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Indication
IDHIFA® (enasidenib) is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase-2 mutation as detected by an FDA-approved test.

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WATCH THE MECHANISM OF ACTION OF ENASIDENIB

The mechanism of action of enasidenib

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TAKE A DIFFERENT APPROACH—RELEASE THE BLOCK ON MYELOID DIFFERENTIATION

IDHIFA®, the only non-cytotoxic, targeted inhibitor of the mutant IDH2 enzyme, releases the block on myeloid differentiation.

IDHIFA® , the only non-cytotoxic, targeted inhibitor of the mutant IDH2 enzyme, releases the block on myeloid differentiation
IDHIFA® , the only non-cytotoxic, targeted inhibitor of the mutant IDH2 enzyme, releases the block on myeloid differentiation
  1. McKenney AS, Levine RL. Isocitrate dehydrogenase mutations in leukemia. J Clin Invest. 2013;123(9):3672-3677.
  2. Su X, Wellen KE, Rabinowitz JD. Metabolic control of methylation and acetylation. Curr Opin Chem Biol. 2016;30:52-60.
  3. Yang H, Ye D, Guan K, et al. IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives. Clin Cancer Res. 2012;18(20):5562-5571.
  4. Genetics Home Reference. Your guide to understanding genetic conditions: IDH2 gene. NIH US National Library of Medicine website. https://ghr.nlm.nih.gov/gene/IDH2. Published February 2016. Accessed May 10, 2017.
  5. Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18:553-567.
  6. Data on file, Celgene Corporation. Summit, New Jersey.

WARNING: DIFFERENTIATION SYNDROME

Patients treated with IDHIFA have experienced symptoms of differentiation syndrome, which can be fatal if not treated. Symptoms may include fever, dyspnea, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, lymphadenopathy, bone pain, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.

WARNINGS AND PRECAUTIONS

Differentiation Syndrome: See Boxed WARNING. In the clinical trial, 14% of patients treated with IDHIFA experienced differentiation syndrome, which may be life-threatening or fatal if not treated. Differentiation syndrome has been observed with and without concomitant hyperleukocytosis, in as early as 1 day and up to 5 months after IDHIFA initiation. Symptoms in patients treated with IDHIFA included acute respiratory distress represented by dyspnea and/or hypoxia and need for supplemental oxygen; pulmonary infiltrates and pleural effusion; renal impairment; fever; lymphadenopathy; bone pain; peripheral edema with rapid weight gain; and pericardial effusion. Hepatic, renal, and multi-organ dysfunction have also been observed. If differentiation syndrome is suspected, initiate systemic corticosteroids and hemodynamic monitoring until improvement. Taper corticosteroids only after resolution of symptoms. Differentiation syndrome symptoms may recur with premature discontinuation of corticosteroids. If severe pulmonary symptoms requiring intubation or ventilator support and/or renal dysfunction persist for more than 48 hours after initiation of corticosteroids, interrupt IDHIFA until signs and symptoms are no longer severe. Hospitalization for close observation and monitoring of patients with pulmonary and/or renal manifestation is recommended.

Embryo-Fetal Toxicity: Based on animal embryo-fetal toxicity studies, IDHIFA can cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential and males with female partners of reproductive potential to use effective non-hormonal contraception during treatment with IDHIFA and for 2 months after the last dose. Advise pregnant women of the potential risk to the fetus.

ADVERSE REACTIONS

  • The most common adverse reactions (≥20%) included total bilirubin increased (81%), calcium decreased (74%), nausea (50%), diarrhea (43%), potassium decreased (41%), vomiting (34%), decreased appetite (34%), and phosphorus decreased (27%)
  • The most frequently reported ≥Grade 3 adverse reactions (≥5%) included total bilirubin increased (15%), potassium decreased (15%), phosphorus decreased (8%), calcium decreased (8%), diarrhea (8%), differentiation syndrome (7%), non-infectious leukocytosis (6%), tumor lysis syndrome (6%), and nausea (5%)
  • Serious adverse reactions were reported in 77.1% of patients. The most frequent serious adverse reactions (≥2%) were leukocytosis (10%), diarrhea (6%), nausea (5%), vomiting (3%), decreased appetite (3%), tumor lysis syndrome (5%), and differentiation syndrome (8%). Differentiation syndrome events characterized as serious included pyrexia, renal failure acute, hypoxia, respiratory failure, and multi-organ failure

DRUG INTERACTIONS

Certain CYP1A2 CYP2C19 Substrates

Avoid concomitant use with IDHIFA unless otherwise recommended in the Prescribing Information for CYP1A2, CYP2C19 substrates where minimal concentration changes may lead to serious adverse reactions. Consider reducing the frequency of caffeine intake from various food and beverages in a 24-hour period while taking IDHIFA because IDHIFA may increase the effect of caffeine in patients who are sensitive to it. Enasidenib is a CYP1A2, CYP2C19 inhibitor. Concomitant use of IDHIFA increases the exposure of CYP1A2, CYP2C19 substrates, which may increase the risk of adverse reactions related to the substrates.

Certain CYP3A substrates

Avoid concomitant use with IDHIFA unless otherwise recommended in the Prescribing Information for CYP3A substrates where minimal concentration changes may lead to reduced efficacy. Do not administer IDHIFA with anti-fungal agents that are substrates of CYP3A due to expected loss of antifungal efficacy. Co-administration of IDHIFA may decrease the concentrations of hormonal contraceptives. Consider alternative methods of contraception in patients receiving IDHIFA. Enasidenib is a CYP3A inducer. Concomitant use of IDHIFA decreases the exposure of CYP3A substrates, which may reduce the efficacy of the substrates.

Certain OATP1B1, OATP1B3, and BCRP Substrates

Avoid coadministration of IDHIFA with OATP1B1, OATP1B3, and BCRP substrates, for which minimal concentration changes may lead to serious toxicities. If coadministration cannot be avoided, decrease the OATP1B1, OATP1B3, and BCRP substrates dosage(s) in accordance with the respective Prescribing Information. Enasidenib is an OATP1B1, OATP1B3, and BCRP transporter inhibitor. Concomitant use of IDHIFA increases the exposure of OATP1B1, OATP1B3, and BCRP, which may increase the risk of adverse reactions related to these substrates.

Certain P-glycoprotein (P-gp) Substrates

When coadministered with IDHIFA, follow recommended P-gp substrates Prescribing Information and monitor more frequently for adverse reactions related to these substrates. Enasidenib is a P-gp transporter inhibitor. Concomitant use of IDHIFA increases the exposure of P-gp substrates, which may increase the risk of adverse reactions related to the substrates.

LACTATION

Because of the potential for adverse reactions in the breastfed child, advise women not to breastfeed during treatment with IDHIFA and for 2 months after the last dose.

  1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Myeloid Leukemia V.1.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed March 4, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
  1. Ramos NR, Mo CC, Karp JE, Hourigan CS. Current approaches in the treatment of relapsed and refractory acute myeloid leukemia. J Clin Med. 2015;4(4):665-695.
  2. Rashidi A, Weisdorf DJ, Bejanyan N. Treatment of relapsed/refractory acute myeloid leukaemia in adults. Br J Haematol. 2018;181(1):27-37.
  3. Bose P, Vachhani P, Cortes JE. Treatment of relapsed/refractory acute myeloid leukemia. Curr Treat Options Oncol. 2017;18(3):17.
  4. Burnett AK. Treatment of acute myeloid leukemia: are we making progress? Hematology Am Soc Hematol Educ Program. 2012;2012:1-6.
  5. Breems DA, Van Putten WL, Huijgens PC, et al. Prognostic index for adult patients with acute myeloid leukemia in first relapse. J Clin Oncol. 2005;23(9):1969-1978.
  6. Bohl SR, Bullinger L, Rucker FG. New targeted agents in acute myeloid leukemia: new hope on the rise. Int J Mol Sci. 2019;23:20(8):1983.
  1. Estey E, Döhner H. Acute myeloid leukaemia. Lancet. 2006;368(9550):1894-1907.
  2. Burnett A, Wetzler M, Löwenberg B. Therapeutic advances in acute myeloid leukemia. J Clin Oncol. 2011;29(5):487-494.
  3. Metzeler KH, Herold T, Rothenberg-Thurley M, et al; on behalf of the AMLCG Study Group. Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia. Blood. 2016;128(5):686-698.
  4. The Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059-2074.
  5. Arber DA, Borowitz MJ, Cessna M, et al. Initial diagnostic workup of acute leukemia: guideline from the College of American Pathologists and the American Society of Hematology. Arch Pathol Lab Med. 2017;141(10):1342-1393.
  6. Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373(12):1136-1152.
  7. Bloomfield CD, Estey E, Pleyer L, et al. Time to repeal and replace response criteria for acute myeloid leukemia? Blood Rev. 2018;32(5):416-425.
  8. Medeiros BC, Fathi AT, DiNardo CD, Pollyea DA, Chan SM, Swords R. Isocitrate dehydrogenase mutations in myeloid malignancies. Leukemia. 2017;31(2):272-281.
  9. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Myeloid Leukemia V.1.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed March 4, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
  10. Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23):2209-2221.
  11. Patel K, Ravandi F, Ma D, et al. Acute myeloid leukemia with IDH1 or IDH2 mutation: frequency and clinicopathologic features. Am J Clin Pathol. 2011;135(1):35-45.
  12. Abbott RealTime [product information]. Abbott Molecular Inc: 2017.
  1. McKenney AS, Levine RL. Isocitrate dehydrogenase mutations in leukemia. J Clin Invest. 2013;123(9):3672-3677.
  2. Su X, Wellen KE, Rabinowitz JD. Metabolic control of methylation and acetylation. Curr Opin Chem Biol. 2016;30:52-60.
  3. Yang H, Ye D, Guan K, et al. IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives. Clin Cancer Res. 2012;18(20):5562-5571.
  4. Genetics Home Reference. Your guide to understanding genetic conditions: IDH2 gene. NIH US National Library of Medicine website. https://ghr.nlm.nih.gov/gene/IDH2. Published February 2016. Accessed May 10, 2017.
  5. Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18:553-567.
  6. Data on file, Celgene Corporation. Summit, New Jersey.
  1. Data on file, Celgene Corporation. Summit, New Jersey.
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03/24  2018-US-2300021