Tolvaptan Poses Risk for Serious Liver Damage, FDA Warns


January 25, 2013

Tolvaptan (Samsca, Otsuka America Pharmaceuticals), indicated for treating clinically significant hypervolemic and euvolemic hyponatremia, poses the risk of causing irreversible and potentially fatal liver injury, the US Food and Drug Administration (FDA) announced today.

Clinicians should perform liver tests as soon as possible in patients who report fatigue, anorexia, right upper abdominal discomfort, dark urine, jaundice, or any other symptom that may suggest liver injury, the FDA said. Patients suspected of having liver injury should stop receiving tolvaptan immediately.

The agency based its warning on a double-blind, 3-year, placebo-controlled trial involving some 1400 patients with autosomal dominant polycystic kidney disease (ADPKD) along an open-label extension trial. Three patients treated with tolvaptan experienced significant increases in serum alanine aminotransferase (ALT) with concomitant, clinically significant increases in serum total bilirubin. The maximum daily dose of tolvaptan in the trials — 90 mg in the morning and 30 mg in the afternoon — exceeded the maximum daily dose of 60 mg approved for hyponatremia.

Tolvaptan is not indicated for treating ADPKD.

All 3 patients with liver enzyme abnormalities improved after tolvaptan was discontinued. A group of liver experts "assessed these 3 cases as being probably or highly likely to be caused by tolvaptan." The FDA said it cannot rule out the possibility that patients receiving the drug for hyponatremia also are at a potential higher risk for irreversible and potentially fatal liver injury.

More information on today's announcement is available on the FDA Web site.

To report problems with tolvaptan, contact MedWatch, the FDA's safety information and adverse event reporting program, by telephone at 1-800-FDA-1088; by fax at 1-800-FDA-0178; online at; with postage-paid FDA form 3500, available at; or by mail to MedWatch, 5600 Fishers Lane, Rockville, Maryland 20852-9787.