Drug Interaction Report

ADJUST DOSING INTERVAL: The concomitant use of bone marrow depressants or cytotoxic agents with strontium-89 chloride may result in additive myelosuppression. Bone marrow toxicity is expected following the administration of strontium-89 chloride alone, especially with regards to white blood cells (WBCs) and platelets. The nadir of platelet depression for most patients is about 4 to 16 weeks after a strontium-89 chloride injection. Recovery can be slow and may not be complete.

MANAGEMENT: Concomitant use of strontium-89 chloride and a bone marrow suppressant or cytotoxic agent is not generally recommended. Some authorities advise separating strontium-89 chloride administration from that of a cytotoxic agent by an interval of at least 12 weeks, provided that the patient's hematological parameters are stable and within the normal range. The product labeling for the concomitant myelosuppressive/cytotoxic medication should be consulted for more specific recommendations. Patients should be advised to contact their physician if they develop signs and symptoms of myelosuppression such as pallor, dizziness, fatigue, lethargy, fainting, easy bruising or bleeding, or signs of infection such as fever, chills, sore throat, body aches, and other influenza-like symptoms.

GENERALLY AVOID: Coadministration of imatinib with strong CYP450 3A4 inhibitors such as grapefruit juice, may significantly increase the plasma concentrations of imatinib, a known substrate of CYP450 3A4. The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism of imatinib by certain compounds present in grapefruits. Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability). In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (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. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict. In a single-dose study, coadministration of imatinib with ketoconazole (a strong CYP450 3A4 inhibitor) increased imatinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 26% and 40%, respectively.

MANAGEMENT: Patients treated with imatinib should preferably avoid the consumption of grapefruit or grapefruit juice. If coadministration is unavoidable, monitor for prolonged and/or increased pharmacologic effects of imatinib, including edema, hematologic toxicity and immunosuppression.