INTERACTIONS Strong CYP3A4 Inhibitors: Reduce the REVUFORJ dose. ( 2.2 , 7.1 ) Strong or moderate CYP3A4 Inducers: Avoid concomitant use with REVUFORJ. ( 7.1 ) QTc Prolonging Drugs: Avoid concomitant use with REVUFORJ. If concomitant use is unavoidable, monitor patients more frequently for QTc interval prolongation. ( 5.2 , 7.1 )
7.1 Effect of Other Drugs on REVUFORJ Strong CYP3A4 Inhibitors If concomitant use of strong CYP3A4 inhibitors is required, reduce the REVUFORJ dosage <span class="opacity-50 text-xs">[see Recommended Dosage (2.2) ]</span> . Revumenib is primarily metabolized by CYP3A4 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Concomitant use with a strong CYP3A4 inhibitor increases revumenib systemic exposure <span class="opacity-50 text-xs">[see Clinical Pharmacology(12.3) ]</span> , which may increase the risk of REVUFORJ adverse reactions. Strong or Moderate CYP3A4 Inducers Avoid concomitant use with strong or moderate CYP3A4 inducers. Revumenib is primarily metabolized by CYP3A4 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Concomitant use with a strong or moderate CYP3A4 inducer may decrease revumenib and increase M1 systemic exposure <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> , which may reduce REVUFORJ efficacy or increase the risk of QT prolongation associated with the M1 metabolite. Drugs that Prolong QTc Interval Avoid concomitant use of REVUFORJ with other drugs with a known potential to prolong QTc interval. If concomitant use cannot be avoided, obtain ECGs when initiating, during concomitant use, and as clinically indicated <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span> . Withhold REVUFORJ if the QTc interval is greater than 480 msec. Restart REVUFORJ after the QTc interval returns to less than or equal to 480 msec <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> . REVUFORJ causes QTc interval prolongation <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) ]</span> . Concomitant use of REVUFORJ with other drugs that prolong QTc interval may result in an increase in the QTc interval and adverse reactions associated with QTc interval prolongation <span class="opacity-50 text-xs">[see Warnings and Precautions(5.2) ]</span>.
AND PRECAUTIONS Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential of potential risk to a fetus and to use effective contraception . ( 5.3 , 8.1 , 8.3 )
5.1 Differentiation Syndrome REVUFORJ can cause fatal or life-threatening differentiation syndrome (DS). Symptoms of differentiation syndrome, including those seen in patients treated with REVUFORJ, include fever, dyspnea, hypoxia, peripheral edema, pleuropericardial effusion, acute renal failure, rash, and/or hypotension. In clinical trials, DS occurred in 60 (25%) of 241 patients treated with REVUFORJ at the recommended dosage for relapsed or refractory acute leukemia <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Among those with a KMT2A translocation, DS occurred in 33% of patients with acute myeloid leukemia (AML), 33% of patients with mixed-phenotype acute leukemia (MPAL), and 9% of patients with acute lymphoblastic leukemia (ALL); DS occurred in 18% of patients with NPM1 mutated AML. DS was Grade 3 or 4 in 12% of patients and fatal in two patients. The median time to initial onset was 9 days (range 3-41 days). Some patients experienced more than 1 DS event. Treatment interruption was required for 7% of patients, and treatment was withdrawn for 1%. Reduce the white blood cell count (WBC) to less than 25 Gi/L prior to starting REVUFORJ. If DS is suspected, immediately initiate treatment with systemic corticosteroids (e.g., dexamethasone 10 mg intravenously every 12 hours in adults or dexamethasone 0.25 mg/kg/dose intravenously every 12 hours in pediatric patients weighing less than 40 kg) for a minimum of 3 days and until resolution of signs and symptoms. Institute supportive measures and hemodynamic monitoring until improvement. Interrupt REVUFORJ if severe signs and/or symptoms persist for more than 48 hours after initiation of systemic corticosteroids, or earlier if life-threatening symptoms occur such as pulmonary symptoms requiring ventilator support. Restart steroids promptly if DS recurs after tapering corticosteroids <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span>.
5.2 QTc Interval Prolongation and Torsades de Pointes REVUFORJ can cause QT (QTc) interval prolongation and Torsades de Pointes <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) ]</span> . Of the 241 patients treated with REVUFORJ at the recommended dosage for relapsed or refractory acute leukemia in clinical trials, QTc interval prolongation was reported as an adverse reaction in 86 (36%) of patients. QTc interval prolongation was Grade 3 in 15% and Grade 4 in 2%. The heart-rate corrected QT interval (using Fridericia’s method) (QTcF) was greater than 500 msec in 10%, and the increase from baseline QTcF was greater than 60 msec in 24%. REVUFORJ dose reduction was required for 7% due to QTc interval prolongation <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span> . QTc prolongation occurred in 21% of the 34 patients less than 17 years old, 35% of the 146 patients 17 years to less than 65 years old, and in 46% of the 61 patients 65 years or older. One patient had a fatal outcome of cardiac arrest, and one patient had nonsustained Torsades de Pointes. Correct electrolyte abnormalities, including hypokalemia and hypomagnesemia, prior to and throughout treatment with REVUFORJ. Perform an ECG prior to initiation of treatment with REVUFORJ, and do not initiate REVUFORJ in patients with QTcF > 450 msec. Perform an ECG at least once a week for the first 4 weeks on treatment, and at least monthly thereafter <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> . In patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, more frequent ECG monitoring may be necessary. Concomitant use of REVUFORJ with drugs known to prolong the QTc interval may increase the risk of QTc interval prolongation. <span class="opacity-50 text-xs">[see Drug Interactions (7.1) , Clinical Pharmacology (12.2) ]</span> . Interrupt REVUFORJ if QTcF increases to greater than 480 msec and less than 500 msec, and restart REVUFORJ at the same dose twice daily after the QTcF interval returns to less than or equal to 480 msec. Interrupt REVUFORJ if QTcF increases to greater than 500 msec or by > 60 msec from baseline, and restart REVUFORJ twice daily at the lower dose level after the QTcF interval returns to less than or equal to 480 msec. Permanently discontinue REVUFORJ in patients with ventricular arrhythmias and in those who develop QTc interval prolongation with signs or symptoms of life- threatening arrhythmia <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .
5.3 Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, REVUFORJ can cause fetal harm when administered to a pregnant woman. In an animal reproduction study, oral administration of revumenib to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality, malformations, and altered fetal growth at maternal exposures approximately 0.5 times the human exposure (AUC) at the recommended dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with REVUFORJ and for 4 months after the last dose <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.3 ) and Clinical Pharmacology (12.3) ]</span>.