Label Changes for:

Propylthiouracil tablets

April 2010

Changes have been made to the BOXED WARNING, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS and ADVERSE REACTIONS sections of the safety label.

Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER) – April 2010

BOXED WARNING

WARNING
  • 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 adult and pediatric patients.
  • Propylthiouracil 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.
  • 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 (see Warnings and Precautions).

CONTRAINDICATIONS

  • Propylthiouracil is contraindicated in patients who have demonstrated hypersensitivity to the drug or any of the other product components.

WARNINGS

Liver Toxicity
  • Liver injury resulting in liver failure, liver transplantation, or death, has been reported with propylthiouracil therapy in adult and pediatric patients. No cases of liver failure have been reported with the use of methimazole in pediatric patients. For this reason, propylthiouracil is not recommended for pediatric patients except when methimazole is not well-tolerated and surgery or radioactive iodine therapy are not appropriate therapies.
  • There are cases of liver injury, including liver failure and death, in women treated with propylthiouracil during pregnancy. Two reports of in utero exposure with liver failure and death of a newborn have been reported. The use of an alternative antithyroid medication (e.g., methimazole) may be advisable following the first trimester of pregnancy.
  • 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. Patients should be informed of the risk of liver failure. Patients should be instructed to report any symptoms of hepatic dysfunction (anorexia, pruritus, right upper quadrant pain, etc.), particularly in the first six months of therapy. When these symptoms occur, propylthiouracil should be discontinued immediately and liver function tests and ALT and AST levels obtained.
Agranulocytosis
  • Agranulocytosis occurs in approximately 0.2% to 0.5% of patients and is a potentially life-threatening side effect of propylthiouracil therapy. Agranulocytosis typically occurs within the first 3 months of therapy. Patients should be instructed to immediately report any symptoms suggestive of agranulocytosis, such as fever or sore throat. Leukopenia, thrombocytopenia, and aplastic anemia (pancytopenia) may also occur. 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.
Hypothyroidism
  • Propylthiouracil can cause hypothyroidism necessitating routine monitoring of TSH and free T4 levels with adjustments in dosing to maintain a euthyroid state. Because the drug readily crosses placental membranes, propylthiouracil can cause fetal goiter and cretinism when administered to a pregnant woman.

PRECAUTIONS

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).

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.
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.
Pregnancy
  • Because propylthiouracil readily crosses placental membranes and can induce goiter and even 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, propylthiouracil can be withdrawn several weeks or months before delivery.
  • 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.
  • Since methimazole may be associated with the rare development of fetal abnormalities such as aplasia cutis and choanal atresia, propylthiouracil may be the preferred agent during organogenesis, in the first trimester of pregnancy. Given the potential maternal adverse effects of propylthiouracil (e.g., hepatotoxicity), it may be preferable to switch from propylthiouracil to methimazole for the second and third trimesters.
Nursing Mothers
  • Propylthiouracil is transferred to breast milk to a small extent and therefore likely results in clinically insignificant doses to the suckling 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.

ADVERSE REACTIONS

  • Major adverse reactions (much less common than the minor adverse reactions) include liver injury resulting in hepatitis, liver failure, a need for liver transplantation or death. Inhibition of myelopoiesis (agranulocytosis, granulopenia, and thrombocytopenia), aplastic anemia, drug fever, a lupus-like syndrome (including splenomegaly and vasculitis), periarteritis, and hypoprothrombinemia and bleeding have been reported.
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