Revuforj
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Parth Vikram Singh
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Black Box Warning
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DIFFERENTIATION SYNDROME
See full prescribing information for complete Boxed Warning.
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.
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Overview
Revuforj is a Menin inhibitor that is FDA approved for the treatment of 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.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Common adverse reactions include hemorrhage, nausea, phosphate increased, musculoskeletal pain, infection, aspartate aminotransferase increased, febrile neutropenia, alanine aminotransferase increased, parathyroid hormone increased, diarrhea, differentiation syndrome, QT prolongation, Hypophosphatemia, triglycerides increased, potassium decreased, decreased appetite, constipation, edema, viral infection, fatigue, and alkaline phosphatase increased..
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
- REVUFORJ is indicated 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.
- 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.
REVUFORJ Recommended Dosage for Patients 1 Year and Older
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. 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.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Revumenib in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Revumenib in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Revuforj FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Revumenib in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Revumenib in pediatric patients.
Contraindications
None.
Warnings
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DIFFERENTIATION SYNDROME
See full prescribing information for complete Boxed Warning.
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.
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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.
Adverse Reactions
Clinical Trials Experience
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.
Postmarketing Experience
There is limited information regarding Revuforj Postmarketing Experience in the drug label.
Drug Interactions
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.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Revuforj in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Revuforj in women who are pregnant.
Labor and Delivery
- 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.
- 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.
Nursing Mothers
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.
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. 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.
Geriatic Use
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.
Gender
There is no FDA guidance on the use of Revuforj with respect to specific gender populations.
Race
There is no FDA guidance on the use of Revuforj with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Revuforj in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Revuforj in patients with hepatic impairment.
Females of Reproductive Potential and Males
• 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.
Immunocompromised Patients
There is no FDA guidance one the use of Revuforj in patients who are immunocompromised.
Administration and Monitoring
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.
IV Compatibility
There is limited information regarding the compatibility of Revuforj and IV administrations.
Overdosage
There is limited information regarding Revuforj overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Revuforj Pharmacology in the drug label.
Mechanism of Action
- 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. The chemical structure is shown in Figure 1.
- 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.
Pharmacodynamics
• 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.
Pharmacokinetics
- 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).4
- Specific Populations
- No clinically significant differences in the pharmacokinetics of revumenib were observed based on age (1 to 82 years), race (71% White, 8% Asian, 8% Black), sex, mild to moderate (CLcr 30 to 89 mL/min) renal impairment, and mild (total bilirubin ≤ upper limit of normal [ULN] and AST > ULN or total bilirubin > 1 to 1.5 × ULN and any AST) or moderate (total bilirubin > 1.5 to 3 × ULN and any AST) hepatic impairment. The effect of severe renal impairment (CLcr less than 30 mL/min), end-stage renal disease (CLcr less than 15 mL/min), or severe (total bilirubin > 3 × ULN and any AST) hepatic impairment is unknown.
- Body weight (8-146 kg) has a significant effect on the pharmacokinetics of revumenib, with higher revumenib exposures in patients with lower body weight (less than 40 kg). This supports the use of BSA-based dosage in patients weighing less than 40 kg.
- Pediatric Patients
- Revumenib geometric mean (CV%) steady-state Cmax was 3137 (39%) ng/mL and AUC0-tau was 14,630 (55%) ng·hr/mL following 95 mg/m2 twice daily (approximately 1.02 times the highest approved recommended adult dosage) with strong CYP3A4 inhibitors.
- Revumenib predicted geometric mean (%CV) steady-state Cmax was 1597 (70%) ng/mL and AUC0-tau was 12,570 (56%) ng·hr/mL following 160 mg/m2 twice daily (approximately 1.02 times the highest approved recommended adult dosage) without strong CYP3A4 inhibitors.
- Drug Interaction Studies
- Clinical Studies
- Strong CYP3A4 Inhibitors: Revumenib AUC and Cmax is increased by 2-fold following concomitant use of multiple doses of revumenib with certain azole antifungals that are strong CYP3A4 inhibitors (i.e., posaconazole, itraconazole, and voriconazole). Similarly, revumenib AUC and Cmax is increased by 2.5-fold following concomitant use of multiple doses of revumenib with cobicistat (strong CYP3A4 inhibitor).
- Strong and Moderate CYP3A4 Inducers: Revumenib exposure is expected to decrease and M1 exposure is expected to increase with strong and moderate CYP3A4 inducers.
- Other Drugs: No clinically significant differences in revumenib pharmacokinetics were observed when used concomitantly with fluconazole (moderate CYP3A4 inhibitor), isavuconazole (moderate CYP3A4 inhibitor).
- In Vitro Studies
- Cytochrome P450 (CYP) Enzymes: Revumenib inhibits CYP3A4, but does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1.
- Revumenib does not induce CYP1A2, CYP2B6, and CYP3A4.
- Transporter Systems: Revumenib is a substrate of OCT1, OCT2, OAT1, OAT3, and MATE1, but is not a substrate of P-gp, BCRP, OATP1B1, OATP1B3, MATE2-K, or BSEP. M1 is a substrate of OATP1B1, but is not a substrate of P-gp, BCRP, OCT2, OAT1, OAT3, OATP1B3, MATE1, or MATE2-K.
- Revumenib inhibits MATE1, but does not inhibit P-gp, BCRP, OCT1, OCT2, OAT1, OAT3, OATP1B1, OATP1B3, BSEP, and MATE2-K. M1 inhibits MATE1, but does not inhibit OAT1, OAT3, OCT2, OATP1B1, OATP1B3, and MATE2-K.
- Clinical Studies
Nonclinical Toxicology
- 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.
Clinical Studies
The efficacy of REVUFORJ was evaluated in a single-arm cohort of an open-label, multicenter trial (SNDX-5613-0700, NCT04065399; AUGMENT-101) in adult and pediatric patients at least 30 days old with relapsed or refractory (R/R) acute leukemia with a KMT2A translocation. Patients with an 11q23 partial tandem duplication were excluded. Eligibility required a QTcF < 450 msec at study baseline. Treatment consisted of REVUFORJ at a dose approximately equivalent to 160 mg in adults orally twice daily with a strong CYP3A4 inhibitor until disease progression, unacceptable toxicity, failure to achieve morphological leukemia-free state by 4 cycles of treatment, or hematopoietic stem cell transplantation (HSCT). Twenty-four (23%) patients underwent HSCT following treatment with REVUFORJ.
Of the 22 patients who achieved a CR or CRh, the median time to CR or CRh was 1.9 months (range: 0.9, 5.6 months). Among the 83 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 12 (14%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. Of the 21 patients who were independent of both RBC and platelet transfusions at baseline, 10 (48%) remained transfusion independent during any 56-day post-baseline period.
How Supplied
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)
Storage
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].
Keep in original container until dispensed.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (Medication Guide) and Instructions for Use.
- Differentiation Syndrome:
Advise patients of the risks of developing differentiation syndrome as early as 1 day after the start of therapy and during treatment. Ask patients to immediately report any symptoms suggestive of differentiation syndrome, such as fever, cough or difficulty breathing, rash, low blood pressure, rapid weight gain, swelling of their arms or legs, or decreased urinary output, to their healthcare provider for further evaluation.
- Prolonged QT Interval:
Advise patients to consult their healthcare provider immediately if they feel faint, lose consciousness, or have signs or symptoms suggestive of arrhythmia. Advise patients with a history of hypokalemia or hypomagnesemia of the importance of monitoring their electrolytes.
- Embryo-Fetal Toxicity:
Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to notify their healthcare provider of a known or suspected pregnancy. Advise females of reproductive potential to use effective contraception during treatment with REVUFORJ and for 4 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with REVUFORJ and for 4 months after the last dose.
- Lactation:
Advise women not to breastfeed during treatment with REVUFORJ and for 1 week after the last dose.
- Infertility:
Advise females and males of reproductive potential of the potential for impaired fertility from REVUFORJ.
- Drug Interactions:
Advise patients to inform their healthcare providers of all concomitant products, including over-the counter products and supplements.
- Dosing Instructions:
Advise patients to swallow tablets whole with a cup of water and not to cut or chew tablets. If patients are unable to swallow the tablets, they may be crushed and dispersed in water. Instruct patients that, if they miss a dose of REVUFORJ, to take it as soon as possible on the same day, and at least 12 hours prior to the next scheduled dose, and return to the normal schedule the following day.
Precautions with Alcohol
Alcohol-Revuforj interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
Brand Names
REVUFORJ
Look-Alike Drug Names
There is limited information regarding Revuforj Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.