Drug Interactions between Slo-Niacin and trabectedin

MONITOR: The risk of rhabdomyolysis may be increased during coadministration of trabectedin with other agents that are also associated with this toxicity, such as colchicine, alectinib, cobimetinib, statins, fibric acid derivatives, and lipid-lowering doses of niacin. Rare cases of rhabdomyolysis have occurred during both clinical trials and postmarketing use of trabectedin, typically in association with myelotoxicity, severe liver function test abnormalities, or renal failure. Multi-organ failure and fatality have also been reported. In clinical trials, creatine phosphokinase (CPK) elevations of any grade were observed in 26% to 32% of patients treated with trabectedin monotherapy, with severe (grade 3 or 4) elevations occurring in 4% to 6% of patients. CPK increases in association with rhabdomyolysis were reported in less than 1% of patients.

MANAGEMENT: Caution is advised when trabectedin is used with other agents associated with rhabdomyolysis. Patients should be advised to seek medical attention if they experience unexplained muscle pain, tenderness or weakness, particularly if accompanied by fever, malaise and/or dark colored urine. Monitoring of CPK levels should occur regularly during trabectedin treatment in accordance with the product labeling, or as often as necessary when clinical symptoms develop. If rhabdomyolysis occurs, supportive measures such as parenteral hydration, urine alkalinization, and dialysis should be promptly established as indicated, and treatment with trabectedin discontinued (some say permanently). Trabectedin must not be used in patients with creatine kinase greater than 2.5 times the upper limit of normal.

MONITOR: The risk of liver injury may be increased during coadministration of trabectedin with other potentially hepatotoxic agents, including alectinib, cobimetinib, statins, fibric acid derivatives, and lipid-lowering doses of niacin. 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: Caution is advised when trabectedin is used with other agents that are potentially hepatotoxic. 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.

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