Brand name: Revuforj
Drug class: Antineoplastic Agents

Introduction

Antineoplastic agent; menin inhibitor.

Uses for Revumenib

Acute Leukemia with KMT2A Translocation

Treatment of relapsed or refractory acute leukemia with a lysine methyltransferase 2A (KMT2A) translocation in adults and pediatric patients ≥1 year of age.

Designated an orphan drug by FDA for treatment of acute myeloid leukemia (AML), acute leukemias of ambiguous lineage, and acute lymphocytic leukemia (ALL).

There is currently no established standard of care for treatment of relapsed or refractory acute leukemia with KMT2A translocation; salvage chemotherapy, investigational agents, and transplant have been used.

Revumenib Dosage and Administration

General

Pretreatment Screening

• Confirm presence of KMT2A translocation in bone marrow cells prior to treatment. The FDA has not approved a companion diagnostic for detecting KMT2A translocations.

• Ensure that patient's WBC count is <25 X 10⁹ cells/L prior to initiation of therapy.

• Perform an ECG prior to initiation of therapy; do not initiate therapy in patients with QT_cF >450 msec.

• Correct electrolyte abnormalities including hypokalemia and hypomagnesemia.

• Assess blood counts, electrolytes, and liver enzymes.

• Verify pregnancy status in female patients of reproductive potential within 7 days prior to initiation of therapy.

Patient Monitoring

• Perform an ECG at least once weekly for the first 4 weeks of treatment and at least monthly thereafter; more frequent monitoring may be necessary in patients with congenital long QT_csyndrome, heart failure, electrolyte abnormalities, or those taking medications known to prolong the QT_c interval.

• Correct hypokalemia and hypomagnesemia that occur during therapy.

• Assess blood counts, electrolytes, and liver enzymes monthly during therapy.

• Monitor QT_c prolongation and manage appropriately.

Administration

Oral Administration

Administer orally around the same time each day without food or with a low-fat meal (e.g., approximately 400 calories with <25% from fat).

Swallow tablets whole. Tablets may be crushed, mixed with water, and taken within 2 hours.

Dosage

Dosage is based on patient weight and concomitant use of a strong CYP3A4 inhibitor.

If a strong CYP3A4 inhibitor is discontinued, wait at least 5 half-lives of the CYP3A4 inhibitor before increasing the revumenib dosage to the standard recommended dosage for patients not receiving a strong CYP3A4 inhibitor.

If a dose is missed, administer the missed dose as soon as possible the same day, at least 12 hours before next dose. Resume regular schedule the next day. Do not take 2 doses within 12 hours.

Commercially available as the citrate salt; dosage expressed in terms of revumenib.

Pediatric Patients

Relapsed or Refractory Acute Leukemia with KMT2A Translocation

Oral

Pediatric patients ≥1 year of age and <40 kg who are not taking a strong CYP3A4 inhibitor: 160 mg/m² twice daily. See manufacturer's Prescribing Information for recommended total tablet dosage by BSA for patients weighing <40 kg.

Pediatric patients ≥1 year of age and <40 kg who are taking a strong CYP3A4 inhibitor: 95 mg/m² twice daily. See manufacturer's Prescribing Information for recommended total tablet dosage by BSA for patients weighing <40 kg.

Pediatric patients ≥1 year of age and ≥40 kg who are nottaking a strong CYP3A4 inhibitor: 270 mg twice daily.

Pediatric patients ≥1 year of age and ≥40 kg who are taking a strong CYP3A4 inhibitor: 160 mg twice daily.

Continue revumenib until disease progression or unacceptable toxicity. If neither occurs, treat for at least 6 months to allow for a clinical response.

Adults

Relapsed or Refractory Acute Leukemia with KMT2A Translocation

Oral

Patients <40 kg who are not taking a strong CYP3A4 inhibitor: 160 mg/m² twice daily. See manufacturer's Prescribing Information for recommended total tablet dosage by BSA for patients weighing <40 kg.

Patients <40 kg who are taking a strong CYP3A4 inhibitor: 95 mg/m² twice daily. See manufacturer's Prescribing Information for recommended total tablet dosage by BSA for patients weighing <40 kg.

Patients ≥40 kg who are nottaking a strong CYP3A4 inhibitor: 270 mg twice daily.

Patients ≥40 kg who are taking a strong CYP3A4 inhibitor: 160 mg twice daily.

Continue revumenib until disease progression or unacceptable toxicity. If neither occurs, treat for at least 6 months to allow for a clinical response.

Dosage Modification for Toxicity

If an adverse reaction occurs, treatment interruption, dosage reduction, and/or discontinuation of therapy may be necessary based on severity.

The manufacturer's recommended dosage reduction schedule and dosing modifications for adverse reactions are provided in Table 1 and the recommended dosages in Tables 2 and 3.

Special Populations

Hepatic Impairment

No specific dosage recommendations.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Cautions for Revumenib

Contraindications

• None.

Warnings/Precautions

Warnings

Differentiation Syndrome

Risk of fatal or life-threatening differentiation syndrome (see Boxed Warning). Signs and symptoms include fever, dyspnea, hypoxia, pulmonary infiltrates, rapid weight gain or peripheral edema, pleuropericardial effusion, acute renal failure, and hypotension.

Reduce WBC to <25 x 10⁹ cells/L before treatment.

If differentiation syndrome suspected, immediately start systemic corticosteroids for at least 3 days until symptoms resolve. Provide supportive care and hemodynamic monitoring.

Interrupt revumenib if severe symptoms persist >48 hours despite therapy with corticosteroids or earlier if life-threatening symptoms occur (e.g., need for ventilatory support). Restart corticosteroids if differentiation syndrome recurs after tapering.

Other Warnings and Precautions

QTc Interval Prolongation

QT_c interval prolongation reported; higher incidence in patients ≥65 years of age compared to younger patients.

Monitor patients for QT_c prolongation and correct electrolyte abnormalities, including hypokalemia and hypomagnesemia, before starting revumenib.

Do not start treatment if QT_cF >450 msec.

Interrupt revumenib if QT_cF increases to >480-500 msec, and resume at same dosage once QT_cF returns to ≤480 msec.

If QT_cF >500 msec or increases by >60 msec from baseline, interrupt and restart at a lower dosage once QT_cF returns to ≤480 msec.

Permanently discontinue in patients with ventricular arrhythmias or QT_c prolongation with life-threatening arrhythmic symptoms.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm if administered during pregnancy.

Advise pregnant women of the potential fetal risk and counsel on the use of effective contraception for both partners during treatment and for 4 months after the last dose.

Specific Populations

Pregnancy

May cause fetal harm based on mechanism of action and findings from animal studies.

Lactation

No data available on whether revumenib is present in human milk; due to the potential for serious adverse reactions, breastfeeding is not recommended during therapy and for 1 week after the last dose.

Females and Males of Reproductive Potential

May impair fertility based on mechanism of action and findings from animal studies. Verify pregnancy status in females of reproductive potential within 7 days of beginning therapy.

Advise both partners to use effective contraception during treatment and for 4 months after the last dose.

Pediatric Use

Safety and efficacy established in pediatric patients ≥1 year of age with relapsed or refractory acute leukemia with a KMT2A translocation.

Geriatric Use

Efficacy was similar across age groups, but QT_c prolongation and edema were more frequent in those ≥65 years.

Hepatic Impairment

No significant pharmacokinetic differences in mild to moderate hepatic impairment; effects in severe hepatic impairment are unknown.

Renal Impairment

No significant pharmacokinetic differences in mild to moderate renal impairment; effects in severe renal impairment or end-stage renal disease are unknown.

Common Adverse Effects

Most common adverse reactions (≥20%): hemorrhage, nausea, phosphate increased, musculoskeletal pain, infection, AST increased, febrile neutropenia, ALT increased, parathyroid hormone intact increased, bacterial infection, diarrhea, differentiation syndrome, QT_c prolongation, phosphate decreased, triglycerides increased, potassium decreased, appetite decreased, constipation, edema, viral infection, fatigue, alkaline phosphatase increased.

Drug Interactions

Primarily metabolized by CYP3A4.

Inhibits CYP3A4, but does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP2E1. Does not induce CYP1A2, CYP2B6, and CYP3A4.

Substrate of organic cation transporter 1 (OCT1), OCT2, and OAT3, and multidrug and toxin extrusion protein 1 (MATE1), but not a substrate of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, MATE2-K, or bile salt export pump (BSEP).

M1, a metabolite of revumenib, is a substrate of OATP1B1 but not of P-gp, BCRP, OCT2, OAT1, OAT3, OATP1B3, MATE1, or MATE2-K.

Revumenib inhibits MATE1 but does not inhibit P-gp, BCRP, OCT1, OCT2, OAT1, OAT3, OATP1B1, OATP1B3, BSEP, or MATE2-K. M1 inhibits MATE1 but does not inhibit OAT1, OAT3, OCT2, OATP1B1, OATP1B3, or MATE2-K.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

If concomitant use of a strong CYP3A4 inhibitor is required, reduce revumenib dosage. Concomitant administration of multiple doses of a strong CYP3A4 inhibitor (i.e., cobicistat, itraconazole, posaconazole, voriconazole) has been shown to increase revumenib exposure by 2-2.5 fold. No clinically significant differences when administered with moderate CYP3A4 inhibitors (i.e., fluconazole, isavuconazole).

Avoid use with strong or moderate CYP3A4 inducers; possible decreased revumenib exposure and efficacy, and increased metabolite exposure which can increase risk of QT prolongation.

Drugs Associated with QT Prolongation

Coadministration with QT_c-prolonging drugs may further increase QT_c and the risk of related adverse effects.

Revumenib Pharmacokinetics

Absorption

Plasma Concentration

Exhibits dose-proportional pharmacokinetics.

Median time to peak plasma concentration when administered with strong CYP3A4 inhibitor: 2 hours (range: 0-6 hours)

Median time to peak plasma concentration when administered without strong CYP3A4 inhibitor: 1 hour (range: 0.5-4 hours)

When administered with strong CYP3A4 inhibitor, maximum exposure at steady state decreased by 45% and AUC decreased by 19%.

Steady-state concentrations reached within 2-3 days.

Food

Administration with a low fat meal did not significantly affect revumenib exposure.

Special Populations

Higher exposure in patients <40 kg, supporting BSA-based dosing.

No clinically significant differences in pharmacokinetics based on age (1-82 years of age), race (71% white, 8% Asian, 8% Black), or sex.

Distribution

Extent

Blood to plasma ratio: 0.8.

Protein Binding

90%.

Elimination

Metabolism

Primarily metabolized by CYP3A4, producing an active metabolite, M1.

Elimination Route

Feces: approximately 49%, with 7% as unchanged drug.

Urine: approximately 27%, with 7% as unchanged drug.

Half-life

Half life, when administered with strong CYP3A4 inhibitor: 7.5 hours.

Half life, when administered without strong CYP3A4 inhibitor: 3.6 hours.

Stability

Storage

Oral

Tablets

Store at 20-25°C; excursions between 15-30°C are permitted.

Actions

• Menin inhibitor.

• Blocks wild-type KMT2A and KMT2A fusion proteins from interacting with menin.

• Disrupts menin-KMT2A binding, altering gene transcription.

Advice to Patients

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

• Advise patients of the risks of developing differentiation syndrome as early as 1 day after the start of therapy and during treatment. 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 arms or legs, or decreased urinary output, to their healthcare provider for further evaluation.

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

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

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

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

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

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

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

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.

Revumenib is available through the designated specialty pharmacy, SyndAccess. Consult the SyndAccess website ([Web]) or the revumenib website ([Web]) for more information.

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