Hepatotoxicity

• Hepatotoxicity, including liver failure and life-threatening vanishing bile duct syndrome (VBDS), ductopenia, and symptomatic cholestasis (including severe pruritis) can occur in patients treated with TURALIO and can occur despite monitoring and prompt drug cessation. The mechanism of cholestatic hepatotoxicity is unknown and its occurrence cannot be predicted. It is unknown whether liver injury can also occur in the absence of increased transaminases.
• Of the first 609 patients who received TURALIO under the REMS program, 32 (5.3%) developed a liver injury event of concern (LIEC), defined as any serious liver-related outcome or any liver abnormality that triggers drug discontinuation per the US Prescribing Information [see Dosage and Administration (2.2)]. These 32 patients developed liver toxicity within 71 days of the first dose of TURALIO; ten required hospitalization, and two developed VBDS. Sixteen of the 32 patients had not fully recovered at the time of the analysis, including 6 patients followed for at least 6 months after discontinuation.
• Among 768 patients who received TURALIO in clinical trials, there were two irreversible cases of cholestatic liver injury. One patient with advanced cancer and ongoing liver toxicity died and one patient with a confirmed case of VBDS required a liver transplant
• In ENLIVEN, 3 of 61 (5%) patients who received TURALIO developed signs of serious liver injury, defined as ALT or AST greater than or equal to 3 × ULN with total bilirubin greater than or equal to 2 × ULN. In these patients, peak ALT ranged from 6 to 9 × ULN, peak total bilirubin ranged from 2.5 to 15 × ULN, and alkaline phosphatase (ALP) was greater than or equal to 2 × ULN. ALT, AST, and total bilirubin improved to <2 × ULN in these three patients 1 to 7 months after discontinuing TURALIO.
• Refer patients to a hepatologist if liver tests do not return to normal. Rechallenge with a reduced dose of TURALIO may result in a recurrence of increased serum transaminases, bilirubin, ALP, or other signs of liver injury. Monitor liver tests weekly for the first month after rechallenge.