[04-21-2010] The United States Food and Drug Administration (FDA) has added a Boxed Warning to the label for propylthiouracil, a drug used to treat hyperthyroidism (overactive thyroid), 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 this medication.
The new warning also states that for patients being started on treatment for hyperthyroidism it may be appropriate to reserve use of propylthiouracil for those who cannot tolerate other treatments such as methimazole, radioactive iodine or surgery. In addition, due to the occurrence of birth defects that have been observed with the use of methimazole during the first trimester of pregnancy (see Data Summary), propylthiouracil may be the treatment of choice during and just before the first trimester of pregnancy.
Propylthiouracil has been shown to be effective in reducing thyroid hormone levels and decreasing symptoms associated with hyperthyroidism. However, to help patients understand the known benefits and potential risks of this medication, as part of a Risk Evaluation and Mitigation Strategy (REMS), FDA is requiring that a Medication Guide be given to every patient filling a prescription for propylthiouracil.
The recommendations in the Boxed Warning and the requirement of a Medication Guide are based on FDA's review of post-marketing safety reports of propylthiouracil (see Data Summary) as well as meetings with the American Thyroid Association, the National Institute of Child Health and Human Development, and the pediatric endocrine clinical community.
Healthcare professionals should be aware of this new safety information in the drug label and follow the recommendations outlined above. Patients should carefully read the Medication Guide each time they get their prescription so they are aware of the risks and benefits of this medication.
- Be aware that severe liver injury has occurred in patients taking propylthiouracil.
- Read the Medication Guide when picking up a prescription for propylthiouracil. It will help you understand the potential risks and benefits of this medication.
- Contact your healthcare professional if you have fever, loss of appetite, nausea, vomiting, tiredness, itchiness, dark colored urine, or yellowing of your skin or eyes while taking propylthiouracil.
- Propylthiouracil may be the treatment of choice during and just before the 1st trimester of pregnancy (weeks 1-12). Talk to your healthcare professional if you are pregnant (or plan to become pregnant) and are taking a medication to treat hyperthyroidism.
- Tell your healthcare professional about any medication you are taking or medical conditions you may have before taking propylthiouracil.
- Do not stop taking propylthiouracil unless told to do so by your healthcare professional.
- Be aware that severe liver injury and acute liver failure, including fatal cases, have been reported in adult and pediatric patients taking propylthiouracil.
- When initiating hyperthyroid treatment, propylthiouracil should be reserved for patients who cannot tolerate methimazole or for patients for whom radioactive iodine therapy or surgery is not appropriate treatment.
- Propylthiouracil may be the treatment of choice when an antithyroid drug is needed during and just prior to the 1st trimester of pregnancy. Fetal abnormalities have been seen with methimazole use during the first trimester of 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.
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.
Severe Liver Injury: FDA, the National Institute of Child Health and Human Development, the American Thyroid Association, and other stakeholders held meetings in 2008 and 2009 to discuss the available data on severe liver injury and propylthiouracil use. In June 2009, FDA issued a communication to Healthcare Professionals about severe liver injury and propylthiouracil use. In addition, FDA Patient Safety News featured information about this safety issue in August 2009.
Propylthiouracil was approved in 1947 for the treatment of hyperthyroidism. To better understand the potential for liver injury with propylthiouracil, FDA conducted a search of postmarketing adverse event reports for propylthiouracil submitted to the agency from 1969, when the Adverse Events Reporting System (AERS) database began tracking adverse event reports, to June 2009. FDA also evaluated postmarketing adverse event reports on methimazole—the only other approved treatment for hyperthyroidism--from 1969 to June 2009. Methimazole was approved in 1950.
The agency identified 34 cases of severe liver injury associated with propylthiouracil. Twenty-three cases were in adult patients and 11 were in pediatric patients. Of the 23 adult cases, 13 deaths and five liver transplants were reported. Among the 11 pediatric cases, two cases resulted in death and seven patients required a liver transplant; one patient died while on the transplant list. FDA identified five cases of severe liver injury reported with methimazole. All five cases were in adult patients and three resulted in death. Based on these findings, and a review of the medical literature, the agency concluded that use of propylthiouracil is associated with a higher risk for clinically serious or fatal liver injury compared to methimazole in both adult and pediatric patients.
Although the number of identified reports of postmarketing cases of severe liver injury with propylthiouracil use between 1969 to 2009 is 34, FDA included information about this adverse event in the Boxed Warning due to the severity of the cases, some of which have been fatal, and to ensure that healthcare professionals are aware of this risk and are vigilant for the signs and symptoms of hepatic toxicity.
Use in Pregnancy: The agency also reviewed post-marketing data to better understand the potential for birth defects from propylthiouracil or methimazole.
FDA's review found that congenital malformations were reported approximately three times more often with prenatal exposure to methimazole compared to propylthiouracil (29 cases with methimazole and 9 cases with propylthiouracil). In addition, there was a distinct and consistent pattern of congenital malformations associated with the use of methimazole, but not with propylthiouracil. Approximately 90% of the congenital malformations with methimazole were craniofacial malformations (e.g., scalp epidermal aplasia [aplasia cutis], facial dysmorphism, and choanal atresia). In the majority of cases, there were multiple malformations which frequently included a combination of craniofacial defects and gastrointestinal atresias or aplasias. These specific birth defects were associated with the use of methimazole during the 1st trimester of pregnancy. They were not found when the drug was given later in pregnancy.
The agency did not find a consistent pattern of birth defects associated with the use of propylthiouracil. FDA concluded there is no convincing evidence of an association between propylthiouracil use and congenital malformations, even with use during the 1st trimester.