enasidenib

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enasidenib

Classes

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

Administration

Emetic Risk
Moderate/High
Administer routine antiemetic prophylaxis prior to treatment.

Oral Administration Oral Solid Formulations

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

Adverse Reactions
Severe

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

Mild

dysgeusia / Early / 12.0-12.0

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

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

Common Brand Names

IDHIFA

Dea Class

Rx

Description

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

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

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

Dosing Considerations
Hepatic Impairment

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

Renal Impairment

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

Drug Interactions

Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with enasidenib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Afatinib: (Moderate) If the concomitant use of enasidenib and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of enasidenib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-gp substrate and enasidenib is a P-gp inhibitor. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
Alpelisib: (Major) Avoid coadministration of alpelisib with enasidenib due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and enasidenib is a BCRP inhibitor.
Amlodipine; Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with enasidenib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp, BCRP, and OATP1B1/3 substrate; enasidenib is a P-gp, BCRP, and OATP1B1/3 inhibitor.
Atogepant: (Major) Limit the dose of atogepant to 10 or 30 mg PO once daily for episodic migraine or 30 mg PO once daily for chronic migraine if coadministered with enasidenib. Concurrent use may increase atogepant exposure and the risk of adverse effects. Atogepant is a substrate of OATP1B1 and OATP1B3 and enasidenib is an OATP inhibitor. Coadministration with an OATP1B1/3 inhibitor resulted in a 2.85-fold increase in atogepant overall exposure and a 2.23-fold increase in atogepant peak concentration.
Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with enasidenib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp, BCRP, and OATP1B1/3 substrate; enasidenib is a P-gp, BCRP, and OATP1B1/3 inhibitor.
Atorvastatin; Ezetimibe: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with enasidenib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp, BCRP, and OATP1B1/3 substrate; enasidenib is a P-gp, BCRP, and OATP1B1/3 inhibitor.
Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking enasidenib. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Berotralstat is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor. Coadministration with another P-gp and BCRP inhibitor increased berotralstat exposure by 69%.
Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving enasidenib. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving enasidenib. Concurrent use may increase betrixaban exposure resulting in an increased bleeding risk; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a P-gp substrate; enasidenib is a P-gp inhibitor. Coadministration of other P-gp inhibitors increased betrixaban exposure by 2 to 3-fold.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with enasidenib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Brincidofovir: (Moderate) Postpone the administration of enasidenib for at least three hours after brincidofovir administration and increase monitoring for brincidofovir-related adverse reactions (i.e., elevated hepatic enzymes and bilirubin, diarrhea, other gastrointestinal adverse events) if concomitant use of brincidofovir and enasidenib is necessary. Brincidofovir is an OATP1B1/3 substrate and enasidenib is an OATP1B1/3 inhibitor. In a drug interaction study, the mean AUC and Cmax of brincidofovir increased by 374% and 269%, respectively, when administered with another OATP1B1/3 inhibitor.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Cobimetinib: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with enasidenib is necessary. In vitro, cobimetinib is a P-gp substrate; enasidenib is a P-gp inhibitor.
Colchicine: (Major) Avoid concomitant use of colchicine and enasidenib due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a P-gp substrate and enasidenib is a P-gp inhibitor.
Cyclosporine: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with enasidenib is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a P-gp substrate and enasidenib is a P-gp inhibitor.
Dabigatran: (Moderate) Monitor for an increase in dabigatran-related adverse reactions if coadministration with enasidenib is necessary in patients with creatinine clearance (CrCl) greater than 50 mL/minute. Avoid coadministration in patients with CrCl less than 50 mL/minute when dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery. Avoid coadministration in patients with CrCl less than 30 mL/minute in patients with non-valvular atrial fibrillation. Serum concentrations of dabigatran are expected to be higher in patients with renal impairment compared to patients with normal renal function. Dabigatran is a P-glycoprotein substrate and enasidenib is a P-gp inhibitor.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with enasidenib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Digoxin: (Moderate) Increase monitoring of serum digoxin concentrations and watch for potential signs and symptoms of clinical toxicity when starting, adjusting, or discontinuing enasidenib. Concurrent use may increase digoxin exposure. Digoxin is a P-gp substrate with a narrow therapeutic index and enasidenib is a P-gp inhibitor. Coadministration of digoxin after multiple doses of enasidenib increased digoxin Cmax by 26% and AUC by 20%.
Dolutegravir: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with enasidenib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with enasidenib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Dolutegravir; Rilpivirine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with enasidenib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with enasidenib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Doxorubicin Liposomal: (Major) Avoid coadministration of enasidenib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Enasidenib is a P-gp inhibitor and doxorubicin is a P-gp substrate. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Doxorubicin: (Major) Avoid coadministration of enasidenib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Enasidenib is a P-gp inhibitor and doxorubicin is a P-gp substrate. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Edoxaban: (Major) Consider an edoxaban dosage reduction for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE) if concomitant use of enasidenib is necessary. Concomitant use may increase edoxaban exposure; edoxaban is a P-gp substrate and enasidenib is a P-gp inhibitor. An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with enasidenib. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of enasidenib. Increased concentrations of edoxaban may occur during concomitant use of enasidenib; monitor for increased adverse effects of edoxaban.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with enasidenib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with enasidenib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Elagolix: (Contraindicated) Coadministration of elagolix with enasidenib is contraindicated as concurrent use may increase elagolix exposure. Elagolix is a substrate of OATP1B1 and enasidenib is a strong OATP1B1 inhibitor.
Elagolix; Estradiol; Norethindrone acetate: (Contraindicated) Coadministration of elagolix with enasidenib is contraindicated as concurrent use may increase elagolix exposure. Elagolix is a substrate of OATP1B1 and enasidenib is a strong OATP1B1 inhibitor.
Elbasvir; Grazoprevir: (Contraindicated) Concomitant use of grazoprevir and enasidenib is contraindicated due to the potential for increased grazoprevir exposure. Grazoprevir is a substrate of OATP1B1/3; enasidenib is an inhibitor of OATP1B1/3.
Eluxadoline: (Major) Reduce the dose of eluxadoline to 75 mg twice daily and monitor for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity) if coadministered with enasidenib. Coadministration may increase exposure of eluxadoline. Eluxadoline is an OATP1B1 substrate and enasidenib is a an OATP1B1 inhibitor. Coadministration with another OATP1B1 inhibitor increased the exposure of eluxadoline by 4.4-fold.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with enasidenib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with enasidenib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with enasidenib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with enasidenib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with enasidenib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with enasidenib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with enasidenib is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-gp substrate and enasidenib is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
Ezetimibe; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with enasidenib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp and OATP1B1 substrate; enasidenib is a P-gp and OATP1B1 inhibitor.
Fluvastatin: (Moderate) Monitor for an increase in fluvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with enasidenib is necessary. Concomitant use may increase fluvastatin exposure. Fluvastatin is a substrate of OATP1B3; enasidenib is an inhibitor of OATP1B3.
Glecaprevir; Pibrentasvir: (Moderate) Monitor for an increase in glecaprevir-related adverse effects if coadministration with enasidenib is necessary. Concomitant use may increase glecaprevir exposure. Glecaprevir is a substrate of P-gp, BCRP, and OATP1B1/3 and enasidenib is a P-gp, BCRP, and OATP1B1/3 inhibitor. (Moderate) Monitor for an increase in pibrentasvir-related adverse effects if concomitant use of enasidenib is necessary. Concomitant use may increase pibrentasvir exposure. Pibrentasvir is a substrate of P-gp and BCRP and enasidenib is a P-gp and BCRP inhibitor.
Glyburide: (Moderate) Monitor for an increase in glyburide-related adverse reactions, such as hypoglycemia, if coadministration with enasidenib is necessary. Concomitant use may increase glyburide exposure. Glyburide is a substrate of OATP1B1/3; enasidenib is an OATP1B1/3 inhibitor.
Glyburide; Metformin: (Moderate) Monitor for an increase in glyburide-related adverse reactions, such as hypoglycemia, if coadministration with enasidenib is necessary. Concomitant use may increase glyburide exposure. Glyburide is a substrate of OATP1B1/3; enasidenib is an OATP1B1/3 inhibitor.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with enasidenib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Lapatinib: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with enasidenib is necessary. Lapatinib is a P-gp substrate and enasidenib is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
Lefamulin: (Major) Avoid coadministration of enasidenib with oral lefamulin unless the benefits outweigh the risks as concurrent use may increase lefamulin exposure and adverse effects; enasidenib may be administered with intravenous lefamulin. Lefamulin is a P-gp substrate and enasidenib is a P-gp inhibitor.
Letermovir: (Moderate) Monitor for an increase in letermovir-related adverse reactions if coadministration with enasidenib is necessary. Concomitant use may increase letermovir exposure. Letermovir is a substrate of OATP1B1/3; enasidenib is an OATP1B1/3 inhibitor.
Loperamide: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with enasidenib. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and enasidenib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Loperamide; Simethicone: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with enasidenib. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and enasidenib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Lovastatin: (Moderate) Monitor for an increase in lovastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with enasidenib is necessary. Concomitant use may increase lovastatin exposure. Lovastatin is a substrate of P-gp; enasidenib is an inhibitor of P-gp.
Maraviroc: (Moderate) Monitor for an increase in maraviroc-related adverse reactions if coadministration with enasidenib is necessary. Concomitant use may increase maraviroc exposure. Maraviroc is a P-gp and OATP1B1 substrate; enasidenib is a P-gp and OATP1B1 inhibitor.
Morphine: (Moderate) Monitor for an increase in morphine-related adverse reactions, including hypotension, sedation, and respiratory depression, if coadministration with enasidenib is necessary; decrease the dose of either drug as necessary. Morphine is a P-gp substrate and enasidenib is a P-gp inhibitor. Coadministration with P-gp inhibitors can increase morphine exposure by about 2-fold.
Morphine; Naltrexone: (Moderate) Monitor for an increase in morphine-related adverse reactions, including hypotension, sedation, and respiratory depression, if coadministration with enasidenib is necessary; decrease the dose of either drug as necessary. Morphine is a P-gp substrate and enasidenib is a P-gp inhibitor. Coadministration with P-gp inhibitors can increase morphine exposure by about 2-fold.
Naldemedine: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with enasidenib. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a P-gp substrate; enasidenib is a P-gp inhibitor.
Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid concomitant use of sirolimus and enasidenib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and enasidenib is a P-gp inhibitor.
Niacin; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with enasidenib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp and OATP1B1 substrate; enasidenib is a P-gp and OATP1B1 inhibitor.
Pazopanib: (Major) Avoid coadministration of pazopanib and enasidenib due to the potential for increased pazopanib exposure. Pazopanib is a P-gp and BCRP substrate; enasidenib is a P-gp and BCRP inhibitor. Consider selection of an alternative concomitant medication with no or minimal potential to inhibit P-gp or BCRP.
Pitavastatin: (Moderate) Monitor for an increase in pitavastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with enasidenib is necessary. Concomitant use may increase pitavastatin exposure. Pitavastatin is a P-gp and OATP1B1 substrate; enasidenib is a P-gp and OATP1B1 inhibitor.
Posaconazole: (Moderate) Monitor for an increase in posaconazole-related adverse reactions if coadministration with enasidenib is necessary. Posaconazole is a P-glycoprotein (P-gp) substrate; enasidenib is a P-gp inhibitor.
Pralsetinib: (Major) Avoid concomitant use of enasidenib with pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the daily dose of pralsetinib by 100 mg. Pralsetinib is a P-gp substrate and enasidenib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased the overall exposure of pralsetinib by 81%.
Pravastatin: (Moderate) Monitor for an increase in pravastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with enasidenib is necessary. Concomitant use may increase pravastatin exposure. Pravastatin is an OATP1B1/3 substrate; enasidenib is an OATP1B1/3 inhibitor.
Probenecid; Colchicine: (Major) Avoid concomitant use of colchicine and enasidenib due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a P-gp substrate and enasidenib is a P-gp inhibitor.
Ranolazine: (Moderate) Monitor for an increase in ranolazine-related adverse reactions if coadministration with enasidenib is necessary; a dose adjustment of ranolazine may be necessary. Ranolazine is a P-gp substrate. Enasidenib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates.
Relugolix: (Major) Avoid concomitant use of relugolix and oral enasidenib. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer enasidenib at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-glycoprotein (P-gp) substrate and enasidenib is a P-gp inhibitor.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral enasidenib. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer enasidenib at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-glycoprotein (P-gp) substrate and enasidenib is a P-gp inhibitor.
Revefenacin: (Major) Avoid concomitant use of revefenacin and enasidenib. Concomitant use may increase exposure to the active metabolite of revefenacin and the risk for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; enasidenib is an inhibitor of OATP1B1 and OATP1B3.
Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with enasidenib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and enasidenib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.
Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with enasidenib; concurrent use may increase rimegepant exposure. Rimegepant is a P-gp substrate and enasidenib is a P-gp inhibitor.
Rosuvastatin: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with enasidenib is necessary. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a substrate of the drug transporters OATP1B1/3 and BCRP and enasidenib is an OATP1B1/3 and BCRP inhibitor. Coadministration of rosuvastatin after multiple doses of enasidenib increased rosuvastatin Cmax by 366% and AUC by 244%.
Rosuvastatin; Ezetimibe: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with enasidenib is necessary. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a substrate of the drug transporters OATP1B1/3 and BCRP and enasidenib is an OATP1B1/3 and BCRP inhibitor. Coadministration of rosuvastatin after multiple doses of enasidenib increased rosuvastatin Cmax by 366% and AUC by 244%.
Saquinavir: (Moderate) Monitor for an increase in saquinavir-related adverse reactions if coadministration with enasidenib is necessary. Saquinavir is a P-glycoprotein (P-gp) substrate; enasidenib is a P-gp inhibitor.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Silodosin: (Major) Avoid coadministration of silodosin and enasidenib due to the potential for increased silodosin exposure. In vitro data indicate that silodosin is a P-glycoprotein substrate; enasidenib is a P-gp inhibitor.
Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with enasidenib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp and OATP1B1 substrate; enasidenib is a P-gp and OATP1B1 inhibitor.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of enasidenib. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and enasidenib is a P-gp inhibitor.
Sodium Phenylbutyrate; Taurursodiol: (Major) Avoid coadministration of sodium phenylbutyrate; taurursodiol and enasidenib. Concomitant use may increase plasma concentrations of sodium phenylbutyrate; taurursodiol. Sodium phenylbutyrate; taurursodiol is an OATP1B3 substrate and enasidenib is an OATP1B3 inhibitor.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid concomitant use of voxilaprevir and enasidenib due to the potential for increased voxilaprevir exposure. Voxilaprevir is a substrate for the drug transporter OATP1B13; enasidenib is an OATP1B1/3 inhibitor.
Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if concomitant use of enasidenib is necessary. Concomitant use may increase talazoparib exposure. Talazoparib is a P-gp and BCRP substrate; enasidenib is a P-gp and BCRP inhibitor.
Temsirolimus: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with enasidenib is necessary due to the risk of increased temsirolimus exposure. Temsirolimus is a P-gp substrate and enasidenib is a P-gp inhibitor. Coadministration is likely to increase plasma concentrations of temsirolimus.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with enasidenib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with enasidenib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with enasidenib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Ticagrelor: (Moderate) Monitor for increased bleeding if ticagrelor is coadministered with enasidenib as concurrent use may increase the exposure of ticagrelor. Ticagrelor is a P-gp substrate and enasidenib is a P-gp inhibitor.
Tipranavir: (Moderate) Monitor for an increase in tipranavir-related adverse reactions if coadministration with enasidenib is necessary. Concomitant use may increase tipranavir exposure. Tipranavir is a P-glycoprotein (P-gp) substrate; enasidenib is a P-gp inhibitor.
Topotecan: (Major) Avoid coadministration of enasidenib with oral topotecan due to increased topotecan exposure; enasidenib may be administered with intravenous topotecan. Oral topotecan is a substrate of P-gp and BCRP and enasidenib is a P-gp and BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with enasidenib. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a substrate of the BCRP and P-gp drug transporters; enasidenib is a BCRP and P-gp inhibitor.
Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with enasidenib due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of enasidenib. Venetoclax is a P-gp substrate and enasidenib is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
Vincristine Liposomal: (Moderate) Monitor for vincristine-related adverse reactions if coadministration of enasidenib is necessary as concurrent use may increase vincristine exposure. Vincristine is a P-gp substrate and enasidenib is a P-gp inhibitor.
Vincristine: (Moderate) Monitor for vincristine-related adverse reactions if coadministration of enasidenib is necessary as concurrent use may increase vincristine exposure. Vincristine is a P-gp substrate and enasidenib is a P-gp inhibitor.
Zavegepant: (Major) Avoid concomitant use of zavegepant and enasidenib. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and enasidenib is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.

How Supplied

Enasidenib Oral Tab: 50mg, 100mg

Maximum Dosage
Adults

100 mg/day PO.

Geriatric

100 mg/day PO.

Adolescents

Safety and efficacy have not been established.

Children

Safety and efficacy have not been established.

Infants

Safety and efficacy have not been established.

Mechanism Of Action

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

Pharmacokinetics

Enasidenib is administered orally. In vitro, enasidenib and its metabolite (AGI-16903) are 98.5% and 96.6% bound to human plasma proteins, respectively. Following oral administration of enasidenib, the mean volume of distribution (Vd) was 55.8 L (coefficient of variance (CV), 29%), the terminal half-life was 7.9 days, and the mean total body clearance was 0.7 L/hour (CV, 62.5%). Following a radiolabeled dose of enasidenib, 89% of the dose was eliminated in the feces and 11% of the dose was eliminated in the urine; unchanged drug accounted for 34% and 0.4% of the radioactivity recovered in the feces and urine, respectively. Additionally, 89% of the radioactivity in the circulation was enasidenib; 10% of the radioactivity in the circulation was the N-dealkylated metabolite, AGI-16903.
Affected cytochrome P450 isoenzymes and transporters: OATP1B1, OATP1B3, BCRP, P-gp
In vitro, enasidenib is metabolized by multiple CYP450 isoenzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) and UDP-glucuronosyl transferases (UGT1A1, UGT1A3, UGT1A4, UGT1A9, UGT2B7, and UGT2B15). AGI-16903 is metabolized by CYP1A2, CYP2C19, CYP3A4, UGT1A1, UGT1A3, and UGT1A9; it is also a substrate of P-glycoprotein and breast cancer resistance protein (BCRP). In vitro studies suggest that enasidenib inhibits CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, UGT1A1, P-gp, BCRP, organic anion transporter (OAT)-1, OAT family members 1B1 (OATP1B1) and OATP1B3, and organic cat anion transporter (OCT)-2 and induces CYP2B6 and CYP3A4. In vitro, AGI-16903 inhibits CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, BCRP, OAT1, OAT3, OATP1B1, and OCT2. P-gp substrates with a narrow therapeutic index and OATP1B1, OATP1B3, and BCRP substrates may require a dosage reduction and increased monitoring for toxicity if coadministered with enasidenib.

Oral Route

Following a single oral 100-mg dose, the absolute bioavailability of enasidenib is approximately 57% and the median time to peak concentration (Tmax) is 4 hours. Following enasidenib 100 mg PO daily, the Cmax level was 13.1 mcg/mL (coefficient of variance (CV), 45%) at steady state (achieved within 29 days). The AUC values increase proportionally over a dosage range of 50 mg to 450 mg daily. Accumulation is approximately 10-fold when administered once daily.

Pregnancy And Lactation
Pregnancy

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

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