Drugs Xagena
Drug-induced liver injury has been observed in clinical trials investigating potential use in patients with autosomal dominant polycystic kidney disease ( ADPKD, an unlicensed indication ) at higher doses than those for the approved indication and in long-term use.
Liver-function tests should be done in patients taking Tolvaptan ( Samsca ) who report signs or symptoms that suggest liver injury. Treatment with Tolvaptan should be stopped during investigations into the probable cause of liver injury and patients treated with alternative appropriate treatment.
Tolvaptan is a selective vasopressin V2-receptor antagonist licensed only for the treatment of adults with hyponatraemia secondary to inappropriate antidiuretic hormone secretion ( SIADH ) at a dose of 15-60 mg once a day.
Tolvaptan increases urine production without affecting sodium excretion, thereby raising serum sodium and lowering the amount of water in the body.
A clinical trial in the USA investigating the potential use of Tolvaptan in about 1400 patients with autosomal dominant polycystic kidney disease ( ADPKD, an unlicensed indication ) has identified an increased risk of serious liver injury in adults assigned 120 mg Tolvaptan daily ( ie, twice the maximum recommended daily dose in the licensed indication ) compared with placebo.
In the ADPKD population, clinically significant increases in both serum alanine aminotransferase ( ALT, greater than 3 times the upper limit of normal [ ULN ] ) and total bilirubin ( greater than 2 times ULN ) were observed in three patients assigned Tolvaptan and no patients assigned placebo.
Furthermore, there were significant elevations to greater than 3 times ULN for ALT ( 4.4% for Tolvaptan vs 1.0% for placebo ) and for serum aspartate aminotransferase ( AST, 3.1% vs 0.8%, respectively ). Most of the liver enzyme abnormalities were observed during the first 18 months of treatment. The elevations gradually improved after discontinuation of Tolvaptan and were not associated with fulminant liver failure, or with permanent liver injury or dysfunction.
Other clinical trials of Tolvaptan for hyponatraemia, including those supporting the European-approved indication, did not show an increased incidence of liver injury compared with placebo. However, patients with hyponatraemia treated with Tolvaptan were more likely to have elevations in total bilirubin or ALT than placebo.
These data cannot exclude the possibility that patients with SIADH ( syndrome of inappropriate antidiuretic hormone secretion ) treated with Tolvaptan for hyponatraemia are potentially at increased risk of liver injury.
Advice for healthcare professionals
Tolvaptan is licensed only for the treatment of adults with hyponatraemia secondary to inappropriate antidiuretic hormone secretion at a dose of 15-60 mg once a day.
Patients taking Tolvaptan who report symptoms that may indicate liver injury should receive prompt liver-function testing. These symptoms include fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.
Patients with liver enzyme abnormalities ( such as elevations of ALT, AST, or bilirubin ) should be investigated to exclude significant hepatotoxicity.
Prescribers should stop Tolvaptan treatment in patients if liver injury is suspected and use alternative appropriate treatment. Tolvaptan should not be restarted in patients, unless the cause of the observed liver injury is definitively established to be unrelated to Tolvaptan treatment. ( Xagena )
Source: Drug Safety Update 2013 vol 6, issue 10: A1
XagenaMedicine_2013
