ADVERSE EFFECTS AND MANAGEMENT

Hepatotoxicity that may result in death or require liver transplant is a concerning risk with these agents; therefore, monitoring liver function (transaminases, bulirubin, and alkaline phosphatase) prior to initiating treatment (baseline) and at specified intervals, or as clinically indicated, throughout treatment is recommended. Liver failure manifests as jaundice, elevated transaminases, and/or hyperbilirubinemia in conjunction with encephalopathy, coagulopathy, and/or renal failure.

Recommended monitoring schedule for patients receiving imatinib is at baseline, then monthly or as clinically indicated. Withold imatinib as follows: elevated bilirubin is greater than 3 times the institutional upper limit of normal (IULN), withhold until less than 1.5 times the IULN; liver transaminases greater than 5 times the IULN, withhold until less than 2.5 times the IULN. When treatment can be resumed, dose reductions are 400 mg to 300 mg, 600 mg to 400 mg, or 800 mg to 600 mg in adult patients; 340 mg/m2/day to 260 mg/m2/day in children.1


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Liver dysfunction was most often characterized by a hepatocellular pattern of injury that occurred within the first 2 months of treatment in patients receiving regorafenib. Due to this incidence, recommended monitoring schedule is at baseline then at least every 2 weeks during the first 2 months of treatment, and monthly beyond the first 2 months, or as clinically indicated. Liver function should be monitored weekly in patients with elevated tests results until improved to less than 3 times the ULN or baseline.3

Regorafenib should be temporarily held, then depending on the severity and persistence of hepatotoxicity, reduce the dose or permanently discontinue. For grade 3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation, reduce dose to 120 mg but only resume if the potential benefit outweighs the risk of hepatotoxicity. If grade 3 AST/ALT elevation occurs at this dose, reduce dose further to 80 mg after recovery. Permanently discontinue treatment if AST or ALT is more than 20 times the ULN, if AST or ALT is more than 3 times the ULN with concurrent bilirubin more than 2 times the ULN, or if AST or ALT recurs at more than 5 times ULN despite dose reduction to 120 mg. Resume treatment only if the potential benefit outweighs the risks after any grade 4 adverse reaction.3

In patients receiving sunitinib, obtain liver function test results at baseline, during each treatment cycle, and as clinically indicated. Interrupt treatment for grade 3 or grade 4 drug-related hepatic adverse events, and discontinue treatment if hepatic adverse events are not resolved. If severe changes in liver function are seen or the patient develops other signs or symptoms of liver failure, do not restart sunitinib. Safety of this drug has not been established for patients with ALT or AST greater than 2.5 times the ULN, or greater than 5.0 times the ULN if due to liver metastases.2