Ivosidenib
Indications
Newly-Diagnosed Acute Myeloid Leukemia: Ivosidenib is indicated for the treatment of newly-diagnosed acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA approved test in adult patients who are ≥ 75 years old or who have comorbidities that preclude use of intensive induction chemotherapy.
Relapsed or Refractory Acute Myeloid Leukemia: Ivosidenib is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test.
Locally Advanced or Metastatic Cholangiocarcinoma: Ivosidenib is indicated for the treatment of adult patients with previously treated, locally advanced or metastatic cholangiocarcinoma with an isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test.
Relapsed or Refractory Acute Myeloid Leukemia: Ivosidenib is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test.
Locally Advanced or Metastatic Cholangiocarcinoma: Ivosidenib is indicated for the treatment of adult patients with previously treated, locally advanced or metastatic cholangiocarcinoma with an isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test.
Dosage & Administration
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.
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.
Interaction
Clinical Studies and Model-Based Approaches: Effect of Strong or Moderate CYP3A4 Inhibitors on Ivosidenib Itraconazole was used as a strong CYP3A4 index inhibitor to evaluate the effect of CYP3A4 inhibition on the pharmacokinetics of Ivosidenib single-dose in a drug-drug interaction study in healthy subjects. Co-administration of 250 mg Ivosidenib with itraconazole (200 mg itraconazole once daily for 18 days) increased Ivosidenib single-dose AUC to 269% of control (90% CI: 245%, 295%) with no change in Cmax. In regards to multiple-dosing, note that because Ivosidenib induces the metabolism of CYP3A4 substrates following Ivosidenib multiple dosing, itraconazole (a CYP3A4 substrate) is not recommended to be used concomitantly with Ivosidenib in patients.
Effect of Strong CYP3A4 Inducers on Ivosidenib: Co-administration of Ivosidenib with a strong CYP3A4 inducer (600 mg rifampin once daily for 15 days) is predicted to decrease Ivosidenib steady-state AUC by 33%.
Effect of Ivosidenib on CYP3A4 Substrates: Ivosidenib induces CYP3A4, including its own metabolism. Co-administration of Ivosidenib with CYP3A4 substrates such as itraconazole is expected to decrease itraconazole steady-state AUC to a clinically relevant extent.
Effect of Gastric Acid Reducing Agents on Ivosidenib: Gastric acid reducing agents (e.g., proton pump inhibitors, H2-receptor antagonists, antacids) do not affect Ivosidenib concentrations.
Effect of Strong CYP3A4 Inducers on Ivosidenib: Co-administration of Ivosidenib with a strong CYP3A4 inducer (600 mg rifampin once daily for 15 days) is predicted to decrease Ivosidenib steady-state AUC by 33%.
Effect of Ivosidenib on CYP3A4 Substrates: Ivosidenib induces CYP3A4, including its own metabolism. Co-administration of Ivosidenib with CYP3A4 substrates such as itraconazole is expected to decrease itraconazole steady-state AUC to a clinically relevant extent.
Effect of Gastric Acid Reducing Agents on Ivosidenib: Gastric acid reducing agents (e.g., proton pump inhibitors, H2-receptor antagonists, antacids) do not affect Ivosidenib concentrations.
Side Effects
The following adverse reactions are discussed in greater detail in other sections of the labeling:
- Differentiation Syndrome in AML
- QTc Interval Prolongation
- Guillain-Barré Syndrome
- Fever
- Cough
- Trouble Breathing
- Rash
- Decreased Urination
- Dizziness or Lightheadedness
- Rapid Weight Gain
- Swelling of Your Arms or Legs
Pregnancy & Lactation
Pregnancy: Based on animal embryo-fetal toxicity studies, Ivosidenib may cause fetal harm when administered to a pregnant woman. There are no available data on Ivosidenib use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal embryo-fetal toxicity studies, oral administration of Ivosidenib to pregnant rats and rabbits during organogenesis was associated with embryo-fetal mortality and alterations to growth starting at 2 times the steady state clinical exposure based on the AUC at the recommended human dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus.
Lactation: There are no data on the presence of Ivosidenib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with Ivosidenib and for at least 1 month after the last dose.
Lactation: There are no data on the presence of Ivosidenib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with Ivosidenib and for at least 1 month after the last dose.
Precautions & Warnings
Differentiation Syndrome in AML: In the clinical trial, 25% (7/28) of patients with newly diagnosed AML and 19% (34/179) of patients with relapsed or refractory AML treated with Ivosidenib experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms of differentiation syndrome in patients treated with Ivosidenib included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumorlysis syndrome and creatinine increased. Of the 7 patients with newly diagnosed AML who experienced differentiation syndrome, 6 (86%) patients recovered. Of the 34 patients with relapsed or refractory AML who experienced differentiation syndrome, 27 (79%) patients recovered after treatment or after dose interruption of Ivosidenib. Differentiation syndrome occurred as early as 1 day and up to 3 months after Ivosidenib initiation and has been observed with or without concomitant leukocytosis.
QTc Interval Prolongation: Patients treated with Ivosidenib can develop QT (QTc) prolongation and ventricular arrhythmias. Of the 258 patients with hematological malignancies treated with Ivosidenib in the clinical trial (AG120-C-001), 9% were found to have a QTc interval greater than 500 msec and 14% of patients had an increase from baseline QTc greater than 60 msec. One patient developed ventricular fibrillation attributed to Ivosidenib. The clinical trial excluded patients with baseline QTc of ≥ 450 msec (unless the QTc ≥ 450 msec was due to a pre-existing bundle branch block) or with a history of long QT syndrome or uncontrolled or significant cardiovascular disease.
Guillain-Barré Syndrome: Guillain-Barré syndrome can develop in patients treated with Ivosidenib. Guillain-Barré syndrome occurred in <1% (2/258) of patients treated with Ivosidenib in study AG120-C-001. Monitor patients taking Ivosidenib for onset of new signs or symptoms of motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing. Permanently discontinue Ivosidenib in patients who are diagnosed with Guillain-Barré syndrome.
QTc Interval Prolongation: Patients treated with Ivosidenib can develop QT (QTc) prolongation and ventricular arrhythmias. Of the 258 patients with hematological malignancies treated with Ivosidenib in the clinical trial (AG120-C-001), 9% were found to have a QTc interval greater than 500 msec and 14% of patients had an increase from baseline QTc greater than 60 msec. One patient developed ventricular fibrillation attributed to Ivosidenib. The clinical trial excluded patients with baseline QTc of ≥ 450 msec (unless the QTc ≥ 450 msec was due to a pre-existing bundle branch block) or with a history of long QT syndrome or uncontrolled or significant cardiovascular disease.
Guillain-Barré Syndrome: Guillain-Barré syndrome can develop in patients treated with Ivosidenib. Guillain-Barré syndrome occurred in <1% (2/258) of patients treated with Ivosidenib in study AG120-C-001. Monitor patients taking Ivosidenib for onset of new signs or symptoms of motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing. Permanently discontinue Ivosidenib in patients who are diagnosed with Guillain-Barré syndrome.
Use in Special Populations
Pediatric Use: The safety and effectiveness of Ivosidenib in pediatric patients have not been established.
Geriatric Use: No overall differences in effectiveness or safety were observed between patients who were 65 years and older compared to younger patients.
Geriatric Use: No overall differences in effectiveness or safety were observed between patients who were 65 years and older compared to younger patients.
Therapeutic Class
Cytotoxic Chemotherapy
Storage Conditions
Store below 30°C, in a cool and dry place. Keep away from light. Keep out of the reach of children.
