Hepatotoxicity

Pexidartinib can cause serious and potentially fatal liver injury and is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) [see Warnings and Precautions (5.2)].

Hepatotoxicity, including liver failure and life-threatening vanishing bile duct syndrome (VBDS), ductopenia, and symptomatic cholestasis (including severe pruritus) can occur in patients treated with pexidartinib 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 pexidartinib 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 pexidartinib; 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 pexidartinib 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 pexidartinib developed signs of serious liver injury, defined as ALT or AST ≥3 × ULN with total bilirubin ≥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 ≥2 × ULN. ALT, AST, and total bilirubin improved to <2 × ULN in these three patients 1 to 7 months after discontinuing pexidartinib .

Avoid pexidartinib in patients with pre-existing increased serum transaminases; total bilirubin or direct bilirubin (>ULN); or active liver or biliary tract disease, including increased ALP. Monitor liver tests, including AST, ALT, total bilirubin, direct bilirubin, ALP, and gamma-glutamyl transferase (GGT) prior to initiation of pexidartinib , weekly for the first 8 weeks, every 2 weeks for the next month and every 3 months thereafter. Withhold and dose reduce, or permanently discontinue pexidartinib based on the severity of the hepatotoxicity [see Dosage and Administration (2.2)]. Refer patients to a hepatologist if liver tests do not return to normal. Rechallenge with a reduced dose of pexidartinib 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.