Ivosidenib

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Tibsovo: 250 mg [contains fd&c blue #2 (indigotine)]

Pharmacology

Mechanism of Action

Ivosidenib is an oral small-molecule inhibitor of the mutant isocitrate dehydrogenase 1 (IDH1) enzyme. Susceptible IDH1 mutations can lead to increased levels of 2-hydroxyglutarate (2-HG) in leukemia cells. 2-HG inhibits alpha-ketoglutarate-dependent enzymes, resulting in impaired hematopoietic differentiation (DiNardo 2018). In IDH1 mutated AML blood samples, ivosidenib decreased intracellular levels of 2-HG, reduced blast counts, and induced differentiation (resulting in increased percentages of mature myeloid cells). IDH1 mutations occur in ~6% to10% of patients with acute myeloid leukemia (DiNardo 2018).

Pharmacokinetics/Pharmacodynamics

Absorption

Rapid (DiNardo 2018)

Distribution

V_dss: 234 L

Metabolism

Hepatic; primarily metabolized via CYP3A4 with minor contributions via the N-dealkylation and hydrolytic pathways.

Excretion

Feces: 77% (67% as unchanged drug); urine: 17% (10% as unchanged drug)

Onset of Action

Maximal inhibition of 2-hydroxyglutarate: By day 14 (DiNardo 2018)

Median time to response: 1.9 months; range: 0.8 to 4.7 months (DiNardo 2018)

Median time to complete remission: 2.8 months; range: 0.9 to 8.3 months (DiNardo 2018)

Time to Peak

~3 hours

Duration of Action

Median duration of response: 6.5 months (DiNardo 2018)

Median duration of complete remission: 9.3 months (DiNardo 2018)

Half-Life Elimination

93 hours

Protein Binding

92% to 96%

Use in Specific Populations

Special Populations: Hepatic Function Impairment

Following a single 500 mg ivosidenib dose, the geometric mean ratio of ivosidenib systemic exposure (AUC_0-INF) in subjects with mild impairment (Child-Pugh class A) and moderate impairment (Child-Pugh class B) was 0.85 and 0.71, respectively (compared with subjects with normal hepatic function).

Use: Labeled Indications

Acute myeloid leukemia (newly diagnosed): Treatment of newly diagnosed acute myeloid leukemia (AML) in adults ≥75 years of age (or with comorbidities that preclude use of intensive induction chemotherapy) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an approved test.

AML (relapsed/refractory): Treatment of relapsed or refractory AML in adults with a susceptible IDH1 mutation as detected by an approved test.

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Dosage and Administration

Dosing: Adult

Note: Confirm isocitrate dehydrogenase-1 (IDH1) mutation status in the blood or bone marrow prior to therapy initiation. IDH1 mutation may emerge during treatment and at relapse, therefore patients without IDH1 mutation at diagnosis should be retested at relapse.

Acute myeloid leukemia (newly diagnosed): Oral: 500 mg once daily (Roboz 2018); continue for a minimum of 6 months and then until disease progression or unacceptable toxicity occurs.

Acute myeloid leukemia (relapsed/refractory): Oral: 500 mg once daily (DiNardo 2018); continue for a minimum of 6 months and then until disease progression or unacceptable toxicity occurs.

Dosage adjustment for concomitant strong CYP3A4 inhibitors: Consider alternate therapies; if concomitant use of a strong CYP3A4 inhibitor cannot be avoided, reduce the ivosidenib dose to 250 mg once daily. After the strong CYP3A4 inhibitor has been discontinued, increase the ivosidenib dose (after at least 5 half-lives of the CYP3A4 inhibitor) to the recommended dose of 500 mg once daily.

Missed dose: If a dose is missed or not administered at the usual time, administer the dose as soon as possible and at least 12 hours prior to the next scheduled dose and return to the normal administration schedule the following day; do not administer 2 doses within 12 hours. If a dose is vomited, do not administer a replacement dose (wait until the next scheduled dose is due).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Differentiation syndrome: If differentiation syndrome is suspected, administer systemic corticosteroids (dexamethasone 10 mg IV every 12 hours [or equivalent]) and monitor hemodynamic status until symptoms resolve and for a minimum of 3 days. Interrupt ivosidenib treatment if severe signs and/or symptoms persist for >48 hours after initiation of systemic corticosteroids. Resume ivosidenib when signs and symptoms improve to grade 2 or lower.

Guillain-Barré syndrome: Permanently discontinue ivosidenib.

Non-infectious leukocytosis (WBC >25,000/mm³ or absolute WBC increase from baseline of >15,000/mm³): Initiate cytoreduction therapy with hydroxyurea and initiate leukapheresis if clinically indicated. Taper hydroxyurea only after leukocytosis improves or resolves. Interrupt ivosidenib treatment if leukocytosis is not improved with hydroxyurea. When leukocytosis has resolved, then resume ivosidenib at 500 mg once daily.

QT prolongation:

QTc interval >480 msec to 500 msec: Monitor electrolytes and supplement as clinically indicated. Review and adjust concomitant medications with known QTc interval-prolonging effects. Interrupt ivosidenib treatment. Restart ivosidenib at 500 mg once daily after the QTc interval returns to ≤480 msec. Monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation.

QTc interval >500 msec: Monitor electrolytes and supplement as clinically indicated. Review and adjust concomitant medications with known QTc interval-prolonging effects. Interrupt ivosidenib treatment. Restart ivosidenib at a reduced dose of 250 mg once daily after the QTc interval returns to within 30 msec of baseline or to ≤480 msec. Monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation. If an alternative etiology for the QTc prolongation can be identified, consider escalating the ivosidenib dose back to 500 mg once daily.

QTc interval prolongation with signs/symptoms of life-threatening arrhythmia: Permanently discontinue ivosidenib.

Other grade 3 or higher toxicity considered to be treatment-related: Interrupt ivosidenib treatment until resolves to grade 2 or lower. Resume ivosidenib at 250 mg once daily; may increase to 500 mg once daily if toxicity resolves to grade 1 or lower. If grade 3 or higher toxicity recurs, discontinue ivosidenib.

Administration

Oral: Administer at the same time each day, either with or without food (do not administer with a high fat meal). Do not split, crush, or chew tablets.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F)

Drug Interactions

Amiodarone: QT-prolonging Kinase Inhibitors (Highest Risk) may enhance the QTc-prolonging effect of Amiodarone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Amisulpride: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Amisulpride. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Azithromycin (Systemic): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Azithromycin (Systemic). Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Chloroquine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Chloroquine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Citalopram: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Citalopram. Avoid combination

Clarithromycin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Clarithromycin. Avoid combination

Clofazimine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Clofazimine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

CloZAPine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of CloZAPine. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Ivosidenib. Avoid combination

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Ivosidenib. Management: Avoid use of moderate CYP3A4 inhibitors with ivosidenib whenever possible. If combined, monitor for increased ivosidenib toxicities. Drugs listed as exceptions are discussed in further detail in separate drug interaction monographs. Exceptions: Crizotinib; Dronedarone; Erythromycin (Systemic); Fluconazole; Nilotinib; Ribociclib. Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Ivosidenib. Management: Avoid use of a strong CYP3A4 inhibitor with ivosidenib whenever possible. When combined use is required, reduce the ivosidenib dose to 250 mg once daily. Drugs listed as exceptions are discussed in further detail in separate drug interaction monographs. Exceptions: Ceritinib; Clarithromycin; Saquinavir; Voriconazole. Consider therapy modification

CYP3A4 Substrates (High risk with Inducers): Ivosidenib may decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Dasatinib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Domperidone: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Domperidone. Avoid combination

Doxepin-Containing Products: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Doxepin-Containing Products. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Dronedarone: Ivosidenib may enhance the QTc-prolonging effect of Dronedarone. Dronedarone may increase the serum concentration of Ivosidenib. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Droperidol: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Droperidol. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Encorafenib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Entrectinib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Avoid combination

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Escitalopram: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Escitalopram. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Estrogen Derivatives (Contraceptive): Ivosidenib may decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Consider alternative methods of contraception (ie, non-hormonal) in patients receiving ivosidenib. Consider therapy modification

Fexinidazole [INT]: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Avoid combination

Fingolimod: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias (including TdP) with a continuous overnight ECG when fingolimod is combined with QT prolonging drugs. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Flecainide: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Flecainide. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Flupentixol: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Flupentixol. Avoid combination

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Gadobenate Dimeglumine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Gadobenate Dimeglumine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Gemifloxacin: QT-prolonging Kinase Inhibitors (Highest Risk) may enhance the QTc-prolonging effect of Gemifloxacin. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Gilteritinib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this combination. If use is necessary, monitor for QTc interval prolongation and arrhythmias. Consider therapy modification

Halofantrine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Halofantrine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Haloperidol: QT-prolonging Kinase Inhibitors (Highest Risk) may enhance the QTc-prolonging effect of Haloperidol. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Inotuzumab Ozogamicin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Inotuzumab Ozogamicin. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Itraconazole: May increase the serum concentration of Ivosidenib. Ivosidenib may decrease the serum concentration of Itraconazole. Avoid combination

Ketoconazole (Systemic): May increase the serum concentration of Ivosidenib. Ivosidenib may decrease the serum concentration of Ketoconazole (Systemic). Avoid combination

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Lefamulin: May enhance the QTc-prolonging effect of QT-prolonging CYP3A4 Substrates. Management: Do not use lefamulin tablets with QT-prolonging CYP3A4 substrates. Lefamulin prescribing information lists this combination as contraindicated. Avoid combination

Levofloxacin-Containing Products (Systemic): QT-prolonging Kinase Inhibitors (Highest Risk) may enhance the QTc-prolonging effect of Levofloxacin-Containing Products (Systemic). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Lofexidine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Lofexidine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

Methadone: QT-prolonging Kinase Inhibitors (Highest Risk) may enhance the QTc-prolonging effect of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Midostaurin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Midostaurin. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Moxifloxacin (Systemic): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Moxifloxacin (Systemic). Avoid combination

Nilotinib: May enhance the QTc-prolonging effect of Ivosidenib. Nilotinib may increase the serum concentration of Ivosidenib. Avoid combination

OLANZapine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of OLANZapine. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Ondansetron: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Ondansetron. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Osimertinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Osimertinib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Pentamidine (Systemic): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Pentamidine (Systemic). Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Pilsicainide: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Pilsicainide. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Pimozide: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Pimozide. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Avoid combination

Piperaquine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Piperaquine. Avoid combination

Posaconazole: May increase the serum concentration of QT-prolonging CYP3A4 Substrates. Such increases may lead to a greater risk for proarrhythmic effects and other similar toxicities. Avoid combination

Probucol: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Probucol. Avoid combination

Progestins (Contraceptive): Ivosidenib may decrease the serum concentration of Progestins (Contraceptive). Management: Consider alternative methods of contraception (ie, non-hormonal) in patients receiving ivosidenib. Consider therapy modification

Propafenone: May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

QT-prolonging Agents (Indeterminate Risk - Avoid): May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Agents (Indeterminate Risk - Caution): May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Class IA Antiarrhythmics (Highest Risk): QT-prolonging Kinase Inhibitors (Highest Risk) may enhance the QTc-prolonging effect of QT-prolonging Class IA Antiarrhythmics (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

QT-prolonging Class III Antiarrhythmics (Highest Risk): QT-prolonging Kinase Inhibitors (Highest Risk) may enhance the QTc-prolonging effect of QT-prolonging Class III Antiarrhythmics (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Dronedarone. Consider therapy modification

QT-prolonging Kinase Inhibitors (Highest Risk): May enhance the QTc-prolonging effect of other QT-prolonging Kinase Inhibitors (Highest Risk). Avoid combination

QT-prolonging Miscellaneous Agents (Highest Risk): QT-prolonging Kinase Inhibitors (Highest Risk) may enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): Ivosidenib may enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Ivosidenib. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Nilotinib; Ribociclib. Consider therapy modification

QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk): Ivosidenib may enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Ivosidenib. Management: Avoid using strong CYP3A4 inhibitors together with ivosidenib if possible. If the combination must be used, reduce the ivosidenib dose to 250 mg once daily. Exceptions: Clarithromycin. Consider therapy modification

QUEtiapine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of QUEtiapine. Avoid combination

Ribociclib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Ribociclib. Avoid combination

RisperiDONE: QT-prolonging Agents (Highest Risk) may enhance the CNS depressant effect of RisperiDONE. QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of RisperiDONE. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Sodium Stibogluconate: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Sodium Stibogluconate. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Sparfloxacin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Sparfloxacin. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Thioridazine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Thioridazine. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Vemurafenib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Vemurafenib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Ziprasidone: May enhance the QTc-prolonging effect of Ivosidenib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Adverse Reactions

>10%:

Cardiovascular: Edema (32% to 43%), prolonged QT interval on ECG (21% to 26%), chest pain (16%), hypotension (12%)

Central nervous system: Fatigue (39% to 50%), dizziness (21%), headache (11% to 16%), neuropathy (12% to 14%)

Dermatologic: Skin rash (14% to 26%), pruritis (14%)

Endocrine & metabolic: Decreased serum potassium (31% to 43%), decreased serum sodium (39%), decreased serum magnesium (25% to 38%), increased uric acid (29% to 32%), decreased serum calcium (25%), decreased serum phosphate (21% to 25%), weight loss (11%)

Gastrointestinal: Diarrhea (34% to 61%), decreased appetite (18% to 39%), nausea (31% to 36%), abdominal pain (16% to 29%), stomatitis (21% to 28%; grades ≥3: 3%), constipation (20% to 21%), vomiting (18% to 21%), dyspepsia (11%)

Hematologic & oncologic: Decreased hemoglobin (54% to 60%; ≥3 grade: 43% to 46%), leukocytosis (36% to 38%; ≥3 grade: 7% to 8%), differentiation syndrome (19% to 25%; ≥3 grade: 11% to 13%)

Hepatic: Increased serum alkaline phosphatase (27% to 46%), increased serum aspartate aminotransferase (27% to 29%), increased serum bilirubin (16%), increased serum alanine aminotransferase (14% to 15%)

Neuromuscular & skeletal: Arthralgia (32% to 36%), myalgia (18% to 25%)

Renal: Increased serum creatinine (23% to 29%)

Respiratory: Dyspnea (29% to 33%), cough (14% to 22%), pleural effusion (13%)

Miscellaneous: Fever (23%)

1% to 10%: Hematologic & oncologic: Tumor lysis syndrome (8%; ≥3 grade: 6%)

Frequency not defined:

Cardiovascular: Facial edema, orthostatic hypotension, peripheral edema

Central nervous system: Ataxia, reversible posterior leukoencephalopathy syndrome

Dermatologic: Acneiform eruption, dermal ulcer, exfoliation of skin, urticaria

Endocrine & metabolic: Hypovolemia

Gastrointestinal: Esophageal pain, rectal pain

Neuromuscular & skeletal: Asthenia

Respiratory: Oropharyngeal pain

<1%, postmarketing, and/or case reports: Guillain-Barré syndrome, progressive multifocal leukoencephalopathy, ventricular arrhythmia, ventricular fibrillation

Warnings/Precautions

Concerns related to adverse effects:

• Differentiation syndrome: [US Boxed Warning]: Patients treated with ivosidenib have experienced symptoms of differentiation syndrome (may be fatal if not treated). Symptoms include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and/or hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells; may be life-threatening. Other symptoms of differentiation syndrome have included noninfectious leukocytosis, pulmonary edema, pneumonitis, rash, fluid overload, tumor lysis syndrome, and/or increased serum creatinine. Of patients who experienced differentiation syndrome, most recovered after corticosteroid treatment or ivosidenib treatment interruption. The onset of differentiation syndrome occurred from 1 day up to 3 months after ivosidenib treatment initiation; may occur with or without concomitant leukocytosis. Dexamethasone 10 mg IV every 12 hours (or equivalent) and hemodynamic monitoring should be initiated and continued until improvement if differentiation syndrome is suspected. If concomitant noninfectious leukocytosis is present, hydroxyurea treatment or leukapheresis should be initiated as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms. Corticosteroids should be administered for a minimum of 3 days; differentiation syndrome symptoms may recur if corticosteroid and/or hydroxyurea treatment are discontinued too early. If severe signs/symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt ivosidenib treatment until signs and symptoms are no longer severe.
• Gastrointestinal toxicity: Mild nausea, vomiting, diarrhea, constipation, mucositis, and abdominal pain have been reported.
• Guillain-Barré syndrome: Guillain-Barré syndrome occurred in a small number of patients treated with ivosidenib. Monitor for onset of new signs or symptoms of motor and/or sensory neuropathy (eg, unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing). Permanently discontinue ivosidenib if Guillain-Barré syndrome is diagnosed.
• QT prolongation: Patients treated with ivosidenib may develop QT (QTc) prolongation and ventricular arrhythmias; some patients were found to have a QTc interval >500 msec and/or an increase from baseline QTc of >60 msec. Ventricular fibrillation (attributed to ivosidenib) was observed rarely. Patients with a baseline QTc of ≥450 msec (unless the QTc ≥450 msec was due to a preexisting bundle branch block) or with a history of long QT syndrome or uncontrolled or significant cardiovascular disease were excluded from the clinical study. Concomitant use of ivosidenib with medications known to prolong the QTc interval (eg, anti-arrhythmics, fluoroquinolones, triazole anti-fungals, 5-HT₃ receptor antagonists) and CYP3A4 inhibitors may increase the risk of QTc interval prolongation. Monitor ECG and electrolytes; more frequent monitoring may be necessary in patients with congenital long QTc syndrome, heart failure, electrolyte abnormalities, or patients taking medications known to prolong the QTc interval. Interrupt ivosidenib treatment if the QTc increases to >480 msec but <500 msec. If the QTc increases to >500 msec, interrupt treatment and then reduce the ivosidenib dose. Permanently discontinue ivosidenib in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.
• Tumor lysis syndrome: Tumor lysis syndrome may occur as a consequence of acute myeloid leukemia therapy; maintain adequate fluid intake, and monitor blood chemistry values and renal function as necessary.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate use: Confirm IDH1 mutation status in the blood or bone marrow prior to therapy initiation. IDH1 mutation may emerge during treatment and at relapse, therefore patients without IDH1 mutation at diagnosis should be retested at relapse. Information on tests approved to detect IDH1 mutation in AML may be found at http://www.FDA.gov/CompanionDiagnostics.

Monitoring Parameters

IDH1 mutation status in blood or bone marrow (prior to therapy initiation). Monitor blood counts and serum chemistries (baseline, at least weekly for the first month, then every other week for the second month, then monthly for the duration of therapy); creatine phosphokinase (weekly for the first month); monitor ECG (at least weekly for the first 3 weeks and then monthly for the duration of therapy; more frequent monitoring may be required if QTc interval prolongation occurs). Monitor for signs/symptoms of differentiation syndrome; monitor hemodynamic status if differentiation syndrome is suspected. Monitor for signs/symptoms of tumor lysis syndrome and onset of new signs or symptoms of motor and/or sensory neuropathy. Monitor adherence.

Pregnancy

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. The use of ivosidenib during pregnancy may cause fetal harm.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience fatigue, muscle pain, joint pain, diarrhea, nausea, vomiting, mouth irritation, mouth sores, abdominal pain, weight loss, constipation, lack of appetite, headache, or acne. Have patient report immediately to prescriber bone pain, cough, shortness of breath, difficulty breathing, weight gain, swelling of arms or legs, swollen glands, dizziness, passing out, signs of kidney problems (unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin), signs of electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting), weakness, burning or numbness feeling, change in senses, change in balance, edema, chest pain, signs of tumor lysis syndrome (fast heartbeat or abnormal heartbeat; any passing out; unable to pass urine; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish), fast heartbeat, or abnormal heartbeat (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.