Enasidenib

Dosage Forms

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

Tablet, Oral:

IDHIFA: 50 mg, 100 mg

Pharmacology

Mechanism of Action

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

Pharmacokinetics/Pharmacodynamics

Distribution

55.8 L

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.

Excretion

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

Time to Peak

4 hours

Half-Life Elimination

Terminal: 7.9 days.

Protein Binding

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

Use: Labeled Indications

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

Contraindications

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

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

Dosage and Administration

Dosing: Adult

Note: Confirm IDH2 mutation status in the blood or bone marrow prior to treatment initiation. Enasidenib is associated with a moderate emetic potential; administer antiemetics prior to treatment to prevent nausea and vomiting.

Acute myeloid leukemia (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.

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.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

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.

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.

Administration

Enasidenib is associated with a moderate emetic potential; administer antiemetics prior to treatment to prevent nausea and vomiting.

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.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). Keep bottle tightly closed. Protect from moisture; store in original bottle (with desiccant canister).

Drug Interactions

There are no known significant interactions.

Adverse Reactions

>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%)

Warnings/Precautions

Concerns related to adverse effects:

• Differentiation syndrome: [US Boxed Warning]: 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. 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. If differentiation syndrome is suspected, initiate IV or oral corticosteroids (eg, dexamethasone 10 mg twice daily); taper corticosteroids only after symptom resolution (symptoms may recur if steroid therapy is stopped early). Interrupt enasidenib therapy for severe pulmonary symptoms requiring intubation or ventilator support and/or renal dysfunction that continues for more than 48 hours after corticosteroid initiation; may resume therapy when signs/symptoms have improved. 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. May require treatment with hydroxyurea (per institutional practice) and therapy interruption.
• 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. Persistent hyperbilirubinemia may require dosage reduction.
• GI toxicity: Enasidenib is associated with a moderate emetic potential; administer antiemetics prior to treatment to prevent nausea and vomiting. Nausea, vomiting, diarrhea, decreased appetite, and taste disturbances have been reported.
• Tumor lysis syndrome: Tumor lysis syndrome may occur; monitor electrolytes and renal function.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

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.

Monitoring Parameters

IDH2 mutation status (prior to treatment initiation); blood counts and blood chemistries prior to therapy initiation and every 2 weeks for at least the first 3 months; liver function tests; renal function; pregnancy test (prior to treatment in in females of reproductive potential); monitor for signs/symptoms of differentiation syndrome (eg, fever, cough, dyspnea, bone pain, rapid weight gain, edema, lymphadenopathy) and tumor lysis syndrome. Monitor adherence.

Pregnancy

Pregnancy Considerations

Based on the mechanism of action and data from animal reproduction studies, the use of enasidenib in pregnancy may cause fetal harm. Women of reproductive potential should have a pregnancy test prior to treatment initiation; effective contraception should be used during therapy and for at least 2 months after the last dose. Male patients with female partners of reproductive potential should also use effective contraception during therapy and for at least 2 months after the last dose.

Patient Education

What is this drug used for?

• It is used to treat a type of leukemia.

Frequently reported side effects of this drug

• Nausea
• Vomiting
• Diarrhea
• Lack of appetite
• Change in taste

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Bone pain
• Cough
• Shortness of breath
• Trouble breathing
• Sudden weight gain
• Swelling of arms or legs
• Swollen glands
• Dizziness
• Passing out
• Yellow skin or eyes
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes
• Electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting
• Tumor lysis syndrome like fast heartbeat or abnormal heartbeat; any passing out; unable to pass urine; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.