Revuforj

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.

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 recommended for patients with risk of central nervous system relapse. Administration: Correct hypokalemia, hypomagnesemia, and other electrolyte abnormalities prior to treatment. Administer REVUFORJ twice daily fasted or with a low-fat meal (e.g., meals with approximately 400 calories, 25% or less fat). Administer REVUFORJ orally around the same time each day. Advise patients to swallow tablets whole and to not cut or chew tablets. If patients are unable to swallow tablets, they may be crushed and dispersed in water and taken within 2 hours of preparation [see Instructions for Use ] . If a dose of REVUFORJ is missed or not taken at the usual time, administer the dose as soon as possible on the same day and at least 12 hours prior to the next scheduled dose. Return to the normal schedule the following day. Do not administer 2 doses within 12 hours. 2.3 Dosage Modifications for Adverse Reactions Assess blood counts, electrolytes, and liver enzymes prior to the initiation of REVUFORJ and monthly thereafter. Perform an electrocardiogram (ECG) prior to the initiation of REVUFORJ, at least once a week for the first 4 weeks, and at least monthly thereafter. Monitor for QTc interval prolongation and manage any abnormalities promptly [see Warnings and Precautions (5.2) and Adverse Reactions (6.1) ] . Interrupt dosing or reduce dose for adverse reactions as per Table 3. Dose levels for dose reductions are listed in Table 4, Table 5, and Table 6. Table 3. Recommended Management and Dosage Modifications for Adverse Reactions *Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening. Severity as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 5.0). **See Tables 4, 5 and 6 for the reduced dose levels. Adverse reaction Recommended action Differentiation Syndrome [see Warnings and Precautions (5.1) ] If differentiation syndrome is suspected, administer systemic corticosteroids and initiate hemodynamic monitoring until symptom resolution and for a minimum of 3 days. [see Warnings and Precautions (5.1) ] . Interrupt REVUFORJ if severe signs and/or symptoms persist for more than 48 hours after initiation of systemic corticosteroids, or earlier for life-threatening symptoms such as pulmonary symptoms requiring ventilator support [see Warnings and Precautions (5.1) ] . Resume REVUFORJ at the same dose when signs and symptoms improve to Grade 1* or lower. Noninfectious leukocytosis Initiate treatment with hydroxyurea in patients with an elevated or rapidly rising leukocyte count. Add leukapheresis if clinically indicated. Taper hydroxyurea only after leukocytosis improves or resolves. QTc interval greater than 480 msec to 500 msec [see Warnings and Precautions(5.2) ] Interrupt REVUFORJ. Check electrolyte levels. Correct hypokalemia and hypomagnesemia [see Warnings and Precautions (5.2) ] . Restart REVUFORJ at the same dose level after the QTc interval returns to less than or equal to 480 msec. QTc interval greater than 500 msec (Grade 3*) [see Warnings and Precautions (5.2) ] Interrupt REVUFORJ. Check electrolyte levels. Correct hypokalemia and hypomagnesemia [see Warnings and Precautions (5.2) ] . Restart REVUFORJ at the reduced dose level** after the QTc interval returns to less than or equal to 480 msec. QTc interval prolongation with signs/symptoms of life-threatening arrhythmia, Torsades de pointes, polymorphic ventricular tachycardia, signs/ symptoms of life-threatening arrhythmia (Grade 4*) [see Warnings and Precautions (5.2) ] . Permanently discontinue REVUFORJ. Potassium 3.6-3.9 mEq/L, and/or Magnesium 1.7-1.9 mg/dL or 0.66-0.81 mmol/L Supplement potassium and/or magnesium. Continue REVUFORJ. Potassium ≤ 3.5 mEq/L, and/or Magnesium ≤ 1.6 mg/dL or ≤ 0.65 mmol/L Supplement potassium and/or magnesium, and recheck levels within 24 hours. On recheck of potassium and magnesium labs within 24 hours, if potassium is greater than 3.5 mEq/L and/or magnesium is greater than 1.6 mg/dL, continue REVUFORJ. If potassium is less than 3.5 mEq/L and/or magnesium is less than 1.6 mg/dL, hold REVUFORJ and continue supplementation; resume REVUFORJ at the same dose level when the correction is complete. Other nonhematological adverse reactions Grade ≥ 3* [see Adverse Reactions (6.1) ] Interrupt REVUFORJ until recovery to Grade 1* or baseline. If recovered in ≤ 7 days, restart REVUFORJ at the same dose level. If the same Grade ≥ 3* toxicity recurs, interrupt REVUFORJ until recovery to Grade 1* or baseline. Restart REVUFORJ at the reduced dose level.** If recovered in > 7 days, restart REVUFORJ at the reduced dose level.** If the same Grade ≥ 3* toxicity recurs, discontinue REVUFORJ. Grade 4* neutropenia or thrombocytopenia [see Adverse Reactions (6.1) ] Interrupt REVUFORJ until recovery to Grade ≤ 2* or baseline. Restart REVUFORJ at the same dose level. If Grade 4* neutropenia or thrombocytopenia recurs without attributable cause, interrupt REVUFORJ until recovery to Grade ≤ 3*. Restart REVUFORJ at the reduced dose level.** Grade 3* or higher allergic reactions [see Adverse Reactions (6.1) ] Permanently discontinue REVUFORJ. Table 4. REVUFORJ Dosage Reduction for Adverse Reactions in Patients NOT on Strong CYP3A4 Inhibitors **See Table 6 for BSA-based dosage recommendations for the reduced dosage of 95 mg/m 2 twice daily. Patients Weighing 40 kg or Greater at Starting Dose 270 mg orally twice daily Patients Weighing Less Than 40 kg at Starting Dose 160 mg/m 2 orally twice daily Reduced Dose 160 mg orally twice daily 95 mg/m 2 orally twice daily* Table 5. REVUFORJ Dosage Reduction for Adverse Reactions in Patients on Strong CYP3A4 Inhibitors *See Table 6 for BSA-based dosage recommendations for the reduced dosage of 65 mg/m 2 twice daily. Patients Weighing 40 kg or Greater at Starting Dose 160 mg orally twice daily Patients Weighing Less Than 40 kg at Starting Dose 95 mg/m 2 orally twice daily Reduced Dose 110 mg orally twice daily 65 mg/m 2 orally twice daily* Table 6: Recommended Reduced 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 95 mg/m 2 REVUFORJ Dosage for 65 mg/m 2 1.4 135 mg twice daily 100 mg twice daily 1.3 135 mg twice daily 75 mg twice daily 1.2 110 mg twice daily 75 mg twice daily 1.1 110 mg twice daily 75 mg twice daily 1 100 mg twice daily 50 mg twice daily 0.9 75 mg twice daily 50 mg twice daily 0.8 75 mg twice daily 50 mg twice daily 0.7 50 mg twice daily 50 mg twice daily 0.6 50 mg twice daily 25 mg twice daily 0.5 50 mg twice daily 25 mg twice daily 0.4 25 mg twice daily 25 mg twice daily

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS 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 [see Adverse Reactions (6.1) ] . 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 [see Dosage and Administration (2.3) ]. 5.2 QTc Interval Prolongation and Torsades de Pointes REVUFORJ can cause QT (QTc) interval prolongation and Torsades de Pointes [see Clinical Pharmacology (12.2) ] . 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 [see Adverse Reactions (6.1)] . 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 [see Dosage and Administration (2.3) ] . 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. [see Drug Interactions (7.1) , Clinical Pharmacology (12.2) ] . 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 [see Dosage and Administration (2.3) ] . 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 [see Use in Specific Populations ( 8.1 , 8.3 ) and Clinical Pharmacology (12.3) ].

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) ].

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, gastrointestinal hemorrhage, vaginal hemorrhage, post- procedural hemorrhage, rectal hemorrhage, subarachnoid hemorrhage, vitreous hemorrhage, catheter site hemorrhage, conjunctival hemorrhage, hematochezia, melaena, retinal hemorrhage, anal hemorrhage, brain stem hemorrhage, cystitis hemorrhagic, eye hematoma, genital contusion, injection site hematoma, lower gastrointestinal hemorrhage, mucosal hemorrhage, oral blood blister, oral contusion, oral purpura, pulmonary hemorrhage, shock hemorrhagic, spinal subdural hematoma d – includes disseminated intravascular coagulation, pulmonary embolism, cerebrovascular accident, superficial vein thrombosis, deep vein thrombosis, acute myocardial infarction, cerebral infarction, embolism, hemorrhoids thrombosed, medical device site thrombosis, myocardial infarction, renal infarction, splenic infarction, thrombosis, and transient ischaemic attack e – includes pneumonia, sepsis, urinary tract infection, septic shock, sinusitis, skin infection, upper respiratory tract infection, osteomyelitis, device related infection, enterocolitis infectious, conjunctivitis, hordeolum, rhinitis, acute sinusitis, diverticulitis, endocarditis, perirectal abscess, rectal abscess, tooth abscess, abscess limb, appendicitis, bronchitis, epididymitis, eye infection, gastroenteritis, infection, mucosal infection, neutropenic sepsis, rash pustular, retinitis, shock, sialadenitis, soft tissue infection, tooth infection, vascular device infection f – includes bacteraemia, clostridium difficile infection, cellulitis, escherichia bacteremia, paronychia, staphylococcal bacteremia, streptococcal bacteremia, alpha hemolytic streptococcal infection, clostridium difficile colitis, clostridium test positive, enterobacter infection, enterobacter sepsis, enterococcal bacteremia, escherichia urinary tract infection, pseudomonal bacteremia, pseudomonas infection, skin bacterial infection, bacteriuria, cellulitis staphylococcal, cornyebacterium bacteremia, enterobacter bacteremia, enterococcal infection, folliculitis, klebsiella infection, klebsiella sepsis, lactobacillus bacteremia, meningitis bacterial, stenotrophomonas infection g – includes COVID-19, rhinovirus infection, herpes simplex reactivation, herpes simplex, herpes zoster, oral herpes, respiratory syncytial virus infection, enterovirus infection, adenovirus infection, coronavirus infection, cytomegalovirus infection, cytomegalovirus infection reactivation, cytomegalovirus viremia, COVID-19 pneumonia, cytomegalovirus test positive, enterovirus test positive, Epstein-Barr virus infection, herpes simplex pharyngitis, herpes virus infection, influenza, norovirus infection, parainfluenzae virus infection, pneumonia cytomegaloviral viremia h – includes arthralgia, back pain, pain in extremity, neck pain, myalgia, musculoskeletal chest pain, myositis, flank pain, musculoskeletal discomfort, and musculoskeletal pain i – includes fatigue, asthenia, malaise j – includes edema peripheral, generalised edema, edema, localized edema, peripheral swelling REVUFORJ N = 241 TEAE All Grades % Grade 3 or 4 % Gastrointestinal disorders Nausea a 48 5 Diarrhea b 29 5 Constipation 20 0 Vascular disorders Hemorrhage #,c 48 10 Thrombosis d 11 6 Infections and infestations Infection without identified pathogen e 46 30 Bacterial infection f 27 18 Viral Infection g 23 6 Blood and lymphatic system disorders Febrile neutropenia 37 35 Musculoskeletal and connective tissue disorders Musculoskeletal pain h 37 6 Investigations Electrocardiogram QT prolonged 36 17 Neoplasms benign, malignant and unspecified (including cysts and polyps) Differentiation syndrome# 25 12 General disorders and administration site conditions Fatigue i 24 5 Edema j 24 0 Metabolism and nutrition disorders Decreased appetite 20 5 Clinically relevant adverse reactions in less than 20% of patients who received REVUFORJ include: Cardiac disorders: Premature ventricular complex, cardiac failure, pericardial effusion, ventricular tachycardia, cardiac arrest Endocrine disorders : Hyperparathyroidism Eye disorders : Cataract Gastrointestinal disorders : Abdominal pain General disorders and administration site conditions : Sudden death Immune system disorders : Drug hypersensitivity Metabolism and nutrition disorders : Hyponatremia, hyperkalemia Nervous system disorders : Taste disorder, syncope, headache, paresthesia Renal disorders : Renal impairment Skin and subcutaneous disorders : Rash Changes in selected post-baseline laboratory values that were observed in patients with relapsed or refractory acute leukemia are shown in Table 8. Table 8. Selected New or Worsening Laboratory Abnormalities in Patients with R/R Acute Leukemia *The denominator used to calculate the rate varied from 139 to 240 based on the number of patients with a baseline value and at least one post baseline value. REVUFORJ Laboratory Abnormality Grades 1-4* % Grades 3-4 % Phosphate increased 51 - Aspartate aminotransferase increased 44 6 Alanine aminotransferase increased 40 8 Creatinine increased 38 2 Potassium decreased 34 12 Parathyroid hormone, intact increased 34 - Alkaline phosphatase increased 33 <1 Triglycerides increased 27 3 Phosphate decreased 25 - Cholesterol increased 17 0 Calcium corrected increased 15 0

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.