Brand name: Revuforj
Drug class: Antineoplastic Agents

Introduction

Revumenib citrate, a menin inhibitor, is an antineoplastic agent.¹

Uses for Revumenib Citrate

Revumenib citrate has the following uses:

Revumenib citrate is indicated for the treatment of relapsed or refractory acute leukemia with a lysine methyltransferase 2A gene (KMT2A) translocation in adult and pediatric patients 1 year of age and older.¹

Revumenib Citrate Dosage and Administration

General

Revumenib citrate is available in the following dosage form(s) and strength(s):

• Tablets: 25 mg, 110 mg, and 160 mg of revumenib¹

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Dosage in Adults and Pediatric Patients ≥1 Year of Age

• Select patients for treatment with revumenib citrate based on the presence of a KMT2A translocation in bone marrow cells. ¹

• Administer revumenib orally twice daily fasted or with a low fat meal at approximately the same time each day. ¹

• The recommended dosage of revumenib varies by patient weight and concomitant use of strong CYP3A4 inhibitors as follows:

• Patients weighing 40 kg or more who are not taking a strong CYP3A4 inhibitor: 270 mg orally twice daily.¹

• Patients weighing 40 kg or more who are taking a strong CYP3A4 inhibitor: 160 mg orally twice daily.¹

• Patients weighing less than 40 kg who are not taking a strong CYP3A4 inhibitor: 160 mg/m² orally twice daily.¹

• Patients weighing less than 40 kg who are taking a strong CYP3A4 inhibitor: 95 mg/m² orally twice daily.¹

• Do not start revumenib therapy until the white blood cell count (WBC) is reduced to less than 25 Gi/L.¹ Continue revumenib until disease progression or unacceptable toxicity.¹ For patients without disease progression or unacceptable toxicity, treat for a minimum of 6 months to allow time for clinical response.¹

• See the manufacturer's prescribing information for the total tablet dosage by body surface area (BSA) for patients weighing less than 40 kg.¹

• See Full Prescribing Information for additional instructions on administration and dosage modifications for adverse reactions.¹

Cautions for Revumenib Citrate

Contraindications

• None.¹

Warnings/Precautions

Differentiation Syndrome

Revumenib can cause fatal or life-threatening differentiation syndrome (DS).¹ Symptoms of differentiation syndrome, including those seen in patients treated with revumenib, include fever, dyspnea, hypoxia, peripheral edema, pleuropericardial effusion, acute renal failure, and/or hypotension.¹

In clinical trials, DS occurred in 39 (29%) of 135 patients treated with revumenib at the recommended dosage for relapsed or refractory acute leukemia with a KMT2A translocation, including 32% of patients with acute myeloid leukemia (AML), 25% of patients with mixed-phenotype acute leukemia (MPAL), and 14% of patients with acute lymphoblastic leukemia (ALL).¹ DS was Grade 3 or 4 in 13% and fatal in one patient.¹ The median time to onset was 10 days (range 3-41 days).¹ Some patients experienced more than 1 DS event.¹ Treatment interruption was required for 7% of patients, and treatment was withdrawn for 1%.¹

Reduce the white blood cell count (WBC) to less than 25 Gi/L prior to starting revumenib.¹ If DS is suspected, immediately initiate treatment with systemic corticosteroids (e.g., dexamethasone 10 mg IV every 12 hours in adults or dexamethasone 0.25 mg/kg/dose IV every 12 hours in pediatric patients weighing less than 40 kg) for a minimum of 3 days and until resolution of signs and symptoms.¹ Institute supportive measures and hemodynamic monitoring until improvement.¹ Interrupt revumenib 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.¹ Restart steroids promptly if DS recurs after tapering corticosteroids.¹

QTC Interval Prolongation

Revumenib can cause QT (QTc) interval prolongation.¹ In the clinical trials, QTc interval prolongation was reported as an adverse reaction in 39 (29%) of 135 patients treated with revumenib at the recommended dosage for relapsed or refractory acute leukemia with a KMT2A translocation; QTc interval prolongation was Grade 3 in 12%.¹ The heart-rate corrected QT interval (using Fridericia’s method) (QTcF) was greater than 500 msec in 8%, and the increase from baseline QTcF was greater than 60 msec in 18%.¹ Revumenib dose reduction was required for 5% of patients due to QTc interval prolongation.¹ QTc prolongation occurred in 16% of the 31 patients less than 17 years of age, 33% of the 88 patients 17 years to less than 65 years of age, and in 50% of the 16 patients 65 years of age or older.¹

Correct electrolyte abnormalities, including hypokalemia and hypomagnesemia, prior to treatment with revumenib.¹ Perform an ECG prior to initiation of treatment with revumenib, and do not initiate therapy in patients with QTcF >450 msec.¹ Perform an ECG at least once a week for the first 4 weeks on treatment, and at least monthly thereafter.¹ 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.¹ Concomitant use of revumenib with drugs known to prolong the QTc interval may increase the risk of QTc interval prolongation.¹

Interrupt revumenib therapy if QTcF increases to greater than 480 msec and less than 500 msec, and restart at the same dose twice daily after the QTcF interval returns to ≤480 msec.¹ Interrupt revumenib therapy if QTcF increases to greater than 500 msec or by >60 msec from baseline, and restart revumenib twice daily at the lower dose level after the QTcF interval returns to ≤480 msec.¹ Permanently discontinue revumenib in patients with ventricular arrhythmias and in those who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.¹

Embryo-fetal Toxicity

Based on findings in animals and its mechanism of action, revumenib can cause fetal harm when administered to a pregnant woman.¹ 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.¹

Advise pregnant women of the potential risk to a fetus.¹ Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with revumenib and for 4 months after the last dose. ¹

Specific Populations

Pregnancy

Based on findings in animals and its mechanism of action, revumenib can cause fetal harm when administered to a pregnant woman.¹ There are no available data on revumenib use in pregnant women to evaluate for a drug-associated risk.¹

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.¹ Advise pregnant women of the potential risk to a fetus.¹

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.¹

Lactation

There are no data on the presence of revumenib or its metabolites in human milk or the effects on the breastfed child or milk production.¹ Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with the drug and for 1 week after the last dose.¹

Females and Males of Reproductive Potential

Based on findings in animals and its mechanism of action, revumenib can cause fetal harm when administered to pregnant women. ¹

Verify pregnancy status in females of reproductive potential within 7 days prior to initiating revumenib.¹

Advise females of reproductive potential to use effective contraception during treatment with revumenib and for 4 months after the last dose.¹

Advise males of reproductive potential to use effective contraception during treatment with revumenib and for 4 months after the last dose.¹

Based on findings in animals, revumenib may impair fertility.¹ The effects on fertility were reversible.¹

Pediatric Use

The safety and efficacy of revumenib have been established in pediatric patients 1 year of age and older with relapsed or refractory acute leukemia with a KMT2A translocation.¹ Use of revumenib for this indication is supported by evidence from adequate and well-controlled trials in adults and pediatric patients and additional pharmacokinetic and safety data in pediatric patients.¹ The patients included 13 infants (age < 2 years), 41 children (age 2 to < 12 years), and 16 adolescents (age 12 to < 17 years).¹ The recommended dosage in patients weighing less than 40 kg is BSA-based.¹

The safety and efficacy of revumenib in pediatric patients less than 1 year of age have not been established.¹

In a repeat dose toxicity study in 6-7 week-old rats treated with revumenib at 75, 150, or 300 mg/kg/day for 13 weeks, an irreversible increase in femur growth plate closure was observed at revumenib exposures approximately 2 times the human exposure (AUC) at the recommended dose.¹ Based on these animal findings, monitor bone growth and development in pediatric patients.¹

Geriatric Use

Of the 135 patients with relapsed or refractory acute leukemia with a KMT2A translocation in clinical studies of revumenib, 16 (12%) patients were 65 years of age and older and 3 (2%) patients were 75 years of age and older.¹

No overall differences were observed in the effectiveness of revumenib between patients who were 65 years of age and older and younger patients.¹ Compared to younger patients, the incidences of QTc prolongation and edema were higher in patients 65 years of age and older.¹

Common Adverse Effects

The most common adverse reactions (≥ 20%), including laboratory abnormalities, are hemorrhage, nausea, phosphate increased, musculoskeletal pain, infection, aspartate aminotransferase increased, febrile neutropenia, alanine aminotransferase increased, parathyroid hormone intact increased, bacterial infection, diarrhea, differentiation syndrome, electrocardiogram QT prolonged, phosphate decreased, triglycerides increased, potassium decreased, decreased appetite, constipation, edema, viral infection, fatigue, and alkaline phosphatase increased. ¹

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Strong CYP3A4 Inhibitors: Reduce the revumenib dose. ¹

• Strong or moderate CYP3A4 Inducers: Avoid concomitant use with revumenib. ¹

• QTc Prolonging Drugs: Avoid concomitant use with revumenib.¹ If concomitant use is unavoidable, monitor patients more frequently for QTc interval prolongation. ¹

Actions

Mechanism of Action

Revumenib is a menin inhibitor and blocks the interaction of both wild-type lysine methyltransferase 2A (KMT2A) and KMT2A fusion proteins with menin.¹ The binding of KMT2A fusion proteins with menin is involved in KMT2A-rearranged (KMT2Ar) acute leukemias through activation of a leukemogenic transcriptional pathway.¹ In nonclinical studies using cells that express KMT2A fusions, inhibition of the menin-KMT2A interaction with revumenib altered the transcription of multiple genes including differentiation markers.¹

In nonclinical in vitro and in vivo studies, revumenib demonstrated antiproliferative and antitumor activity in leukemia cells harboring KMT2A fusion proteins.¹

Advice to Patients

• Advise patients to read the FDA-approved patient labeling (Medication Guide) and Instructions for Use.¹

• Advise patients of the risks of developing differentiation syndrome as early as 1 day after the start of therapy and during treatment.¹ Advise patients to immediately report any symptoms suggestive of differentiation syndrome, such as fever, cough or difficulty breathing, rash, low blood pressure, rapid weight gain, swelling of their arms or legs, or decreased urinary output, to their healthcare provider for further evaluation.¹

• Advise patients to consult their healthcare provider immediately if they feel faint, lose consciousness, or have signs or symptoms suggestive of arrhythmia.¹ Advise patients with a history of hypokalemia or hypomagnesemia of the importance of monitoring their electrolytes.¹

• Advise pregnant women and females of reproductive potential of the potential risk to a fetus.¹ Advise females of reproductive potential to notify their healthcare provider of a known or suspected pregnancy. ¹

• Advise females of reproductive potential to use effective contraception during treatment with revumenib and for 4 months after the last dose.¹ Advise males with female partners of reproductive potential to use effective contraception during treatment with revumenib and for 4 months after the last dose. ¹

• Advise women not to breastfeed during treatment with revumenib and for 1 week after the last dose.¹

• Advise females and males of reproductive potential of the potential for impaired fertility from revumenib.¹

• Advise patients to inform their healthcare providers of all concomitant products, including over-the counter (OTC) products and supplements.¹

• Advise patients to swallow tablets whole with a cup of water, and to not cut or chew tablets.¹ If patients are unable to swallow the tablets, they may be crushed and dispersed in water.¹ Instruct patients that, if they miss a dose of revumenib, to take it as soon as possible on the same day, and at least 12 hours prior to the next scheduled dose, and return to the normal schedule the following day.¹

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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