Drug Interactions between amoxicillin / clarithromycin / vonoprazan and revumenib

GENERALLY AVOID: Revumenib causes dose-related prolongation of the QT interval. Coadministration with other agents that can prolong the QT interval may result in additive effects and an increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In clinical trials, QT interval prolongation was reported as an adverse reaction in 29% of patients treated with revumenib at the recommended dosage for relapsed or refractory acute leukemia with a KMT2A translocation. Additionally, Grade 3 QT interval prolongation occurred in 12% of those patients and a greater than 60 msec increase in Fridericia-corrected QT interval (QTcF) from baseline was reported in 18% of patients. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypocalcemia). Moreover, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of revumenib, which has been shown to be primarily metabolized by the isoenzyme. In pharmacokinetic studies in patients with relapsed or refractory acute leukemia, revumenib area under the concentration-time curve (AUC) and peak plasma concentration (Cmax) increased 2-fold following concomitant use with the potent CYP450 3A4 inhibitors posaconazole, itraconazole, and voriconazole, and 2.5-fold following concomitant use with the potent CYP450 3A4 inhibitor cobicistat.

MANAGEMENT: Concomitant use of revumenib with potent CYP450 3A4 inhibitors that can also prolong the QT interval should be avoided when possible. If concomitant use is required, the manufacturer recommends a dose reduction of revumenib. For patients weighing 40 kilograms or more, reduce the dose from 270 mg orally twice daily to 160 mg orally twice daily. For patients weighing less than 40 kilograms, reduce the dose from 160 mg/m2 orally twice daily to 95 mg/m2 orally twice daily based on the patient's body surface area (BSA). Following discontinuation of the potent CYP450 3A4 inhibitor, revumenib dosing may be increased to the recommended dose for patients not receiving a potent CYP450 3A4 inhibitor, after at least 5 half-lives of the inhibitor. Patient tolerability should be assessed throughout treatment, and for those experiencing certain serious adverse effects (e.g., QT prolongation and torsade de pointes arrhythmia, differentiation syndrome, neutropenia, thrombocytopenia), revumenib treatment should be interrupted and/or the dose should be further reduced in accordance with product labeling. Additional adverse effects to closely monitor for include nausea, infection, hypokalemia, hemorrhage, and musculoskeletal pain. It is also advised to obtain electrocardiograms (ECGs) when initiating, during concomitant use, and as clinically indicated. Serum electrolytes, including potassium, magnesium, and calcium, should be monitored before starting revumenib therapy and monthly during treatment. Revumenib should not be started if baseline QTc is greater than 450 msec. Likewise, treatment should be interrupted and the dose adjusted in patients who develop QTc prolongation greater than 480 msec. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope. Permanently discontinue revumenib in patients who develop QTc interval prolongation with life-threatening arrhythmia.

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.

Coadministration with mild or moderate inhibitors of CYP450 3A4 may increase the plasma concentrations of revumenib, which has been shown to be primarily metabolized by the isoenzyme. However, clinically significant differences in revumenib pharmacokinetics were not observed when used concomitantly with the moderate CYP450 3A4 inhibitors fluconazole and isavuconazole. Based on these observations, revumenib may be administered with mild or moderate CYP450 3A4 inhibitors without the need for dose adjustments.