Drug Interaction Report

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: Agents that cause urinary alkalinization can reduce serum salicylate concentrations in patients receiving anti-inflammatory dosages of aspirin or other salicylates. The mechanism involves reduction in salicylate renal tubular reabsorption due to increased urinary pH, resulting in increased renal salicylate clearance especially above urine pH of 7. This interaction is sometimes exploited in the treatment of salicylate toxicity.

MANAGEMENT: Patients treated chronically with urinary alkalinizers and large doses of salicylates (i.e. 3 g/day or more) should be monitored for potentially diminished or inadequate analgesic and anti-inflammatory effects, and the salicylate dosage adjusted if necessary.

GENERALLY AVOID: The concurrent use of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) and ethanol may lead to gastrointestinal (GI) blood loss. The mechanism may be due to a combined local effect as well as inhibition of prostaglandins leading to decreased integrity of the GI lining.

MANAGEMENT: Patients should be counseled on this potential interaction and advised to refrain from alcohol consumption while taking aspirin or NSAIDs.

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.