BETHESDA, MD 25 January 2013—The significant concomitant increases in serum alanine aminotransferase and serum total bilirubin concentrations that occurred during a Phase III study of tolvaptan in patients with autosomal dominant polycystic kidney disease were probably or highly likely due to the drug, experts have determined.
and Otsuka America Pharmaceutical Inc. (PDF) said this week the experts' findings indicate that tolvaptan "has the potential to cause irreversible and potentially fatal liver injury."
The regulatory agency and pharmaceutical company acknowledged that the Phase III study used a higher dosage of tolvaptan than what is recommended in its U.S. labeling and that the drug is not approved for the treatment of autosomal dominant polycystic kidney disease.
Nonetheless, FDA and the company now recommend that health care providers promptly undertake liver-function tests in any tolvaptan user who reports symptoms suggestive of liver injury, such as fatigue, discomfort in the right-upper abdominal quadrant, or dark urine. And if health care providers suspect the patient has liver injury, they should promptly discontinue tolvaptan therapy, initiate appropriate treatment, and investigate to determine the probable cause of the injury.
A U.S.-based sister company of Otsuka America launched the Phase III study several months before submitting a new drug application on a different indication, hyponatremia treatment, according to publicly available records.
FDA approved that application in May 2009, and Otsuka America started marketing tolvaptan, or Samsca, for the treatment of clinically significant hypervolemic and euvolemic hyponatremia.
The drug is a selective vasopressin V2-receptor antagonist.
The Phase III study known as the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes 3:4 trial enrolled 1445 patients, investigators reported in late 2012.
According to their article in the New England Journal of Medicine, two patients who received tolvaptan had a high alanine aminotransferase or aspartate aminotransferase serum level—more than three times the upper limit of the normal range—at the same time as a serum bilirubin level exceeding two times the upper limit of the normal range. These abnormalities later resolved or returned toward baseline values, the investigators reported, adding that no reports of "persistent sequelae" were received.
Otsuka America on Tuesday announced that those concomitant elevations in serum alanine aminotransferase and serum bilirubin levels occurred in three patients who received tolvaptan during the three-year study and its "extension trial."
The three patients "improved," the company reported.
As for patients with hyponatremia, tolvaptan's labeled indication, the company said those with underlying liver disease may have an impaired ability to recover from liver injury.
The company advised health care providers that they may be able to reduce the risk of new liver injury in tolvaptan users with hyponatremia and underlying liver disease by limiting the duration of therapy with the drug.