The antithyroid drug propylthiouracil (PTU) has been associated with severe liver injuries and deaths in patients and should be reserved for those in the first trimester of pregnancy or those who are intolerant of or allergic to methimazole, according to a warning by the Food and Drug Administration.
“If PTU therapy is chosen, the patient should be closely monitored for symptoms and signs of liver injury, especially during the first 6 months after initiating therapy,” Dr. Amy Egan, deputy director for safety at the FDA's division of metabolism and endocrinology products at the Center for Drug Evaluation and Research, said in a statement that was posted on the agency's MedWatch Web site. From 1969, when the agency's adverse event reporting program was established, through October 2008, 32 cases of serious liver injury associated with PTU were reported to the FDA. Of these cases, 22 were in adults, and included 12 fatalities and 5 liver transplants. Among the 10 pediatric cases, there was 1 fatality and 6 reports of liver transplants.
Based on an analysis of these reports, the FDA determined that the risk of hepatotoxicity is greater with PTU than with methimazole (MMI). Like PTU, MMI is indicated for the treatment of hyperthyroidism caused by Graves' disease. The FDA received only five reports of serious liver injury associated with MMI, which was approved in 1950.
PTU, approved in 1947, is considered a second-line therapy for patients with Graves' disease, with the exception of those who are intolerant of or allergic to MMI. But because of rare cases of embryopathy reported in association with MMI treatment during pregnancy, PTU “may be more appropriate” for treating women with Graves' disease in the first trimester of pregnancy, according to the FDA.
The FDA plans to change the prescribing information for PTU to reflect the hepatotoxicity warning, and said that the American Thyroid Association (ATA) plans to update its Graves' disease treatment guidelines.
In April, PTU-induced liver failure was among the topics on the agenda at a public meeting on the role of PTU in managing Graves' disease in adults. The ATA/American Association of Clinical Endocrinologists Hyperthyroidism Guidelines Task Force is finalizing recommendations on the use of antithyroid drugs, including during pregnancy and childhood, and will cover the role of monitoring hepatic function in patients on PTU, according to the ATA.
Hepatoxicity has been recognized as one of the more serious but rare side effects associated with PTU, Dr. David Cooper, professor of medicine at Johns Hopkins University, Baltimore, said in an interview. MMI also can be hepatotoxic, but is usually associated with cholestatic dysfunction, while PTU causes hepatocellular necrosis.
With input from the ATA, the FDA decided to issue the warning, said Dr. Cooper, who directs the Johns Hopkins thyroid clinic. He and Dr. Scott Rivkees of the Yale Pediatric Thyroid Center, New Haven, Conn., coauthored an editorial in which they wrote, “one could reasonably conclude that PTU should never be used as a first line agent in either children or adults, with the possible exception of pregnant women and patients with life-threatening thyrotoxicosis” (J. Clin. Endocrinol. Metab. 2009; 94:1881-2).
Dr. Cooper said that most patients who can't take MMI should be treated with radioactive iodine or surgery. Patients who develop jaundice, fatigue, or other symptoms should stop PTU immediately, and contact their physicians. White blood cell count and bilirubin, alkaline phosphatase, and transaminase levels should be checked in such patients, he said.?
A link to the FDA's alert is available at www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm162701.htmwww.fda.gov/MedWatch/report.htm