Drug Interactions between trabectedin and vimseltinib

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MONITOR: Coadministration of trabectedin with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. Reversible, acute increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have occurred frequently in patients treated with trabectedin alone or with pegylated liposomal doxorubicin in clinical trials. In one U.S. trial with 378 patients, grade 3 or 4 elevated liver function tests (defined as elevations in ALT, AST, total bilirubin, or alkaline phosphatase) were reported in 35% of patients receiving trabectedin. ALT or AST elevations greater than eight times the upper limit of normal (ULN) occurred in 18% of patients, and drug-induced liver injury (defined as concurrent elevations in ALT or AST more than three times ULN, alkaline phosphatase less than two times ULN, and total bilirubin at least two times ULN) occurred in 1.3% of patients.

MANAGEMENT: The risk of hepatic injury should be considered when trabectedin is used with other potentially hepatotoxic agents (e.g., acetaminophen; alcohol; androgens and anabolic steroids; antituberculous agents; azole antifungal agents; ACE inhibitors; cyclosporine (high dosages); disulfiram; endothelin receptor antagonists; interferons; ketolide and macrolide antibiotics; kinase inhibitors; minocycline; nonsteroidal anti-inflammatory agents; nucleoside reverse transcriptase inhibitors; proteasome inhibitors; retinoids; sulfonamides; tamoxifen; thiazolidinediones; tolvaptan; vincristine; zileuton; anticonvulsants such as carbamazepine, hydantoins, felbamate, and valproic acid; lipid-lowering medications such as fenofibrate, lomitapide, mipomersen, niacin, and statins; herbals and nutritional supplements such as black cohosh, chaparral, comfrey, DHEA, kava, pennyroyal oil, and red yeast rice). Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice. Monitoring of alkaline phosphatase, bilirubin, AST, and ALT should occur regularly during trabectedin treatment in accordance with the product labeling, or as often as necessary when clinical symptoms develop. Trabectedin must not be used in patients with elevated bilirubin at the time of initiation of cycle. Elevated liver function tests should be managed with treatment interruption, dosage reduction, or permanent discontinuation depending on the severity and duration of abnormality.