Tolvaptan (Samsca▼): risk of liver injury
- Medicines and Healthcare products Regulatory Agency
- 29 May 2013
- Therapeutic area:
- Endocrinology, diabetology and metabolism
liver-function testing recommended in patients with symptoms that may indicate liver injury.
Article date: May 2013
Tolvaptan (Samsca▼) 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 trial1 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, >3 times the upper limit of normal [ULN]) and total bilirubin (>2 times ULN) were observed in three patients assigned tolvaptan and no patients assigned placebo. Furthermore, there were significant elevations to >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 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 (SIADH) 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.
Suspected hepatic adverse drug reactions to tolvaptan should be reported to us on a Yellow Card.
BNF section 6.5.2 Posterior pituitary hormones and antagonists
Article citation: Drug Safety Update May 2013 vol 6, issue 10: A1.
Torres VE, et al. N Engl J Med 2012; 367: 2407–18. ↩
Published: 29 May 2013
Therapeutic area: Endocrinology, diabetology and metabolism