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Enasidenib (Canada: Withdrawn from market): Drug information

Enasidenib (Canada: Withdrawn from market): Drug information
(For additional information see "Enasidenib (Canada: Withdrawn from market): Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Special Alerts
Canadian Market Withdrawal and Continued Access June 2023

Health Canada has announced that IDHIFA (enasidenib) will be withdrawn from the Canadian market on June 30, 2023. IDHIFA failed to demonstrate improved overall survival in adult patients with late-stage acute myeloid leukemia and an IDH2 mutation when compared with conventional care regimens in a phase 3 confirmatory study. Health care providers are advised to:

  • Not initiate IDHIFA in new patients.

  • Discuss with their patients whether to continue treatment with IDHIFA.

  • Apply to Health Canada's Special Access Program to request IDHIFA for patients who require continued treatment.

Further information may be found at https://recalls-rappels.canada.ca/en/alert-recall/idhifa-enasidenib-mesylate-market-withdrawal-and-continued-access.

ALERT: US Boxed Warning
Differentiation syndrome:

Patients treated with enasidenib 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.

Brand Names: US
  • IDHIFA
Brand Names: Canada
  • IDHIFA [DSC]
Pharmacologic Category
  • Antineoplastic Agent, IDH2 Inhibitor
Dosing: Adult

Note: Confirm IDH2 mutation status in the blood or bone marrow prior to treatment initiation. Enasidenib is associated with a moderate or high emetic potential; antiemetics are recommended to prevent nausea and vomiting (ASCO [Hesketh 2020]).

Acute myeloid leukemia, IDH2-mutated

Acute myeloid leukemia, IDH2-mutated, relapsed/refractory: Oral: 100 mg once daily until disease progression or unacceptable toxicity; treat for a minimum of 6 months in patients without disease progression or unacceptable toxicity to allow time for clinical response.

Acute myeloid leukemia, IDH2-mutated, newly diagnosed (off-label use): Patients ≥60 years of age (and unfit for standard therapy): Oral: 100 mg once daily until disease progression or unacceptable toxicity (Pollyea 2019; Stein 2020b).

Myelodysplastic syndromes, IDH2-mutated, high-risk, relapsed/refractory

Myelodysplastic syndromes, IDH2-mutated, high-risk, relapsed/refractory (off-label use): Oral: 100 mg once daily until disease progression or unacceptable toxicity (Stein 2020a; Venugopal 2021).

Missed dose: If a dose is vomited, missed, or delayed, administer the dose as soon as possible on the same day; return to the normal administration schedule the following day.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling; however, this level of renal function does not have a clinically significant effect on enasidenib pharmacokinetics. No dosage adjustment is necessary (Krens 2019).

CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling. However, no need for dosage adjustment is expected (Krens 2019).

Hemodialysis: No need for dosage adjustment is expected (Krens 2019).

Dosing: Hepatic Impairment: Adult

Hepatic impairment prior to treatment initiation:

Mild (total bilirubin within ULN and AST > ULN or total bilirubin 1 to 1.5 times ULN and any AST) impairment: There are no dosage adjustments provided in the manufacturer's labeling; however, mild hepatic impairment does not have a clinically significant effect on enasidenib pharmacokinetics. No dosage adjustment is necessary (Krens 2019).

Moderate impairment (total bilirubin >1.5 to 3 times ULN and any AST): There are no dosage adjustments provided in the manufacturer's labeling. However, a 50% dosage reduction may be considered (Krens 2019).

Severe impairment (total bilirubin >3 times ULN and any AST): There are no dosage adjustments provided in the manufacturer's labeling. Use is not recommended (Krens 2019).

Hepatotoxicity during treatment: Bilirubin >3 times ULN for ≥2 weeks without elevated transaminases or other hepatic disorders: Reduce dose to 50 mg once daily. Resume enasidenib at 100 mg once daily if bilirubin elevation resolves to <2 times ULN.

Dosing: Adjustment for Toxicity: Adult

Differentiation syndrome: If differentiation syndrome is suspected, initiate systemic corticosteroids (eg, dexamethasone IV or oral 10 mg twice daily) and monitor hemodynamics. Interrupt enasidenib for severe pulmonary symptoms requiring intubation or ventilator support and/or renal dysfunction persisting for more than 48 hours after systemic corticosteroid initiation. Resume enasidenib when signs/symptoms improve to ≤ grade 2. Taper systemic corticosteroids only after symptom resolution (symptoms may recur if corticosteroids are discontinued prematurely).

Noninfectious leukocytosis (WBC >30,000/mm3): Initiate hydroxyurea (per standard institutional practice); interrupt enasidenib if leukocytosis is not improved with hydroxyurea therapy, then resume enasidenib at 100 mg once daily when WBC <30,000/mm3.

Other toxicity: Grade 3 or higher (attributed to enasidenib [including tumor lysis syndrome]): Interrupt enasidenib until toxicity improves to ≤ grade 2. Resume enasidenib at 50 mg once daily; may increase to 100 mg once daily if toxicity resolves to ≤ grade 1. If ≥ grade 3 toxicity recurs, discontinue enasidenib.

Dosing: Older Adult

Refer to adult dosing.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%:

Endocrine & metabolic: Decreased serum calcium (74%), decreased serum potassium (41%)

Gastrointestinal: Nausea (50%), diarrhea (43%), decreased appetite (34%), vomiting (34%), dysgeusia (12%)

Hematologic & oncologic: Abnormal phosphorus levels (27%; ≥3 grade: 8%; decreased), differentiation syndrome (14%), leukocytosis (12%; ≥3 grade: 6%; noninfectious)

Hepatic: Increased serum bilirubin (81%)

1% to 10%:

Hematologic & oncologic: Tumor lysis syndrome (6%)

Respiratory: Acute respiratory distress (≤10%), pulmonary edema (≤10%)

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Additional contraindications (not in the US labeling): Hypersensitivity to enasidenib or any component of the formulation.

Warnings/Precautions

Concerns related to adverse effects:

• Differentiation syndrome: Patients treated with enasidenib 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. Differentiation syndrome, which is associated with rapid proliferation and differentiation of myeloid cells, has occurred (with and without concomitant hyperleukocytosis) as early as 1 day and up to 5 months after initiating enasidenib. Hospitalization is recommended for patients with pulmonary and/or renal toxicity for close monitoring.

• Electrolyte imbalance: Hypocalcemia, hypokalemia, and hypophosphatemia have been reported.

• Hematologic effects: Noninfectious leukocytosis may occur due to myeloid proliferation leading to a rapid rise in white blood cell count.

• Hepatotoxicity: Hyperbilirubinemia has been commonly reported; the majority of patients did not have concomitant transaminase elevation or other severe toxicity due to other liver disorders. Enasidenib may interfere with bilirubin metabolism through UGT1A1 inhibition.

• Tumor lysis syndrome: Tumor lysis syndrome may occur.

Other warnings/precautions:

• Appropriate use: Confirm IDH2 mutation status prior to therapy initiation. Information on tests approved to detect IDH2 mutation in AML may be found at http://www.FDA.gov/CompanionDiagnostics.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

IDHIFA: 50 mg, 100 mg

Generic Equivalent Available: US

No

Pricing: US

Tablets (IDHIFA Oral)

50 mg (per each): $1,359.78

100 mg (per each): $1,359.78

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral:

IDHIFA: 50 mg [DSC], 100 mg [DSC]

Prescribing and Access Restrictions

Enasidenib is available through select specialty pharmacies and authorized distributors. Refer to http://www.idhifa.com for further information.

Administration: Adult

Enasidenib is associated with a moderate or high emetic potential; antiemetics are recommended to prevent nausea and vomiting (ASCO [Hesketh 2020]).

Oral: Administer orally once daily with or without food at approximately the same time each day. Swallow whole with a glass of water. Do not chew, crush, or split tablets.

Hazardous Drugs Handling Considerations

This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Enasidenib may cause teratogenicity and reproductive toxicity.

Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).

Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209606s004lbl.pdf#page=17

Use: Labeled Indications

Acute myeloid leukemia (relapsed/refractory): Treatment of relapsed or refractory acute myeloid leukemia (AML) in adults with an isocitrate dehydrogenase-2 (IDH2) mutation as detected by an approved test.

Use: Off-Label: Adult

Acute myeloid leukemia, newly diagnosed; Myelodysplastic syndromes, high-risk, relapsed/refractory

Medication Safety Issues
Sound-alike/look-alike issues:

Enasidenib may be confused with afatinib, avapritinib, ceritinib, dasatinib, encorafenib, entrectinib, erdafitinib, erlotinib, idelalisib, imatinib, ivosidenib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, niraparib, ponatinib, regorafenib, SUNItinib

High alert medication:

This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

Metabolism/Transport Effects

Substrate of CYP1A2 (minor), CYP2B6 (minor), CYP2C19 (minor), CYP2C8 (minor), CYP2C9 (minor), CYP2D6 (minor), CYP3A4 (minor), UGT1A1, UGT1A3, UGT1A4, UGT1A9, UGT2B15, UGT2B7; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits BCRP/ABCG2, CYP1A2 (strong), CYP2C19 (weak), CYP2D6 (weak), OATP1B1/1B3 (SLCO1B1/1B3); Induces CYP3A4 (weak)

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Agomelatine: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Agomelatine. Risk X: Avoid combination

Alosetron: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Alosetron. Risk X: Avoid combination

Alpelisib: BCRP/ABCG2 Inhibitors may increase the serum concentration of Alpelisib. Management: Avoid coadministration of BCRP/ABCG2 inhibitors and alpelisib due to the potential for increased alpelisib concentrations and toxicities. If coadministration cannot be avoided, closely monitor for increased alpelisib adverse reactions. Risk D: Consider therapy modification

Anagrelide: CYP1A2 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Anagrelide. CYP1A2 Inhibitors (Strong) may increase the serum concentration of Anagrelide. Risk C: Monitor therapy

Antifungal Agents (Azole Derivatives, Systemic): Enasidenib may decrease the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). Risk X: Avoid combination

Asenapine: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Asenapine. Risk C: Monitor therapy

Asunaprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Asunaprevir. Risk X: Avoid combination

Atogepant: Enasidenib may increase the serum concentration of Atogepant. Enasidenib may decrease the serum concentration of Atogepant. Management: Consider avoiding this combination if possible, as enasidenib is both an OATP1B1/1B3 inhibitor and weak CYP3A4 inducer, with unknown net effects on atogepant exposure. Risk D: Consider therapy modification

Bendamustine: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Bendamustine. Concentrations of the active metabolites of bendamustine may be decreased. Management: Consider alternatives to strong CYP1A2 inhibitors during therapy with bendamustine due to the potential for increased bendamustine plasma concentrations and increased bendamustine toxicity. Risk D: Consider therapy modification

Berotralstat: BCRP/ABCG2 Inhibitors may increase the serum concentration of Berotralstat. Management: Decrease the berotralstat dose to 110 mg daily when combined with BCRP inhibitors. Risk D: Consider therapy modification

Brincidofovir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Brincidofovir. Management: Consider alternatives to OATP1B/1B3 inhibitors in patients treated with brincidofovir. If coadministration is required, administer OATP1B1/1B3 inhibitors at least 3 hours after brincidofovir and increase monitoring for brincidofovir adverse reactions. Risk D: Consider therapy modification

Bromazepam: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Bromazepam. Risk C: Monitor therapy

Caffeine and Caffeine Containing Products: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Caffeine and Caffeine Containing Products. Risk C: Monitor therapy

CarBAMazepine: CYP3A4 Inducers (Weak) may decrease the serum concentration of CarBAMazepine. Risk C: Monitor therapy

Cladribine: BCRP/ABCG2 Inhibitors may increase the serum concentration of Cladribine. Management: Avoid concomitant use of BCRP inhibitors during the 4 to 5 day oral cladribine treatment cycles whenever possible. If combined, consider dose reduction of the BCRP inhibitor and separation in the timing of administration. Risk D: Consider therapy modification

CloBAZam: CYP2C19 Inhibitors (Weak) may increase serum concentrations of the active metabolite(s) of CloBAZam. CYP2C19 Inhibitors (Weak) may increase the serum concentration of CloBAZam. Risk C: Monitor therapy

ClomiPRAMINE: CYP1A2 Inhibitors (Strong) may increase the serum concentration of ClomiPRAMINE. Risk C: Monitor therapy

CloZAPine: CYP1A2 Inhibitors (Strong) may increase the serum concentration of CloZAPine. Management: Reduce the dose of clozapine to one-third of the original dose when adding a strong CYP1A2 inhibitor and monitor patient response closely. Return to the original clozapine dose when the strong CYP1A2 inhibitor is discontinued. Risk D: Consider therapy modification

Digoxin: Enasidenib may increase the serum concentration of Digoxin. Risk C: Monitor therapy

DULoxetine: CYP1A2 Inhibitors (Strong) may increase the serum concentration of DULoxetine. Risk X: Avoid combination

Elagolix: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Elagolix. Risk X: Avoid combination

Elagolix, Estradiol, and Norethindrone: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Elagolix, Estradiol, and Norethindrone. Specifically, concentrations of elagolix may be increased. Risk X: Avoid combination

Elbasvir and Grazoprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Elbasvir and Grazoprevir. Risk X: Avoid combination

Eluxadoline: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Eluxadoline. Management: Decrease the eluxadoline dose to 75 mg twice daily if combined with OATP1B1/1B3 inhibitors and monitor patients for increased eluxadoline effects/toxicities. Risk D: Consider therapy modification

Fenfluramine: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Fenfluramine. Management: Limit fenfluramine dose to 20 mg/day without concurrent stiripentol or to 17 mg/day with concomitant stiripentol and clobazam when used with a strong CYP1A2 inhibitor. Risk D: Consider therapy modification

Fezolinetant: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Fezolinetant. Risk X: Avoid combination

Fosphenytoin-Phenytoin: CYP2C19 Inhibitors (Weak) may increase the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

Hormonal Contraceptives: CYP3A4 Inducers (Weak) may decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing a weak CYP3A4 inducer to ensure contraceptive reliability. Risk D: Consider therapy modification

Levobupivacaine: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine. Risk C: Monitor therapy

Lidocaine (Systemic): CYP1A2 Inhibitors (Strong) may increase the serum concentration of Lidocaine (Systemic). Risk C: Monitor therapy

Mavacamten: CYP2C19 Inhibitors (Weak) may increase the serum concentration of Mavacamten. Management: Start mavacamten at 5 mg/day if stable on a weak CYP2C19 inhibitor. For those stable on mavacamten who are initiating a weak CYP2C19 inhibitor, reduce mavacamten dose by one dose level. Risk D: Consider therapy modification

Melatonin: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Melatonin. Risk X: Avoid combination

Mexiletine: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Mexiletine. Risk C: Monitor therapy

Mitapivat: May decrease the serum concentration of UGT1A1 Substrates. Risk C: Monitor therapy

Momelotinib: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Momelotinib. Risk C: Monitor therapy

NiMODipine: CYP3A4 Inducers (Weak) may decrease the serum concentration of NiMODipine. Risk C: Monitor therapy

OLANZapine: CYP1A2 Inhibitors (Strong) may increase the serum concentration of OLANZapine. Risk C: Monitor therapy

PAZOPanib: BCRP/ABCG2 Inhibitors may increase the serum concentration of PAZOPanib. Risk X: Avoid combination

Pentoxifylline: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Pentoxifylline. Risk C: Monitor therapy

Pirfenidone: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Pirfenidone. Management: Avoid concomitant use of pirfenidone and strong CYP1A2 inhibitors whenever possible. If combined, decrease the pirfenidone dose to 801 mg per day (267 mg three times daily) and monitor for increased pirfenidone toxicities. Risk D: Consider therapy modification

Pomalidomide: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Pomalidomide. Management: Avoid when possible. If coadministration is necessary, reduce the pomalidomide dose to 2 mg and monitor for increased pomalidomide effects/toxicities. Risk D: Consider therapy modification

Propranolol: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Propranolol. Management: Use a lower initial propranolol dose and be more cautious during propranolol dose titration when combined with strong CYP1A2 inhibitors. Risk D: Consider therapy modification

Ramelteon: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Ramelteon. Risk X: Avoid combination

Ramosetron: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Ramosetron. Risk C: Monitor therapy

Rasagiline: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Rasagiline. Management: Limit rasagiline dose to 0.5 mg once daily in patients taking strong CYP1A2 inhibitors. Risk D: Consider therapy modification

Revefenacin: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentrations of the active metabolite(s) of Revefenacin. Risk X: Avoid combination

Riluzole: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Riluzole. Risk C: Monitor therapy

ROPINIRole: CYP1A2 Inhibitors (Strong) may increase the serum concentration of ROPINIRole. Risk C: Monitor therapy

ROPivacaine: CYP1A2 Inhibitors (Strong) may increase the serum concentration of ROPivacaine. Risk C: Monitor therapy

Rosuvastatin: Enasidenib may increase the serum concentration of Rosuvastatin. Management: Limit the dose of rosuvastatin to 10 mg once daily when combined with enasidenib. Risk D: Consider therapy modification

Selpercatinib: CYP3A4 Inducers (Weak) may decrease the serum concentration of Selpercatinib. Risk C: Monitor therapy

Sirolimus (Conventional): CYP3A4 Inducers (Weak) may decrease the serum concentration of Sirolimus (Conventional). Risk C: Monitor therapy

Sirolimus (Protein Bound): CYP3A4 Inducers (Weak) may decrease the serum concentration of Sirolimus (Protein Bound). Risk C: Monitor therapy

Tacrolimus (Systemic): CYP3A4 Inducers (Weak) may decrease the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy

Talazoparib: BCRP/ABCG2 Inhibitors may increase the serum concentration of Talazoparib. Risk C: Monitor therapy

Tasimelteon: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Tasimelteon. Risk X: Avoid combination

Taurursodiol: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Taurursodiol. Risk X: Avoid combination

Theophylline Derivatives: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Theophylline Derivatives. Management: Consider avoidance of this combination. If coadministration is necessary, consider an empiric theophylline dose reduction to one-third of the original theophylline dose. Monitor for increased theophylline serum concentrations and toxicities when combined. Risk D: Consider therapy modification

Thioridazine: CYP2D6 Inhibitors (Weak) may increase the serum concentration of Thioridazine. Management: Consider avoiding concomitant use of thioridazine and weak CYP2D6 inhibitors. If combined, monitor closely for QTc interval prolongation and arrhythmias. Some weak CYP2D6 inhibitors list use with thioridazine as a contraindication. Risk D: Consider therapy modification

TiZANidine: CYP1A2 Inhibitors (Strong) may increase the serum concentration of TiZANidine. Risk X: Avoid combination

Topotecan: BCRP/ABCG2 Inhibitors may increase the serum concentration of Topotecan. Risk X: Avoid combination

Ubrogepant: Enasidenib may increase the serum concentration of Ubrogepant. Enasidenib may decrease the serum concentration of Ubrogepant. Management: Consider avoiding this combination if possible, as enasidenib is both an BCRP inhibitor and weak CYP3A4 inducer, with unknown net effects on ubrogepant exposure. Risk D: Consider therapy modification

Voxilaprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Voxilaprevir. Risk X: Avoid combination

Zavegepant: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Zavegepant. Risk X: Avoid combination

Reproductive Considerations

Verify pregnancy status prior to treatment initiation; patients who could become pregnant should use effective nonhormonal contraception during therapy and for 2 months after the last enasidenib dose. Patients with partners who could become pregnant should also use effective contraception during therapy and for 2 months after the last dose of enasidenib.

Enasidenib may decrease concentrations of combined hormonal contraception. Consult drug interactions database for more detailed information specific to use of enasidenib and specific contraceptives.

Pregnancy Considerations

Based on data from animal reproduction studies, in utero exposure to enasidenib may cause fetal harm.

Breastfeeding Considerations

It is not known if enasidenib is present in breast milk.

According to the manufacturer, breastfeeding is not recommended during therapy and for 2 months after the last enasidenib dose.

Monitoring Parameters

IDH2 mutation status (prior to treatment initiation); blood counts and blood chemistries prior to therapy initiation and every 2 weeks for at least the first 3 months; LFTs; renal function. Verify pregnancy status (prior to treatment in patients who could become pregnant). Monitor for signs/symptoms of differentiation syndrome (eg, fever, cough, dyspnea, bone pain, rapid weight gain, edema, lymphadenopathy; initiate hemodynamic monitoring if differentiation syndrome is suspected; consider close observation/monitoring in a hospital in patients with pulmonary and/or kidney manifestations) and tumor lysis syndrome. Monitor adherence.

The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.

Mechanism of Action

Enasidenib is a small molecule inhibitor of the enzyme isocitrate dehydrogenase 2 (IDH2); it targets the mutant IDH2 variants R140Q, R172S, and R172K at ~40-fold lower concentrations than the wild-type enzyme. Mutant IDH2 inhibition results in decreased 2-hydroxyglutarate (2-HG) levels, reduced abnormal histone hypermethylation, and restored myeloid differentiation (Stein 2017). Additionally, enasidenib reduces blast counts and increases percentages of mature myeloid cells.

Pharmacokinetics (Adult Data Unless Noted)

Distribution: 55.8 L.

Protein binding: Parent drug: 98.5%; AGI-16903 (metabolite): 96.6%.

Metabolism: In vitro data suggests that metabolism of parent drug is hepatic through multiple CYP enzymes (eg, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4), and by multiple UGTs (UGT1A1, UGT1A3, UGT1A4, UGT1A9, UGT2B7, and UGT2B15). The metabolite AGI-16903 is further metabolized by CYP1A2, CYP2C19, CYP3A4, UGT1A1, UGT1A3, and UGT1A9.

Bioavailability: ~57% (100 mg dose).

Half-life elimination: Terminal: 7.9 days.

Time to peak: 4 hours.

Excretion: Feces (89%; 34% as unchanged drug); urine (11%; <1% as unchanged drug).

Clearance: 0.7 L/hour.

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (PR) Puerto Rico: Idhifa
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  11. US Department of Health and Human Services; Centers for Disease Control and Prevention; National Institute for Occupational Safety and Health. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings 2016. https://www.cdc.gov/niosh/docs/2016-161/default.html. Updated September 2016. Accessed August 2, 2017.
  12. Venugopal S, Dinardo CD, Takahashi K, et al. Phase II study of the IDH2-inhibitor enasidenib in patients with high-risk IDH2-mutated myelodysplastic syndromes (MDS). Journal of Clinical Oncology. 2021;39(15). https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.15_suppl.7010. Published May 28, 2021. Accessed May 31, 2022.
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