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Revumenib

FDA Drug Information • Also known as: Revuforj

Brand Names
Revuforj
Route
ORAL
Dosage Form
TABLET, FILM COATED
Product Type
HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING: DIFFERENTIATION SYNDROME, QTc PROLONGATION and TORSADES DE POINTES Differentiation syndrome, which can be fatal, has occurred with REVUFORJ. Signs and symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and renal dysfunction. If differentiation syndrome is suspected, immediately initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution. [see Dosage and Administration (2.3 ) , Warnings and Precautions (5.1) , and Adverse Reactions (6.1) ] . QTc prolongation and Torsades de Pointes have occurred in patients receiving REVUFORJ. Correct hypokalemia and hypomagnesemia prior to and during treatment. Do not initiate REVUFORJ in patients with QTcF > 450 msec. If QTc interval prolongation occurs, interrupt, reduce, or permanently discontinue REVUFORJ. [see Dosage and Administration (2.3) , Warnings and Precautions (5.2) , and Adverse Reactions (6.1) ] WARNING: DIFFERENTIATION SYNDROME, and QTc PROLONGATION and TORSADES DE POINTES See full prescribing information for complete boxed warning. Differentiation syndrome, which can be fatal, has occurred with REVUFORJ. If differentiation syndrome is suspected, immediately initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution ( 2.3 , 5.1 ) QTc prolongation and Torsades de Pointes have occurred in patients receiving REVUFORJ. Correct hypokalemia and hypomagnesemia prior to and during treatment. Do not initiate REVUFORJ in patients with QTcF > 450 msec. If QTc interval prolongation occurs, interrupt, reduce, or permanently discontinue REVUFORJ. ( 2.3 , 5.2 ).

Description

11 DESCRIPTION REVUFORJ contains revumenib, a menin inhibitor. Revumenib is present as revumenib citrate hydrate with a chemical name of benzamide, N -ethyl-2-[[4-[7-[[trans-4- [(ethylsulfonyl)amino]cyclohexyl]methyl]-2,7-diazaspiro[3.5]non-2-yl]-5-pyrimidinyl]oxy]-5-fluoro- N -[1- methylethyl]-, 2-hydroxypropane-1,2,3-tricarboxylic acid, hydrate (1:1:1). The molecular formula is C32H47FN6O4S●C6H8O7●H2O with a molecular weight 840.96 g/mol. Revumenib citrate hydrate is a white to faint pink solid. Revumenib citrate hydrate is soluble at pH 1.2 and 6.8, and sparingly soluble at pH 4.5. The chemical structure is shown in Figure 1. Figure 1: Chemical structure of Revumenib Citrate REVUFORJ is available as tablets for oral use. Each 25 mg strength tablet contains 25 mg revumenib, equivalent to 33.4 mg revumenib citrate, and the following inactive ingredients: microcrystalline cellulose, dicalcium phosphate, crospovidone, hypromellose, sodium bicarbonate, hydrophobic colloidal silica, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and red iron oxide. Each 110 mg strength tablet contains 110 mg revumenib, equivalent to 146.5 mg revumenib citrate, and the following inactive ingredients: microcrystalline cellulose, dicalcium phosphate, crospovidone, hypromellose, sodium bicarbonate, hydrophobic colloidal silica, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, red iron oxide, and yellow iron oxide. Each 160 mg strength tablet contains 160 mg revumenib equivalent to 213.2 mg revumenib citrate, and the following inactive ingredients: microcrystalline cellulose, dicalcium phosphate, crospovidone, hypromellose, sodium bicarbonate, hydrophobic colloidal silica, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, red iron oxide, and FD&C blue #2/indigo carmine aluminum lake. Chemical Structure of Revumenib Citrate

What Is Revumenib Used For?

1 INDICATIONS AND USAGE REVUFORJ is a menin inhibitor indicated for: the treatment of relapsed or refractory acute leukemia with a lysine methyltransferase 2A gene ( KMT2A ) translocation as determined by an FDA-authorized test in adult and pediatric patients 1 year and older. ( 1 ) the treatment of relapsed or refractory acute myeloid leukemia (AML) with a susceptible nucleophosmin 1 ( NPM1 ) mutation in adult and pediatric patients 1 year and older who have no satisfactory alternative treatment options. ( 1 ) Relapsed or Refractory Acute Leukemia REVUFORJ is indicated for the treatment of relapsed or refractory acute leukemia with a lysine methyltransferase 2A gene ( KMT2A ) translocation as determined by an FDA-authorized test in adult and pediatric patients 1 year and older. REVUFORJ is indicated for the treatment of relapsed or refractory acute myeloid leukemia with a susceptible nucleophosmin 1 ( NPM1 ) mutation [see Dosage and Administration (2.1) , Clinical Pharmacology (12.1) , and Clinical Studies (14.1) ] in adult and pediatric patients 1 year and older who have no satisfactory alternative treatment options.

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Select patients for treatment with REVUFORJ based on the presence of a KMT2A translocation or an NPM1 mutation. ( 2.1 ) Administer REVUFORJ orally twice daily fasted or with a low-fat meal at approximately the same time each day. ( 2.2 ) See Full Prescribing Information for recommended REVUFORJ dosage regimen, dosage modifications, and administration instructions. ( 2.2 , 2.3 ) 2.1 Patient Selection Relapsed or Refractory Acute Leukemia with a KMT2A Translocation Select patients for treatment with REVUFORJ based on the presence of a KMT2A translocation [see Clinical Studies (14.1) ] . Information on FDA authorized tests for the detection of a KMT2A translocation to determine eligibility for treatment is available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/denovo.cfm?id=DEN240067 Relapsed or Refractory Acute Myeloid Leukemia with an NPM1 mutation Select patients for treatment with REVUFORJ based on the presence of an NPM1 mutation [see Clinical Pharmacology (12.1 ) and Clinical Studies (14.2) ] . An FDA-approved companion diagnostic for the detection of an NPM1 mutation is not currently available. 2.2 Recommended Dosage The recommended dosage of REVUFORJ varies by patient weight and concomitant use of strong CYP3A4 inhibitors. See Table 1 for the recommended dosage for patients 1 year and older. Do not start REVUFORJ until the WBC is reduced to less than 25 Gi/L. Continue REVUFORJ until disease progression or unacceptable toxicity. For patients without disease progression or unacceptable toxicity, treat for a minimum of 6 months to allow time for clinical response. Table 1. REVUFORJ Recommended Dosage for Patients 1 Year and Older *See Table 2 for the total tablet dosage by BSA (body surface area) for patients weighing less than 40 kg. Patient Weight Without Strong CYP3A4 Inhibitors With Strong CYP3A4 Inhibitors 40 kg or more 270 mg orally twice daily 160 mg orally twice daily Less than 40 kg 160 mg/m 2 orally twice daily* 95 mg/m 2 orally twice daily* Table 2: Recommended Dosage using Tablets* for Patients Weighing Less than 40 kg * If needed, attain the desired dose by combining different strengths of REVUFORJ tablets. BSA (m 2 ) REVUFORJ Dosage for 160 mg/m 2 REVUFORJ Dosage for 95 mg/m 2 1.4 220 mg twice daily 135 mg twice daily 1.3 220 mg twice daily 135 mg twice daily 1.2 185 mg twice daily 110 mg twice daily 1.1 185 mg twice daily 110 mg twice daily 1 160 mg twice daily 100 mg twice daily 0.9 135 mg twice daily 75 mg twice daily 0.8 135 mg twice daily 75 mg twice daily 0.7 110 mg twice daily 50 mg twice daily 0.6 100 mg twice daily 50 mg twice daily 0.5 75 mg twice daily 50 mg twice daily 0.4 50 mg twice daily 25 mg twice daily If the strong CYP3A4 inhibitor is discontinued, increase the REVUFORJ dose after at least 5 half-lives of the strong CYP3A4 inhibitor to the recommended dosage without strong CYP3A4 inhibitors (Table 1). Concurrent use of standard intrathecal chemotherapy prophylaxis is...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Differentiation Syndrome [see Warnings and Precautions (5.1) ] QTc Interval Prolongation and Torsades de Pointes [see Warnings and Precautions (5.2) ] The most common adverse reactions (≥ 20%) including laboratory abnormalities, are phosphate increased, hemorrhage, nausea, infection without identified pathogen, aspartate aminotransferase increased, alanine aminotransferase increased, creatinine increased, musculoskeletal pain, febrile neutropenia, electrocardiogram QT prolonged, potassium decreased, parathyroid hormone intact increased, alkaline phosphatase increased, diarrhea, bacterial infection, triglycerides increased, differentiation syndrome, fatigue, edema, viral infection, phosphate decreased, decreased appetite, and constipation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Syndax Pharmaceuticals, Inc., at 1-888-539-3REV or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of REVUFORJ reflects exposure in 241 patients (207 adult and 34 pediatric patients) with relapsed or refractory (R/R) acute leukemia with a KMT2A translocation or an NPM1 mutation treated with REVUFORJ at a dose approximately equivalent to 160 mg in adults orally twice daily with a strong CYP3A4 inhibitor [see Clinical Studies (14) ] . The median duration of exposure to REVUFORJ was 2.5 months (range < 1 to 40 months), and 10% of patients were exposed for more than 6 months. Fatal adverse reactions occurred in 9 (4%) patients who received REVUFORJ, including 4 with sudden death, 2 with differentiation syndrome, 2 with hemorrhage, and 1 with cardiac arrest. Serious adverse reactions were reported in 184 (76%) patients. The most frequent serious adverse reactions (≥ 10%) were infection (29%), febrile neutropenia (20%), bacterial infection (15%), differentiation syndrome (13%), and hemorrhage (11%). Adverse reactions leading to dose interruption occurred in 49% of patients. The most common adverse reactions (≥ 5%) leading to dose interruption were electrocardiogram QT prolonged, infection, febrile neutropenia, differentiation syndrome, nausea, and hypokalemia. Adverse reactions leading to dose reduction occurred in 12% of patients who received REVUFORJ. Adverse reactions leading to a dose reduction (≥ 5%) included electrocardiogram QT prolonged. Adverse reactions leading to permanent discontinuation occurred in 20% of patients. Adverse reactions resulting in permanent discontinuation (> 1%) included infection. The most common (≥ 20%) adverse reactions were phosphate increased, hemorrhage, nausea, infection without identified pathogen, aspartate aminotransferase increased, alanine aminotransferase increased, creatinine increased, musculoskeletal pain, febrile neutropenia, electrocardiogram QT prolonged, potassium decreased, parathyroid hormone intact increased, alkaline phosphatase increased, diarrhea, bacterial infection, triglycerides increased, differentiation syndrome, fatigue, edema, viral infection, phosphate decreased, decreased appetite, and constipation. The common adverse reactions are summarised in Table 7. Table 7. Adverse Reactions Reported in ≥ 20% (Any Grade) or ≥ 5% (Grade 3 or 4) in Patients with R/R Acute Leukemia # Includes the following fatal adverse reactions: DS (n=2); hemorrhage (n=2) a – Includes nausea and vomiting b – includes diarrhea, colitis, and neutropenic colitis c – includes epistaxis, contusion, petechiae, gingival bleeding, hematoma, hemoptysis, hemorrhoidal hemorrhage, mouth hemorrhage, hematuria, ecchymosis, hemorrhage intracranial, subdural hematoma, upper gastrointestinal hemorrhage,...

Drug Interactions

7 DRUG 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 [see Recommended Dosage (2.2) ] . Revumenib is primarily metabolized by CYP3A4 [see Clinical Pharmacology (12.3) ] . Concomitant use with a strong CYP3A4 inhibitor increases revumenib systemic exposure [see Clinical Pharmacology(12.3) ] , 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 [see Clinical Pharmacology (12.3) ] . Concomitant use with a strong or moderate CYP3A4 inducer may decrease revumenib and increase M1 systemic exposure [see Clinical Pharmacology (12.3) ] , 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 [see Warnings and Precautions (5.2) ] . 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 [see Dosage and Administration (2.3) ] . REVUFORJ causes QTc interval prolongation [see Clinical Pharmacology (12.2) ] . 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 [see Warnings and Precautions(5.2) ].

Contraindications

4 CONTRAINDICATIONS None. None. ( 4 )

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary Based on findings in animals and its mechanism of action [see Clinical Pharmacology (12.1) ], REVUFORJ can cause fetal harm when administered to a pregnant woman. There are no available data on REVUFORJ use in pregnant women to evaluate for a drug-associated risk. 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 (see Data). Advise pregnant women of the potential risk to a fetus. 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. Data Animal Data In an embryo-fetal development study, revumenib was administered once daily via oral gavage at doses of 30, 100, and 300 mg/kg/day to pregnant rats during the period of organogenesis (gestation days 6-17). Decreased maternal body weight gain and adverse embryo-fetal findings including decreases in the number of live fetuses, increases in resorptions and post-implantation loss, and decreases in fetal body weight were observed at all doses. At 300 mg/kg/day, total litter resorption and eye malformations were observed. At the dose of 30 mg/kg/day in rats, the maternal exposures (AUC) were approximately 0.5 times the human exposure at the recommended dose.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING 25 mg: Pink modified oval film-coated tablet debossed with “S” on one side and “25” on the other side. 30-count bottles with a desiccant and child resistant closure (NDC 73555-500-00) 110 mg: Beige modified oval film-coated tablet debossed with “S” on one side and “110” on the other side. 30-count bottles with a desiccant and child resistant closure (NDC 73555-501-00) 160 mg: Purple modified oval film-coated tablet debossed with “S” on one side and “160” on the other side. 30-count bottles with a desiccant and child resistant closure (NDC 73555-502-00) Store tablets at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store and dispense in the orginal container.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.