Drug Interaction Report

MONITOR: Lenvatinib use in combination with or after recent use of other medications associated with osteonecrosis of the jaw (ONJ) may increase the risk of this rare side effect. Theories as to how ONJ develops include inhibition of bone remodeling, inflammation or infection, angiogenesis inhibition, innate or acquired immune dysfunction, as well as genetic predisposition; however, the pathophysiology is likely related to multiple factors. Medication-related ONJ (MRONJ) is a rare, but severe and debilitating condition whose exact cause remains unknown. Known risk factors for MRONJ include cancer, duration of antiresorptive therapy, dentoalveolar operations (such as tooth extraction), preexisting inflammatory dental disease, and concurrent use of multiple medications associated with a risk of ONJ (such as bisphosphonates, denosumab, romosozumab, angiogenesis inhibitors, and corticosteroids).

MANAGEMENT: Caution is advised when lenvatinib is used with other agents that are also associated with the development of ONJ. A routine oral examination should be performed prior to initiation of either treatment. Patients should be advised regarding good oral hygiene practices and to have regular preventive dentistry performed throughout treatment. For patients requiring invasive dental procedures, discontinuation of lenvatinib may be recommended. Patients should be advised to seek medical attention if they experience signs and symptoms of ONJ, such as: pain in the mouth, teeth, or jaw; swelling or sores inside the mouth; numbness or a feeling of heaviness in the jaw; loosening of a tooth; or exposure of bone in the jaw. Those who are suspected of having or who develop ONJ during lenvatinib therapy should receive care by a dentist or an oral surgeon. In all circumstances involving MRONJ, clinical judgment and a risk-benefit assessment should guide the management plan of each patient based on their specific clinical circumstances.

GENERALLY AVOID: Coadministration with grapefruit juice is likely to increase the plasma concentrations of ponatinib, 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: The consumption of grapefruit, grapefruit juice, and supplements that contain grapefruit extract should be avoided during treatment with ponatinib.

The recommended maximum number of medicines in the 'VEGF/VEGFR inhibitors' category to be taken concurrently is usually one. Your list includes two medicines belonging to the 'VEGF/VEGFR inhibitors' category:

• Iclusig (ponatinib)
• lenvatinib

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.

The recommended maximum number of medicines in the 'multikinase inhibitors' category to be taken concurrently is usually one. Your list includes two medicines belonging to the 'multikinase inhibitors' category:

• Iclusig (ponatinib)
• lenvatinib

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.