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Ivosidenib: Drug information

Ivosidenib: Drug information
(For additional information see "Ivosidenib: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Differentiation syndrome in acute myeloid leukemia

Patients treated with ivosidenib have experienced symptoms of differentiation syndrome, which can be fatal. Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.

Brand Names: US
  • Tibsovo
Pharmacologic Category
  • Antineoplastic Agent, IDH1 Inhibitor
Dosing: Adult

Note: Confirm isocitrate dehydrogenase-1 (IDH1) mutation status in the blood or bone marrow prior to therapy initiation for acute myeloid leukemia (AML); select patients for treatment of locally advanced or metastatic cholangiocarcinoma based on the presence of IDH1 mutations. In AML, 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, IDH1-mutated

Acute myeloid leukemia, newly diagnosed, IDH1-mutated (in adults ≥75 years of age and/or with comorbidities):

Monotherapy: Oral: 500 mg once daily (Roboz 2020); continue for a minimum of 6 months and then until disease progression or unacceptable toxicity occurs.

In combination with azacitidine: Oral: 500 mg once daily (in combination with azacitidine) for a minimum of 6 cycles or until relapse, disease progression, or unacceptable toxicity (Montesinos 2022). Refer to protocol for additional details.

Acute myeloid leukemia, relapsed/refractory, IDH1-mutated

Acute myeloid leukemia, relapsed/refractory, IDH1-mutated: Oral: 500 mg once daily (DiNardo 2018); continue for a minimum of 6 months and then until disease progression or unacceptable toxicity occurs.

Cholangiocarcinoma, locally advanced or metastatic, IDH1-mutated

Cholangiocarcinoma, locally advanced or metastatic, IDH1-mutated: Oral: 500 mg once daily; continue until disease progression or unacceptable toxicity (Abou-Alfa 2020; Zhu 2021).

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).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

Note: Kidney function may be estimated using the MDRD formula.

eGFR ≥30 mL/minute/1.73 m2: No dosage adjustment necessary.

eGFR <30 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer's labeling (pharmacokinetics are unknown); consider risks versus potential benefits in patients with preexisting severe renal impairment.

End-stage renal disease requiring dialysis: There are no dosage adjustments provided in the manufacturer's labeling (pharmacokinetics are unknown); consider risks versus potential benefits in patients with preexisting end-stage renal disease requiring dialysis.

Dosing: Hepatic Impairment: Adult

Mild or moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer's labeling (pharmacokinetics are unknown); consider risks versus potential benefits in patients with preexisting severe hepatic impairment.

Dosing: Older Adult

Refer to adult dosing.

Dosing: Adjustment for Toxicity: Adult

Differentiation syndrome (in acute myeloid leukemia [AML]): 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. Taper corticosteroids after resolution of symptoms.

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 adverse reactions:

AML monotherapy: Interrupt ivosidenib treatment until resolves to ≤ grade 2. Resume ivosidenib at 250 mg once daily; may increase to 500 mg once daily if toxicity resolves to ≤ grade 1. If ≥ grade 3 toxicity recurs, discontinue ivosidenib.

AML (in combination with azacitidine) or cholangiocarcinoma:

Grade 3 toxicity: Interrupt ivosidenib treatment until resolves to ≤ grade 1 or baseline. Resume ivosidenib at 500 mg once daily. If grade 3 toxicity recurs, reduce ivosidenib to 250 mg once daily until resolution, then may increase to 500 mg once daily. If grade 3 toxicity occurs a third time, discontinue ivosidenib.

Grade 4 toxicity: Interrupt ivosidenib treatment until resolves to ≤ grade 1 or baseline. Resume ivosidenib at 250 mg once daily. If grade 4 toxicity recurs, discontinue ivosidenib.

Dosage Forms: US

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

Tablet, Oral:

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

Generic Equivalent Available: US

No

Prescribing and Access Restrictions

Ivosidenib is available through a network of select specialty pharmacies. Please refer to http://www.myagios.com or call 844-409-1411 for more information.

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Tibsovo: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/211192s009lbl.pdf#page=34

Administration: Adult

Oral: Administer at approximately 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.

Hazardous Drugs Handling Considerations

This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Ivosidenib may cause reproductive toxicity and teratogenicity.

Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).

Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.

Use: Labeled Indications

Acute myeloid leukemia, newly diagnosed: Treatment of newly diagnosed acute myeloid leukemia (AML), either as monotherapy or in combination with azacitidine, 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.

Acute myeloid leukemia, relapsed/refractory: Treatment of relapsed or refractory AML in adults with a susceptible IDH1 mutation as detected by an approved test.

Cholangiocarcinoma, locally advanced or metastatic: Treatment of previously treated, locally advanced, or metastatic cholangiocarcinoma in adults with an IDH1 mutation as detected by an approved test.

Medication Safety Issues
Sound-alike/look-alike issues:

Ivosidenib may be confused with enasidenib, ibrutinib, idelalisib, imatinib, ixazomib.

High alert medication:

This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%:

Cardiovascular: Chest pain (16%), edema (32% to 43%), hypotension (12%), prolonged QT interval on ECG (10% to 26%)

Dermatologic: Pruritus (14%), skin rash (14% to 26%)

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

Gastrointestinal: Abdominal pain (16% to 35%), constipation (20% to 21%), decreased appetite (18% to 39%), diarrhea (34% to 61%), dyspepsia (11%), nausea (31% to 41%), stomatitis (21% to 28%; grades ≥3: 3%), vomiting (18% to 23%)

Hematologic & oncologic: Anemia (18%; ≥3 grade: 7%), differentiation syndrome (19% to 25%; ≥3 grade: 11% to 13%), leukocytosis (36% to 38%; ≥3 grade: 7% to 8%)

Hepatic: Ascites (23%), increased serum alanine aminotransferase (14% to 15%), increased serum alkaline phosphatase (27% to 46%), increased serum aspartate aminotransferase (27% to 34%)

Nervous system: Dizziness (21%), fatigue (39% to 50%; severe fatigue: 7%), headache (11% to 16%), neuropathy (12% to 14%), peripheral neuropathy (11%)

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

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

Respiratory: Cough (14% to 27%), dyspnea (29% to 33%), pleural effusion (13%)

Miscellaneous: Fever (23%)

1% to 10%:

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

Hepatic: Cholestatic jaundice (≥2%), hyperbilirubinemia (≥2%)

Respiratory: Pneumonia (≥2%)

<1%:

Cardiovascular: Ventricular fibrillation

Nervous system: Guillain-Barré syndrome, progressive multifocal leukoencephalopathy, reversible posterior leukoencephalopathy syndrome

Frequency not defined: Renal: Acute kidney injury

Contraindications

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

Warnings/Precautions

Concerns related to adverse effects:

• Differentiation syndrome: Patients with acute myeloid leukemia (AML) treated with ivosidenib have experienced symptoms of differentiation syndrome (may be fatal). 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. 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.

• Guillain-Barré syndrome: Guillain-Barré syndrome occurred in a small number of patients treated with ivosidenib.

• 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 (case report). Patients with a baseline QTc of ≥450 or ≥470 msec (refer to specific trial for exclusion criteria) or with a history of long QT syndrome, uncontrolled or significant cardiovascular disease, or arrhythmic events (eg, heart failure, hypokalemia, family history of long QT syndrome) were excluded from clinical studies. 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.

Other warnings/precautions:

• Appropriate use: Confirm isocitrate dehydrogenase-1 (IDH1) mutation status in the blood or bone marrow prior to therapy initiation for AML. IDH1 mutation may emerge during AML treatment and at relapse; therefore, patients without IDH1 mutation at diagnosis should be retested at relapse. Select patients for treatment of locally advanced or metastatic cholangiocarcinoma based on the presence of IDH1 mutations. Information on tests approved to detect IDH1 mutation may be found at http://www.FDA.gov/CompanionDiagnostics.

Metabolism/Transport Effects

Substrate of CYP3A4 (major), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

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. Risk D: Consider therapy modification

Amisulpride (Oral): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Amisulpride (Oral). 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 greater risk. Risk D: 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. Risk D: Consider therapy modification

Carbetocin: May enhance the QTc-prolonging effect of QT-prolonging 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. Risk D: Consider therapy modification

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. Risk D: Consider therapy modification

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

Clarithromycin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Clarithromycin. Risk X: 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. Risk D: Consider therapy modification

ClomiPRAMINE: May enhance the QTc-prolonging effect of QT-prolonging 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. Risk D: 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. Risk D: Consider therapy modification

CYP2C9 Substrates (Narrow Therapeutic Index/Sensitive with Inducers): Ivosidenib may decrease the serum concentration of CYP2C9 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Management: Consider alternatives to this combination when possible. If combined, monitor for decreased effectiveness of these CYP2C9 substrates if combined with ivosidenib. Risk D: Consider therapy modification

CYP3A4 Inducers (Strong): May decrease the serum concentration of Ivosidenib. Risk X: 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, including QTc prolongation. Risk D: 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 and monitor for increased ivosidenib toxicities, including QTc interval prolongation. Risk D: Consider therapy modification

CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers): Ivosidenib may decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Management: Consider alternatives to this combination when possible. If combined, monitor for decreased effectiveness of these CYP3A4 substrates if combined with ivosidenib. Risk D: Consider therapy modification

Dabrafenib: May enhance the QTc-prolonging effect of QT-prolonging 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. Risk D: 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. Risk D: Consider therapy modification

Domperidone: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Domperidone. Risk X: 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. Risk D: 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. Risk D: 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. Risk D: 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. Risk D: Consider therapy modification

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

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. Risk D: Consider therapy modification

Etelcalcetide: May enhance the QTc-prolonging effect of QT-prolonging 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. Risk D: Consider therapy modification

Fexinidazole: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Risk X: 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. Risk C: 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. Risk D: Consider therapy modification

Fluorouracil Products: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Fluorouracil Products. 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. Risk D: Consider therapy modification

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

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: 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. Risk D: 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. Risk D: 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. Risk D: 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. Risk D: 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. Risk D: Consider therapy modification

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

HydrOXYzine: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Risk C: Monitor therapy

Imipramine: May enhance the QTc-prolonging effect of QT-prolonging 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. Risk D: Consider therapy modification

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. Risk D: Consider therapy modification

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

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

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. Risk X: 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. Risk D: 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. Risk D: Consider therapy modification

Meglumine Antimoniate: May enhance the QTc-prolonging effect of QT-prolonging 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. Risk D: 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. Risk D: 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. Risk D: Consider therapy modification

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

Nilotinib: May enhance the QTc-prolonging effect of Ivosidenib. Nilotinib may increase the serum concentration of Ivosidenib. Risk X: 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. Risk D: 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. Risk D: 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. Risk D: Consider therapy modification

Oxytocin: May enhance the QTc-prolonging effect of QT-prolonging 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. Risk D: Consider therapy modification

Pacritinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Pacritinib. 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. Risk C: Monitor therapy

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

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. Risk D: 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. Risk D: 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. Risk X: Avoid combination

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

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

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. Risk D: Consider therapy modification

Propofol: May enhance the QTc-prolonging effect of QT-prolonging 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. Risk D: 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. Risk C: 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. Risk C: 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. Risk D: 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. Risk D: Consider therapy modification

QT-Prolonging Inhalational Anesthetics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging 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. Risk D: Consider therapy modification

QT-prolonging Kinase Inhibitors (Highest Risk): May enhance the QTc-prolonging effect of other QT-prolonging Kinase Inhibitors (Highest Risk). Risk X: 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. Risk D: 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. Risk D: Consider therapy modification

QT-prolonging Strong CYP3A4 Inhibitors (Highest Risk): May enhance the QTc-prolonging effect of Ivosidenib. QT-prolonging Strong CYP3A4 Inhibitors (Highest 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 and monitor for increased ivosidenib toxicities, including QTc interval prolongation. Risk D: 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 and monitor for increased ivosidenib toxicities, including QTc interval prolongation. Risk D: Consider therapy modification

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

Ribociclib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Ribociclib. Risk X: 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. Risk D: Consider therapy modification

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

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

SUNItinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of SUNItinib. 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. Risk D: Consider therapy modification

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

Toremifene: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Toremifene. 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. Risk D: Consider therapy modification

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. Risk D: Consider therapy modification

Food Interactions

Administration of a single ivosidenib dose with a high-fat meal (~900 to 1,000 calories, 500 to 600 fat calories, 250 carbohydrate calories, and 150 protein calories) increased ivosidenib Cmax 1.98-fold and AUC 1.24-fold. Management: Do not administer with a high-fat meal.

Pregnancy Considerations

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

Breastfeeding Considerations

It is not known if ivosidenib is present in breast milk.

Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy or for 1 month after the last ivosidenib dose.

Monitoring Parameters

Isocitrate dehydrogenase-1 (IDH1) mutation status prior to therapy initiation (for acute myeloid leukemia [AML], obtain in blood or bone marrow). For AML, 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). For all patients, monitor ECG (prior to therapy initiation, 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, in patients with congenital long QTc syndrome, heart failure, electrolyte abnormalities, or patients taking medications known to prolong the QTc interval). Monitor for signs/symptoms of differentiation syndrome (in patients with AML); 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 for Guillain-Barré syndrome (eg, unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing). Monitor adherence.

The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.

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 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% to 10% of patients with acute myeloid leukemia (DiNardo 2018) and up to ~20% of patients with intrahepatic cholangiocarcinoma (Zhu 2021).

Pharmacokinetics

Onset:

Maximal inhibition of 2-hydroxyglutarate: Acute myeloid leukemia (AML): By day 14 (DiNardo 2018).

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

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

Duration:

Median duration of response: AML: 6.5 months (DiNardo 2018).

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

Absorption: Rapid (DiNardo 2018).

Distribution: Vdss: 403 L (relapsed/refractory AML); 504 L (newly diagnosed AML in combination with azacitidine); 706 L (cholangiocarcinoma).

Protein binding: 92% to 96%.

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

Bioavailability: A high-fat meal (~900 to 1,000 calories, 500 to 600 fat calories, 250 carbohydrate calories and 150 protein calories) increased ivosidenib Cmax 1.98-fold and AUC 1.24-fold.

Half-life elimination: 58 hours (relapsed/refractory AML); 98 hours (newly diagnosed AML in combination with azacitidine); 129 hours (cholangiocarcinoma).

Time to peak: 3 hours (relapsed/refractory AML); 2 hours (cholangiocarcinoma and newly diagnosed AML in combination with azacitidine).

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

Clearance: 5.6 L/hour (relapsed/refractory AML); 4.6 L/hour (newly diagnosed AML in combination with azacitidine); 6.1 L/hour (cholangiocarcinoma).

Pricing: US

Tablets (Tibsovo Oral)

250 mg (per each): $601.66

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Tibsovo (IN)


For country code abbreviations (show table)
  1. <800> Hazardous Drugs–Handling in Healthcare Settings. United States Pharmacopeia and National Formulary (USP 43-NF 38). Rockville, MD: United States Pharmacopeia Convention; 2020:74-92.
  2. Abou-Alfa GK, Macarulla T, Javle MM, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(6):796-807. doi:10.1016/S1470-2045(20)30157-1 [PubMed 32416072]
  3. DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 2018;378(25):2386-2398. [PubMed 29860938]
  4. Hwang JP, Feld JJ, Hammond SP, et al. Hepatitis B virus screening and management for patients with cancer prior to therapy: ASCO provisional clinical opinion update. J Clin Oncol. 2020;38(31):3698-3715. doi:10.1200/JCO.20.01757 [PubMed 32716741]
  5. Montesinos P, Recher C, Vives S, et al. Ivosidenib and azacitidine in IDH1-mutated acute myeloid leukemia. N Engl J Med. 2022;386(16):1519-1531. doi:10.1056/NEJMoa2117344 [PubMed 35443108]
  6. Roboz GJ, DiNardo CD, Stein EM, et al. Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. Blood. 2020;135(7):463-471. doi:10.1182/blood.2019002140 [PubMed 31841594]
  7. Tibsovo (ivosidenib) [prescribing information]. Boston, MA: Servier Pharmaceuticals; May 2022.
  8. US Department of Health and Human Services; Centers for Disease Control and Prevention; National Institute for Occupational Safety and Health. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings 2016. https://www.cdc.gov/niosh/docs/2016-161/. Updated September 2016. Accessed July 25, 2018.
  9. Zhu AX, Macarulla T, Javle MM, et al. Final overall survival efficacy results of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation: the phase 3 randomized clinical ClarIDHy trial. JAMA Oncol. 2021;7(11):1669-1677. doi:10.1001/jamaoncol.2021.3836 [PubMed 34554208]
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