Enasidenib

FDA label, Celgene Corporation, oral, effective 2025-01-16. Full label on DailyMed

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Boxed warning

WARNING: DIFFERENTIATION SYNDROME Patients treated with IDHIFA 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 [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ] . WARNING: DIFFERENTIATION SYNDROME See full prescribing information for complete boxed warning.

Patients treated with IDHIFA have experienced symptoms of differentiation syndrome, which can be fatal if not treated. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution ( 5.1 , 6.1 ).

Dosing in kidney impairment

Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells. While there is no diagnostic test for differentiation syndrome, symptoms in patients treated with IDHIFA included acute respiratory distress represented by dyspnea and/or hypoxia (68%) and need for supplemental oxygen (76%); pulmonary infiltrates (73%) and pleural effusion (45%); renal impairment (70%); fever (36%); lymphadenopathy (33%); bone pain (27%); peripheral edema with rapid weight gain (21%); and pericardial effusion (18%).

Hepatic, renal, and multi-organ dysfunction have also been observed. Differentiation syndrome has been observed with and without concomitant hyperleukocytosis, in as early as 1 day and up to 5 months after IDHIFA initiation. If differentiation syndrome is suspected, initiate oral or intravenous corticosteroids (e.g., dexamethasone 10 mg every 12 hours) and hemodynamic monitoring until improvement.

Taper corticosteroids only after resolution of symptoms. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid treatment. If severe pulmonary symptoms requiring intubation or ventilator support, and/or renal dysfunction persist for more than 48 hours after initiation of corticosteroids, interrupt IDHIFA until signs and symptoms are no longer severe [see Dosage and Administration ] .

Hospitalization for close observation and monitoring of patients with pulmonary and/or renal manifestation is recommended. 5.2 Embryo-Fetal Toxicity Based on animal embryo-fetal toxicity studies, IDHIFA can cause embryo-fetal harm when administered to a pregnant woman. In animal embryo-fetal toxicity studies, enasidenib caused embryo-fetal toxicities starting at 0.1 times the steady state clinical exposure based on the area under the concentration-time curve (AUC) at the recommended human dose.

Differentiation syndromeIf differentiation syndrome is suspected, administer systemic corticosteroids and initiate hemodynamic monitoring [see Warnings and Precautions (5.1)].Interrupt IDHIFA if severe pulmonary symptoms requiring intubation or ventilator support, and/or renal dysfunction persist for more than 48 hours after initiation of corticosteroids [see Warnings and Precautions (5.1)].Resume IDHIFA when signs and symptoms improve to Grade 2* or lower.Noninfectious leukocytosis (white blood cell [WBC] count greater than 30 × 109/L) Initiate treatment with hydroxyurea, as per standard institutional practices.Interrupt IDHIFA if leukocytosis is not improved with hydroxyurea, and then resume IDHIFA at 100 mg daily when WBC is less than 30 × 109/L.Elevation of bilirubin greater than 3 times the upper limit of normal (ULN) sustained for ≥2 weeks without elevated transaminases or other hepatic disordersReduce IDHIFA dose to 50 mg daily.Resume IDHIFA at 100 mg daily if bilirubin elevation resolves to less than 2 × ULN.Other Grade 3* or higher toxicity considered related to treatment including tumor lysis syndromeInterrupt IDHIFA until toxicity resolves to Grade 2* or lower.Resume IDHIFA at 50 mg daily; may increase to 100 mg daily if toxicities resolve to Grade 1* or lower.If Grade 3* or higher toxicity recurs, discontinue IDHIFA.
Table 1: Dosage Modifications for IDHIFA-Related Toxicities
*Grade 1 is mild, Grade 2 is moderate, Grade 3 is serious, Grade 4 is life-threatening.
Adverse ReactionRecommended Action
•
•••
•
••
•
••
•
•••

Dosing in liver impairment

Differentiation syndromeIf differentiation syndrome is suspected, administer systemic corticosteroids and initiate hemodynamic monitoring [see Warnings and Precautions (5.1)].Interrupt IDHIFA if severe pulmonary symptoms requiring intubation or ventilator support, and/or renal dysfunction persist for more than 48 hours after initiation of corticosteroids [see Warnings and Precautions (5.1)].Resume IDHIFA when signs and symptoms improve to Grade 2* or lower.Noninfectious leukocytosis (white blood cell [WBC] count greater than 30 × 109/L) Initiate treatment with hydroxyurea, as per standard institutional practices.Interrupt IDHIFA if leukocytosis is not improved with hydroxyurea, and then resume IDHIFA at 100 mg daily when WBC is less than 30 × 109/L.Elevation of bilirubin greater than 3 times the upper limit of normal (ULN) sustained for ≥2 weeks without elevated transaminases or other hepatic disordersReduce IDHIFA dose to 50 mg daily.Resume IDHIFA at 100 mg daily if bilirubin elevation resolves to less than 2 × ULN.Other Grade 3* or higher toxicity considered related to treatment including tumor lysis syndromeInterrupt IDHIFA until toxicity resolves to Grade 2* or lower.Resume IDHIFA at 50 mg daily; may increase to 100 mg daily if toxicities resolve to Grade 1* or lower.If Grade 3* or higher toxicity recurs, discontinue IDHIFA.
Table 1: Dosage Modifications for IDHIFA-Related Toxicities
*Grade 1 is mild, Grade 2 is moderate, Grade 3 is serious, Grade 4 is life-threatening.
Adverse ReactionRecommended Action
•
•••
•
••
•
••
•
•••

Drug interactions

Check enasidenib against a medication list
Label text (6 paragraphs)

7 DRUG INTERACTIONS • Certain CYP1A2 and CYP2C19 Substrates: Avoid concomitant use unless otherwise recommended in the Prescribing Information ( 7.1 ). • Certain CYP3A Substrates: Avoid concomitant use unless otherwise recommended in the Prescribing Information ( 7.1 ). • Certain OATP1B1, OATP1B3, and BCRP Substrates: Avoid concomitant use unless otherwise recommended in the Prescribing Information ( 7.1 ).

7.1 Effect of IDHIFA on Other Drugs Certain CYP1A2 Substrates Avoid concomitant use with IDHIFA unless otherwise recommended in the Prescribing Information for CYP1A2 substrates where minimal concentration changes may lead to serious adverse reactions. Consider reducing the frequency of caffeine intake from various food and beverages in a 24 hour period while taking IDHIFA because IDHIFA may increase the effect of caffeine in patients who are sensitive to it. Enasidenib is a CYP1A2 inhibitor. Concomitant use of IDHIFA increases the exposure of CYP1A2 substrates [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to the substrates.

Certain CYP2C19 substrates Avoid concomitant use with IDHIFA unless otherwise recommended in the Prescribing Information for CYP2C19 substrates where minimal concentration changes may lead to serious adverse reactions. Enasidenib is a CYP2C19 inhibitor. Concomitant use of IDHIFA increases the exposure of CYP2C19 substrates [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to these substrates. Certain CYP3A substrates Avoid concomitant use with IDHIFA unless otherwise recommended in the Prescribing Information for CYP3A substrates where minimal concentration changes may lead to reduced efficacy.

Do not administer IDHIFA with anti-fungal agents that are substrates of CYP3A due to expected loss of antifungal efficacy. Co-administration of IDHIFA may decrease the concentrations of hormonal contraceptives. Consider alternative methods of contraception in patients receiving IDHIFA [See use in Specific Population (8.1 , 8.3 )] . Enasidenib is a CYP3A inducer. Concomitant use of IDHIFA decreases the exposure of CYP3A substrates [see Clinical Pharmacology (12.3) ] , which may reduce the efficacy of the substrates.

Certain OATP1B1, OATP1B3, and BCRP Substrates Avoid coadministration of IDHIFA with OATP1B1, OATP1B3, and BCRP substrates, for which minimal concentration changes may lead to serious toxicities. If coadministration cannot be avoided, decrease the OATP1B1, OATP1B3, and BCRP substrates dosage(s) in accordance with the respective Prescribing Information. Enasidenib is an OATP1B1, OATP1B3, and BCRP transporter inhibitor. Concomitant use of IDHIFA increases the exposure of OATP1B1, OATP1B3, and BCRP substrates [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to these substrates.

Certain P-glycoprotein (P-gp) Substrates When coadministered with IDHIFA, follow recommended P-gp substrates Prescribing Information and monitor more frequently for adverse reactions related to these substrates. Enasidenib is a P-gp transporter inhibitor. Concomitant use of IDHIFA increases the exposure of P-gp substrates [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to the substrates.

Contraindications

None. None ( 4 ).

Pregnancy and lactation

Pregnancy

8.1 Pregnancy Risk Summary Based on animal embryo-fetal toxicity studies, IDHIFA can cause fetal harm when administered to a pregnant woman. There are no available data on IDHIFA use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal embryo-fetal toxicity studies, oral administration of enasidenib to pregnant rats and rabbits during organogenesis was associated with embryo-fetal mortality and alterations to growth starting at 0.1 times the steady state clinical exposure based on the AUC at the recommended human dose (see Data). Advise pregnant women of the potential risk to a fetus. In the U.S.

general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. Data Animal Data Enasidenib administered to pregnant rats at a dose of 30 mg/kg twice daily during organogenesis (gestation days 6-17) was associated with maternal toxicity and adverse embryo-fetal effects including post-implantation loss, resorptions, decreased viable fetuses, lower fetal birth weights, and skeletal variations. These effects occurred in rats at approximately 1.6 times the clinical exposure at the recommended human daily dose of 100 mg/day.

In pregnant rabbits treated during organogenesis (gestation days 7-19), enasidenib was maternally toxic at doses equal to 5 mg/kg/day or higher (exposure approximately 0.1 to 0.6 times the steady state clinical exposure at the recommended daily dose) and caused spontaneous abortions at 5 mg/kg/day (exposure approximately 0.1 times the steady state clinical exposure at the recommended daily dose).

For breastfeeding, also see LactMed (National Library of Medicine), which summarizes milk levels and infant effects.

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