FDA Warns About Serious Liver Injury Associated With Anti-Thyroid Drug

FDA NEWS RELEASE
For Immediate Release: June 3, 2009
Media Inquiries: Karen Riley, 301-796-4674
Consumer Inquiries: 888-INFO-FDA

FDA Warns About Serious Liver Injury Associated With Anti-Thyroid Drug
The U.S. Food and Drug Administration today warned health care professionals about the risk of serious liver injury associated with the use of the anti-thyroid drug propylthiouracil for the treatment of Graves' disease.

"After analyzing adverse event reports, the FDA has identified an increased risk of liver injury with propylthiouracil when compared to an alternative treatment for Graves' disease, methimazole," said Amy Egan, M.D., deputy director for safety, Division of Metabolism and Endocrinology Products, in the FDA’s Center for Drug Evaluation and Research. "Health care professionals should carefully consider which drug to initiate in a patient recently diagnosed with Graves' disease. If propylthiouracil therapy is chosen, the patient should be closely monitored for symptoms and signs of liver injury, especially during the first six months after initiating therapy."

Propylthiouracil was approved for marketing in 1947. A total of 32 cases of serious liver injury associated with the use of propylthiouracil were reported to the FDA's Adverse Event Reporting System since that system was established in 1969 through October 2008. Of the 22 adult cases, the FDA identified 12 deaths and five liver transplants. Of the 10 pediatric cases, there was one death and six reports of liver transplant.

Graves' disease is an autoimmune disorder that leads to overactivity of the thyroid gland. The thyroid gland, located in the front of the neck just below the Adam’s Apple, releases hormones that regulate the rate of the body’s metabolism and are critical for body temperature control, energy, weight, mood, and blood calcium levels.

Propylthiouracil is considered second-line drug therapy, except in certain patients who are allergic to, or intolerant of, methimazole. Because a rare birth defect has been reported with methimazole and not with propylthiouracil, propylthiouracil may be more appropriate for patients with Graves' disease who are in the first trimester of pregnancy.

Information for Healthcare Professionals, Propylthiouracil-Induced Liver Failure

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FDA Warns About Serious Liver Injury Associated With Anti-Thyroid Drug

Propylthiouracil-Induced Liver Failure
FDA ALERT [06/04/2009]:

FDA is notifying healthcare professionals of the risk of serious liver injury, including liver failure and death, with the use of propylthiouracil in adult and pediatric patients.

Reports to FDA’s Adverse Event Reporting System (AERS) suggest there is an increased risk of hepatotoxicity with when compared to methimazole. Although both propylthiouracil and methimazole are indicated for the treatment of hyperthyroidism due to Graves’ disease, healthcare professionals should carefully consider which drug to initiate in a patient recently diagnosed with Graves’ disease. Physicians should closely monitor patients on propylthiouracil therapy for symptoms and signs of liver injury, especially during the first six months after initiation of therapy. Propylthiouracil and methimazole were approved in 1947 and 1950, respectively.

FDA has identified 32 AERS cases (22 adult and 10 pediatric) of serious liver injury associated with propylthiouracil use. Of the adult cases, 12 deaths and 5 liver transplants occurred. Among the pediatric patients, 1 case resulted in death and 6 in liver transplants.

In contrast, for methimazole 5 AERS cases of serious liver injury were identified. All five cases were in adult patients and 3 resulted in death.

In general, propylthiouracil is considered second-line drug therapy except in patients who are allergic to or intolerant of methimazole. Rare cases of embryopathy, including aplasia cutis, have been reported with use of methimazole during pregnancy, while no such cases have been reported with propylthiouracil use. Thus, propylthiouracil may be more appropriate for patients with Graves’ disease who are in their first trimester of pregnancy.

On April 18, 2009, FDA held a public workshop with the American Thyroid Association (ATA) to discuss propylthiouracil-related hepatotoxicity. FDA is continuing to monitor these serious reported adverse events and working to make changes to the propylthiouracil prescribing information, particularly for use in pediatric patients. Also, the ATA plans to update its treatment guidelines for Graves’ disease in the upcoming months.

This information reflects FDA’s current analysis of data available to FDA concerning propylthiouracil. Posting this information does not mean that FDA has concluded there is a causal relationship between the drug product and the emerging safety issue. Nor does it mean that FDA is advising health care professionals to discontinue prescribing the product. FDA intends to update this document when additional information or analyses become available.
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Adverse reactions or quality problems experienced with the use of this Product may be reported to the FDA's MedWatch Adverse Event Reporting program either online, by regular mail or by fax, using the contact information at the bottom of this sheet.

Recommendations and Information for Healthcare Professionals:
- Reserve propylthiouracil use for patients who are in their first trimester of pregnancy, or who are allergic to or intolerant of methimazole.
- Closely monitor patients on propylthiouracil therapy for signs and symptoms of liver injury, especially during the first six months after initiation of therapy.
- If liver injury is suspected, promptly discontinue propylthiouracil therapy and evaluate the patient for evidence of liver injury and provide supportive care.
- Propylthiouracil should not be used in pediatric patients unless the patient is allergic to or intolerant of methimazole, and there are no other treatment options available.
- Rare cases of embryopathy, including aplasia cutis, have been reported with use of methimazole during pregnancy. No such cases have been reported with propylthiouracil use during pregnancy. Therefore, propylthiouracil may be more appropriate for patients with Graves’ disease who are in their first trimester of pregnancy.
- Counsel patients to promptly advise you if they note any of the following signs or symptoms: fatigue, weakness, vague abdominal pain, loss of appetite, itching, easy bruising or yellowing of the eyes or skin.


References
Rivkees SA. The treatment of Graves’ disease in children. J Pediatr Endocrinol Metab 2006 Sep;19(9):1095-111.

The Food and Drug Administration and American Thyroid Association. Propylthiouracil-Related Liver Toxicity: Public Workshop, April 19, 2009, Washington, D.C.