Drug Interaction Report

MONITOR CLOSELY: Coadministration of drotrecogin alfa with other drugs that can interfere with coagulation or platelet function may potentiate the risk of bleeding complications. Drotrecogin alfa inactivates blood clotting factors Va and VIIIa and may prolong the activated partial thromboplastin time (APTT). Treatment with drotrecogin alfa alone has been associated with serious and life-threatening bleeding episodes, including gastrointestinal, intracranial and retroperitoneal hemorrhage, although most severely ill septic patients are already at a high risk of bleeding because of coagulopathies associated with prolonged APTT and prothrombin time (PT). In a phase 3 study, the incidence of serious bleeding events during the 28-day study period was 3.5% for drotrecogin alfa versus 2.0% for placebo, with the difference occurring primarily during the infusion period.

MANAGEMENT: The potentially increased risk of bleeding versus the benefits of drotrecogin alfa therapy should be carefully considered in seriously ill septic patients who are currently receiving, or have recently received, agents that could affect hemostasis such as anticoagulants, antiplatelet agents, nonsteroidal anti-inflammatory drugs (NSAIDs), thrombolytics, thrombin inhibitors, or agents that commonly cause thrombocytopenia. Close clinical and laboratory monitoring for bleeding complications is recommended if concurrent therapy is required. Drotrecogin alfa should be discontinued immediately if clinically significant bleeding occurs. Continued use of other agents that may have contributed to the bleeding should be carefully assessed. Once adequate hemostasis is attained, drotrecogin alfa may be resumed if necessary.

ADJUST DOSING INTERVAL: Food may alter the oral bioavailability of cabozantinib. When healthy subjects were given a single 140 mg oral dose with a high-fat meal, cabozantinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 41% and 57%, respectively, relative to administration under fasting conditions. In clinical studies, patients were administered cabozantinib without food.

GENERALLY AVOID: Coadministration with grapefruit juice is likely to increase the plasma concentrations of cabozantinib, which is primarily metabolized by CYP450 3A4. However, the interaction has not been studied. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

MANAGEMENT: Cabozantinib should be administered at least one hour before or two hours after a meal. The consumption of grapefruit, grapefruit juice, and supplements that contain grapefruit extract should be avoided.