Drug Interactions between dexamethasone / ketorolac / moxifloxacin and revumenib

MONITOR CLOSELY: Concomitant administration of corticosteroids may potentiate the risk of tendinitis and tendon rupture associated with fluoroquinolone treatment. The mechanism is unknown. Tendinitis and tendon rupture have most frequently involved the Achilles tendon, although cases involving the rotator cuff (the shoulder), the hand, the biceps, and the thumb have also been reported. Some have required surgical repair or resulted in prolonged disability. Tendon rupture can occur during or up to several months after completion of fluoroquinolone therapy.

MANAGEMENT: Caution is recommended if fluoroquinolones are prescribed in combination with corticosteroids, particularly in patients with other concomitant risk factors (e.g., age over 60 years; recipient of kidney, heart, and/or lung transplant). Patients should be advised to stop taking the fluoroquinolone, avoid exercise and use of the affected area, and promptly contact their physician if they experience pain, swelling, or inflammation of a tendon. In general, fluoroquinolones should only be used to treat conditions that are proven or strongly suspected to be caused by bacteria and only if the benefits outweigh the risks.

GENERALLY AVOID: Coadministration with potent or moderate inducers of CYP450 3A4 may significantly decrease the plasma concentrations of revumenib and increase plasma concentrations of its active metabolite M1, as revumenib has been shown to be primarily metabolized by the isoenzyme. Reduced therapeutic efficacy of revumenib and an increased risk of QT interval prolongation due to increased systemic exposures of M1 are expected. However, pharmacokinetic and clinical data from drug interaction studies are unavailable. In addition, when two or more medications with similar adverse effect profiles are given concurrently, the likelihood of experiencing these adverse reactions may be increased. For example, coadministration with other agents that can prolong the QT interval (e.g., apalutamide, encorafenib, enzalutamide) may result in additive effects and an increased risk of ventricular arrhythmias like torsade de pointes.

MANAGEMENT: Concomitant use of revumenib with potent or moderate CYP450 3A4 inducers should generally be avoided. If coadministration is required, pharmacologic response to revumenib should be monitored more closely whenever a CYP450 3A4 inducer is added to or withdrawn from therapy, and more frequent monitoring for QT interval prolongation are recommended. It is recommended to obtain electrocardiograms (ECGs) at the start of revumenib treatment, during concurrent use with moderate or potent CYP450 3A4 inducers, 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 adjusted in accordance with the product labeling in patients who develop QTc prolongation greater than 480 msec. Patients should be counseled to seek immediate medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, syncope, palpitations, irregular heartbeat, and/or shortness of breath.

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).

MANAGEMENT: It is recommended to avoid revumenib in combination with other drugs that can prolong the QT interval. If concomitant use cannot be avoided, 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 adjusted in accordance with the product labeling 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.

MONITOR: The combined use of corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the potential for serious gastrointestinal (GI) toxicity, including inflammation, bleeding, ulceration, and perforation. In a large, case-control study of elderly patients, those who used corticosteroids and NSAIDs concurrently had an estimated relative risk (RR) for peptic ulcer disease and GI hemorrhage of 14.6 compared to those who used neither. Corticosteroid use was associated with a doubling of the risk (estimated RR = 2.0), but the risk was confined to those who also used NSAIDs. It is possible that both categories of agents are ulcerogenic and have additive effects on the GI mucosa during coadministration. Some investigators have also suggested that the primary effect of corticosteroids in this interaction is to delay healing of erosions caused by NSAIDs rather than cause de novo ulcerations.

MANAGEMENT: Caution is advised if corticosteroids and NSAIDs are used together, especially in patients with a prior history of peptic ulcer disease or GI bleeding and in elderly and debilitated patients. During concomitant therapy, patients should be advised to take the medications with food and to immediately report signs and symptoms of GI ulceration and bleeding such as severe abdominal pain, dizziness, lightheadedness, and the appearance of black, tarry stools. The selective use of prophylactic anti-ulcer therapy (e.g., antacids, H2-antagonists) may be considered.

MONITOR: Coadministration with nonsteroidal anti-inflammatory drugs (NSAIDs) may potentiate the risk of central nervous system toxicity sometimes associated with fluoroquinolone use. The interaction has been reported most often with enoxacin. It may occur with other fluoroquinolones as well, but is poorly documented. The exact mechanism of interaction is unknown. Some investigators suggest that the piperazine ring of fluoroquinolones may inhibit the binding of gamma-aminobutyric acid (GABA) to brain receptors and that NSAIDs may synergistically add to this effect. Patients with a history of seizures may be at greater risk.

MANAGEMENT: Clinical monitoring for signs of CNS stimulation such as tremors, involuntary muscle movements, hallucinations, or seizures is recommended if fluoroquinolone antibiotics are prescribed in combination with NSAIDs.