Drug Interactions between aspirin / caffeine / dihydrocodeine and tovorafenib

MONITOR CLOSELY: Coadministration of tovorafenib and drugs that interfere with platelet function or coagulation may potentiate the risk of bleeding complications. Major hemorrhagic events, such as tumor hemorrhage, gastrointestinal hemorrhage, subdural hemorrhage, intracranial tumor hemorrhage, and hemoptysis have been reported during tovorafenib therapy. In the safety evaluation of tovorafenib monotherapy in 137 patients with pediatric low-grade glioma harboring a BRAF alteration, serious bleeding events (Grade 3 or 4) were reported in 5% of patients, including a Grade 5 tumor hemorrhage in one patient.

MANAGEMENT: Concomitant use of other medications that interfere with platelet function or coagulation should be considered cautiously in patients treated with tovorafenib. Close clinical and laboratory observation for bleeding complications is recommended during therapy. Patients should be advised to promptly report any signs and symptoms of bleeding to their physician. Refer to the product labeling for guidance on tovorafenib dosage adjustments in patients with Grade 2 to 4 hemorrhage.

MONITOR: Coadministration with tovorafenib may decrease the plasma concentrations of drugs that are substrates of CYP450 3A4. The proposed mechanism is increased clearance due to tovorafenib-mediated induction of CYP450 3A4 metabolism. According to the manufacturer, tovorafenib is predicted to decrease the peak plasma concentration (Cmax) and systemic exposure (AUC) of sensitive 3A4 substrate midazolam by at least 20%. However, data from formal clinical drug interaction studies are not available.

MANAGEMENT: Caution is recommended with the concomitant use of tovorafenib and CYP450 3A4 substrates. In particular, the manufacturer of tovorafenib advises that concomitant use with sensitive CYP450 3A4 substrates with narrow therapeutic ranges should generally be avoided. If coadministration is required, patients should be monitored carefully for potential loss of therapeutic effects.

One study has reported that coadministration of caffeine and aspirin lead to a 25% increase in the rate of appearance and 17% increase in maximum concentration of salicylate in the plasma. A significantly higher area under the plasma concentration time curve of salicylate was also reported when both drugs were administered together. The exact mechanism of this interaction has not been specified. Physicians and patients should be aware that coadministration of aspirin and caffeine may lead to higher salicylate levels faster.