Drug Interaction Report

MONITOR CLOSELY: Coadministration of radium Ra 223 dichloride (Ra-223 dichloride) with other agents that can cause bone marrow suppression or myelosuppression may result in additive toxicity. Ra-223 dichloride alone is associated with thrombocytopenia, neutropenia, pancytopenia, and leukopenia; death from bone marrow failure has also been reported. In a randomized clinical trial in patients with metastatic castration-resistant prostate cancer with bone metastases, 2% of the patients on Ra-223 dichloride experienced bone marrow failure or ongoing pancytopenia compared to no patients in the placebo group. Grade 3-4 adverse reactions of thrombocytopenia and neutropenia were more commonly reported in patients who had received prior docetaxel. However, data from clinical drug interaction studies are lacking.

MANAGEMENT: Caution and close monitoring for additive hematologic toxicity are recommended if concomitant use of Ra-223 dichloride with other agents that can cause bone marrow suppression or myelosuppression is required. The manufacturer advises that Ra-223 dichloride be discontinued in patients requiring administration of chemotherapy, other systemic radioisotopes, or hemibody external radiotherapy. If concomitant use is required, the manufacturer's product labeling should be consulted for specific hematologic monitoring and dose adjustment recommendations. Some authorities recommend not initiating subsequent systemic cancer treatment for at least 30 days after the last administration of Ra-223 dichloride. Patients should be advised to contact their physician if they develop signs or symptoms of myelosuppression or infection including but not limited to pallor, dizziness, fatigue, lethargy, fainting, easy bruising or bleeding, fever, chills, sore throat, body aches, and/or other influenza-like symptoms.

GENERALLY AVOID: Grapefruit and Seville oranges may increase the plasma concentrations of lurbinectedin. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit and Seville oranges. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit or Seville oranges, but pharmacokinetic data are available for potent and moderate CYP450 3A4 inhibitors. In a clinical drug interaction study, coadministration of itraconazole, a potent CYP450 3A4 inhibitor, increased the systemic exposure (AUC) of total lurbinectedin by 2.7-fold and unbound lurbinectedin by 2.4-fold. In a Phase 1 study, coadministration of aprepitant, a moderate CYP450 3A4 inhibitor, decreased lurbinectedin plasma clearance by 33% compared to lurbinectedin alone. In general, the effect of grapefruit and Seville oranges is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice and Seville oranges (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased exposure may increase the incidence and severity of adverse reactions of lurbinectedin, such as myelosuppression and hepatotoxicity.

MANAGEMENT: Patients should avoid consumption of grapefruit, grapefruit juice, and Seville oranges during treatment with lurbinectedin.