgia,109 paresthesia,109 headache,109 drowsiness,109 neuritis,109 vertigo,109 jaundice,109 sialadenopathy,109 lymphadenopathy.109

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Do not run out of propylthiouracil.
• Avoid driving and doing other tasks or actions that call for you to be alert until you see how this medicine affects you.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• You will have more chance of getting infections. Avoid crowds and people with infections, colds, or flu.
• You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.
• If you are taking warfarin, talk with your doctor. You may need to have your blood work checked more closely while you are taking it with propylthiouracil.
• Use with care in children. Talk with the doctor.
• This medicine may cause harm to the unborn baby if you take it while you are pregnant. If you are pregnant or you get pregnant while taking this medicine, call your doctor right away.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

General

Patients should be instructed to report any symptoms of hepatic dysfunction (anorexia, pruritus, jaundice, light colored stools, dark urine, right upper quadrant pain, etc.), particularly in the first six months of therapy. When these symptoms occur, measurement should be made of liver function (bilirubin, alkaline phosphatase) and hepatocellular integrity (ALT/AST levels).

Patients who receive Propylthiouracil should be under close surveillance and should be counseled regarding the necessity of immediately reporting any evidence of illness, particularly sore throat, skin eruptions, fever, headache, or general malaise. In such cases, white blood cell and differential counts should be obtained to determine whether agranulocytosis has developed. Particular care should be exercised with patients who are receiving concomitant drugs known to be associated with agranulocytosis.

Information for Patients

Patients should be advised that if they become pregnant or intend to become pregnant while taking an antithyroid drug, they should contact their physician immediately about their therapy.

Patients should report immediately any evidence of illness, in particular sore throat, skin eruptions, fever, headache, or general malaise. They also should report symptoms suggestive of hepatic dysfunction (anorexia, pruritus, right upper quadrant pain, etc.).

Laboratory Tests

Because Propylthiouracil may cause hypoprothrombinemia and bleeding, monitoring of prothrombin time should be considered during therapy with the drug, especially before surgical procedures.

Thyroid function tests should be monitored periodically during therapy. Once clinical evidence of hyperthyroidism has resolved, the finding of an elevated serum TSH indicates that a lower maintenance dose of Propylthiouracil should be employed.

Drug Interactions

Anticoagulants (oral): Due to the potential inhibition of vitamin K activity by Propylthiouracil, the activity of oral anticoagulants (e.g., warfarin) may be increased; additional monitoring of PT/INR should be considered, especially before surgical procedures.

Beta-adrenergic blocking agents: Hyperthyroidism may cause an increased clearance of beta blockers with a high extraction ratio. A reduced dose of beta-adrenergic blockers may be needed when a hyperthyroid patient becomes euthyroid.

Digitalis glycosides: Serum digitalis levels may be increased when hyperthyroid patients on a stable digitalis glycoside regimen become euthyroid; a reduced dose of digitalis glycosides may be needed.

Theophylline: Theophylline clearance may decrease when hyperthyroid patients on a stable theophylline regimen become euthyroid; a reduced dose of theophylline may be needed.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Laboratory animals treated with Propylthiouracil for greater than 1 year have demonstrated thyroid hyperplasia and carcinoma formation. Such animal findings are seen with continuous suppression of thyroid function by sufficient doses of a variety of antithyroid agents, as well as in dietary iodine deficiency, subtotal thyroidectomy, and implantation of autonomous thyrotropic hormone-secreting pituitary tumors. Pituitary adenomas have also been described.

Pregnancy

Pregnancy Category D.

See WARNINGS.

In pregnant women with untreated or inadequately treated Graves’ disease, there is an increased risk of adverse events of maternal heart failure, spontaneous abortion, preterm birth, stillbirth and fetal or neonatal hyperthyroidism.

If Propylthiouracil is used during pregnancy, or if the patient becomes pregnant while taking Propylthiouracil, the patient should be warned of the rare potential hazard to the mother and fetus of liver damage.

Because Propylthiouracil crosses placental membranes and can induce goiter and cretinism in the developing fetus, it is important that a sufficient, but not excessive, dose be given during pregnancy. In many pregnant women, the thyroid dysfunction diminishes as the pregnancy proceeds; consequently a reduction of dosage may be possible. In some instances, antithyroid therapy can be discontinued several weeks or months prior to delivery.

Since methimazole may be associated with the rare development of fetal abnormalities Propylthiouracil may be the preferred agent during the first trimester of pregnancy. Given the potential for maternal hepatotoxicity from Propylthiouracil, it may be preferable to switch from Propylthiouracil to methimazole for the second and third trimesters during pregnancy.

Nursing Mothers

Propylthiouracil is present in breast milk to a small extent and therefore likely results in clinically insignificant doses to the nursing infant. In one study, nine lactating women were administered 400 mg of Propylthiouracil by mouth. The mean amount of Propylthiouracil excreted during 4 hours after drug administration was 0.025% of the administered dose.

Pediatric Use

Postmarketing reports of severe liver injury including hepatic failure requiring liver transplantation or resulting in death have been reported in the pediatric population. No such reports have been observed with methimazole. As such, Propylthiouracil is not recommended for use in the pediatric population except in rare instances in which methimazole is not well-tolerated and surgery or radioactive iodine therapy are not appropriate.

When used in children, parents and patients should be informed of the risk of liver failure. If patients taking Propylthiouracil develop tiredness, nausea, anorexia, fever, pharyngitis, or malaise, Propylthiouracil should be discontinued immediately by the patient, a physician should be contacted, and a white blood cell count, liver function tests, and transaminase levels obtained.

Signs and Symptoms

Nausea, vomiting, epigastric distress, headache, fever, arthralgia, pruritus, edema, and pancytopenia. Agranulocytosis is the most serious effect. Rarely, exfoliative dermatitis, hepatitis, neuropathies or CNS stimulation or depression may occur.

No information is available on the following: LD50; concentration of Propylthiouracil in biologic fluids associated with toxicity and/or death; the amount of drug in a single dose usually associated with symptoms of overdosage; or the amount of Propylthiouracil in a single dose likely to be life-threatening.

Treatment

To obtain up-to-date information about the treatment of overdose, a good resource is the certified Regional Poison Control Center. In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in the patient.

In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient’s medical status.

Propylthiouracil is administered orally. The total daily dosage is usually given in 3 equal doses at approximately 8-hour intervals.

Adults

The initial dose is 300 mg daily. In patients with severe hyperthyroidism, very large goiters, or both, the initial dose may be increased to 400 mg daily; an occasional patient will require 600 to 900 mg daily initially. The usual maintenance dose is 100 to 150 mg daily.

Pediatric Patients

Propylthiouracil is generally not recommended for use in the pediatric patient population except in rare instances in which other alternative therapies are not appropriate options. Studies evaluating appropriate dosing regimen have not been conducted in the pediatric population although general practice would suggest initiation of therapy in patients 6 years or older at a dosage of 50 mg daily with careful upward titration based on clinical response and evaluation of TSH and free T4 levels. Although cases of severe liver injury have been reported with doses as low as 50 mg/day, most cases were associated with doses of 300 mg/day and higher.

Geriatric Patients

Clinical studies of Propylthiouracil did not include sufficient numbers of subjects aged 65 or over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Refer to adult dosing; use with caution.

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

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.

US BOXED WARNINGS:
-Severe liver injury and acute liver failure, in some cases fatal, have been reported in both adult and pediatric patients treated with this drug. Some of these cases required liver transplantation.
-This drug should be reserved for patients who cannot tolerate methimazole and in whom radioactive iodine therapy or surgery are not appropriate treatments for the management of hyperthyroidism.
-This drug may be the treatment of choice when an antithyroid drug is indicated during or just prior to the first trimester of pregnancy.

Safety and efficacy have not been established in patients younger than 6 years.

Consult WARNINGS section for additional precautions.

Summary of Use during Lactation

Propylthiouracil (PTU) had been considered the antithyroid drug of choice during lactation;[1][2] however, findings that the rates of liver injury higher with PTU than with methimazole has altered this judgement.[3] Some experts now recommend that methimazole should be considered the antithyroid drug of choice in nursing mothers.[4][5] No cases of PTU-induced liver damage have been reported in breastfed infants and it is unknown if the small amounts of the drug in breastmilk can cause liver damage. The drug or breastfeeding should be discontinued if liver toxicity is suspected. Dosages of PTU should be limited to 450 mg daily during breastfeeding.[6]

The American Thyroid Association recommends only monitoring infants for appropriate growth and development during routine pediatric health and wellness evaluations and routine assessment of serum thyroid function in the child is not recommended.[6] Rare idiosyncratic reactions (e.g., agranulocytosis) might occur, and the infant should be watched for signs of infection. Monitoring of the infant's complete blood count and differential is advisable if there is a suspicion of a drug-induced blood dyscrasia.

Drug Levels

Maternal Levels. A woman (time postpartum not stated) given a single dose of 100 mg of propylthiouracil (PTU) excreted a total of 0.077% of the dose in her breastmilk in 24 hours.[7]

After a single oral dose of 400 mg of propylthiouracil (PTU) in 9 women who were 1 to 9 months postpartum, peak milk levels averaging 0.7 mg/L were reached 1.5 hours after the dose. The authors estimated that the infant of a mother taking 200 mg 3 times a day would receive no more than 462 mcg daily or a maximum of 0.025% (range 0.07 to 0.077%) of the maternal dosage.[8]

Infant Levels. Relevant published information was not found as of the revision date.

Effects in Breastfed Infants

A mother was taking oral propylthiouracil 100 mg daily during pregnancy and 125 mg daily after delivery. In her infant, serum thyroxine (T4) concentration dropped slightly below the lower limit of normal on day 4 of life, but both T4 and thyrotropin (TSH) concentrations were normal on day 19 with continued maternal PTU therapy.[9] The drop in T4 was possibly due to propylthiouracil in breastmilk, but more likely from PTU received transplacentally.

An infant whose mother was taking propylthiouracil 200 to 300 mg daily was followed for 5 months and found to have normal thyroid function tests.[8]

A mother took PTU in a starting dose of 100 mg 3 times daily that was tapered to 50 mg twice daily over a period of 6 months. Her breastfed infant had normal thyroid function tests during this period at the ages of 9 to 13 months of age.[10]

Eight mothers taking PTU during pregnancy and doses of 50 to 300 mg daily after delivery exclusively or nearly exclusively breastfed their infants. The infants all had slightly low free T4 levels at birth and TSH levels were above normal in 7 of the 8, indicating that they had been affected by PTU in utero. All of their infants had normal free T4 and TSH levels when measured between 18 days and 8 months of age and none had any adverse effects reported from PTU in milk.[11]

The mothers of 11 fully breastfed infants were taking 300 to 750 mg daily of PTU starting at various times between delivery and 11 months postpartum. One infant had slightly elevated TSH level at 19 weeks of age when his mother was taking PTU 450 mg daily. Two other infants had elevated TSH levels at birth. TSH normalized in both infants with maternal PTU doses of 600 mg daily in one and a dose starting at 300 mg daily at term and increasing to 600 mg daily in the other.[12]

Two other infants were reported to be hypothyroid at birth, but to have normal thyroid function at 1 month of age despite maternal PTU therapy during breastfeeding.[13]

Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

References

1. Cooper DS. Antithyroid drugs: to breast-feed or not to breast-feed. Am J Obstet Gynecol. 1987;157:234-5. PMID: 2441601

2. Mandel SJ, Cooper DS. The use of antithyroid drugs in pregnancy and lactation. J Clin Endocrinol Metab. 2001;86:2354-9. PMID: 11397822

3. U.S. Food and Drug Administration. Propylthiouracil (PTU)-induced liver failure. FDA Alert. June 3, 2009. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm162701.htm

4. Karras S, Tzotzas T, Krassas GE. Antithyroid drugs used in the treatment of hyperthyroidism during breast feeding. An update and new perspectives. Hormones (Athens). 2009;8:254-7. PMID: 20058397

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