Drug Interaction Report

MONITOR: Coadministration of romosozumab with bisphosphonates, denosumab, angiogenesis inhibitors, or corticosteroids may increase the risk of developing osteonecrosis of the jaw (ONJ). The condition can occur spontaneously and is generally associated with tooth extraction and/or local infection with delayed healing. Other risk factors for ONJ include cancer, chemotherapy, radiotherapy to the head and neck, poor oral hygiene, preexisting dental disease or infection, anemia, and coagulopathy.

MANAGEMENT: Caution is advised when romosozumab is used with other agents that are also associated with osteonecrosis of the jaw. A routine oral examination should be performed by the prescriber prior to initiation of romosozumab treatment. For patients requiring invasive dental procedures, clinical judgment and risk-benefit assessment should guide the management plan of each patient based on their clinical circumstances. 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 romosozumab therapy should receive care by a dentist or an oral surgeon. In these patients, dental surgery to treat ONJ may exacerbate the condition. Discontinuation of romosozumab should be considered based on benefit-risk assessment.

GENERALLY AVOID: Coadministration of imatinib with strong CYP450 3A4 inhibitors such as grapefruit juice, may significantly increase the plasma concentrations of imatinib, a known substrate of CYP450 3A4. The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism of imatinib by certain compounds present in grapefruits. Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability). In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict. In a single-dose study, coadministration of imatinib with ketoconazole (a strong CYP450 3A4 inhibitor) increased imatinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 26% and 40%, respectively.

MANAGEMENT: Patients treated with imatinib should preferably avoid the consumption of grapefruit or grapefruit juice. If coadministration is unavoidable, monitor for prolonged and/or increased pharmacologic effects of imatinib, including edema, hematologic toxicity and immunosuppression.