Enasidenib

Approved Indications:

• Relapsed or Refractory Acute Myeloid Leukemia (AML):
  Enasidenib is indicated for the treatment of adult patients with relapsed or refractory AML harboring an isocitrate dehydrogenase-2 (IDH2) mutation, as detected by an FDA-approved test.

Important Off-label (Clinically Accepted) Uses:

• Maintenance therapy in AML post-induction (under investigation or institutional use only)
• IDH2-mutant myelodysplastic syndromes (MDS) (early clinical settings)
• Combination regimens with hypomethylating agents or other targeted agents in IDH2-mutant hematological malignancies (based on clinical trials)

General Administration:

• Route: Oral
• Formulation: Tablets
• Administration: With or without food, at the same time each day.

Adults (≥18 years):

• Recommended Dose: 100 mg orally once daily
• Duration: Continue until disease progression or unacceptable toxicity. A minimum trial of 6 months is recommended to assess clinical response.

Elderly:

• No dose adjustment required based on age.

Renal Impairment:

• No dose adjustment required in mild-to-moderate impairment. Severe impairment: Use with caution due to limited data.

Hepatic Impairment:

• Mild to moderate: No dose adjustment needed.
• Severe: Use with caution; monitor liver function closely.

Dose Modifications:

• For differentiation syndrome: Initiate systemic corticosteroids and interrupt Enasidenib until resolution.
• For grade ≥3 non-hematologic toxicities or persistent hyperbilirubinemia: Interrupt until recovery, then resume at same or reduced dose.

Enasidenib is a selective inhibitor of mutant isocitrate dehydrogenase 2 (IDH2) enzymes, which are mutated in a subset of AML cases. These mutations result in the abnormal production of 2-hydroxyglutarate (2-HG), an oncometabolite that promotes leukemogenesis by blocking cellular differentiation and altering epigenetic regulation. Enasidenib reduces 2-HG levels, thereby allowing differentiation of leukemic cells into mature blood cells. Unlike traditional cytotoxic agents, Enasidenib promotes cell maturation rather than direct apoptosis.

• Absorption: Oral bioavailability ~57%; Tmax ~4 hours
• Distribution: High volume of distribution (~55.8 L); plasma protein binding ~98.5%
• Metabolism: Primarily via CYP3A4, with contributions from CYP2B6 and CYP1A2
• Active Metabolites: Several metabolites including M1 and M2 with lower activity
• Elimination: Mainly fecal (~89%); minimal renal (~11%)
• Half-life: ~137 hours (long half-life allows once-daily dosing)
• Steady-State: Achieved in approximately 29 days

• Pregnancy Risk: Enasidenib may cause embryo-fetal toxicity. Not assigned a formal FDA category under the PLLR format. Avoid use in pregnancy. Use effective contraception during and for at least 2 months after the last dose.
• Lactation: Unknown whether Enasidenib is excreted in human milk. Breastfeeding is not recommended during treatment and for at least 2 months after the final dose due to potential serious adverse effects in the infant.

• Primary Class: Antineoplastic Agent
• Subclass: IDH2 Inhibitor
• Targeted Therapy Class: Differentiation-inducing agent (non-cytotoxic)

• Known hypersensitivity to Enasidenib or any of its excipients
• Pregnancy and lactation (due to potential fetal harm)
• Concurrent use with strong CYP3A4 inducers (relative contraindication due to reduced efficacy)

• Differentiation Syndrome: May be life-threatening. Monitor for signs (fever, dyspnea, pulmonary infiltrates, weight gain). Initiate corticosteroids promptly.
• Tumor Lysis Syndrome (TLS): Risk in early treatment phase. Monitor renal function and electrolytes.
• Hyperbilirubinemia: Common due to UGT1A1 inhibition. Monitor liver function tests routinely.
• QT Prolongation: Monitor ECG in patients with cardiac risk factors or concomitant QT-prolonging drugs.
• Embryo-Fetal Toxicity: Strict contraceptive use required during and after therapy.
• Impaired hepatic/renal function: Close monitoring recommended.

Common Adverse Effects (≥10%):

• Hematologic: Anemia, leukocytosis, thrombocytopenia
• Gastrointestinal: Nausea, diarrhea, vomiting, decreased appetite
• Hepatic: Elevated bilirubin
• General: Fatigue, fever

Serious or Rare Effects:

• Differentiation syndrome (10–20%)
• Tumor lysis syndrome
• Severe infections (e.g., sepsis, pneumonia)
• QT prolongation
• Pancreatitis (rare)
• Rash or hypersensitivity reactions

Onset: Many side effects, including differentiation syndrome, occur within the first 2–3 months of therapy.

• CYP3A4 Inhibitors: May increase Enasidenib levels – monitor for toxicity.
• CYP3A4 Inducers: (e.g., rifampin, phenytoin) may decrease Enasidenib efficacy – avoid use.
• UGT1A1 Inhibitors/Substrates: Enasidenib may elevate bilirubin due to UGT1A1 inhibition.
• QT-Prolonging Drugs: Caution with other QT-prolonging agents (e.g., azole antifungals, macrolides).
• Alcohol: No direct interaction reported, but caution advised due to hepatic metabolism.

Enzyme Pathways Involved: Primarily CYP3A4, secondary involvement of CYP1A2, CYP2B6, and UGT1A1 inhibition.

• FDA Label Updates: Emphasis on managing differentiation syndrome with corticosteroids and hospitalization when required.
• New Clinical Data: Ongoing trials assessing combination therapies (e.g., with azacitidine or venetoclax).
• NCCN Guidelines (AML): Enasidenib remains a category 2A recommendation for IDH2-mutant relapsed/refractory AML.
• EU Regulatory Status: Approved in select regions for specific IDH2-mutant AML settings; local availability may vary.

• Temperature: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C–30°C.
• Humidity: Protect from moisture.
• Light Protection: Store in original packaging to protect from light.
• Handling: Do not crush, chew, or split tablets. Handle with care; wash hands after handling.