Drug Interactions between lenvatinib and Zometa

MONITOR: Administration of lenvatinib with or after recent use of bisphosphonates may increase the risk of developing osteonecrosis of the jaw (ONJ). Medication-related ONJ (MRONJ) is a rare, but severe and debilitating condition whose exact cause is currently unknown. Theories as to how MRONJ 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. Known risk factors for MRONJ include cancer, route and 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, angiogenesis inhibitors, or corticosteroids).

MANAGEMENT: Caution is advised when lenvatinib is used sequentially after or concomitantly with other agents that are also associated with ONJ, such as bisphosphonates. 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 and/or the bisphosphonate 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. This includes whether to hold therapy, discontinue therapy, or restart therapy with lenvatinib and/or the bisphosphonate.

MONITOR: Coadministration of intravenous (IV) bisphosphonate formulations with lenvatinib may increase the risk and severity of renal impairment due to additive effects on the kidney. Lenvatinib, being a vascular endothelial growth factor inhibitor, can cause proteinuria which is a known risk factor for declining renal function. The use of both IV bisphosphonates and lenvatinib have been associated with nephrotoxicity manifested as deterioration of renal function and renal failure. There is also a risk of hypocalcemia when lenvatinib is combined with bisphosphonates (both IV and oral formulations) as both types of medications have been associated with hypocalcemia when used as monotherapy. Bisphosphonates, both oral and IV formulations, often cause mild, asymptomatic hypocalcemia via inhibitive effects on bone resorption and possibly chelation of blood calcium. The pathophysiology of hypocalcemia in lenvatinib treated patients is not currently known. Several theories exist including that it is related to other treatment related side effects (such as nausea, vomiting, anorexia, and/or diarrhea), vitamin D and/or magnesium malabsorption, tumor lysis syndrome (excess phosphate being released into the bloodstream which binds to the calcium), or even a potential direct effect on bone metabolism which results in lower calcium levels.

MANAGEMENT: Caution is advised if lenvatinib must be used in patients who have recently received or are receiving treatment with bisphosphonates. Renal function, urine protein levels, and serum electrolytes should be monitored regularly. Patients should have serum creatinine and calcium levels assessed prior to each IV bisphosphonate treatment and treatment should be withheld for renal deterioration. Hypocalcemia should be corrected prior to treatment with IV or oral bisphosphonates. See individual product labeling for more specific recommendations regarding hypocalcemia, proteinuria, renal failure, or acute renal impairment as therapy may need to be held or doses adjusted.

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