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 mo …

3 DOSAGE FORMS AND STRENGTHS Tablets: 25 mg, 110 mg, 160 mg ( 3 ) Tablets: 25 mg of revumenib: Pink modified oval film-coated tablet debossed with “S” on one side and “25” on the other side. 110 mg of revumenib: Beige modified oval film-coated tablet debossed with “S” on one side and “110” on the other side. 160 mg of revumenib: Purple modified oval film-coated tablet debossed with “S” on one side and “160” on the other side.

4 CONTRAINDICATIONS None. None. ( 4 )

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%) 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, …

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) ].

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed ( 8.2 ) 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. 8.2 Lactation Risk Summary 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. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with REVUFORJ and for 1 week after the last dose. 8.3 Females and Males of Reproductive Potential Based on findings in animals and its mechanism of action, REVUFORJ can cause fetal harm when administered to pregnant women [ see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify pregnancy status in females of reproductive potential within 7 days prior to initiating REVUFORJ. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with REVUFORJ and for 4 months after the last dose. Males Advise males of reproductive potential to use effective contraception during treatment with REVUFORJ and for 4 months after the last dose. Infertility Females and Males Based on findings in animals, REVUFORJ may impair fertility. The effects on fertility were reversible [see Nonclinical Toxicology (13.1) ] . 8.4 Pediatric Use The safety and efficacy of REVUFORJ have been established in pediatric patients 1 year and older with relapsed or refractory acute leukemia with a KMT2A translocation or an NPM1 mutation. Use of REVUFORJ for this indication is supported by evidence from adequate and well-controlled trials in adults and pediatric patients [see Clinical Studies (14) ] and additional pharmacokinetic and safety data in pediatric patients [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3) ] . The patients included 25 infants (age < 2 years), 78 children (age 2 to < 12 years) and 29 adolescents (age 12 to < 17 years). The recommended dosage in patients weighing less than 40 kg is BSA-based. The safety and efficacy of REVUFORJ in pediatric patients less than 1 year old have not been established . Animal Data 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. Based on the findings in animals, monitor bone growth and development in pediatric patients. 8.5 Geriatric Use Of the 241 p …

12.1 Mechanism of Action Revumenib is a menin inhibitor that blocks the interaction of both wild-type lysine methyltransferase 2A (KMT2A) and KMT2A fusion proteins with menin. The binding of wild-type KMT2A or KMT2A fusion proteins with menin is involved in NPM1 mutated acute myeloid leukemias and KMT2A - rearranged acute leukemias, respectively, through activation of a leukemogenic transcriptional pathway. Susceptible NPM1 mutations are defined as those that result in loss of the nucleolar localization signal and the insertion of a new nuclear export signal leading to the accumulation of mutant NPM1 in the cytoplasm of AML cells. The most common of such NPM1 mutations in patients with AML are Types A, B, and D. 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. In nonclinical in vitro and in vivo studies, revumenib demonstrated antiproliferative and antitumor activity in leukemia cells harboring KMT2A fusion proteins. Revumenib also showed antiproliferative activity in vitro in leukemia cells with an NPM1 mutation.

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

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.