Version July 2025
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.
Dosage guidance:
Clinical considerations: Enasidenib is associated with a moderate or high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Ref).
Acute myeloid leukemia, relapsed or refractory, IDH2 mutated:
Note: Confirm IDH2 mutation status in the blood or bone marrow prior to treatment initiation.
Oral: 100 mg once daily; continue until disease progression or unacceptable toxicity (Ref). Treat for a minimum of 6 months in patients without disease progression or unacceptable toxicity to allow time for clinical response (Ref).
Acute myeloid leukemia, newly diagnosed, IDH2 mutated (off-label use): Patients ≥60 years of age (and unfit for standard therapy): Oral: 100 mg once daily; continue until disease progression or unacceptable toxicity (Ref).
Myelodysplastic syndromes, high risk, relapsed or refractory, IDH2 mutated (off-label use): Oral: 100 mg once daily; continue until disease progression or unacceptable toxicity (Ref).
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.
Kidney impairment prior to treatment initiation:
Note: Kidney function is defined using the Cockcroft-Gault formula.
CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling; however, this level of kidney function does not have a clinically significant effect on enasidenib pharmacokinetics. No dosage adjustment is necessary (Ref).
CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling. However, no need for dosage adjustment is expected (Ref).
Hemodialysis: No need for dosage adjustment is expected (Ref).
Acute kidney toxicity during treatment:
Kidney dysfunction (secondary to differentiation syndrome) persisting >48 hours after initiation of systemic corticosteroids: Interrupt enasidenib; then resume when signs/symptoms of differentiation syndrome improve to ≤ grade 2.
Hepatic impairment prior to treatment initiation:
Mild (Child-Turcotte-Pugh class A or total bilirubin ≤ 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.
Moderate impairment (Child-Turcotte-Pugh class B or total bilirubin >1.5 to 3 times ULN and any AST): There are no dosage adjustments provided in the manufacturer's labeling; however, moderate hepatic impairment does not have a clinically significant effect on enasidenib pharmacokinetics.
Severe impairment (Child-Turcotte-Pugh class C or total bilirubin >3 to 10 times ULN and any AST): There are no dosage adjustments provided in the manufacturer's labeling; however, severe hepatic impairment does not have a clinically significant effect on enasidenib pharmacokinetics.
Acute hepatotoxicity during treatment: Bilirubin >3 times ULN for ≥2 weeks without elevated transaminases or other hepatic disorders: Reduce enasidenib dose to 50 mg once daily. Resume enasidenib at 100 mg once daily if bilirubin elevation resolves to <2 times ULN.
|
Adverse reaction |
Severity |
Enasidenib dosage modification |
|---|---|---|
|
Differentiation syndrome |
Suspected |
Administer systemic corticosteroids (eg, dexamethasone 10 mg IV or oral every 12 hours) and monitor hemodynamic status until symptom improvement. Taper corticosteroids after resolution of symptoms (symptoms of differentiation syndrome may recur if corticosteroids are stopped prematurely). |
|
Severe pulmonary symptoms (requiring intubation or ventilator support) and/or kidney dysfunction persisting for >48 hours after initiation of systemic corticosteroids |
Interrupt enasidenib; then resume when signs/symptoms of differentiation syndrome improve to ≤ grade 2. Hospitalization for close observation is recommended. | |
|
Noninfectious leukocytosis |
WBC >30,000/mm3 |
Initiate cytoreductive treatment with hydroxyurea (per standard institutional practice). Leukocytosis not improved with hydroxyurea: Interrupt enasidenib until WBC <30,000/mm3; then resume enasidenib at 100 mg once daily. |
|
Other treatment related adverse reactions (including tumor lysis syndrome) |
≥ Grade 3 |
Interrupt enasidenib until toxicity resolves to ≤ grade 2; then resume enasidenib at 50 mg once daily. May increase enasidenib to 100 mg once daily if toxicity resolves to ≤ grade 1. Recurrent ≥ grade 3 toxicity: Discontinue enasidenib. |
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Endocrine & metabolic: Abnormal serum phosphorus level (27%; grades ≥3: 8%; decreased), decreased serum calcium (74%), decreased serum potassium (41%)
Gastrointestinal: Decreased appetite (34%), diarrhea (43%), dysgeusia (12%), nausea (50%), vomiting (34%)
Hematologic & oncologic: Differentiation syndrome (14%), leukocytosis (12%; grades ≥3: 6%; noninfectious)
Hepatic: Increased serum bilirubin (81%)
1% to 10%:
Hematologic & oncologic: Tumor lysis syndrome (6%)
Respiratory: Acute respiratory distress (≤10%), pulmonary edema (≤10%)
Frequency not defined:
Cardiovascular: Prolonged QT interval on ECG
Gastrointestinal: Stomatitis
Hematologic & oncologic: Anemia, neutropenia, thrombocytopenia
Nervous system: Fatigue
Renal: Kidney failure
Respiratory: Dyspnea
There are no contraindications listed in the manufacturer's labeling.
Concerns related to adverse effects:
• Differentiation syndrome: Patients treated with enasidenib have experienced differentiation syndrome, which can be life-threatening or fatal if not treated. There is no diagnostic test for differentiation syndrome. Symptoms may include fever, acute respiratory distress (eg, dyspnea and/or hypoxia and need for supplemental oxygen), pulmonary infiltrates, pleural or pericardial effusions, peripheral edema with rapid weight gain, lymphadenopathy, bone pain, and hepatic, kidney, 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 kidney 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: For the treatment of relapsed or refractory acute myeloid leukemia (AML), newly diagnosed AML (off-label use), or high-risk, relapsed or refractory myelodysplastic syndromes (off-label use), confirm IDH2 mutation status in the blood or bone marrow prior to therapy initiation. Information on tests approved to detect IDH2 mutation in AML may be found at http://www.FDA.gov/CompanionDiagnostics.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
IDHIFA: 50 mg, 100 mg
No
Tablets (IDHIFA Oral)
50 mg (per each): $1,441.37
100 mg (per each): $1,441.37
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.
Enasidenib is available through select specialty pharmacies and authorized distributors. Refer to http://www.idhifa.com for further information.
Enasidenib is associated with a moderate or high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Ref).
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.
This medication is not on the NIOSH (2024) list; however, it may meet the criteria for a hazardous drug. Enasidenib may cause 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 2023; NIOSH 2024; 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.
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Idhifa: https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/209606s007lbl.pdf#page=18
Acute myeloid leukemia, relapsed/refractory, IDH2 mutated: Treatment of relapsed or refractory acute myeloid leukemia (AML) in adults with an isocitrate dehydrogenase-2 (IDH2) mutation (as detected by an approved test).
Acute myeloid leukemia, newly diagnosed, IDH2 mutated; Myelodysplastic syndromes, high-risk, relapsed/refractory, IDH2 mutated
Enasidenib may be confused with afatinib, avapritinib, ceritinib, dasatinib, encorafenib, ensartinib, entrectinib, erdafitinib, erlotinib, idelalisib, imatinib, ivosidenib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, niraparib, ponatinib, regorafenib, SUNItinib
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (chemotherapeutic agent, parenteral and oral) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care, Community/Ambulatory Care, and Long-Term Care Settings).
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, CYP1A2 (Strong), CYP2C19 (Weak), CYP2D6 (Weak), OATP1B1/1B3; Induces CYP3A4 (Weak);
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 drug interactions program by clicking on the “Launch drug interactions program” link above.
Agomelatine: CYP1A2 Inhibitors (Strong) may increase serum concentration of Agomelatine. Risk X: Avoid
Alosetron: CYP1A2 Inhibitors (Strong) may increase serum concentration of Alosetron. Risk X: Avoid
Alpelisib: BCRP/ABCG2 Inhibitors may increase 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 concentration of Anagrelide. CYP1A2 Inhibitors (Strong) may increase active metabolite exposure of Anagrelide. Risk C: Monitor
Antifungal Agents (Azole Derivatives, Systemic): Enasidenib may decrease serum concentration of Antifungal Agents (Azole Derivatives, Systemic). Risk X: Avoid
Asenapine: CYP1A2 Inhibitors (Strong) may increase serum concentration of Asenapine. Risk C: Monitor
Atazanavir: May increase serum concentration of UGT1A1 Substrates. Management: Do not use UGT1A1 substrates for which small increases in exposure can cause serious adverse effects together with atazanavir, and use caution with any UGT1A1 substrate, even when small changes in exposure are less likely to cause serious adverse effects. Risk D: Consider Therapy Modification
Atogepant: Enasidenib may increase serum concentration of Atogepant. Enasidenib may decrease 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
Atrasentan: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentration of Atrasentan. Risk X: Avoid
Belumosudil: May increase serum concentration of UGT1A1 Substrates. Management: Avoid coadministration of belumosudil with substrates of UGT1A1 for which minimal concentration increases can cause serious adverse effects. If coadministration is required, dose reductions of the UGT1A1 substrate may be required. Risk D: Consider Therapy Modification
Bendamustine: CYP1A2 Inhibitors (Strong) may increase 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
Brincidofovir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase 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 serum concentration of Bromazepam. Risk C: Monitor
Caffeine and Caffeine Containing Products: CYP1A2 Inhibitors (Strong) may increase serum concentration of Caffeine and Caffeine Containing Products. Risk C: Monitor
CarBAMazepine: CYP3A4 Inducers (Weak) may decrease serum concentration of CarBAMazepine. Risk C: Monitor
Cladribine: BCRP/ABCG2 Inhibitors may increase 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 concentration of CloBAZam. CYP2C19 Inhibitors (Weak) may increase active metabolite exposure of CloBAZam. Risk C: Monitor
ClomiPRAMINE: CYP1A2 Inhibitors (Strong) may increase serum concentration of ClomiPRAMINE. Risk C: Monitor
CloZAPine: CYP1A2 Inhibitors (Strong) may increase 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
Diazoxide Choline: CYP1A2 Inhibitors (Strong) may increase serum concentration of Diazoxide Choline. Risk D: Consider Therapy Modification
Digoxin: Enasidenib may increase serum concentration of Digoxin. Risk C: Monitor
DULoxetine: CYP1A2 Inhibitors (Strong) may increase serum concentration of DULoxetine. Risk X: Avoid
Elagolix, Estradiol, and Norethindrone: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentration of Elagolix, Estradiol, and Norethindrone. Specifically, concentrations of elagolix may be increased. Risk X: Avoid
Elagolix: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentration of Elagolix. Risk X: Avoid
Elbasvir and Grazoprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentration of Elbasvir and Grazoprevir. Risk X: Avoid
Eluxadoline: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase 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 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 serum concentration of Fezolinetant. Risk X: Avoid
Fosphenytoin-Phenytoin: CYP2C19 Inhibitors (Weak) may increase serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
Hormonal Contraceptives: CYP3A4 Inducers (Weak) may decrease 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 serum concentration of Levobupivacaine. Risk C: Monitor
Lidocaine (Systemic): CYP1A2 Inhibitors (Strong) may increase serum concentration of Lidocaine (Systemic). Risk C: Monitor
Mavacamten: CYP2C19 Inhibitors (Weak) may increase serum concentration of Mavacamten. Management: Start mavacamten at 5 mg/day if stable on a weak CYP2C19 inhibitor, and reduce the mavacamten dose by one dose level if initiating a weak CYP2C19 inhibitor. Avoid initiating weak CYP2C19 inhibitors in patients on mavacamten 2.5 mg/day. Risk D: Consider Therapy Modification
Melatonin: CYP1A2 Inhibitors (Strong) may increase serum concentration of Melatonin. Risk X: Avoid
Mexiletine: CYP1A2 Inhibitors (Strong) may increase serum concentration of Mexiletine. Risk C: Monitor
Mitapivat: May decrease serum concentration of UGT1A1 Substrates. Risk C: Monitor
Momelotinib: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentration of Momelotinib. Risk C: Monitor
NiMODipine: CYP3A4 Inducers (Weak) may decrease serum concentration of NiMODipine. Risk C: Monitor
OLANZapine: CYP1A2 Inhibitors (Strong) may increase serum concentration of OLANZapine. Risk C: Monitor
PAZOPanib: BCRP/ABCG2 Inhibitors may increase serum concentration of PAZOPanib. Risk X: Avoid
Pentoxifylline: CYP1A2 Inhibitors (Strong) may increase serum concentration of Pentoxifylline. Risk C: Monitor
Pirfenidone: CYP1A2 Inhibitors (Strong) may increase 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 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 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 serum concentration of Ramelteon. Risk X: Avoid
Ramosetron: CYP1A2 Inhibitors (Strong) may increase serum concentration of Ramosetron. Risk C: Monitor
Rasagiline: CYP1A2 Inhibitors (Strong) may increase 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
Resmetirom: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentration of Resmetirom. Risk X: Avoid
Revefenacin: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase active metabolite exposure of Revefenacin. Risk X: Avoid
Riluzole: CYP1A2 Inhibitors (Strong) may increase serum concentration of Riluzole. Risk C: Monitor
ROPINIRole: CYP1A2 Inhibitors (Strong) may increase serum concentration of ROPINIRole. Risk C: Monitor
ROPivacaine: CYP1A2 Inhibitors (Strong) may increase serum concentration of ROPivacaine. Risk C: Monitor
Rosuvastatin: Enasidenib may increase serum concentration of Rosuvastatin. Management: Limit the dose of rosuvastatin to 10 mg once daily when combined with enasidenib. Patients treated with the rosuvastatin/ezetimibe combination product should not exceed doses of 10 mg/10 mg daily. Risk D: Consider Therapy Modification
Seladelpar: BCRP/ABCG2 Inhibitors may increase serum concentration of Seladelpar. Risk C: Monitor
Selpercatinib: CYP3A4 Inducers (Weak) may decrease serum concentration of Selpercatinib. Risk C: Monitor
Sirolimus (Conventional): CYP3A4 Inducers (Weak) may decrease serum concentration of Sirolimus (Conventional). Risk C: Monitor
Sirolimus (Protein Bound): CYP3A4 Inducers (Weak) may decrease serum concentration of Sirolimus (Protein Bound). Risk C: Monitor
Tacrolimus (Systemic): CYP3A4 Inducers (Weak) may decrease serum concentration of Tacrolimus (Systemic). Risk C: Monitor
Talazoparib: BCRP/ABCG2 Inhibitors may increase serum concentration of Talazoparib. Risk C: Monitor
Tasimelteon: CYP1A2 Inhibitors (Strong) may increase serum concentration of Tasimelteon. Risk X: Avoid
Taurursodiol: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentration of Taurursodiol. Risk X: Avoid
Theophylline Derivatives: CYP1A2 Inhibitors (Strong) may increase 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 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 serum concentration of TiZANidine. Risk X: Avoid
Topotecan: BCRP/ABCG2 Inhibitors may increase serum concentration of Topotecan. Risk X: Avoid
Ubrogepant: Enasidenib may increase serum concentration of Ubrogepant. Enasidenib may decrease 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
Vorasidenib: CYP1A2 Inhibitors (Strong) may increase serum concentration of Vorasidenib. Risk X: Avoid
Voxilaprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentration of Voxilaprevir. Risk X: Avoid
Zavegepant: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentration of Zavegepant. Risk X: Avoid
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.
Based on data from animal reproduction studies, in utero exposure to enasidenib may cause fetal harm.
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.
IDH2 mutation status in the blood or bone marrow (prior to treatment initiation). Blood counts and blood chemistries prior to therapy initiation and a minimum of 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.
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.
Distribution: Vd: 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: Median: 4 hours.
Excretion: Feces (89%; 34% as unchanged drug); urine (11%; <1% as unchanged drug).
Clearance: 0.7 L/hour.
