FDA Limits Use of Samsca (Tolvaptan) Due to Liver Injury Risk

April 30, 2013

The US Food and Drug Administration (FDA) today announced it has placed restrictions on the use of tolvaptan (Samsca, Otsuka American Pharmaceutical, Inc) because of the risk for serious and potentially fatal liver injury.

Tolvaptan, indicated for treating clinically significant hypervolemic and euvolemic hyponatremia, should be used for no longer than 30 days, and it should not be used in patients with underlying liver disease such as cirrhosis. Such patients are at increased risk for severe liver injury (potentially requiring liver transplantation) or death, according to the FDA.

Today's announcement follows a previous FDA alert released in January, warning of an increased risk for liver injury.

In addition, the FDA reminds healthcare professionals that patients suspected of having liver injury should stop receiving tolvaptan immediately. 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 in its previous alert.

Tolvaptan received a boxed warning when it was approved that requires drug initiation and re-initiation to entail close monitoring of serum sodium in a hospital setting.

The agency based its warning on a double-blind, 3-year, placebo-controlled trial involving some 1400 patients with autosomal dominant polycystic kidney disease along with an open-label extension trial. Three patients treated with tolvaptan experienced significant increases in serum alanine aminotransferase 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 a selective vasopressin V2-receptor antagonist used to treat patients with clinically significant hypervolemic and euvolemic hyponatremia (serum sodium < 125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including patients with heart failure and the syndrome of inappropriate antidiuretic hormone.

From the drug's approval in May 2009 through February 2013, approximately 16,000 prescriptions were dispensed to 4500 patients from US outpatient retail pharmacies.

"Sales to outpatient retail pharmacies accounted for approximately 40% of tolvaptan sales; 41% was distributed to non-retail pharmacies, and 18% to mail-order/specialty pharmacies during this time," the FDA said.

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 https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm; with postage-paid FDA form 3500, available at http://www.fda.gov/MedWatch/getforms.htm; or by mail to MedWatch, 5600 Fishers Lane, Rockville, Maryland 20852-9787.

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