Revuforj Drug Information

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 . 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

Effect of Other Drugs on

REVUFORJ Strong CYP3A4 Inhibitors If concomitant use of strong CYP3A4 inhibitors is required, reduce the REVUFORJ dosage . Revumenib is primarily metabolized by CYP3A4 . Concomitant use with a strong CYP3A4 inhibitor increases revumenib systemic exposure , 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 . Concomitant use with a strong or moderate CYP3A4 inducer may decrease revumenib and increase M1 systemic exposure , 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 . 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 . REVUFORJ causes QTc interval prolongation . 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.

Pregnancy Risk Summary Based on findings in animals and its mechanism of action, 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.

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 and additional pharmacokinetic and safety data in pediatric patients . 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.