The FDA has issued additional warnings and limitations to Tolvaptan, a drug that is used to treat heart failure patients.
They have issued a drug safety communication concerning Tolvaptan (Samsca, Otsuka), a selective vasopression V2-receptor antagonist used in heart failure patients to treat clinically significant hypervolemic and euvolemic hyponatremia.
The FDA said tolvaptan “should not be used for longer than 30 days and should not be used in patients with underlying liver disease because it can cause liver injury, potentially leading to liver transplant or death.”
The liver injury risk was discovered in clinical trials testing tolvaptan in patients with autosomal dominant polycystic kidney disease (ADPKD). The drug label has been updated and now states that use of the drug should be limited to 30 days and that it is no longer indicated in patients with cirrhosis. The FDA recommended that Tolvaptan should be discontinued in patients with liver disease who are currently taking the drug.
This announcement follows a previous FDA alert released in January, warning of an increased risk for liver injury.
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 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 Tolvaptan. These findings indicate that Samsca (Tolvaptan) has the potential to cause irreversible and potentially fatal liver injury. These data is not adequate to exclude the possibility that patients receiving Samsca for its indicated use of clinically significant hypervolemic
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.
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.
To report problems with Tolvaptan, contact MedWatch, the FDA’s safety information and adverse event reporting program.