May 7, 2013
In January 2013, FDA issued an alert informing healthcare professionals of an association between significant hepatic injury and the use of tolvaptan (Samsca). The manufacturer has updated the tovaptan product label to include the following information based on recommendations from FDA:
- Limit the use of tolvaptan to 30 days.
- Do not use tolvaptan in patients with cirrhosis and avoid use in patients with baseline hepatic dysfunction.
- Discontinue tolvaptan in patients with symptoms of liver injury.
The updated tolvaptan label will also include information regarding the types of liver injuries occurring in clinical trials.
Warnings regarding hepatic risk associated with tolvaptan and the new labeling recommendations are based on data from a randomized, double-blind, placebo-controlled trial and an open-label extension trial of subjects with Autosomal Dominant Polycystic Kidney Disease (ADPKD). Three patients treated with tolvaptan were found to have significantly elevated concentrations of serum alanine aminotransferase (ALT) and total bilirubin. The doses of tolvaptan in the trial were 90 mg in the morning and 30 mg in the afternoon. However, the maximum recommended dose per product labeling is 60 mg once daily. Many of the hepatic enzyme abnormalities were reported during the first 18 months following tolvaptan exposure. The abnormalities improved after discontinuing tolvaptan. Liver injury was not reported in trials evaluating the efficacy of tolvaptan in patients with hyponatremia or heart failure; however, patients in these trials were only exposed to tolvaptan for about 30 days.
Tolvaptan is a selective vasopressin antagonist labeled to treat significant euvolemic and hypovolemic hyponatremia in patients with heart failure and Syndrome of Inappropriate Antidiuretic Hormone (SIADH). Tolvaptan is not approved for treating ADPKD. However, the results from this clinical trial suggest there is a potential risk for developing irreversible or fatal liver injury in patients receiving tolvaptan for its indicated use.
Monitor liver function if signs or symptoms of liver injury (eg, abdominal discomfort, anorexia, dark urine, fatigue, jaundice) are detected. Discontinue tolvaptan immediately if liver injury is suspected, and treat the patient appropriately. Limit the use of tolvaptan to 30 days and do not use in patients with cirrhosis or other baseline hepatic dysfunction.
Report any related adverse events to FDA’s MedWatch Adverse Event Reporting program online: http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm
Additional information is available at the following links:
- MedWatch Alert:
- Drug Safety Communication:
- Healthcare Provider Letter:
- Prescribing Information (4/9/2013):
- Medication Guide:
May 7, 2013; January 28, 2013; University of Utah, Drug Information Service. Copyright 2013, Drug Information Service, University of Utah, Salt Lake City, UT.