REVUFORJ Film-coated tablet Ref.[116086] Active ingredients: Revumenib

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 Treatment interruption was required for 7% of patients, and treatment was withdrawn for 1%.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)].

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)]

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

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.

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)].

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.

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.

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)].

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.

Of the 241 patients with relapsed or refractory acute leukemia with a KMT2A translocation or an NPM1 mutation in clinical studies of REVUFORJ, 61 (25%) patients were 65 years of age and older and 25 (10%) patients were 75 years of age and older [see Clinical Studies (14)].

No overall differences were observed in the effectiveness of REVUFORJ between patients who were 65 years and older and younger patients [see Clinical Studies (14.1) and Clinical Pharmacology (12.3)]. Compared to younger patients, the incidences of QTc prolongation and edema were higher in patients 65 years and older [see Warnings and Precautions (5.2)].