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.
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, 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 (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.
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).
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.
Refer to adult dosing.
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.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
IDHIFA: 50 mg, 100 mg
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
IDHIFA: 50 mg, 100 mg
Enasidenib is available through select specialty pharmacies and authorized distributors. Refer to http://www.idhifa.com for further information.
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
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 split or crush tablets.
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.
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.
Acute myeloid leukemia, newly diagnosed; Myelodysplastic syndromes, high-risk, relapsed/refractory
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
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.
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%)
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.
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.
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, OATP1B1/1B3 (SLCO1B1/1B3)
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.
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
Asunaprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Asunaprevir. Risk X: Avoid combination
Atogepant: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Atogepant. Management: The recommended dose of atogepant when coadministered with OATP1B1/1B3 inhibitors is 10 mg once daily or 30 mg once daily. 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
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
Digoxin: Enasidenib may increase the serum concentration of Digoxin. Risk C: Monitor therapy
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
Mitapivat: May decrease the serum concentration of UGT1A1 Substrates. Risk C: Monitor therapy
PAZOPanib: BCRP/ABCG2 Inhibitors may increase the serum concentration of PAZOPanib. Risk X: Avoid combination
Revefenacin: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentrations of the active metabolite(s) of Revefenacin. Risk X: Avoid combination
Rosuvastatin: BCRP/ABCG2 Inhibitors may increase the serum concentration of Rosuvastatin. Risk C: Monitor therapy
Talazoparib: BCRP/ABCG2 Inhibitors may increase the serum concentration of Talazoparib. Risk C: Monitor therapy
Taurursodiol: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Taurursodiol. Risk X: Avoid combination
Topotecan: BCRP/ABCG2 Inhibitors may increase the serum concentration of Topotecan. Risk X: Avoid combination
Ubrogepant: BCRP/ABCG2 Inhibitors may increase the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 50 mg and second dose (at least 2 hours later if needed) of 50 mg when used with a BCRP inhibitor. Risk D: Consider therapy modification
Voxilaprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Voxilaprevir. Risk X: Avoid combination
Verify pregnancy status prior to treatment initiation; patients who could become pregnant should use effective contraception during therapy and for at least 2 months after the last enasidenib dose. Patients with partners who could become pregnant should also use effective contraception during therapy and for at least 2 months after the last dose of enasidenib.
Based on animal reproduction studies, in utero exposure to enasidenib during pregnancy 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 or for at least 2 months after the last enasidenib dose.
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.
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: 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.
Tablets (IDHIFA Oral)
50 mg (per each): $1,180.68
100 mg (per each): $1,180.68
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