FDA warns of potential risk of liver injury with use of tolvaptan

Healthcare professionals have been notified by Otsuka and FDA of significant liver injury associated with the use of tolvaptan (Samsca, Otsuka).

Samsca is a selective vasopressin V2-receptor antagonist indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia. Samsca is not approved for the treatment of ADPKD.

"Hepatotoxicity is a significant side effect," said Formulary Advisor James M. Wooten, PharmD, associate professor, department of medicine, University of Missouri-Kansas City, School of Medicine.  "Many drugs can cause liver dysfunction within a wide range of mild to severe.  Knowing how and when to monitor patients for this adverse reaction is the key. Tolvaptan is a drug that is generally used for patients who are having difficulty regulating fluid volume. Medical conditions associated with volume regulation include heart failure, cirrhosis, and Syndrome of Inappropriate Antidiuretic Hormone-which can also be caused by medication use. In other words tolvaptan is usually being utilized in patients who are already sick and have other medical conditions. Tolvaptan induced hepatotoxicity may be devastating in these patients and must be monitored closely.  Before the drug is utilized a thorough risk/benefit assessment must be considered."

In a double-blind, 3-year, placebo-controlled trial in about 1,400 patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) and its open-label extension trial, 3 patients treated with the drug developed significant increases in serum alanine aminotransferase (ALT) with concomitant, clinically significant increases in serum total bilirubin. In the trials the maximum daily dose of Samsca administered (90 mg in the morning and 30 mg in the afternoon) was higher than the maximum 60 mg daily dose approved for the treatment of hyponatremia.

Most of the liver enzyme abnormalities were observed during the first 18 months of therapy. Following discontinuation of treatment, all 3 patients improved. An external panel of liver experts assessed these 3 cases as being either probably or highly likely to be caused by Samsca. These findings indicate that tolvaptan has the potential to cause irreversible and potentially fatal liver injury. 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 providers should perform liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. If hepatic injury is suspected, Samsca should be promptly discontinued, appropriate treatment should be instituted, and investigations should be performed to determine probable cause. Samsca should not be re-initiated in patients unless the cause for the observed liver injury is definitively established to be unrelated to treatment with Samsca.

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:

•   Complete and submit the report online: www.fda.gov/MedWatch/report.htm

•   Download form or call (800) 332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to (800) FDA-0178

Read the MedWatch safety alert, including links to the Dear Health Provider letter and prescribing information, at:

http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm336669.htm