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Idhifa

Generic Name: Enasidenib Mesylate
Class: Antineoplastic Agents
- Isocitrate Dehydrogenase-2 Inhibitor
- IDH2 Inhibitor
Chemical Name: 2-propanol, 2-methyl-1-[[4-[6-(trifluoromethyl)pyridin-2-yl]-6-[[2-(trifluoromethyl)pyridin-4-yl]amino]-1,3,5-triazin-2-yl]amino] methane sulfonate (1:1)
Molecular Formula: C20H21F6N7O4S
CAS Number: 1650550-25-6

Medically reviewed on Oct 8, 2018

Warning

    Differentiation Syndrome
  • Differentiation syndrome reported with or without concomitant leukocytosis.1 May be life-threatening or fatal.1

  • If signs or symptoms suggestive of the syndrome occur, initiate corticosteroid therapy and monitor hemodynamic parameters until symptoms improve.1 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 therapy.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

  • If pulmonary and/or renal manifestations occur, close monitoring in a hospital setting is recommended.1

Introduction

See also: Xospata

Antineoplastic agent; potent and selective inhibitor of isocitrate dehydrogenase-2 (IDH2).1 9

Uses for Idhifa

Acute Myeloid Leukemia (AML)

For the treatment of relapsed or refractory AML with IDH2 mutation1 2 (designated an orphan drug by FDA for this use).4

FDA-approved diagnostic test (e.g., Abbott RealTime IDH2 assay) required to confirm the presence of IDH2 mutation prior to initiation of therapy.1

Idhifa Dosage and Administration

General

  • Confirm presence of IDH2 mutation (peripheral blood or bone marrow) prior to initiation of therapy.1

  • Monitor CBC counts and blood chemistries prior to initiation of therapy and at least every 2 weeks for at least the initial 3 months of therapy.1 Manage laboratory abnormalities promptly.1 (See Dosage Modification for Toxicity under Dosage.)

Restricted Distribution Program

  • Obtain enasidenib only through designated specialty pharmacies and distributors.3

  • Consult the Idhifa website (https://idhifapro.com/) for specific ordering and availability information.3

Administration

Oral Administration

Administer orally once daily without regard to meals.1 Take at approximately the same time each day.1

Swallow tablets whole with water; do not chew, crush, or split.1

Dosage

Available as enasidenib mesylate; dosage expressed in terms of enasidenib.1

Adults

AML
Oral

100 mg once daily.1 Continue therapy until disease progression or unacceptable toxicity occurs.1 Most patients achieve best response within 6 months of initiating enasidenib; therefore, continue therapy for ≥6 months to allow time for response.1

In patients presenting with leukocytosis (WBC count >30,000/mm3) in absence of infection, initiate hydroxyurea therapy according to standard practices.1 If leukocytosis persists, temporary interruption of enasidenib therapy may be necessary.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

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.1

Leukocytosis
Oral

If leukocytosis persists despite hydroxyurea therapy, withhold enasidenib.1 When WBC count decreases to <30,000/mm3, resume therapy at the same dosage (100 mg daily).1 (See AML under Dosage.)

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.1 When serum bilirubin concentrations improve to <2 times the ULN, re-escalate dosage to 100 mg daily.1 (See Hepatic Effects under Cautions.)

Tumor Lysis Syndrome
Oral

If grade 3 or greater tumor lysis syndrome occurs, withhold enasidenib.1 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.1

If grade 3 or greater tumor lysis syndrome recurs, discontinue enasidenib.1

Other Toxicity
Oral

If grade 3 or greater adverse reaction occurs, withhold enasidenib.1 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.1

If grade 3 or greater adverse reaction recurs, discontinue enasidenib.1

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.1 5 (See Hepatic Impairment under Cautions.)

Renal Impairment

eGFR ≥30 mL/minute: No dosage adjustment required.5 (See Renal Impairment under Cautions.)

Geriatric Patients

No dosage adjustment required.1 (See Geriatric Use under Cautions.)

Cautions for Idhifa

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Warnings

Differentiation Syndrome

Differentiation syndrome associated with IDH2 inhibitor therapy (e.g., enasidenib), 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.1 7 12 Onset: 10 days or up to 5 months after initiation of enasidenib.1 Approximately one-half of patients continue therapy without interruption.7

Risk is increased in patients with bone marrow blast counts >20% and those who have received fewer prior antileukemic therapies.7 12

Differentiation syndrome should be suspected if there is no clear alternate etiology.7 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.1 7 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.1 7 (See Dosage Modification for Toxicity under Dosage and Administration.)

If pulmonary and/or renal manifestations occur, close monitoring in a hospital setting is recommended.1

Other Warnings and Precautions

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity, embryotoxicity, and fetotoxicity demonstrated in animals.1

Confirm pregnancy status prior to initiating enasidenib therapy.1 Avoid pregnancy during therapy.1 Women of childbearing potential and men who are partners of such women should use adequate methods of contraception while receiving the drug and for ≥1 month after the drug is discontinued.1 (See Specific Drugs under Interactions.) If used during pregnancy or if the patient or their partner becomes pregnant during therapy, apprise of potential fetal hazard.1

Hepatic Effects

Elevated serum bilirubin concentrations, sometimes during initial month of therapy, may occur.1 Metabolism of bilirubin may be affected by inhibition of UGT1A1.1 (See Drug Interactions.) Generally not associated with concomitant elevations in ALT and/or AST or other severe hepatic effects.1 Temporary interruption or permanent discontinuance of the drug may be necessary.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Impairment of Fertility

Animal studies suggest enasidenib may impair female and male fertility.1

Specific Populations

Pregnancy

May cause fetal harm.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Confirm pregnancy status prior to initiating enasidenib therapy.1

Lactation

Not known whether enasidenib is distributed into milk.1 Discontinue nursing during therapy and for ≥1 month after drug discontinuance.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

No overall differences in safety and efficacy relative to younger adults.1 (See Special Populations under Pharmacokinetics.)

Hepatic Impairment

In a population pharmacokinetic analysis, systemic exposure not altered by mild hepatic impairment.1 5 (See Special Populations under Pharmacokinetics.) However, exposure may be increased, since enasidenib is principally metabolized by the liver.5

Renal Impairment

Formal pharmacokinetic studies not conducted in patients with renal impairment.5

In a population pharmacokinetic analysis, systemic exposure not altered by renal impairment.1 5 (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Relapsed or refractory AML: Nausea,1 diarrhea,1 decreased appetite,1 vomiting,1 differentiation syndrome,1 dysgeusia,1 noninfectious leukocytosis (may present as a rapid rise in WBC),1 tumor lysis syndrome,1 hyperbilirubinemia,1 hypocalcemia,1 hypokalemia,1 hypophosphatemia.1

Interactions for Idhifa

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.1

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

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 OAT3.1

Enasidenib is not a substrate of P-gp, BCRP, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2.1

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

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

AGI-16903 inhibits BCRP, OAT1, OAT3, OATP1B1, and OCT2; does not inhibit P-gp, MRP2, or OATP1B3.1

AGI-16903 is a substrate of P-gp and BCRP.1 Not a substrate of MRP2, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2.1

Specific Drugs

Drug

Interaction

Combination hormonal contraceptives (e.g., estrogen-progestin combinations)

Possible increased or decreased plasma concentrations of combination hormonal contraceptive1

Clinical relevance unknown1

Idhifa Pharmacokinetics

Absorption

Bioavailability

Absolute oral bioavailability is 57%.1

AUC is dose proportional over the enasidenib dosage range of 50–450 mg daily.1

Following oral administration of a single dose, peak plasma concentrations are attained in a median of 4 hours.1

Mean systemic accumulation ratio is tenfold when administered daily.1

Steady-state concentrations are achieved within 29 days.1

Food

High-fat meal increased systemic exposure of enasidenib by 50%.5

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.1 5

In a population pharmacokinetic analysis, renal impairment did not alter systemic exposure.1 5

Age (19–100 years), gender, race, body weight (39–136 kg), or body surface area do not affect pharmacokinetics.1 5

Distribution

Extent

Not known whether enasidenib or its metabolites are distributed into human milk.1

Plasma Protein Binding

Enasidenib: 98.5%.1

AGI-16903: 96.6%.1

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 2B15.1

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

Elimination Route

Eliminated mainly in feces (89%) and to a lesser extent in urine (11%), mainly as metabolites.1

Half-life

137 hours.1

Stability

Storage

Oral

Tablets

20–25ºC (may be exposed to 15–30ºC).1

Actions

  • Potent and selective inhibitor of IDH2.1 9

  • Approximately 15–20% of AML cases carry IDH2 mutations.2 8 Most common IDH2 mutation is point mutation at active site arginine residue R140Q of IDH2 (IDH2 R140Q);6 8 9 10 13 point mutation at active site arginine residue R172K (IDH2 R172K) occurs less frequently.8 10 13

  • 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.2 5 10 11 12 13

  • In vitro, inhibits IDH2 with R140Q, R172S, and R172K mutations at approximately 40-fold lower concentrations than IDH2 wild-type enzymes.1

  • Decreased 2-hydroxyglutarate levels and induced myeloid cell differentiation in vitro and in mice bearing tumor xenografts that expressed IDH2 mutation.1

  • Decreased 2-hydroxyglutarate levels, reduced blast cell counts, and increased percentages of mature myeloid cells in patients with AML that expressed IDH2 mutation.1

Advice to Patients

  • Importance of advising patients to swallow enasidenib tablets whole with a full glass of water and not to chew, crush, or split the tablets.1

  • Importance of advising patients to take enasidenib as directed by their clinician and at approximately the same time each day.1 If a dose is missed, importance of administering the missed dose on the same day as soon as it is remembered.1 Advise patients not to take 2 doses on the same day to make up for a missed dose.1

  • Risk of developing differentiation syndrome.1 Importance of advising 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.1

  • Risk of tumor lysis syndrome.1 Importance of monitoring blood chemistry and maintaining adequate hydration during enasidenib therapy.1

  • Risk of diarrhea, nausea, vomiting, decreased appetite, and taste changes.1 Importance of contacting clinician if any of these adverse reactions occur.1

  • Risk of elevated serum bilirubin concentrations.1 Importance of contacting clinician if jaundice occurs.1

  • Risk of fetal harm.1 Necessity of advising women of childbearing potential and men who are partners of such women that they should use adequate methods of contraception while receiving the drug and for ≥1 month after the drug is discontinued.1 Importance of informing patients of potential pharmacokinetic interaction between enasidenib and combination hormonal contraceptives.1 Importance of patients informing their clinicians if they or their partners are pregnant or think they may be pregnant.1 If pregnancy occurs, advise patient of potential risk to fetus.1

  • Importance of advising women to discontinue nursing during therapy and for ≥1 month after discontinuance of the drug.1

  • 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.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

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 distributors.3 (See Restricted Distribution under Dosage and Administration: General.)

Enasidenib Mesylate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

50 mg (of enasidenib)

Idhifa

Celgene

100 mg (of enasidenib)

Idhifa

Celgene

AHFS DI Essentials™. © Copyright 2019, Selected Revisions October 8, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Celgene. Idhifa (enasidenib) tablets prescribing information. Summit, NJ; 2017 Aug.

2. Stein EM, DiNardo CD, Pollyea DA et al. Enasidenib in mutant relapsed or refractory acute myeloid leukemia. Blood. 2017; 130:722-731. http://www.ncbi.nlm.nih.gov/pubmed/28588020?dopt=AbstractPlus

3. Celgene. Idhifa: Access and support resources and celgene patient support. From Celgene for Healthcare Professionals website. Accessed 2018 May 11. https://idhifapro.com/access-and-support/

4. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2018 May 11. http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm

5. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 209606Orig1s000: Multi-discipline review. From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf

6. Chen J, Yang J, Sun X et al. Allosteric inhibitor remotely modulates the conformation of the orthestric pockets in mutant IDH2/R140Q. Sci Rep. 2017; 7:16458. http://www.ncbi.nlm.nih.gov/pubmed/29184081?dopt=AbstractPlus

7. Fathi AT, DiNardo CD, Kline I et al. Differentiation Syndrome Associated With Enasidenib, a Selective Inhibitor of Mutant Isocitrate Dehydrogenase 2: Analysis of a Phase 1/2 Study. JAMA Oncol. 2018; http://www.ncbi.nlm.nih.gov/pubmed/29346478?dopt=AbstractPlus

8. Stein EM. Molecular Pathways: IDH2 Mutations-Co-opting Cellular Metabolism for Malignant Transformation. Clin Cancer Res. 2016; 22:16-9. http://www.ncbi.nlm.nih.gov/pubmed/26553750?dopt=AbstractPlus

9. Yen K, Travins J, Wang F et al. AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic Mutations. Cancer Discov. 2017; 7:478-493. http://www.ncbi.nlm.nih.gov/pubmed/28193778?dopt=AbstractPlus

10. Perl AE. The role of targeted therapy in the management of patients with AML. Blood Adv. 2017; 1:2281-2294. http://www.ncbi.nlm.nih.gov/pubmed/29296877?dopt=AbstractPlus

11. Nassereddine S, Lap CJ, Haroun F et al. The role of mutant IDH1 and IDH2 inhibitors in the treatment of acute myeloid leukemia. Ann Hematol. 2017; 96:1983-1991. http://www.ncbi.nlm.nih.gov/pubmed/29090344?dopt=AbstractPlus

12. Patel SA. Enasidenib-Induced Differentiation Syndrome in IDH2-Mutant Acute Myeloid Leukemia. JAMA Oncol. 2018; http://www.ncbi.nlm.nih.gov/pubmed/29346477?dopt=AbstractPlus

13. Stein EM. Enasidenib, a targeted inhibitor of mutant IDH2 proteins for treatment of relapsed or refractory acute myeloid leukemia. Future Oncol. 2018; 14:23-40. http://www.ncbi.nlm.nih.gov/pubmed/29243965?dopt=AbstractPlus

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