Enasinib Enasidenib tablets

I. Full Name

Chinese Generic Name: Enasidenib Tablets

English Generic Name: Enasidenib Tablets

Brand Names: IDHIFA, Enasinib

Specification: 50 mg × 30 tablets/box

Manufacturer: Everest Pharmaceuticals Ltd.

Chemical Name: 2-methyl-1-[4-[1-(4-chlorophenyl)-4-oxo-3-(pyridin-4-yl)pyrazol-5-yl]piperidin-1-yl]propan-1-one mesylate

Drug Classification: IDH2 (Isocitrate Dehydrogenase 2) small-molecule targeted inhibitor; a precision-targeted therapy for relapsed/refractory AML.

II. Composition

Active Ingredient: Enasidenib mesylate (calculated as the free base, Enasidenib)

Excipients: Microcrystalline cellulose, lactose monohydrate, crospovidone, magnesium stearate, film coating premix.

III. Description

Oval, film-coated tablets; white to off-white in color when the coating is removed.

IV. Indications

Indicated for the treatment of adult patients with relapsed or refractory Acute Myeloid Leukemia (AML) who have an isocitrate dehydrogenase-2 (IDH2) mutation, as detected by an FDA-approved test.

Target Population: Adult patients with IDH2-mutated AML who have failed prior multi-line therapies (including chemotherapy), experienced disease relapse, or exhibited primary resistance without achieving remission.

V. Dosage and Administration

1. Standard Recommended Dosage

100 mg orally once daily. Treatment should be continued until disease progression, occurrence of intolerable toxicity, or achievement of clinical remission.

Administration Method: May be taken with or without food. The tablet should be swallowed whole with warm water; it must not be broken, chewed, or crushed.

Initial Treatment Duration: For patients who show no disease progression and experience no severe intolerance, treatment should be continued for at least 6 months to allow sufficient time for clinical remission to manifest. 2. Dose Adjustment (Toxicity Reduction Regimen)

Grade 1 Toxicity: Maintain original dose; monitor closely.

Persistent Grade 2 Toxicity: Reduce dose to 50 mg once daily.

Grade 3–4 Severe Toxicity: Suspend administration; resume at 50 mg once daily once toxicity resolves to Grade 1 or lower. If toxicity recurs, permanently discontinue the drug.

3. Management of Missed Doses/Vomiting

Missed Dose: If remembered on the same day, take the missed dose as soon as possible. If it is already close to the scheduled time for the next dose, skip the missed dose and take the next dose at the regular scheduled time; do not take a double dose to make up for the missed one.

Vomiting After Dosing: No need to take a replacement dose; simply resume the regular dosing schedule the following day.

VI. Boxed Warning (Primary Safety Alert)

Differentiation Syndrome (Potentially Fatal)

May occur following drug administration; onset can range from as early as 1 day to as late as 5 months after initiation, and is not necessarily correlated with an elevated white blood cell count.

Typical Symptoms: Fever, dyspnea, hypoxia, pulmonary infiltrates, pleural/pericardial effusions, rapid weight gain, peripheral edema, lymphadenopathy, bone pain, and multi-organ dysfunction (hepatic/renal impairment).

Management: If highly suspected, immediately initiate corticosteroid therapy while providing hemodynamic monitoring until symptoms completely resolve; do not abruptly discontinue the drug.

VII. Adverse Reactions

Common (≥10%)

Nausea, vomiting, diarrhea, decreased appetite, elevated bilirubin, jaundice, thrombocytopenia, anemia, leukocytosis, fatigue, fever, arthralgia/myalgia.

Uncommon

Hypophosphatemia, hypokalemia, dehydration, dizziness, rash, elevated transaminases.

Serious Adverse Reactions

1. Differentiation Syndrome (Risk of fatality; see Boxed Warning)

2. Hyperleukocytosis

3. Hepatotoxicity, cholestatic liver injury

4. Severe hemorrhage, myelosuppression

5. Tumor Lysis Syndrome

VIII. Contraindications

1. Contraindicated in patients with hypersensitivity to enasidenib, mesylates, or any of the excipients contained in this product. 2. Contraindicated in pregnant women (embryo-fetal toxicity).

IX. Precautions

1. Monitoring for Differentiation Syndrome

Maintain vigilance for the aforementioned symptoms throughout the entire course of treatment; if suspected, initiate hormonal intervention immediately. Early intervention is associated with a favorable prognosis.

2. Hematological and Bone Marrow Monitoring

Periodically perform complete blood counts (CBC), peripheral blood smears, and bone marrow assessments to monitor blood cell differentiation and the status of bone marrow remission.

3. Liver Function Monitoring

This product is prone to causing elevated bilirubin levels and cholestasis; monitor liver function prior to and periodically during treatment. If liver enzymes remain persistently and significantly elevated, suspend treatment.

4. Management of Hyperleukocytosis

Following administration, the differentiation and maturation of blast cells may lead to a transient increase in leukocyte counts; if necessary, intervene with leukapheresis or hydroxyurea.

5. Reproductive Safety and Contraception

Females: Strict contraception is required during treatment and for 2 months following the final dose; contraindicated during pregnancy. There is a risk of reproductive impairment.

Males: During treatment and for 2 months following the final dose, effective contraception must be used with female partners of childbearing potential.

Lactation: Breastfeeding is prohibited during treatment and for 2 months following the discontinuation of the drug.

6. Special Populations

Children (<18 years): Safety and efficacy have not been established; use is not recommended.

Elderly Patients: No initial dose adjustment is required; enhanced monitoring for toxicity is sufficient.

Hepatic and Renal Impairment: No dose adjustment is required for mild to moderate impairment; use with caution in cases of severe hepatic impairment due to insufficient data.

7. Drug Interactions

This product is a P-gp inhibitor; co-administration with P-gp substrate drugs may increase the plasma concentrations of the latter. Closely monitor for adverse reactions associated with the substrate drugs; avoid co-administration with sensitive P-gp substrates whenever possible.

X. Pharmacology and Toxicology

Mechanism of Action

A highly selective small-molecule inhibitor of the mutated IDH2 enzyme.

Mutated IDH2 leads to the abnormal and excessive synthesis of 2-hydroxyglutarate (2-HG), which blocks the normal differentiation of hematopoietic cells and induces leukemia. This product precisely inhibits mutated IDH2, reduces intracellular levels of 2-HG, relieves the block in hematopoietic differentiation, and induces malignant leukemia progenitor cells to mature and differentiate into normal, functional blood cells, thereby achieving disease remission. Unlike chemotherapy, it does not exert direct cytotoxic killing effects.

Pharmacokinetics

The product demonstrates good oral absorption, a consistent time to peak concentration, and a long half-life; once-daily dosing is sufficient to provide sustained and steady enzyme inhibition. It is primarily metabolized by the liver, with minimal renal excretion. Food intake does not affect overall systemic exposure, and there is no significant risk of drug accumulation.

XI. Storage

Keep tightly sealed. Store in a cool, dry place protected from light at temperatures below 25°C. Retain the desiccant packet inside the bottle. Keep away from high heat and humidity, and keep out of the reach of children.

XII. Overdosage

Manifestations of Overdosage: Severe differentiation syndrome, marked elevations in liver enzymes and/or bilirubin, severe myelosuppression, and multi-organ dysfunction.

Management: Discontinue the medication immediately. Provide symptomatic and supportive care, corticosteroid intervention, hepatoprotective measures, and hematological monitoring. There is no specific antidote.

Product Specifications

Product Name: Enasidenib Tablets (50 mg × 30 tablets/box)

Common Name: Enasidenib Tablets

Active Ingredient: Enasidenib

Dosage Form: Tablets

Specification: 50 mg × 30 tablets/box

Manufacturer: Everest Pharmaceuticals Ltd.

Indications: For the treatment of adult patients with relapsed or refractory Acute Myeloid Leukemia (AML) who have been confirmed—via an FDA-approved diagnostic test—to harbor an IDH2 gene mutation.

Target Population: Adult patients with IDH2-mutated AML who have failed prior multi-line therapies (including chemotherapy), experienced disease relapse, or demonstrated primary resistance without achieving remission.

Dosage and Administration: 1. Standard Recommended Dose

100 mg, taken orally once daily. Treatment should be continued until disease progression, the development of intolerable toxicity, or the achievement of clinical remission/cure.

Administration Method: May be taken with or without food. Swallow the tablet whole with warm water; do not break, chew, or crush the tablet. Initial Treatment Course: For patients exhibiting no disease progression and no severe intolerance, treatment should be administered for a minimum of 6 months to allow sufficient time for clinical remission to take effect.

2. Dosage Adjustment (Toxicity-Based Dose Reduction)

Grade 1 Toxicity: Maintain the original dosage while monitoring closely.

Persistent Grade 2 Toxicity: Reduce the dosage to 50 mg once daily.

Severe Grade 3–4 Toxicity: Suspend administration; once toxicity resolves to Grade 1 or lower, resume treatment at a dosage of 50 mg once daily. If toxicity recurs, permanently discontinue the medication.

3. Management of Missed Doses or Vomiting

Missed Dose: If remembered on the same day, take the missed dose as soon as possible. If it is already close to the scheduled time for the next dose, skip the missed dose and resume the regular dosing schedule; do not take a double dose to compensate.

Vomiting After Administration: No replacement dose is required; simply resume the regular dosing schedule at the usual time the following day.