Version May 2024
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.
Dosage guidance:
Clinical considerations: Select patients for treatment of acute myeloid leukemia (AML), cholangiocarcinoma, and myelodysplastic syndromes (MDS) based on the presence of IDH1 mutations.
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 until disease progression or unacceptable toxicity. In patients without disease progression or unacceptable toxicity, continue for a minimum of 6 months to allow time for clinical response.
In combination with azacitidine: Oral: 500 mg once daily (in combination with azacitidine) beginning on day 1 of each 28-day cycle until relapse, disease progression, or unacceptable toxicity (Montesinos 2022). In patients without disease progression or unacceptable toxicity, continue for a minimum of 6 months to allow time for clinical response. Refer to protocol for additional details.
Acute myeloid leukemia, relapsed or refractory, IDH1-mutated: Oral: 500 mg once daily (DiNardo 2018); continue until disease progression or unacceptable toxicity occurs. In patients without disease progression or unacceptable toxicity, continue for a minimum of 6 months to allow time for clinical response.
Cholangiocarcinoma, locally advanced or metastatic, previously treated, IDH1-mutated: Oral: 500 mg once daily; continue until disease progression or unacceptable toxicity (Abou-Alfa 2020; Zhu 2021)
Myelodysplastic syndromes, relapsed or refractory, IDH1- mutated : Oral: 500 mg once daily; continue until disease progression or unacceptable toxicity. In patients without disease progression or unacceptable toxicity, continue for a minimum of 6 months to allow time for clinical response.
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.
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 kidney impairment.
End-stage kidney 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 kidney disease requiring dialysis.
Hepatic impairment prior to treatment initiation:
Mild or moderate impairment (Child-Turcotte-Pugh class A or B): No dosage adjustment necessary.
Severe impairment (Child-Turcotte-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.
|
Adverse reaction |
Severity |
Ivosidenib dosage modification |
|---|---|---|
|
a AML = acute myeloid leukemia; MDS = myelodysplastic syndromes. | ||
|
Hematologic toxicity | ||
|
Noninfectious leukocytosis |
WBC >25,000/mm3 or An absolute increase in total WBC of >15,000/mm3 from baseline |
Initiate cytoreductive therapy with hydroxyurea and/or leukapheresis if clinically indicated. Taper hydroxyurea once leukocytosis improves or resolves. Leukocytosis not improved with hydroxyurea: Withhold ivosidenib; then resume ivosidenib at 500 mg once daily when leukocytosis has resolved. |
|
Nonhematologic toxicity | ||
|
Differentiation syndrome (AMLa and MDSa) |
Suspected |
Administer systemic corticosteroids (dexamethasone 10 mg IV every 12 hours [or equivalent]) and monitor hemodynamic status until symptoms resolve. Administer corticosteroids for a minimum of 3 days (symptoms of differentiation syndrome may recur if corticosteroids are stopped prematurely). |
|
Severe signs and/or symptoms persisting for >48 hours after initiation of systemic corticosteroids |
Withhold ivosidenib; resume when signs/symptoms of differentiation syndrome resolve to ≤ grade 2. | |
|
Guillain-Barré syndrome |
Any |
Permanently discontinue ivosidenib. |
|
QTc prolongation |
QTc >480 msec to 500 msec |
Monitor electrolytes and supplement as clinically indicated. Review and adjust concomitant medications with known QTc interval-prolonging effects. Withhold ivosidenib; resume at 500 mg once daily when QTc ≤480 msec. Monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation. |
|
QTc >500 msec |
Monitor electrolytes and supplement as clinically indicated. Review and adjust concomitant medications with known QTc interval-prolonging effects. Withhold ivosidenib; resume at a reduced dose of 250 mg once daily when QTc is within 30 msec of baseline or ≤480 msec. Consider re-escalation of dose to 500 mg once daily if alternative etiology for QTc prolongation can be identified. Monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation. | |
|
Signs/symptoms of life-threatening arrhythmia |
Permanently discontinue ivosidenib. | |
|
Other clinically significant toxicities | ||
|
AML and MDS – single-agent therapy |
≥ Grade 3 |
Withhold ivosidenib; resume at 250 mg once daily when toxicity resolves to ≤ grade 2 (may increase to 500 mg if toxicity resolves to ≤ grade 1). Recurrent ≥ grade 3 toxicity: Discontinue ivosidenib. |
|
AML in combination with azacitidine or cholangiocarcinoma |
≥ Grade 3 |
Withhold ivosidenib; resume at 500 mg once daily (grade 3 toxicity) or 250 mg once daily (grade 4 toxicity) when toxicity resolves to ≤ grade 1 or baseline. Recurrent grade 3 toxicity (second occurrence): Reduce ivosidenib to 250 mg once daily until toxicity resolves, then escalate to 500 mg once daily. Recurrent grade 3 toxicity (third occurrence) or recurrent grade 4 toxicity: Discontinue ivosidenib. |
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for monotherapy in adults.
>10%:
Cardiovascular: Chest pain (16%), edema (32%), hypotension (12%), prolonged QT interval on ECG (10% to 26%)
Dermatologic: Skin rash (15% to 26%)
Endocrine & metabolic: Decreased serum magnesium (38%), decreased serum phosphate (25%), decreased serum potassium (31%), decreased serum sodium (39%), increased uric acid (32%)
Gastrointestinal: Abdominal pain (16% to 35%), constipation (20%), decreased appetite (18% to 24%), diarrhea (34% to 35%; grades ≥3: 2%), nausea (31% to 41%; grades ≥3: 1% to 2%), stomatitis (28%; grades ≥3: 3%), vomiting (18% to 23%; grades ≥3: 1% to 2%)
Hematologic & oncologic: Anemia (18%; grades ≥3: 7%), differentiation syndrome (19%; grades ≥3: 13%), leukocytosis (38%; grades ≥3: 8%)
Hepatic: Ascites (23%), increased serum alanine aminotransferase (15%), increased serum alkaline phosphatase (27%), increased serum aspartate aminotransferase (27% to 34%), increased serum bilirubin (16% to 30%, including hyperbilirubinemia)
Nervous system: Fatigue (39% to 43%), headache (13% to 16%), neuropathy (12%), peripheral neuropathy (11%)
Neuromuscular & skeletal: Arthralgia (36%), myalgia (18%)
Renal: Increased serum creatinine (23%)
Respiratory: Cough (22% to 27%), dyspnea (33%), pleural effusion (13%)
Miscellaneous: Fever (23%)
1% to 10%:
Hematologic & oncologic: Tumor lysis syndrome (8%; grades ≥3: 6%)
Hepatic: Cholestatic jaundice (serious: ≥2%)
Respiratory: Pneumonia (serious: ≥2%)
<1%:
Cardiovascular: Ventricular fibrillation
Nervous system: Guillain-Barré syndrome, progressive multifocal leukoencephalopathy
Frequency not defined: Renal: Acute kidney injury
There are no contraindications listed in the manufacturer's labeling.
Concerns related to adverse effects:
• Differentiation syndrome: Patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) treated with ivosidenib have experienced symptoms of differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells; may be life-threatening or fatal. Symptoms include noninfectious leukocytosis, peripheral edema, fever, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary infiltrates, pulmonary edema, pneumonitis, pericardial effusions, rash, fluid overload, rapid weight gain, tumor lysis syndrome, hepatic, renal, or multiorgan dysfunction, 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: Select patients for treatment of AML, cholangiocarcinoma, and MDS based on the presence of IDH1 mutations. Information on tests approved to detect IDH1 mutation may be found at http://www.FDA.gov/CompanionDiagnostics.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Tibsovo: 250 mg [contains fd&c blue #2 (indigotine,indigo carmine)]
No
Tablets (Tibsovo Oral)
250 mg (per each): $663.09
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.
Ivosidenib is available through specialty pharmacies and various specialty institutions or accounts; distribution information is available at http://www.myagios.com or call 844-409-1411.
Oral: Administer at approximately the same time each day, with or without food (do not administer with a high fat meal). Do not split, crush, or chew tablets.
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.
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/2023/211192s011lbl.pdf#page=38
Acute myeloid leukemia, newly diagnosed, IDH1-mutated: 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 or refractory, IDH1-mutated: Treatment of relapsed or refractory AML in adults with a susceptible IDH1 mutation as detected by an approved test.
Cholangiocarcinoma, locally advanced or metastatic, previously treated, IDH1-mutated: Treatment of previously treated, locally advanced, or metastatic cholangiocarcinoma in adults with an IDH1 mutation as detected by an approved test.
Myelodysplastic syndromes, relapsed or refractory, IDH 1-mutated: Treatment of relapsed or refractory myelodysplastic syndromes in adults with a susceptible IDH1 mutation as detected by an approved test.
Ivosidenib may be confused with enasidenib, ibrutinib, idelalisib, imatinib, ixazomib, olutasidenib.
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.
Substrate of CYP3A4 (major), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
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
Atazanavir: May increase the serum concentration of Ivosidenib. Ivosidenib may decrease the serum concentration of Atazanavir. Risk X: Avoid combination
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 Ivosidenib. Encorafenib may decrease the serum concentration of Ivosidenib. Risk X: Avoid combination
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
Quizartinib: 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
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
Terbutaline: 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
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
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.
Based on data from animal reproduction studies, in utero exposure to ivosidenib may cause fetal harm.
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.
Isocitrate dehydrogenase-1 (IDH1) mutation status prior to therapy initiation. For acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), monitor blood counts and serum chemistries (prior to therapy initiation, 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 ECG 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 and MDS); 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.
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).
Onset:
Maximal inhibition of 2-hydroxyglutarate: Acute myeloid leukemia (AML): By day 14 (DiNardo 2018); cholangiocarcinoma: By day 28 (Lowery 2019).
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, Lowery 2019).
Distribution: Vdss: 403 L (relapsed or refractory AML); 504 L (newly diagnosed AML in combination with azacitidine); 706 L (cholangiocarcinoma); 552 L (relapsed or refractory myelodysplastic syndromes [MDS]).
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 or refractory AML); 98 hours (newly diagnosed AML in combination with azacitidine); 129 hours (cholangiocarcinoma); 96 hours (relapsed or refractory MDS).
Time to peak: 3 hours (relapsed or refractory AML and relapsed or refractory MDS); 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 or refractory AML); 4.6 L/hour (newly diagnosed AML in combination with azacitidine); 6.1 L/hour (cholangiocarcinoma); 5.1 L/hour (relapsed or refractory MDS).
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