TOLVAPTAN SHOULD BE USED ONLY FOR 30 DAYS 

ROCKVILLE, Md -- April 30, 2013 -- The US Food and Drug Administration (FDA) has determined that the drug tolvaptan (Samsca) 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 requiring liver transplant or death.

An increased risk of liver injury was observed in recent large clinical trials evaluating tolvaptan for a new use in patients with autosomal dominant polycystic kidney disease (ADPKD)

The FDA has worked with the manufacturer to revise the tolvaptan drug label to include these new limitations.

The tolvaptan drug label has been updated to include the following information:

• Limitation of the duration of tolvaptan treatment to 30 days (Dosage and Administration and Warnings and Precautions sections)

• Removal of the indication for use in patients with cirrhosis. Use of tolvaptan in patients with underlying liver disease, including cirrhosis, should be avoided because the ability to recover from liver injury may be impaired (Indications and Usage and Use in Specific Populationssections).

• Description of liver injuries seen in clinical trials of patients with ADPKD.

• Recommendation to discontinue tolvaptan in patients with symptoms of liver injury.

Data Summary

Tolvaptan was approved in May 2009 for the treatment of clinically significant euvolemic and hypervolemic hyponatremia. Patients should be in a hospital for initiation and re-initiation of therapy to evaluate the therapeutic response before subsequently receiving tolvaptan in the outpatient setting.

Tolvaptan is being studied for another indication: delay in progression of renal disease in adult patients with ADPKD. Three cases of serious liver injury attributed to tolvaptan were observed in a placebo-controlled trial in ADPKD and its open-label extension study, indicating the potential for the drug to cause liver injury that could progress to liver failure.

In addition, tolvaptan was associated with an increased incidence of ALT elevations greater than 3 times the upper limit of normal: 42 of 958 (4.4%) patients in the tolvaptan group versus 5 of 484 (1.0%) patients in the placebo group. The serious liver injury cases were consistent with Hy’s law.

Analysis of safety information in the clinical trials that supported the hyponatremia indication (and in other populations such as those with heart failure) did not demonstrate hepatotoxicity. However, the controlled hyponatremia trials were of short duration --about 30 days.

Although the FDA has received spontaneous post-marketing reports of elevated liver enzymes and other liver events in patients taking tolvaptan, these reports are difficult to interpret because many of the patients had underlying disease that can be associated with elevated liver enzymes or liver injury (cirrhosis, heart failure or cancer).

Based on the cases of liver injury in patients participating in the ADPKD trials, the FDA worked with the manufacturer to revise the tolvaptan drug label to include the above information, to reduce the potential for serious liver injury.