Ivosidenib

Indications

Ivosidenib is used for: Acute Myeloid Leukemia

Adult Dose

Acute Myeloid Leukemia Newly-diagnosed acute myeloid leukemia (AML) Indicated for treatment of newly-diagnosed acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test in adults who are ?75 years old or who have comorbidities that preclude use of intensive induction chemotherapy 500 mg PO qDay Continue until disease progression or unacceptable toxicity; treat for a minimum of 6 months to allow time for clinical response Relapsed or refractory AML Indicated for patients with relapsed or refractory AML with a susceptible IDH1 mutation as detected by an FDA-approved test 500 mg PO qDay Continue until disease progression or unacceptable toxicity; treat for a minimum of 6 months to allow time for clinical response Hepatic impairment Mild to moderate (Child- Pugh A or B): No clinically meaningful effects on the pharmacokinetics Severe (Child-Pugh C): Unknown Pre-existing severe hepatic impairment: Consider risks and potential benefits before initiating treatment

Child Dose

Renal Dose

Renal impairment Mild or moderate (eGFR ?30 mL/min/1.73 m²): No clinically meaningful effects on the pharmacokinetics Severe (eGFR <30 mL/min/1.73 m²) or patients requiring dialysis: Unknown

Administration

Administer with or without food Do not administer with high-fat; increases ivosidenib concentration and possibly risk of adverse effects Swallow tablets whole; do not split or crush Administer orally about the same time each day

Contra Indications

Precautions

In the clinical trial, patients with relapsed or refractory AML treated with ivosidenib experienced differentiation syndrome Patients can develop QT (QTc) prolongation and ventricular arrhythmias; 9% of 258 patients treated with ivosidenib in clinical trials were found to have a QTc interval >500 msec and 14% had a QTc >60 msec; in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary Guillain-Barré syndrome occurred in the clinical study; monitor 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

Pregnancy-Lactation

Pregnancy Based on animal embryo-fetal toxicity studies, fetal harm may occur when administered to a pregnant woman There are no available data on use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage 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 Animal data 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 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 and for at least 1 month after the last dose

Interactions

Coadministration with strong CYP3A4 inducers decreased ivosidenib plasma concentrations; avoid use Strong to moderate CYP3A4 inhibitors Coadministration with strong or moderate CYP3A4 inhibitors increased ivosidenib plasma concentrations; increased ivosidenib plasma concentrations may increase the risk of QTc interval prolongation Avoid use; if ivosidenib must be coadministered, decrease dose Ivosidenib induces CYP3A4 and may induce CYP2C9 Coadministration decrease concentrations of sensitive CYP3A4 substrates and may decrease concentrations of sensitive CYP2C9 substrates Use alternant therapies that are not sensitive CYP3A4 and CYP2C9 substrates during treatment Do not administer with itraconazole or ketoconazole (CYP3A4 substrates) owing to expected loss of antifungal efficacy May decrease efficacy of hormonal contraceptives owing to lower systemic exposure; consider other contraception methods If coadministration of sensitive CYP3A4 or CYP2C9 substrates are unavoidable, monitor for loss of therapeutic effect of these drugs

Adverse Effects

Side effects of Ivosidenib : >10% (All Grades) Decreased hemoglobin (60%) Fatigue (39-50%) Edema (32-43%) Decreased sodium (39%) Decreased appetite (18-39%) Leukocytosis (36-38%) Decreased magnesium (38%) Mucositis (21-38%) Arthralgia (32-36%) Diarrhea (34-61%) Dyspnea (29-33%) Decreased uric acid (32%) Nausea (31-36%) Decreased potassium (31%) Abdominal pain (16-29%) Increased alkaline phosphatase (27%) Increased aspartate aminotransferase (27%) Rash (14-26%) Decreased phosphate (25%) Differentiation syndrome (19-25%) Myalgia (18-25%) Increased creatinine (23%) Pyrexia (23%) Cough (14-22%) Constipation (20-21%) Dizziness (21%) Vomiting (18%) Headache (11-16%) Chest pain (16%) Increased bilirubin (16%) Increased alanine aminotransferase (15%) Neuropathy (12-14%) Pleural effusion (13%) Hypotension (12%) Dyspepsia (11%) Decreased weight (11%) >10% (Grades ≥3) Decreased hemoglobin (46%) Differentiation syndrome (13%) Fatigue (3-14%) Decreased potassium (6-11%)

Mechanism of Action

IDH1 inhibitor; inhibits selected IDH1 R132 mutants at much lower concentrations than wild-type IDH1 in vitro Inhibition of mutated IDH1 enzyme by ivosidenib led to decreased 2-HG levels and induced myeloid differentiation in vitro and in vivo in mouse xenograft models of IDH1-mutated AML In blood samples from patients with AML with mutated IDH1, ivosidenib decreased 2-HG levels ex vivo, reduced blast counts, and increased percentages of mature myeloid cells