FDA limits use of tolvaptan; irreversible liver damage possible

April 30, 2013

Clinical trials find tolvaptan may cause injury leading to liver transplant or death

FDA has issued a Drug Safety Communication indicating that the drug tolvaptan (Samsca, Otsuka American Pharmaceuticals), used in the treatment of electrolyte disturbances, can cause irreversible liver injury with the potential to result in liver transplant or death.

FDA has determined that use of tolvaptan be limited to not more than 30 days. Patients with underlying liver disease, including cirrhosis, should not use it at all. Patients using tolvaptan who begin to show signs of liver disease should terminate use of the drug.

Tolvaptan is a selective vasopression V2-receptor antagonist indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia. It is also given to patients with heart failure and Syndrome of Inappropriate Antidiuretic Hormone (SIADH).

Recent large clinical trials evaluated Samsca for a new use in patients with autosomal dominant polycystic kidney disease (ADPKD). The increased risk of liver injury was uncovered in these trials.

On January 22 of this year, the manufacturer released a “Dear Healthcare Provider” letter, outlining these findings. The letter noted that three patients out of 1,400 trial participants developed significant (>3x ULN) increases in serum alanine aminotransferase (ALT) with concomitant, clinically significant (>2x ULN) increases in serum total bilirubin. 

Following discontinuation of treatment, all three patients improved. An external panel of liver experts assessed these three cases as being either probably or highly likely to be caused by tolvaptan and concluded that tolvaptan has the potential to cause irreversible and potentially fatal liver injury. 

Other findings showed increased ALT levels (greater than 3x ULN). Most of the liver enzyme abnormalities were observed during the first 18 months of therapy. The elevations gradually improved after discontinuation of tolvaptan.  

SAMSCA is not approved for the treatment of ADPKD.

In other clinical trials of SAMSCA, including the trials supporting the approved indication (clinically significant euvolemic or hypervolemic hyponatremia), liver damage has not been reported. However, the letter continued, these data are not adequate to exclude the possibility that patients receiving SAMSCA for its indicated use of clinically significant hypervolemic and euvolemic hyponatremia are at a potential increased risk for irreversible and potentially fatal liver injury.

Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of this product to the FDA's MedWatch Safety Information and Adverse Event Reporting Program by:

Completing and submitting the report online at www.fda.gov/MedWatch/report.htm or

Downloading the form (or calling 1-800-332-1088 to request a reporting form) and then completing and returning it by mail to the address on the pre-addressed form, or by faxing to 1-800-FDA-0178.

Addition information about SAMSCA can be obtained from Otsuka Medical Affairs. Call 1-800-441-6763 (9 a.m. to 5 p.m. ET, Monday through Friday), or visit www.Samsca.com.