Drug Interactions between Pacaps and Yondelis

MONITOR: Barbiturates may increase the hepatotoxic potential of acetaminophen and decrease its therapeutic effects. The mechanism may be related to accelerated CYP450 metabolism of acetaminophen with consequent increase in hepatotoxic metabolites. This interaction is of greatest concern in cases of acetaminophen overdose.

MANAGEMENT: Monitoring for altered efficacy and safety is recommended. Prolonged use or high doses of acetaminophen should be avoided by patients on barbiturate therapy.

Switch to consumer interaction data

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.

Switch to consumer interaction data

MONITOR: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of trabectedin, which is primarily metabolized by the isoenzyme. In 9 study patients with advanced malignancies, administration of a single 1.3 mg/m2 infusion of trabectedin on day 6 of treatment with rifampin (600 mg daily for 6 days), a potent CYP450 3A4 inducer, resulted in a 22% decrease in mean trabectedin peak plasma concentration (Cmax) and 31% decrease in mean systemic exposure (AUC) compared to infusion of trabectedin alone. Results from a population pharmacokinetic analysis (n = 831) indicated that the plasma clearance of trabectedin was 19% higher in patients who received concomitant dexamethasone, a moderate CYP450 3A4 inducer, compared to those who did not.

MANAGEMENT: The possibility of diminished therapeutic effects should be considered when trabectedin is prescribed with CYP450 3A4 inducers. Close clinical and laboratory monitoring is recommended whenever a CYP450 3A4 inducer is added to or withdrawn from trabectedin therapy, and the dosage adjusted if necessary.

Switch to consumer interaction data