Reports of severe liver injury prompt black box warning and new recommendations for propylthiouracil use

As early as April 2009, FDA and the American Thyroid Association began recommending that propylthiouracil not be prescribed as first-line therapy in most adults or children based on reports of propylthiouracil-related serious liver injury from both the FDA Adverse Event Reporting System and liver transplantation monitoring programs.

Propylthiouracil carries FDA approval for the treatment of hyperthyroidism (also referred to as overactive thyroid or Graves’ disease) and until recently has been considered a first-line treatment. However, as early as April 2009, FDA and the American Thyroid Association (ATA) began recommending that propylthiouracil not be prescribed as first-line therapy in most adults or children based on reports of propylthiouracil-related serious liver injury from both the FDA Adverse Event Reporting System (a total of 34 cases, resulting in 15 deaths and 12 transplants) and liver transplantation monitoring programs.

As an additional safety measure, on April 21, 2010, FDA announced it was requiring a black box warning be added to the label of propylthiouracil to include information about reports of severe liver injury and acute liver failure, some of which have been fatal, in adult and pediatric patients using the medication. It is estimated that 1 in 10,000 adults taking propylthiouracil develop acute liver failure, which may occur at any point in therapy, with a sudden onset and rapid progression to liver failure.

The new label also suggests that for patients being started on treatment for hyperthyroidism, that propylthiouracil should be reserved for those who cannot tolerate other treatments including methimazole (a similar drug within the same class of agents), radioactive iodine, or surgery.

According to this most recent drug safety communication, “The new Boxed Warning and Risk Evaluation and Mitigation Strategy (REMS), are based on FDA’s review of post-marketing safety reports of propylthiouracil, as well as meetings held with the American Thyroid Association, the National Institute of Child Health and Human Development, and the pediatric endocrine clinical community.

Instances where propylthiouracil is still recommended over methimazole include the initiation of therapy in the first trimester of pregnancy (fetal abnormalities have been seen with methimazole use in the first trimester) or in the setting of life-threatening thyrotoxicosis or thyroid storm.

FDA’s REMS for propylthiouracil now requires that a medication guide be given to every patient filling a prescription for propylthiouracil.