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.

H2 antagonists may alter the pharmacokinetic disposition of some nonsteroidal anti-inflammatory drugs (NSAIDs), resulting in increased or decreased plasma concentrations. Data have been varied, even for the same NSAID. The mechanism may involve inhibition of metabolism, changes in gastric pH resulting in altered absorption, and/or reduced urinary elimination of the affected NSAIDs. Statistically significant changes have been small and of limited clinical significance when interactions have been observed.

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.

H2 antagonists may reduce the clearance of nicotine. Cimetidine, 600 mg given twice a day for two days, reduced clearance of an intravenous nicotine dose by 30%. Ranitidine, 300 mg given twice a day for two days, reduced clearance by 10%. The clinical significance of this interaction is not known. Patients should be monitored for increased nicotine effects when using the patches or gum for smoking cessation and dosage adjustments should be made as appropriate.