Drugs Xagena
Significant liver injury associated with the use of Tolvaptan ( Samsca ) has been reported. In a large double-blind, 3-year, placebo-controlled trial ( TEMPO 3:4 ) in about 1400 patients with autosomal dominant polycystic kidney disease ( ADPKD ) and its open-label extension trial in patients, 3 patients treated with Tolvaptan developed significant ( greater than 3x ULN ) increases in serum alanine aminotransferase ( ALT ) with concomitant, clinically significant ( greater than 2x ULN ) increases in serum total bilirubin. 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 Tolvaptan has the potential to cause irreversible and potentially fatal liver injury.
Additionally, Tolvaptan was associated with an increased incidence compared to placebo of significant ( greater than 3x ULN ) elevations of ALT. Specifically, 4.4% ( 42/958 ) of ADPKD patients on Tolvaptan and 1.0% ( 5/484 ) of patients on placebo exhibited elevations greater than 3x ULN of ALT.
Most of the liver enzyme abnormalities were observed during the first 18 months of therapy. The elevations gradually improved after discontinuation of Tolvaptan.
In the ADPKD 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.
Samsca is not approved for the treatment of ADPKD.
In other clinical trials of Tolvaptan, including the trials supporting the approved indication ( clinically significant euvolemic or hypervolemic hyponatremia ), liver damage has not been reported.
However, these data are not adequate to exclude the possibility that patients receiving Tolvaptan for its indicated use of clinically significant hypervolemic and euvolemic hyponatremia are at a potential increased risk for irreversible and potentially fatal liver injury.
The ability to recover from liver injury may be impaired in patients with hyponatremia in the setting of underlying liver disease, including cirrhosis. Limiting the duration of Tolvaptan therapy may reduce the risk of developing 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, Tolvaptan should be promptly discontinued, appropriate treatment should be instituted, and investigations should be performed to determine probable cause.
Tolvaptan 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. ( Xagena )
Source: FDA, 2013
XagenaMedicine_2013
