Ivosenib

• Approved Indications:
• Treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test.
• Newly diagnosed AML patients with IDH1 mutation who are ≥75 years old or who have comorbidities precluding intensive chemotherapy.
• Off-label/Clinically Accepted Uses:
• Investigational use in other IDH1-mutated cancers such as cholangiocarcinoma and glioma (not widely approved).

• Adult Dose:
• 500 mg orally once daily with or without food.
• Pediatrics:
• Safety and efficacy not established.
• Elderly:
• No dosage adjustment necessary solely based on age.
• Renal Impairment:
• No adjustment required for mild to moderate impairment; use cautiously in severe impairment.
• Hepatic Impairment:
• Mild or moderate impairment: no dose adjustment.
• Severe impairment: use with caution; limited data.
• Administration:
• Oral tablets, swallow whole, do not crush or chew.
• Duration:
• Continue until disease progression or unacceptable toxicity.

Ivosidenib is a targeted small-molecule inhibitor of the mutated isocitrate dehydrogenase-1 (IDH1) enzyme. IDH1 mutations cause abnormal production of the oncometabolite 2-hydroxyglutarate (2-HG), which impairs cellular differentiation and promotes leukemogenesis. By inhibiting mutant IDH1, ivosidenib reduces 2-HG levels, restores normal cell differentiation, and suppresses leukemia cell proliferation, thereby exerting its antineoplastic effects in AML with IDH1 mutations.

• Absorption:
• Oral absorption with peak plasma concentration (Tmax) around 3 hours post-dose.
• Bioavailability:
• High, unaffected significantly by food.
• Distribution:
• Volume of distribution approximately 234 L, moderately protein-bound (~92%).
• Metabolism:
• Primarily metabolized by CYP3A4 enzymes in the liver.
• Half-life:
• Approximately 93 hours (range 56–138 hours).
• Elimination:
• Excreted mainly via feces; minimal renal elimination.

• Pregnancy:
• No well-controlled human studies; likely teratogenic based on animal data. Use effective contraception during treatment and for at least 1 month after last dose.
• Lactation:
• Unknown if excreted in human milk; breastfeeding not recommended during treatment and for 1 month after.

• Primary Class: Antineoplastic agent
• Subclass: IDH1 mutation inhibitor (targeted therapy)

• Known hypersensitivity to ivosidenib or any component of the formulation.

• Differentiation Syndrome:
• Potentially fatal; monitor for fever, respiratory distress, rapid weight gain, and hypotension. Treat promptly with corticosteroids.
• QT Interval Prolongation:
• Monitor ECG and electrolytes periodically. Avoid concomitant QT-prolonging drugs.
• Hepatotoxicity:
• Monitor liver function tests; dose interruption or discontinuation may be necessary.
• Tumor Lysis Syndrome:
• Risk at treatment initiation; monitor renal function and electrolytes.
• Drug Interactions:
• Strong CYP3A4 inhibitors/inducers may alter ivosidenib levels; dose adjustments may be required.

Common Adverse Effects:

• Fatigue
• Nausea, vomiting
• Diarrhea
• Arthralgia (joint pain)
• Prolonged QT interval
• Elevated liver enzymes (ALT, AST)
• Differentiation syndrome symptoms

Serious/Rare Effects:

• Differentiation syndrome (may be life-threatening)
• Severe hepatotoxicity
• Cardiac arrhythmias
• Tumor lysis syndrome

• CYP3A4 Inhibitors: (e.g., ketoconazole) may increase ivosidenib plasma concentration → increased toxicity risk.
• CYP3A4 Inducers: (e.g., rifampin) may decrease efficacy by lowering plasma levels.
• Drugs that prolong QT interval: additive risk of cardiac arrhythmias.
• Avoid grapefruit juice (CYP3A4 inhibitor).

• The FDA recently expanded approval to include newly diagnosed AML patients with IDH1 mutation unsuitable for intensive chemotherapy.
• Updated warnings on differentiation syndrome and QT prolongation management emphasized.
• EMA and NCCN guidelines include ivosidenib as a preferred targeted therapy for IDH1-mutated AML.

• Store tablets at 20°C to 25°C (68°F to 77°F).
• Protect from moisture and light.
• Keep in original container tightly closed.
• No refrigeration or special handling required.