Enasidenib Mesylate (Monograph)

Brand name: Idhifa
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Jun 10, 2024. Written by ASHP.

Introduction

Antineoplastic agent; potent and selective inhibitor of isocitrate dehydrogenase-2 (IDH2).

Uses for Enasidenib Mesylate

Acute Myeloid Leukemia (AML)

For the treatment of relapsed or refractory AML with IDH2 mutation (designated an orphan drug by FDA for this use).

FDA-approved diagnostic test (e.g., Abbott RealTime IDH2 assay) required to confirm the presence of IDH2 mutation prior to initiation of therapy.

Enasidenib Mesylate Dosage and Administration

General

Pretreatment Screening

• Confirm presence of IDH2 mutation (peripheral blood or bone marrow) prior to initiation of therapy.

• Assess CBC and blood chemistries for leukocytosis and tumor lysis syndrome prior to initiation of therapy.

• Verify pregnancy status in females of reproductive potential prior to initiation of therapy.

Patient Monitoring

• Monitor CBC and blood chemistries at least every 2 weeks for at least the initial 3 months of therapy.

• Monitor for signs and symptoms of differentiation syndrome (e.g., fever, dyspnea, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusion, rapid weight gain, peripheral edema, lymphadenopathy, bone pain, and hepatic, renal, or multiorgan dysfunction).

Administration

Oral Administration

Administer orally once daily without regard to meals. Take at approximately the same time each day.

Swallow tablets whole with water; do not chew, crush, or split.

If a dose is vomited, missed, or not taken at the usual time, administer the dose as soon as possible on the same day, and then return to the normal schedule the following day. Do not take 2 doses to make up for a missed dose.

Dosage

Available as enasidenib mesylate; dosage expressed in terms of enasidenib.

Adults

AML

Oral

100 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs. Most patients achieve best response within 6 months of initiating enasidenib; therefore, continue therapy for ≥6 months to allow time for response.

In patients presenting with leukocytosis (WBC count >30,000/mm³) in absence of infection, initiate hydroxyurea therapy according to standard practices. If leukocytosis persists, temporary interruption of enasidenib therapy may be necessary.

Dosage Modification for Toxicity

Differentiation Syndrome

Oral

If severe pulmonary symptoms requiring respiratory support (i.e., intubation, assisted respiration) occur and/or renal dysfunction persists for >48 hours despite systemic corticosteroid therapy, withhold enasidenib until toxicity improves to grade 2 or less.

Leukocytosis

Oral

If leukocytosis persists despite hydroxyurea therapy, withhold enasidenib. When WBC count decreases to <30,000/mm³, resume therapy at the same dosage (100 mg daily).

Hepatotoxicity

Oral

If serum bilirubin concentrations >3 times the ULN for ≥2 weeks (in the absence of elevated ALT/AST concentrations or other hepatic disorders), continue therapy at a reduced dosage of 50 mg daily. When serum bilirubin concentrations improve to <2 times the ULN, re-escalate dosage to 100 mg daily.

Tumor Lysis Syndrome

Oral

If grade 3 or greater tumor lysis syndrome occurs, withhold enasidenib. When tumor lysis syndrome improves to grade 2 or less, resume enasidenib at a reduced dosage of 50 mg daily; may re-escalate dosage to 100 mg daily when tumor lysis syndrome improves to grade 1 or less.

If grade 3 or greater tumor lysis syndrome recurs, discontinue enasidenib.

Other Toxicity

Oral

If grade 3 or greater adverse reaction occurs, withhold enasidenib. When toxicity improves to grade 2 or less, resume enasidenib at a reduced dosage of 50 mg daily; may re-escalate dosage to 100 mg daily when toxicity improves to grade 1 or less.

If grade 3 or greater adverse reaction recurs, discontinue enasidenib.

Special Populations

Hepatic Impairment

Mild hepatic impairment (total bilirubin concentration not exceeding the ULN with AST concentration exceeding the ULN or total bilirubin concentration 1–1.5 times the ULN with any AST concentration): No dosage adjustment required.

Renal Impairment

eGFR ≥30 mL/minute: No dosage adjustment required.

Geriatric Patients

No dosage adjustment required.

Cautions for Enasidenib Mesylate

Contraindications

• None.

Warnings/Precautions

Warnings

Differentiation Syndrome

Differentiation syndrome associated with IDH2 inhibitor therapy (e.g., enasidenib) reported. (See Boxed Warning.) Characterized by acute respiratory distress (dyspnea and/or hypoxia), hypoxia requiring supplemental oxygen, pulmonary infiltrates, renal or hepatic impairment, multiorgan dysfunction, pyrexia, lymphadenopathy, bone pain, peripheral edema, rapid weight gain, and pleural or pericardial effusions; can occur with or without concomitant leukocytosis. Onset is 1 day or up to 5 months after initiation of enasidenib. Approximately one-half of patients continue therapy without interruption.

Risk is increased in patients with bone marrow blast counts >20% and those who have received fewer prior antileukemic therapies.

Early recognition and treatment of differentiation syndrome lessens the likelihood of severe illness and death. Differentiation syndrome should be suspected if there is no clear alternate etiology. If signs or symptoms suggestive of the syndrome occur, initiate IV or oral corticosteroid therapy (e.g., dexamethasone 10 mg every 12 hours until symptoms resolve followed by tapering of the dexamethasone dosage) and monitor hemodynamic parameters until symptoms improve. If severe pulmonary symptoms requiring respiratory support (i.e., intubation, assisted respiration) occur and/or renal dysfunction persists for >48 hours despite corticosteroid therapy, interrupt enasidenib therapy.

If pulmonary and/or renal manifestations occur, close monitoring in a hospital setting is recommended.

Other Warnings and Precautions

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity, embryotoxicity, and fetotoxicity demonstrated in animals.

Avoid pregnancy during therapy. Females of reproductive potential and males who are partners of such females should use adequate methods of contraception while receiving the drug and for 2 months after the drug is discontinued. Patients using hormonal contraceptives should use an effective non-hormonal contraceptive method during treatment with enasidenib and for 2 months after final dose.

Specific Populations

Pregnancy

May cause fetal harm.

Confirm pregnancy status prior to initiating enasidenib therapy. If used during pregnancy or if the patient or their partner becomes pregnant during therapy, inform patient of potential fetal hazard.

Lactation

Not known whether enasidenib is distributed into human milk. Discontinue nursing during therapy and for 2 months after drug discontinuance.

Females and Males of Reproductive Potential

Females of reproductive potential and males who are partners of such females should use adequate methods of contraception while receiving the drug and for 2 months after the drug is discontinued. Advise patients using hormonal contraceptives to use an effective non-hormonal contraceptive method during treatment with enasidenib and for 2 months after final dose.

Animal studies suggest enasidenib may impair female and male fertility.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No overall differences in safety and efficacy relative to younger adults.

Hepatic Impairment

In a population pharmacokinetic analysis, systemic exposure not altered by mild hepatic impairment. However, exposure may be increased, since enasidenib is principally metabolized by the liver.

Renal Impairment

In a population pharmacokinetic analysis, systemic exposure not altered by renal impairment.

Common Adverse Effects

Common adverse reactions (≥20%): nausea, vomiting, diarrhea, elevated bilirubin, decreased appetite

Drug Interactions

Enasidenib is metabolized by CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 and by UGT1A1, 1A3, 1A4, 1A9, 2B7, and 2B15 to active AGI-16903 metabolite.

Enasidenib inhibits CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4; also inhibits UGT1A1. Induces CYP isoenzymes 2B6 and 3A4.

Enasidenib inhibits P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporter (OAT) 1, organic anion transport protein (OATP) 1B1, OATP1B3, and organic cation transporter (OCT) 2; does not inhibit multidrug resistance protein 2 (MRP2) or OAT3.

Enasidenib is not a substrate of P-gp, BCRP, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2.

AGI-16903 is metabolized by CYP isoenzymes 1A2, 2C19, and 3A4 and by UGT1A1, 1A3, and 1A9.

AGI-16903 inhibits CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, and 2D6.

AGI-16903 inhibits BCRP, OAT1, OAT3, OATP1B1, and OCT2; does not inhibit P-gp, MRP2, or OATP1B3.

AGI-16903 is a substrate of P-gp and BCRP. Not a substrate of MRP2, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2.

Drugs Affecting or Affected by Hepatic Microsomal Enzymes

Substrates of CYP1A2 and CYP2C19: Potential increased systemic exposure to substrate drug and increased risk of adverse reactions to the drug. Avoid concomitant use with enasidenib unless otherwise recommended in the prescribing information for CYP1A2 or CYP2C19 substrates where minimal concentration changes may lead to serious adverse reactions. For caffeine, consider reducing frequency of caffeine intake in a 24 hour period while taking enasidenib as the drug may increase caffeine-related effects in sensitive individuals.

Substrates of CYP3A: Potential decreased systemic exposure to substrate drug and reduced efficacy of the drug. Avoid concomitant use with enasidenib unless otherwise recommended in the prescribing information for CYP3A substrates where minimal concentration changes may lead to reduced efficacy. Do not administer antifungal agents that are CYP3A substrates with enasidenib. Concomitant administration of enasidenib with hormonal contraceptives may reduce plasma concentrations of the hormonal contraceptive; consider alternative methods of contraception if receiving enasidenib.

Substrates of Transport Systems

Substrates of OATP1B1, OATP1B3, and BCRP: Potential increased systemic exposure to substrate drug and increased risk of adverse reactions to the drug. If concomitant use of enasidenib with a OATP1B1, OATP1B3, and BCRP substrate is necessary, the dosage of the substrate drug should be reduced in accordance with the respective prescribing information.

Substrates of P-gp: Potential increased systemic exposure to substrate drug and increased risk of adverse reactions to the drug. If concomitant use of enasidenib with a sensitive P-gp substrate is necessary, follow recommendations within the P-gp substrate prescribing information and monitor more frequently for adverse reactions.

Specific Drugs

Enasidenib Mesylate Pharmacokinetics

Absorption

Bioavailability

Absolute oral bioavailability is 57%.

AUC is dose proportional over the enasidenib dosage range of 50–450 mg daily.

Following oral administration of a single dose, peak plasma concentrations are attained in a median of 4 hours.

Mean systemic accumulation ratio is tenfold when administered daily.

Steady-state concentrations are achieved within 29 days.

Food

High-fat meal increased systemic exposure of enasidenib by 50%.

Special Populations

In a population pharmacokinetic analysis, mild hepatic impairment (total bilirubin concentration not exceeding the ULN with AST concentration exceeding the ULN or total bilirubin concentration 1–1.5 times the ULN with any AST concentration) did not alter systemic exposure.

In a population pharmacokinetic analysis, renal impairment did not alter systemic exposure.

Age (19–100 years), gender, race, body weight (39–136 kg), or body surface area do not affect pharmacokinetics.

Distribution

Extent

Not known whether enasidenib or its metabolites are distributed into human milk.

Plasma Protein Binding

Enasidenib: 98.5%.

AGI-16903: 96.6%.

Elimination

Metabolism

Enasidenib: Metabolized to active AGI-16903 metabolite by CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 and by UGT1A1, 1A3, 1A4, 1A9, 2B7, and 2B15.

AGI-16903 subsequently metabolized by CYP isoenzymes 1A2, 2C19, and 3A4 and by UGT1A1, 1A3, and 1A9.

Elimination Route

Eliminated mainly in feces (89%) and to a lesser extent in urine (11%), mainly as metabolites.

Half-life

7.9 days.

Stability

Storage

Oral

Tablets

20–25ºC (excursions permitted between 15–30ºC); store in original container with desiccant.

Actions

• Potent and selective inhibitor of IDH2.

• Approximately 15–20% of AML cases carry IDH2 mutations. Most common IDH2 mutation is point mutation at active site arginine residue R140Q of IDH2 (IDH2 R140Q); point mutation at active site arginine residue R172K (IDH2 R172K) occurs less frequently.

• IDH2 mutations cause a reduction of α-ketoglutarate to the oncometabolite 2-hydroxyglutarate resulting in epigenetic dysregulation and subsequent histone and DNA hypermethylation and differentiation arrest of hematopoietic stem cells.

• In vitro, inhibits IDH2 with R140Q, R172S, and R172K mutations at approximately 40-fold lower concentrations than IDH2 wild-type enzymes.

• Decreased 2-hydroxyglutarate levels and induced myeloid cell differentiation in vitro and in mice bearing tumor xenografts that expressed IDH2 mutation.

• Decreased 2-hydroxyglutarate levels, reduced blast cell counts, and increased percentages of mature myeloid cells in patients with AML that expressed IDH2 mutation.

Advice to Patients

• Advise patients to swallow enasidenib tablets whole with a full glass of water and not to chew, crush, or split the tablets.

• Advise patients to take enasidenib as directed by their clinician and at approximately the same time each day. If a dose is missed, administer the missed dose on the same day as soon as it is remembered. Advise patients not to take 2 doses on the same day to make up for a missed dose.

• Risk of developing differentiation syndrome. Advise patients to immediately report possible symptoms of differentiation syndrome (e.g., pyrexia, cough, difficulty breathing, bone pain, rapid weight gain, peripheral edema) to their clinician.

• Risk of tumor lysis syndrome. Importance of monitoring blood chemistry and maintaining adequate hydration during enasidenib therapy.

• Risk of diarrhea, nausea, vomiting, decreased appetite, and taste changes. Importance of contacting clinician if any of these adverse reactions occur.

• Risk of elevated serum bilirubin concentrations. Importance of contacting clinician if jaundice occurs.

• Risk of fetal harm. Advise females of reproductive potential and males who are partners of such females that they should use adequate methods of contraception while receiving the drug and for 2 months after the drug is discontinued. Advise females of reproductive potential to use an effective non-hormonal contraceptive method while receiving the drug and for 2 months after the last dose. Importance of patients informing their clinicians if they or their partners are pregnant or think they may be pregnant. If pregnancy occurs, advise patient of potential risk to fetus.

• Advise females to discontinue nursing during therapy and for 2 months after discontinuance of the drug.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (e.g,. combination hormonal contraceptives) and dietary or herbal supplements, as well as any concomitant illnesses.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Enasidenib mesylate can only be obtained through select specialty pharmacies and distributors. Consult manufacturer's website for specific availability information.

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Frequently asked questions

• What is Idhifa used to treat?

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