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    Small Molecule Antineoplastic Isocitrate Dehydrogenase-2 (IDH-2) Inhibitors

    BOXED WARNING

    Differentiation syndrome, fever, nephrotoxicity, pericardial effusion, peripheral edema, pleural effusion, pulmonary toxicity, respiratory distress syndrome

    Differentiation syndrome with or without concomitant hyperleukocytosis has been reported with enasidenib therapy; this syndrome may be fatal if not treated. Monitor patients for signs and symptoms of differentiation syndrome such as fever, cough, dyspnea, acute respiratory distress syndrome, pulmonary infiltrates, pleural effusion or pericardial effusion, rapid weight gain of more than 10 pounds within a week, peripheral edema, cervical, axillary, or inguinal lymphadenopathy, dizziness, bone pain, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, start corticosteroid therapy (e.g., dexamethasone 10 mg PO/IV every 12 hours) and closely monitor hemodynamic parameters. Taper corticosteroids after symptoms resolve; premature corticosteroid discontinuation may lead to symptom recurrence. Interrupt enasidenib therapy if renal dysfunction and/or severe pulmonary symptoms requiring intubation or ventilator support persist after 48 hours of corticosteroid therapy. Resume enasidenib therapy when sign and symptoms of toxicity resolve to grade 2 or less. Hospitalization is recommended in patients who develop pulmonary toxicity and/or nephrotoxicity. Differentiation syndrome may occur as soon as 1 day and up to 5 months after starting enasidenib.

    DEA CLASS

    Rx

    DESCRIPTION

    Isocitrate dehydrogenase-2 inhibitor
    Used for relapsed or refractory acute myeloid leukemia with an IDH2 mutation
    Differentiation syndrome may occur; initiate corticosteroids and hemodynamic monitoring if suspected

    COMMON BRAND NAMES

    IDHIFA

    HOW SUPPLIED

    Enasidenib Oral Tab: 50mg, 100mg

    DOSAGE & INDICATIONS

    For the treatment of acute myelogenous leukemia (AML).
    The FDA has designated enasidenib as an orphan drug for the treatment of AML.
    For the treatment of relapsed or refractory AML with an isocitrate dehydrogenase-2 (IDH2) mutation.
    NOTE: Evaluate patients for the presence of the IDH2 mutation in the blood or bone marrow using an FDA-approved detection test (http://www.fda.gov/CompanionDiagnostics).
    Oral dosage
    Adults

    100 mg PO once daily until disease progression. Treat patients without disease progression for a minimum of 6 months to allow time for clinical response. Therapy interruption, dose reduction, or drug discontinuation may be necessary in patients who develop toxicity. Treatment with enasidenib resulted in a complete remission (CR) or a CR with partial hematologic recovery (CRh) rate of 23% in patients with IDH2 (R140, 78%; R172, 22%)-mutated relapsed or refractory AML in a phase I/II trial (n = 199). In patients who achieved a CR/CRh, the median duration of response was 8.2 months, the median time to first response was 1.9 months (range, 0.5 to 7.5 months), and the median time to best response was 3.7 months (range, 0.6 to 11.2 months). Of the 157 patients who were dependent on red blood cell or platelet transfusions at baseline, 34% of patients became transfusion independent during any 56-day post baseline period. In this trial, patients (median age, 68 years; range, 19 to 100 years) had received a median of 2 prior therapies (range, 1 to 6 therapies); 13% of patients had undergone prior stem-cell transplantation.

    MAXIMUM DOSAGE

    Adults

    100 mg/day PO.

    Geriatric

    100 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline hepatic impairment: Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
    Treatment-related hepatic impairment: For a bilirubin level of greater than 3-times the upper limit of normal (ULN) that persists for 2 weeks or longer without elevated transaminases or other hepatic disorders, decrease the enasidenib dose to 50 mg PO once daily; may increase to 100 mg PO once daily if the bilirubin level decreases to 2-times the ULN or less.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Take enasidenib orally with or without food at approximately the same time each day.
    Swallow tablets whole; do not split, crush, or chew tablets.
    If a dose is missed, vomited, or not taken at the usual time, take the dose as soon as possible on the same day and return to the normal schedule the following day; do not take 2 doses to make up for the missed dose.
    Store tablets in the original container; keep the bottle tightly closed with the desiccant canister inside to protect the tablets from moisture.

    STORAGE

    IDHIFA:
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    Differentiation syndrome, fever, nephrotoxicity, pericardial effusion, peripheral edema, pleural effusion, pulmonary toxicity, respiratory distress syndrome

    Differentiation syndrome with or without concomitant hyperleukocytosis has been reported with enasidenib therapy; this syndrome may be fatal if not treated. Monitor patients for signs and symptoms of differentiation syndrome such as fever, cough, dyspnea, acute respiratory distress syndrome, pulmonary infiltrates, pleural effusion or pericardial effusion, rapid weight gain of more than 10 pounds within a week, peripheral edema, cervical, axillary, or inguinal lymphadenopathy, dizziness, bone pain, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, start corticosteroid therapy (e.g., dexamethasone 10 mg PO/IV every 12 hours) and closely monitor hemodynamic parameters. Taper corticosteroids after symptoms resolve; premature corticosteroid discontinuation may lead to symptom recurrence. Interrupt enasidenib therapy if renal dysfunction and/or severe pulmonary symptoms requiring intubation or ventilator support persist after 48 hours of corticosteroid therapy. Resume enasidenib therapy when sign and symptoms of toxicity resolve to grade 2 or less. Hospitalization is recommended in patients who develop pulmonary toxicity and/or nephrotoxicity. Differentiation syndrome may occur as soon as 1 day and up to 5 months after starting enasidenib.

    Hepatic disease, hepatotoxicity

    Hepatotoxicity (i.e., hyperbilirubinemia) has been reported with enasidenib therapy. Enasidenib may interfere with bilirubin metabolism through UGT1A1 inhibition; therefore, use enasidenib with caution in patients with pre-existing hepatic disease. Monitor liver function tests, including bilirubin levels, prior to starting enasidenib and periodically during treatment. Therapy interruption, dose reduction, or drug discontinuation may be necessary in patients who develop severe hyperbilirubinemia.

    Leukocytosis, tumor lysis syndrome (TLS)

    Leukocytosis and tumor lysis syndrome (TLS) have been reported with enasidenib therapy; enasidenib may induce myeloid proliferation resulting in a rapid increase in white blood cell (WBC) count and/or a rapid reduction in tumor cells. Monitor complete blood counts and other blood chemistries such as serum uric acid, serum electrolytes, and renal function (e.g., BUN/serum creatinine levels) prior to starting enasidenib and then at least every 2 weeks for the first 3 months or longer during treatment. Start hydroxyurea per standard clinical practice in patients who have or develop a WBC count greater than 30 x 109 cells/L. Interrupt enasidenib therapy if leukocytosis is not improved with hydroxyurea. Resume enasidenib therapy when the WBC count is less than 30 x 109 cells/L. Manage other laboratory abnormalities promptly. Therapy interruption, dose reduction, or drug discontinuation may be necessary in patients who develop severe TLS.

    Pregnancy

    Enasidenib may cause fetal harm when administered during pregnancy, based on animal studies. Females of reproductive potential should avoid becoming pregnant while taking enasidenib. Discuss the potential hazard to the fetus if enasidenib is used during pregnancy or if a patient becomes pregnant while taking this drug. Embryo-fetal toxicities including decreased fetal birth weights and skeletal variations were observed when enasidenib was administered to pregnant rabbits during organogenesis at doses resulting in exposures of approximately 1.6-times the exposure in humans (at the recommended dose); postimplantation loss, resorptions, and decreased viable fetuses were also reported. Additionally, spontaneous abortion occurred in pregnant rabbits with enasidenib doses resulting in exposures approximately 0.1-times the exposure in humans.

    Contraception requirements, infertility, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during enasidenib treatment. Pregnancy testing prior to starting enasidenib therapy is recommended for females of reproductive potential. These patients should avoid pregnancy and use effective contraception during therapy and for at least 2 months after the last enasidenib dose. Concomitant use of enasidenib and hormonal contraceptives may increase or decrease the concentrations of combined hormonal contraceptives; the clinical significance of this potential drug interaction is unknown. Due to the risk of male-mediated teratogenicity, men with female partners of reproductive potential should avoid fathering a child and use effective contraception during and for at least 2 months after enasidenib therapy. Based on information from animal studies, infertility may occur in females or males of reproductive potential. It is not known if infertility is reversible.

    Breast-feeding

    It is not known if enasidenib or its metabolites are secreted in human milk or if it has effects on the breast-fed infant or on milk production. Because there is a potential for adverse reactions in nursing infants from enasidenib, women should discontinue breast-feeding during enasidenib therapy and for at least 2 months after the last dose.

    ADVERSE REACTIONS

    Severe

    hyperbilirubinemia / Delayed / 15.0-15.0
    hypokalemia / Delayed / 15.0-15.0
    hypocalcemia / Delayed / 8.0-8.0
    hypophosphatemia / Delayed / 8.0-8.0
    diarrhea / Early / 8.0-8.0
    leukocytosis / Delayed / 7.0-7.0
    tumor lysis syndrome (TLS) / Delayed / 6.0-6.0
    nausea / Early / 5.0-5.0
    anorexia / Delayed / 4.0-4.0
    vomiting / Early / 2.0-2.0

    Mild

    dysgeusia / Early / 12.0-12.0

    DRUG INTERACTIONS

    Dienogest; Estradiol valerate: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many oral hormonal contraceptives are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown
    Drospirenone: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many oral hormonal contraceptives are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown
    Drospirenone; Estradiol: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many oral hormonal contraceptives are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown
    Drospirenone; Ethinyl Estradiol: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many oral hormonal contraceptives are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many oral hormonal contraceptives are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown
    Elagolix; Estradiol; Norethindrone acetate: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many oral hormonal contraceptives are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown
    Estradiol; Levonorgestrel: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many oral hormonal contraceptives are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown
    Estradiol; Norethindrone: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many oral hormonal contraceptives are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown
    Estradiol; Norgestimate: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many oral hormonal contraceptives are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown
    Ethinyl Estradiol: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many oral hormonal contraceptives are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown
    Ethinyl Estradiol; Desogestrel: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many oral hormonal contraceptives are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown
    Ethinyl Estradiol; Ethynodiol Diacetate: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many oral hormonal contraceptives are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown
    Ethinyl Estradiol; Etonogestrel: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown. (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many oral hormonal contraceptives are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown
    Ethinyl Estradiol; Levonorgestrel: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many oral hormonal contraceptives are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many oral hormonal contraceptives are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many oral hormonal contraceptives are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown
    Ethinyl Estradiol; Norelgestromin: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown. (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many oral hormonal contraceptives are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown
    Ethinyl Estradiol; Norethindrone Acetate: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many oral hormonal contraceptives are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many oral hormonal contraceptives are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown
    Ethinyl Estradiol; Norethindrone: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many oral hormonal contraceptives are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many oral hormonal contraceptives are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown
    Ethinyl Estradiol; Norgestimate: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many oral hormonal contraceptives are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown
    Ethinyl Estradiol; Norgestrel: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many oral hormonal contraceptives are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown
    Etonogestrel: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown.
    Leuprolide; Norethindrone: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many oral hormonal contraceptives are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown
    Levonorgestrel: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many oral hormonal contraceptives are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown
    Mestranol; Norethindrone: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many oral hormonal contraceptives are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown
    Non-oral combination contraceptives: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown.
    Norethindrone: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many oral hormonal contraceptives are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown
    Norgestrel: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many oral hormonal contraceptives are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown
    Oral Contraceptives: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many oral hormonal contraceptives are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown
    Segesterone Acetate; Ethinyl Estradiol: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown. (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many oral hormonal contraceptives are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown

    PREGNANCY AND LACTATION

    Pregnancy

    Enasidenib may cause fetal harm when administered during pregnancy, based on animal studies. Females of reproductive potential should avoid becoming pregnant while taking enasidenib. Discuss the potential hazard to the fetus if enasidenib is used during pregnancy or if a patient becomes pregnant while taking this drug. Embryo-fetal toxicities including decreased fetal birth weights and skeletal variations were observed when enasidenib was administered to pregnant rabbits during organogenesis at doses resulting in exposures of approximately 1.6-times the exposure in humans (at the recommended dose); postimplantation loss, resorptions, and decreased viable fetuses were also reported. Additionally, spontaneous abortion occurred in pregnant rabbits with enasidenib doses resulting in exposures approximately 0.1-times the exposure in humans.

    It is not known if enasidenib or its metabolites are secreted in human milk or if it has effects on the breast-fed infant or on milk production. Because there is a potential for adverse reactions in nursing infants from enasidenib, women should discontinue breast-feeding during enasidenib therapy and for at least 2 months after the last dose.

    MECHANISM OF ACTION

    Enasidenib is an oral isocitrate dehydrogenase-2 (IDH2) inhibitor that targets the mutant IDH2 variants including R140Q, R172S, and R172K; IDH2 inhibition decreases levels of the oncologic metabolite, 2-hydroxyglutarate (2-HG), and causes increased myeloid differentiation, increased mature myeloid cell count, and reduced blast counts in IDH2-mutated acute myelogenous leukemia. In vitro, enasidenib inhibits the mutant IDH2 enzyme at approximately 40-fold lower concentrations than the wild-type enzyme.

    PHARMACOKINETICS

    Enasidenib is administered orally. In vitro, enasidenib and its metabolite (AGI-16903) are 98.5% and 96.6% bound to human plasma proteins, respectively. Following oral administration of enasidenib, the mean volume of distribution (Vd) was 55.8 L (coefficient of variance (CV), 29%), the terminal half-life was 7.9 days, and the mean total body clearance was 0.7 L/hour (CV, 62.5%). Following a radiolabeled dose of enasidenib, 89% of the dose was eliminated in the feces and 11% of the dose was eliminated in the urine; unchanged drug accounted for 34% and 0.4% of the radioactivity recovered in the feces and urine, respectively. Additionally, 89% of the radioactivity in the circulation was enasidenib; 10% of the radioactivity in the circulation was the N-dealkylated metabolite, AGI-16903.
    Affected cytochrome P450 isoenzymes and transporters: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, UGT1A1, UGT1A3, UGT1A4, UGT1A9, UGT2B7, UGT2B15, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporter (OAT)-1, OATP1B1, OATP1B3, and ), and organic cat anion transporter (OCT)-2
    In vitro, enasidenib is metabolized by multiple CYP450 isoenzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) and UDP-glucuronosyltransferases (UGT1A1, UGT1A3, UGT1A4, UGT1A9, UGT2B7, and UGT2B15). AGI-16903 is metabolized by CYP1A2, CYP2C19, CYP3A4, UGT1A1, UGT1A3, and UGT1A9; it is also a substrate of P-gp and BCRP. In vitro studies suggest that enasidenib inhibits CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, UGT1A1, P-gp, BCRP, OAT1, OATP1B1, OATP1B3, and OCT2 and induces CYP2B6 and CYP3A4. In vitro, AGI-16903 inhibits CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, BCRP, OAT1, OAT3, OATP1B1, and OCT2.

    Oral Route

    Following a single oral 100-mg dose, the absolute bioavailability of enasidenib is approximately 57% and the median time to peak concentration (Tmax) is 4 hours. Following enasidenib 100 mg PO daily, the Cmax level was 13.1 mcg/mL (coefficient of variance (CV), 44.8%) at steady state (achieved within 29 days). The AUC values increase proportionally over a dosage range of 50 mg to 450 mg daily. Accumulation is approximately 10-fold when administered once daily.