Revumenib

{{DrugProjectFormSinglePage |authorTag=Parth Vikram Singh |genericName=Revumenib |aOrAn=a |drugClass=Menin inhibitor |indicationType=treatment |indication=Revumenib is a menin inhibitor that is FDA approved for the treatment of relapsed or refractory acute leukemia with a lysine methyltransferase 2A gene (KMT2A) translocation in adult and pediatric patients 1 year and older. |hasBlackBoxWarning=Yes |adverseReactions=Common adverse reactions include hemorrhage, nausea, phosphate increased, musculoskeletal pain, infection, aspartate aminotransferase increased, febrile neutropenia, alanine aminotransferase increased, parathyroid hormone intact increased, bacterial infection, diarrhea, differentiation syndrome, electrocardiogram QT prolonged, phosphate decreased, triglycerides increased, potassium decreased, decreased appetite, constipation, edema, viral infection, fatigue, and alkaline phosphatase increased. |blackBoxWarningTitle=TITLE DIFFERENTIATION SYNDROME |blackBoxWarningBody=Condition Name: (Content)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. |fdaLIADAdult=Select patients for treatment with Revumenib based on the presence of a KMT2A translocation. Administer Revumenib orally twice daily fasted or with a low fat meal at approximately the same time each day. The recommended dosage of REVUFORJ varies by patient weight. For patients 1 year and older weighing 40 kg or more, the dosage is 270 mg orally twice daily without strong CYP3A4 inhibitors and 160 mg orally twice daily with strong CYP3A4 inhibitors. For patients weighing less than 40 kg, the dosage is 160 mg/m² orally twice daily without strong CYP3A4 inhibitors and 95 mg/m² orally twice daily with strong CYP3A4 inhibitors. |offLabelAdultGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Revumenib in adult patients. |offLabelAdultNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Revumenib in adult patients. |offLabelPedGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Revumenib in pediatric patients. |offLabelPedNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Revumenib in pediatric patients. |contraindications=None. |warnings=• Differentiation Syndrome o 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, and/or hypotension. o In clinical trials, DS occurred in 39 (29%) of 135 patients treated with REVUFORJ at the recommended dosage for relapsed or refractory acute leukemia with a KMT2A translocation, including 32% of patients with acute myeloid leukemia (AML), 25% of patients with mixed-phenotype acute leukemia (MPAL), and 14% of patients with acute lymphoblastic leukemia (ALL). DS was Grade 3 or 4 in 13% and fatal in one patient. The median time to onset was 10 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%. o 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.

• QTc Interval Prolongation o REVUFORJ can cause QT (QTc) interval prolongation. In the clinical trials, QTc interval prolongation was reported as an adverse reaction in 39 (29%) of 135 patients treated with REVUFORJ at the recommended dosage for relapsed or refractory acute leukemia with a KMT2A translocation; QTc interval prolongation was Grade 3 in 12%. The heart-rate corrected QT interval (using Fridericia’s method) (QTcF) was greater than 500 msec in 8%, and the increase from baseline QTcF was greater than 60 msec in 18%. REVUFORJ dose reduction was required for 5% due to QTc interval prolongation. QTc prolongation occurred in 16% of the 31 patients less than 17 years old, 33% of the 88 patients 17 years to less than 65 years old, and in 50% of the 16 patients 65 years or older. o Correct electrolyte abnormalities, including hypokalemia and hypomagnesemia, prior to 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. 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. o 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.

• Embryo-Fetal Toxicity o 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. o 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. |clinicalTrials=Vascular Disorders:

Hemorrhage: Observed in 53% of patients, with 9% experiencing grade 3 or 4 severity.

Thrombosis: Occurred in 10% of patients, with 5% experiencing grade 3 or 4 severity.

Gastrointestinal Disorders:

Nausea: Reported in 51% of patients, with 4% experiencing grade 3 or 4 severity.

Diarrhea: Occurred in 30% of patients, with 4% experiencing grade 3 or 4 severity.

Constipation: Reported in 23% of patients, with 1% experiencing grade 3 or 4 severity.

Musculoskeletal and Connective Tissue Disorders:

Musculoskeletal Pain: Experienced by 42% of patients, with 6% experiencing grade 3 or 4 severity.

Infections and Infestations:

Infection: Affected 41% of patients, with 29% experiencing grade 3 or 4 severity.

Bacterial Infection: Reported in 31% of patients, with 20% experiencing grade 3 or 4 severity.

Viral Infection: Occurred in 23% of patients, with 4% experiencing grade 3 or 4 severity.

Blood and Lymphatic System Disorders:

Febrile Neutropenia: Observed in 35% of patients, with 33% experiencing grade 3 or 4 severity.

Leukocytosis: Reported in 8% of patients, with 5% experiencing grade 3 or 4 severity.

Neoplasms Benign, Malignant, and Unspecified (Including Cysts and Polyps):

Differentiation Syndrome: Occurred in 29% of patients, with 13% experiencing grade 3 or 4 severity.

Investigations:

Electrocardiogram QT Prolonged: Reported in 29% of patients, with 12% experiencing grade 3 or 4 severity.

Metabolism and Nutrition Disorders:

Decreased Appetite: Experienced by 24% of patients, with 8% experiencing grade 3 or 4 severity.

General Disorders and Administration Site Conditions:

Edema: Reported in 23% of patients, with 1% experiencing grade 3 or 4 severity.

Fatigue: Experienced by 22% of patients, with 5% experiencing grade 3 or 4 severity. |useInLaborDelivery=• 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. |useInNursing=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. |useInPed=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. 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 13 infants (age < 2 years), 41 children (age 2 to < 12 years) and 16 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. |useInGeri=Of the 135 patients with relapsed or refractory acute leukemia with a KMT2A translocation in clinical studies of REVUFORJ, 16 (12%) patients were 65 years of age and older and 3 (2%) patients were 75 years of age and older. No overall differences were observed in the effectiveness of REVUFORJ between patients who were 65 years and older and younger patients. Compared to younger patients, the incidences of QTc prolongation and edema were higher in patients 65 years and older. |useInReproPotential=• Based on findings in animals and its mechanism of action, REVUFORJ can cause fetal harm when administered to pregnant women. o Pregnancy Testing: Verify pregnancy status in females of reproductive potential within 7 days prior to initiating REVUFORJ.

• Contraception o Females: Advise females of reproductive potential to use effective contraception during treatment with REVUFORJ and for 4 months after the last dose. o 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. |administration=• 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. |monitoring=In the case of Differentiation Syndrome, if suspected, the recommended action is as follows: • Administer systemic corticosteroids and initiate hemodynamic monitoring until symptom resolution, and continue for at least 3 days. • Interrupt REVUFORJ if severe signs and/or symptoms persist for more than 48 hours after starting corticosteroids, or if life-threatening symptoms like pulmonary issues requiring ventilator support occur. • Once symptoms improve to Grade 1 or lower, resume REVUFORJ at the same dose. For Noninfectious Leukocytosis, the following steps are recommended: • Initiate treatment with hydroxyurea in patients with an elevated or rapidly rising leukocyte count. • Add leukapheresis if clinically necessary. • Taper hydroxyurea only after the leukocytosis has improved or resolved. When the QTc interval is greater than 480 msec to 500 msec, the action plan is: • Interrupt REVUFORJ and check electrolyte levels. • Correct any hypokalemia or hypomagnesemia. • Restart REVUFORJ at the same dose level once the QTc interval returns to 480 msec or lower. If the QTc interval exceeds 500 msec (Grade 3), the following steps should be taken: • Interrupt REVUFORJ and check electrolyte levels. • Correct any hypokalemia or hypomagnesemia. • Restart REVUFORJ at a reduced dose level after the QTc interval is brought down to 480 msec or less. For QTc interval prolongation with life-threatening arrhythmia (Grade 4), such as Torsades de Pointes or polymorphic ventricular tachycardia, the action is: • Permanently discontinue REVUFORJ. Regarding Potassium and Magnesium Levels: • If potassium is 3.6-3.9 mEq/L and/or magnesium is 1.7-1.9 mg/dL (or 0.66-0.81 mmol/L), supplement the respective mineral and continue REVUFORJ. • If potassium is ≤ 3.5 mEq/L and/or magnesium is ≤ 1.6 mg/dL (or ≤ 0.65 mmol/L), supplement potassium and/or magnesium and recheck levels within 24 hours. • If the levels improve (potassium > 3.5 mEq/L and/or magnesium > 1.6 mg/dL), continue REVUFORJ. If they remain low, hold REVUFORJ and continue supplementation, resuming REVUFORJ once the correction is complete. For Other Nonhematological Adverse Reactions Grade ≥ 3, the following guidelines apply: • Interrupt REVUFORJ until recovery to Grade 1 or baseline. • If recovery occurs within 7 days, restart REVUFORJ at the same dose. • If the same Grade ≥ 3 toxicity recurs, interrupt REVUFORJ again until recovery, and then restart at a reduced dose level. • If recovery takes longer than 7 days, restart REVUFORJ at a reduced dose. If the toxicity recurs, permanently discontinue REVUFORJ. For Grade 4 Neutropenia or Thrombocytopenia, the action is: • Interrupt REVUFORJ until recovery to Grade ≤ 2 or baseline. • Restart REVUFORJ at the same dose level. • If Grade 4 neutropenia or thrombocytopenia recurs without an attributable cause, interrupt REVUFORJ until recovery to Grade ≤ 3 and restart at a reduced dose level. In the case of Grade 3 or higher allergic reactions, the recommendation is: • Permanently discontinue REVUFORJ. |mechAction=Revumenib is a menin inhibitor and blocks the interaction of both wild-type lysine methyltransferase 2A (KMT2A) and KMT2A fusion proteins with menin. The binding of KMT2A fusion proteins with menin is involved in KMT2A-rearranged (KMT2Ar) acute leukemias through activation of a leukemogenic transcriptional pathway. 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. |structure=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.

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. |PD=• Revumenib exposure-response relationships have not been fully characterized and the time course of pharmacodynamic response is unknown. • Cardiac Electrophysiology: The effect of REVUFORJ on the QTc interval was evaluated across a dose range of 113 mg to 339 mg twice daily (1.2 times the highest adult approved recommended dosage) with and without strong CYP3A4 inhibitors in patients with relapsed or refractory acute leukemia with KMT2Ar. The increase in QTc interval was concentration dependent with an increase in QTc predicted to be 27 msec (upper bound of 90% confidence interval: 30 msec) at the mean steady-state maximum concentration (Cmax) observed in patients at the highest approved recommended dosage without CYP3A4 inhibitors. The increase in QTc interval was predicted to be 19 msec (upper bound of 90% confidence interval: 22 msec) at steady-state Cmax after administration of 163 mg twice daily with strong CYP3A4 inhibitors. |PK=The recommended dosage for REVUFORJ varies depending on the presence of strong CYP3A4 inhibitors. When taken with strong CYP3A4 inhibitors, the dosage is 163 mg twice daily. In the absence of strong CYP3A4 inhibitors, the dosage increases to 276 mg twice daily.

Regarding general pharmacokinetic information, the Cmax (maximum concentration) is 3220 ng/mL with strong CYP3A4 inhibitors, which represents a 34% increase, while it is 2052 ng/mL without such inhibitors, showing a 79% increase. The AUC0-12h (area under the curve over 12 hours) is 22,610 ng•h/mL with strong inhibitors, representing a 50% increase, and 10,150 ng•h/mL without inhibitors, showing a 69% increase. Dose proportionality is observed, with increases in Cmax and AUC0-12h corresponding to dose increases. The time to steady-state concentration is between 2 to 3 days, with a 2-fold accumulation.

In terms of absorption, the median time to reach the maximum concentration (Tmax) is 2 hours (range 0-6 hours) with strong CYP3A4 inhibitors, and 1 hour (range 0.5-4 hours) without. When taken with a low-fat meal, there are no clinically significant differences observed in REVUFORJ pharmacokinetics, although Cmax and AUC decrease by 27% and 12%, respectively.

For distribution, the apparent volume of distribution is 78 L, with a 50% variability. REVUFORJ has a high protein binding rate of 90%, and the blood to plasma ratio is 0.8.

Regarding elimination, the half-life of REVUFORJ is 7.5 hours (with a 57% variability) when taken with strong CYP3A4 inhibitors, and 3.6 hours (with a 36% variability) without. The apparent clearance rate is 7 L/h (with a 51% variability) when inhibitors are present, and 27 L/h (with a 69% variability) when they are absent.

The primary metabolism of REVUFORJ occurs via CYP3A4, and the active metabolite is M1. In terms of excretion, approximately 49% of the drug is excreted in the feces (with 7% unchanged), and approximately 27% is excreted in the urine (also with 7% unchanged). |nonClinToxic=• Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with revumenib. In a repeat dose toxicity study in rats treated with revumenib for 13 weeks, lymphoma was observed in multiple organs in one animal. Revumenib was not genotoxic in an in vitro bacterial reverse mutation (Ames) assay, an in vitro micronucleus assay in human peripheral blood lymphocytes, or an in vivo rat peripheral blood reticulocyte micronucleus assay. Fertility studies in animals have not been conducted with revumenib. In a repeat dose toxicity study in dogs treated with revumenib at 12.5, 25 or 40 mg/kg/day for 13 weeks, microscopic findings in the testes and epididymis consisted of depletion of germ cells and decreased sperm at ≥12.5 mg/kg/day. In females, microscopic changes of atrophy in the mammary glands, uterus, and vagina and decreased number of corpora lutea in the ovaries were observed at ≥12.5 mg/kg/day. At the end of the 13-week recovery period, the findings in the female reproductive organs were reversed at all doses, and the testicular and epididymal effects were reversed at 12.5 mg/kg/day. At the dose of 12.5 mg/kg/day in dogs, exposures (AUC) were approximately 1.3 times the human exposure (AUC) at the recommended dose. • Animal Toxicology and/or Pharmacology In a repeat dose toxicity study in dogs treated with revumenib at 12.5, 25, or 40 mg/kg/day for 13 weeks, microscopic findings of nerve fiber degeneration in the brain, sciatic nerves, and spinal cord segments were observed at ≥ 12.5 mg/kg/day and were not reversed at the end of a 13-week recovery period. In a repeat dose toxicity study in rats treated with revumenib at 75, 150, 300 mg/kg/day for 13 weeks, dose dependent ocular findings of lens opacities were observed at ≥ 75 mg/kg/day; the findings progressed during the dosing and recovery periods and were not reversed. Hyperplasia was observed in multiple organs including the testes, mammary gland, uterus, pancreas, and kidney in rats treated at ≥ 75 mg/kg/day for up to 13 weeks. The findings were irreversible in the testes, mammary gland, and pancreas. Revumenib exposures at 75 mg/kg/day in rats are approximately 2 times the human exposure (AUC) at the recommended dose. |alcohol=Alcohol-Revumenib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. }}