The FDA has issued a warning to healthcare professionals about the potential for significant liver injury associated with the use of tolvaptan (Samsca), a drug approved for the treatment of hyponatremia.

In a double-blind, three-year, placebo-controlled trial in about 1,400 patients with autosomal dominant polycystic kidney disease and its open-label extension trial, three patients treated with the drug experienced significant increases in serum alanine aminotransferase with concomitant, clinically significant increases in serum total bilirubin, the FDA stated on its website (

In the trials, the maximum daily dose of tolvaptan 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.

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Most of the liver enzyme abnormalities were observed during the first 18 months of therapy, according to the FDA. Following discontinuation of treatment, all three patients improved.

The FDA recommends that healthcare providers 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, tolvaptan should be promptly discontinued, appropriate treatment should be instituted, and investigations should be performed to determine probable cause, the FDA says. The drug should not be re-initiated in patients unless the cause for the observed liver injury is definitively established to be unrelated to treatment with tolvaptan.

The FDA encourages healthcare professionals and patients to report adverse events or side effects related to the use of tolvaptan to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.