FDA Adds Boxed Warning to Propylthiouracil

Roxanne Nelson


April 21, 2010

April 21, 2010 — The US Food and Drug Administration (FDA) has added a boxed warning to the drug label for propylthiouracil about reports of severe liver injury and acute liver failure, in some cases fatal, that have been reported in both adult and pediatric patients who used this drug.

Notice of the warning was sent today in an alert from MedWatch, the FDA's safety information and adverse event reporting program.

The new warning also states that for patients just beginning treatment for hyperthyroidism, it may be appropriate to reserve the use of propylthiouracil for those unable to tolerate other therapies, including methimazole, radioactive iodine, or surgery. In pregnant patients, propylthiouracil may be the treatment of choice during and just before the first trimester of pregnancy because of the observed occurrence of birth defects with methimazole use.

From 1969, when the Adverse Events Reporting System database first began tracking reports of adverse events, 34 cases of severe liver injury associated with propylthiouracil have been identified in adults and children. Of the 23 adult cases, 13 deaths and 5 liver transplantation were reported, whereas among the 11 pediatric cases, 2 children died and 7 required liver transplantation.

In comparison, 5 cases of severe liver injury have been reported with methimazole, with 3 associated deaths. On the basis of these findings and the medical literature, the FDA concluded that propylthiouracil is associated with a higher risk for clinically serious or fatal liver injury compared with methimazole in both adults and children.

In June 2009, the FDA issued a communication to healthcare professionals about severe liver injury and propylthiouracil use. The earlier communication states that physicians need to closely monitor patients on propylthiouracil therapy for signs and symptoms of liver injury, particularly during the first 6 months after beginning treatment. Propylthiouracil also should not be administered to pediatric patients unless the patient is allergic to or unable to tolerate methimazole and there are no other available options.

The FDA has also reviewed postmarketing data regarding the potential for birth defects from either propylthiouracil or methimazole. The review found that congenital malformations were reported approximately 3 times more often with prenatal exposure to methimazole compared with propylthiouracil (29 cases with methimazole vs 9 cases with propylthiouracil).

There was also a "distinct and consistent pattern of congenital malformations associated with the use of methimazole, but not with propylthiouracil." No consistent pattern of birth defects associated with the use of propylthiouracil was observed, and the FDA has thus concluded that "there is no convincing evidence of an association between propylthiouracil use and congenital malformations, even with use during the 1st trimester."

In summary, the FDA's recommendations for healthcare professionals are as follows:

  • Be aware that severe liver injury and acute liver failure, including fatal cases, have been reported in adult and pediatric patients taking propylthiouracil.

  • Propylthiouracil should be reserved for patients who cannot tolerate methimazole or for patients for whom radioactive iodine therapy or surgery is not appropriate treatment when initiating treatment.

  • Propylthiouracil may be the treatment of choice during and just before the first trimester of pregnancy, as fetal abnormalities have been observed with methimazole in early pregnancy.

  • Propylthiouracil is not recommended for use in pediatric patients except in rare instances in which other alternative treatments are not appropriate.

  • Encourage patients to read the medication guide when picking up their prescription for propylthiouracil.

  • Review the newly revised label for complete information on the use of propylthiouracil.

Propylthiouracil is approved for the treatment of hyperthyroidism associated with Graves' disease or toxic multinodular goiter, and to ameliorate symptoms in preparation for thyroidectomy or radioactive iodine therapy in patients who are intolerant of methimazole.

More information is available on the MedWatch Web site.

Any adverse events associated with propylthiouracil should be communicated to the FDA's MedWatch reporting program by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at https://www.fda.gov/medwatch, or by mail to 5600 Fishers Lane, Rockville, Maryland 20852-9787.


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