Newly-Diagnosed Acute Myeloid Leukemia (AML): Ivosidenib is used to treat newly diagnosed acute myeloid leukemia (AML) in adult patients who have an IDH1 mutation confirmed by an FDA-approved test, especially those aged 75 years or older or those who cannot undergo intensive chemotherapy due to other health conditions.

Relapsed or Refractory Acute Myeloid Leukemia (AML): Ivosidenib is indicated for adult patients with AML that has returned (relapsed) or does not respond to treatment (refractory), and who have an IDH1 mutation confirmed by an FDA-approved test.

Locally Advanced or Metastatic Cholangiocarcinoma: Ivosidenib is used in adult patients with previously treated, locally advanced or metastatic cholangiocarcinoma (bile duct cancer) who have an IDH1 mutation confirmed by an FDA-approved test.

Acute Myeloid Leukemia: Select patients for the treatment of AML with Ivosidenib based on the presence of IDH1 mutations in the blood or bone marrow. Patients with AML without IDH1 mutations at diagnosis should be retested at relapse because a mutation in IDH1 may emerge during treatment and at relapse.

Locally Advanced or Metastatic Cholangiocarcinoma: Select patients for the treatment of locally advanced or metastatic cholangiocarcinoma with Ivosidenib based on the presence of IDH1 mutations.

Recommended Dosage: The recommended dose of Ivosidenib is 500 mg taken orally once daily until disease progression or unacceptable toxicity. Administer Ivosidenib with or without food. Do not administer Ivosidenib with a high-fat meal because of an increase in Ivosidenib. Do not split or crush Ivosidenib tablets. Administer Ivosidenib tablets orally about the same time each day. If a dose of Ivosidenib is vomited, do not administer a replacement dose; wait until the next scheduled dose is due. If a dose of Ivosidenib is missed or not taken at the usual time, administer the dose as soon as possible and at least 12 hours prior to the next scheduled dose. Return to the normal schedule the following day. Do not administer 2 doses within 12 hours.

Patients with Acute Myeloid Leukemia: For patients without disease progression or unacceptable toxicity, treat for a minimum of 6 months to allow time for clinical response.

Patients with the Comorbidities of Severe Renal or Severe Hepatic Impairment: Treatment with Ivosidenib has not been studied in patients with pre-existing severe renal or hepatic impairment. For patients with pre-existing severe renal or hepatic impairment, consider the risks and potential benefits before initiating treatment with Ivosidenib.

Clinical Studies and Model-Based Approaches: The effect of strong or moderate CYP3A4 inhibitors on Ivosidenib was evaluated using itraconazole as a strong CYP3A4 inhibitor in healthy subjects. Co-administration of Ivosidenib (250 mg once daily) with itraconazole (200 mg once daily for 18 days) increased the single-dose AUC of Ivosidenib to 269% of control (90% CI: 245%–295%) without affecting Cmax. With multiple dosing, since Ivosidenib induces CYP3A4 metabolism, itraconazole (a CYP3A4 substrate) is not recommended for concurrent use with Ivosidenib.

Effect of Strong CYP3A4 Inducers on Ivosidenib: Co-administration with strong CYP3A4 inducers (e.g., rifampin 600 mg once daily for 15 days) is expected to reduce the steady-state AUC of Ivosidenib by approximately 33%.

Effect of Ivosidenib on CYP3A4 Substrates: Ivosidenib induces CYP3A4, including its own metabolism. Co-administration with CYP3A4 substrates (e.g., itraconazole) may significantly decrease their steady-state AUC.

Effect of Gastric Acid Reducing Agents on Ivosidenib: Agents that reduce gastric acidity (e.g., proton pump inhibitors, H2-receptor antagonists, antacids) do not significantly affect Ivosidenib concentrations.

The following adverse reactions are described in more detail in other sections of the labeling:

• Differentiation Syndrome in AML
• QTc Interval Prolongation
• Guillain-Barré Syndrome
• Fever
• Cough
• Difficulty Breathing
• Rash
• Reduced Urination
• Dizziness or Lightheadedness
• Rapid Weight Gain
• Swelling of Arms or Legs

Pregnancy: Based on animal embryo-fetal toxicity studies, Ivosidenib may cause fetal harm when given during pregnancy. There are no adequate data in pregnant women to determine the risk of major birth defects or miscarriage. In animal studies, oral administration of Ivosidenib during organ development caused embryo-fetal death and growth abnormalities at doses approximately 2 times the human exposure. If used during pregnancy or if pregnancy occurs during treatment, patients should be informed about potential fetal risk.

Lactation: There are no available data on the presence of Ivosidenib or its metabolites in human milk, its effects on the breastfed infant, or on milk production. Because many drugs pass into breast milk and may cause adverse effects, women are advised not to breastfeed during treatment and for at least 1 month after the last dose.

Differentiation Syndrome in AML: In clinical studies, differentiation syndrome occurred in 25% (7/28) of patients with newly diagnosed AML and 19% (34/179) of patients with relapsed or refractory AML treated with Ivosidenib. This condition is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening if untreated. Reported symptoms include noninfectious leukocytosis, peripheral edema, fever, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and elevated creatinine. Among newly diagnosed patients, 86% recovered, while 79% of relapsed/refractory patients improved after treatment or dose interruption. Onset may occur as early as 1 day and up to 3 months after starting therapy, with or without leukocytosis.

QTc Interval Prolongation: Ivosidenib may cause QT (QTc) interval prolongation and ventricular arrhythmias. In clinical trials, 9% of patients had QTc >500 msec and 14% showed an increase of more than 60 msec from baseline. One case of ventricular fibrillation was reported. Patients with baseline QTc >450 msec (unless due to bundle branch block), long QT syndrome, or significant cardiovascular disease were excluded from trials.

Guillain-Barré Syndrome: Guillain-Barré syndrome has been reported in <1% (2/258) of patients receiving Ivosidenib. Monitor for symptoms such as muscle weakness (unilateral or bilateral), sensory disturbances, paresthesia, or breathing difficulty. Discontinue Ivosidenib permanently if this condition is diagnosed.

Pediatric Use: Safety and effectiveness have not been established.
Geriatric Use: No major differences in safety or effectiveness compared to younger patients.

Cytotoxic Chemotherapy

Store below 30°C in a cool and dry place. Protect from light and keep out of reach of children.