Ivosidenib

Class: Antineoplastic Agents
- Isocitrate Dehydrogenase-1 Inhibitor
- IDH1 Inhibitor
Chemical Name: (2S)-N-{(1S)-1-(2-Chlorophenyl)-2-[(3,3-difluorocyclobutyl)amino]-2-oxoethyl}-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide
Molecular Formula: C₂₈H₂₂ClF₃N₆O₃
CAS Number: 1448347-49-6
Brands: Tibsovo

Medically reviewed by Drugs.com on Dec 13, 2021. Written by ASHP.

Introduction

Antineoplastic agent; potent and selective inhibitor of isocitrate dehydrogenase-1 (IDH1).

Uses for Ivosidenib

Acute Myeloid Leukemia (AML)

Treatment of newly diagnosed AML with susceptible IDH1 mutation in patients who are ≥75 years of age or who are not candidates for intensive induction chemotherapy.

Treatment of relapsed or refractory AML with susceptible IDH1 mutation.

Susceptible IDH1 mutations defined as those resulting in increased 2-hydroxyglutarate levels in leukemic cells and where efficacy is predicted by clinically meaningful remissions at the recommended dosage of ivosidenib and/or inhibition of IDH1 mutation activity is expected at ivosidenib concentrations sustainable at the recommended dosage.

FDA-approved diagnostic test (e.g., Abbott RealTime IDH1 assay) required to confirm the presence of IDH1 mutation prior to initiation of therapy.

Designated an orphan drug by FDA for treatment of AML.

Ivosidenib Dosage and Administration

General

• Confirm presence of IDH1 mutation (peripheral blood or bone marrow) prior to initiation of therapy. Because IDH1 mutation may emerge during treatment, patients without IDH1 mutation at diagnosis of AML should be retested at relapse.

• Monitor CBC counts and blood chemistries at baseline, at least once weekly for the initial month of therapy, every other week for the next month, and then once monthly thereafter. Monitor serum CK concentrations once weekly for the first month of therapy. Manage laboratory abnormalities promptly. (See Dosage Modification for Toxicity under Dosage and Administration.)

• Perform ECG at least once weekly for the first 3 weeks of therapy and then at least once monthly thereafter. More frequent monitoring may be necessary in patients with additional risk factors for developing QT interval prolongation. (See Prolongation of QT Interval under Cautions.)

Pretreatment Screening

• Confirm presence of IDH1 mutation (peripheral blood or bone marrow) prior to initiation of therapy. Because IDH1 mutation may emerge during treatment, patients without IDH1 mutation at diagnosis of AML should be retested at relapse.

• CBC counts and blood chemistries.

Patient Monitoring

• Monitor CBC counts and blood chemistries at least once weekly for the initial month of therapy, every other week for the next month, and then once monthly thereafter.

• Monitor serum CK concentrations once weekly for the first month of therapy.

• Perform ECG at least once weekly for the first 3 weeks of therapy and then at least once monthly thereafter. More frequent monitoring may be necessary in patients with additional risk factors for developing QT interval prolongation (e.g., congenital long QT syndrome, CHF, electrolyte abnormalities, concomitant use of CYP3A4 inhibitors or drugs known to prolong the QT_c interval) .

• Signs or symptoms of motor and/or sensory neuropathy (e.g., unilateral or bilateral weakness, sensory alterations, paresthesias, difficulty breathing).

Administration

Oral Administration

Administer orally once daily at approximately the same time each day without regard to meals; however, avoid high-fat meals. (See Absorption under Pharmacokinetics.)

Swallow tablets whole; do not chew, crush, or split.

Dosage

Adults

AML

Newly Diagnosed AML

Oral

500 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs. Most patients achieve best response within 6 months of initiating ivosidenib; therefore, continue therapy for ≥6 months to allow time for response.

In patients presenting with leukocytosis (WBC count >25,000/mm³ or total WBC count >15,000/mm³ above baseline) in absence of infection, initiate hydroxyurea therapy according to standard practices and perform leukapheresis as needed. If leukocytosis persists, temporary interruption of ivosidenib therapy may be necessary. (See Dosage Modification for Toxicity under Dosage and Administration.)

Relapsed or Refractory AML

Oral

500 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs. Most patients achieve best response within 6 months of initiating ivosidenib; therefore, continue therapy for ≥6 months to allow time for response.

In patients presenting with leukocytosis (WBC count >25,000/mm³ or total WBC count >15,000/mm³ above baseline) in absence of infection, initiate hydroxyurea therapy according to standard practices and perform leukapheresis as needed. If leukocytosis persists, temporary interruption of ivosidenib therapy may be necessary. (See Dosage Modification for Toxicity under Dosage and Administration.)

Dosage Modification for Toxicity

Differentiation Syndrome

Oral

If severe signs or symptoms (e.g., pyrexia, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusion, hypotension, peripheral edema, rapid weight gain, hepatic or renal impairment, multiorgan dysfunction) persist for >48 hours despite systemic corticosteroid therapy, withhold ivosidenib until toxicity improves to grade 2 or less. (See Differentiation Syndrome under Cautions.)

Leukocytosis

Oral

If leukocytosis persists despite hydroxyurea therapy, withhold ivosidenib. Upon resolution of leukocytosis, resume therapy at initial dosage (500 mg daily). (See AML under Dosage.)

Prolongation of QT Interval

Oral

If QT_c interval 480–500 msec, withhold ivosidenib therapy; resume therapy at the same dosage (500 mg daily) when QT_c interval improves to ≤480 msec. (See Prolongation of QT Interval under Cautions.)

If QT_c interval >500 msec occurs, withhold ivosidenib therapy; resume therapy at reduced dosage of 250 mg daily when QT_c interval improves to ≤480 msec or ≤30 msec from baseline. If alternate etiology for prolongation of QT interval is confirmed, re-escalate dosage to 500 mg daily.

If symptomatic QT_c interval prolongation (e.g., life-threatening arrhythmias) occurs, permanently discontinue ivosidenib.

Guillain-Barré Syndrome

Oral

If Guillain-Barré syndrome occurs, permanently discontinue ivosidenib.

Other Toxicity

Oral

If grade 3 or greater adverse reaction occurs, withhold ivosidenib. When toxicity improves to grade 2 or less, resume ivosidenib at a reduced dosage of 250 mg daily; may re-escalate dosage to 500 mg daily when toxicity improves to grade 1 or less.

If grade 3 or greater adverse reaction recurs, discontinue ivosidenib.

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment (Child-Pugh class A or B): No initial dosage adjustment required. (See Hepatic Impairment under Cautions.)

Severe hepatic impairment (Child-Pugh class C): Not studied. Consider potential risks and benefits of drug prior to initiating therapy.

Renal Impairment

Mild or moderate renal impairment (eGFR 30 to <90 mL/minute per 1.73 m²): No initial dosage adjustment required. (See Renal Impairment under Cautions.)

Severe renal impairment (eGFR <30 mL/minute per 1.73 m²) or dialysis: Not studied. Consider potential risks and benefits of drug prior to initiating therapy.

Geriatric Patients

Manufacturer makes no special dosage recommendations. (See Geriatric Use under Cautions.)

Cautions for Ivosidenib

Contraindications

• Manufacturer states none known.

Warnings/Precautions

Warnings

Differentiation Syndrome

Differentiation syndrome associated with IDH1 inhibitor therapy (e.g., ivosidenib), characterized by acute respiratory distress (dyspnea and/or hypoxia), pulmonary infiltrates, renal impairment, multiorgan dysfunction, pyrexia, pulmonary or peripheral edema, rapid weight gain, rash, hypotension, tumor lysis syndrome, leukocytosis without infectious etiology, and pleural or pericardial effusions, can occur with or without concomitant leukocytosis. Onset: 1 day to 3 months after initiation of ivosidenib.

Differentiation syndrome should be suspected if there is no clear alternate etiology.

If signs or symptoms suggestive of differentiation syndrome occur, initiate IV or oral corticosteroid therapy (e.g., 10 mg of dexamethasone IV every 12 hours [or equivalent]) for ≥3 days and until symptoms resolve, followed by tapering of the corticosteroid dosage, and monitor hemodynamic parameters until symptoms improve.

If concomitant leukocytosis without infectious etiology occurs, initiate hydroxyurea therapy according to standard practices and perform leukapheresis as needed.

If signs or symptoms of differentiation syndrome persist for >48 hours despite corticosteroid therapy, interrupt ivosidenib therapy. (See Dosage Modification for Toxicity under Dosage and Administration.)

Other Warnings and Precautions

Prolongation of QT Interval

QT_c interval prolongation and ventricular arrhythmias (i.e., ventricular fibrillation) reported.

Monitor ECG at least once weekly for the first 3 weeks of therapy and then at least once monthly thereafter.

Congenital long QT syndrome, CHF, electrolyte abnormalities, CYP3A4 inhibitors, and drugs known to prolong the QT_c interval (e.g., antiarrhythmic agents, fluoroquinolone anti-infectives, azole antifungals, type 3 serotonin [5-HT₃] receptor antagonists) increase risk for QT interval prolongation. (See Interactions.) More frequent monitoring (i.e., ECGs, serum electrolytes) may be necessary.

Monitor blood chemistries at baseline, at least once weekly for the initial month of therapy, every other week for the next month, and then once monthly thereafter. Correct electrolyte abnormalities prior to initiation of ivosidenib therapy and during therapy as clinically indicated.

If QT_c interval prolongation occurs, temporary interruption, dosage reduction, or discontinuance of ivosidenib may be necessary. (See Dosage Modification for Toxicity under Dosage and Administration.) Monitor ECGs at least once weekly until 2 weeks following resolution of QT_c interval prolongation.

Guillain-Barré Syndrome

Guillain-Barré syndrome reported infrequently.

Monitor for signs or symptoms of motor and/or sensory neuropathy (e.g., unilateral or bilateral weakness, sensory alterations, paresthesias, difficulty breathing). If Guillain-Barré syndrome occurs, discontinue ivosidenib.

Specific Populations

Pregnancy

May cause fetal harm; embryofetal toxicity and teratogenicity demonstrated in animals.

Avoid pregnancy during therapy. Patients should use adequate methods of contraception during therapy. (See Specific Drugs under Interactions.) If used during pregnancy, apprise of potential fetal hazard.

Lactation

Not known whether ivosidenib or its metabolites are distributed into human milk or if drug has any effect on milk production or the nursing infant. Discontinue nursing during therapy and for ≥1 month after the last dose.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Relapsed or refractory AML: No overall differences in safety and efficacy relative to younger adults.

Hepatic Impairment

Mild or moderate hepatic impairment (Child-Pugh class A or B) decreased systemic exposure of ivosidenib. (See Absorption: Special Populations, under Pharmacokinetics.)

Not studied in patients with severe hepatic impairment (Child-Pugh class C).

Renal Impairment

In a population pharmacokinetic analysis, systemic exposure not altered by mild or moderate renal impairment (eGFR 30 to <90 mL/minute per 1.73 m²). (See Absorption: Special Populations, under Pharmacokinetics.)

Not studied in patients with severe renal impairment (eGFR <30 mL/minute per 1.73 m²) and those requiring dialysis.

Common Adverse Effects

Newly diagnosed AML (≥10%): Diarrhea, fatigue, edema, decreased appetite, leukocytosis, nausea, arthralgia, abdominal pain, dyspnea, differentiation syndrome, myalgia, constipation, dizziness, mucositis, vomiting, QT interval prolongation, cough, neuropathy, pruritus, rash, decreased weight, dyspepsia, headache, decreased hemoglobin concentrations, elevated alkaline phosphatase concentrations, decreased potassium concentrations, decreased sodium concentrations, elevated uric acid concentrations, elevated ALT and/or AST concentrations, elevated S_cr concentrations, decreased magnesium concentrations, decreased calcium concentrations, decreased phosphate concentrations.

Relapsed or refractory AML (≥10%): Fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, nausea, mucositis, rash, QT interval prolongation, pyrexia, cough, constipation, differentiation syndrome, decreased appetite, myalgia, vomiting, abdominal pain, chest pain, headache, pleural effusion, hypotension, neuropathy, decreased hemoglobin concentrations, decreased sodium concentrations, decreased magnesium concentrations, increased uric acid concentrations, decreased potassium concentrations, elevated alkaline phosphatase concentrations, elevated ALT or AST concentrations, decreased phosphate concentrations, elevated S_cr concentrations, elevated bilirubin concentrations.

Interactions for Ivosidenib

Principally metabolized by CYP3A4 and, to a lesser extent, by N-dealkylation and hydrolysis.

In vitro, induces CYP3A4 resulting in induction of its own metabolism. Ivosidenib has potential to induce CYP isoenzymes 2B6, 2C8, and 2C9.

Inhibits P-glycoprotein (P-gp) and organic anion transporter (OAT) 3, but not breast cancer resistance protein (BCRP), organic anion transport protein (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, and organic cation transporter (OCT) 2.

Substrate of P-gp, but not BCRP, OATP1B1, or OATP1B3.

Drugs Affecting Hepatic Microsomal Enzymes

Moderate or potent CYP3A4 inhibitors: Possible increased systemic exposure of ivosidenib and increased risk of toxicity (e.g., prolongation of QT interval). Consider alternative agent with less CYP3A inhibition potential. If concomitant use of a potent CYP3A4 inhibitor cannot be avoided, reduce ivosidenib dosage from 500 mg once daily to 250 mg once daily. When concomitant use of the potent CYP3A4 inhibitor is discontinued, return ivosidenib dosage (after at least 5 elimination half-lives of the potent CYP3A4 inhibitor) to 500 mg once daily. Monitor patients receiving concomitant moderate or potent CYP3A4 inhibitors for signs of ivosidenib toxicity (i.e., QT interval prolongation). (See Prolongation of QT Interval under Cautions and also see Specific Drugs under Interactions.)

Potent CYP3A4 inducers: Possible decreased ivosidenib exposure. Avoid concomitant use. (See Specific Drugs under Interactions.)

Drugs Metabolized by Hepatic Microsomal Enzymes

Sensitive CYP3A4 substrates: Possible decreased exposure to the CYP3A4 substrate and decreased efficacy of the substrate. Avoid concomitant use; consider alternative agent that is not a sensitive CYP3A4 substrate. If concomitant use cannot be avoided, monitor for loss of efficacy of the substrate drug. (See Specific Drugs under Interactions.)

Drugs that Prolong QT Interval

Potential additive effect on QT interval prolongation. Avoid concomitant use; consider alternative agent that does not prolong the QT interval. If concomitant use cannot be avoided, monitor ECG and electrolytes more frequently. (See Prolongation of QT Interval under Cautions and also see Specific Drugs under Interactions.)

Specific Drugs

Ivosidenib Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations and AUC are less than dose proportional over the ivosidenib dosage range of 200–1200 mg daily.

Peak plasma ivosidenib concentrations attained in a median of approximately 3 hours.

Steady-state concentrations are achieved within 14 days of once-daily dosing; systemic accumulation observed (approximately 1.5- and 1.9-fold increases in peak plasma concentration and AUC, respectively).

Pharmacokinetics at steady state in patients with newly diagnosed AML and those with relapsed or refractory disease are similar.

Food

Administration of a single 500-mg dose with a high-fat meal (900–1000 calories with 500–600 calories from fat) increases ivosidenib peak plasma concentrations and AUC by 98 and approximately 25%, respectively. (See Administration under Dosage and Administration.)

Special Populations

Mild hepatic impairment (Child-Pugh class A): Systemic exposure not substantially altered.

Moderate hepatic impairment (Child-Pugh class B): AUC or peak plasma concentration decreased by 28 or 44%, respectively.

Severe hepatic impairment (Child-Pugh class C): Not studied.

Mild or moderate renal impairment (eGFR 30 to <90 mL/minute per 1.73 m²): In a population pharmacokinetic analysis, systemic exposure not altered.

Severe renal impairment (eGFR <30 mL/minute per 1.73 m²) or dialysis: Not studied.

Distribution

Extent

Not known whether ivosidenib or its metabolites distribute into human milk.

Plasma Protein Binding

92–96%.

Elimination

Metabolism

Principally metabolized by CYP3A4 and, to a lesser extent, by N-dealkylation and hydrolysis.

Unchanged ivosidenib accounts for >92% of plasma total radioactivity following a radiolabeled dose.

Elimination Route

Eliminated mainly in feces (77%; 67% as unchanged drug) and to a lesser extent in urine (17%; 10% as unchanged drug).

Half-life

93 hours.

Special Populations

Age (range: 18–89 years), sex, race, body weight (range: 38–150 kg), and Eastern Cooperative Oncology Group (ECOG) performance status do not substantially affect clearance of ivosidenib.

Stability

Storage

Oral

Tablets

20–25ºC (may be exposed to 15–30ºC).

Actions

• Potent and selective inhibitor of IDH1.

• Approximately 6–16% of AML cases carry IDH1 mutations.

• IDH1 mutations cause a reduction of α-ketoglutarate to the oncometabolite 2-hydroxyglutarate resulting in epigenetic dysregulation and subsequent histone and DNA hypermethylation and differentiation arrest of hematopoietic stem cells.

• Susceptible IDH1 mutations defined as those resulting in increased 2-hydroxyglutarate levels in leukemic cells and where efficacy of ivosidenib is predicted by clinically meaningful remissions at the recommended dosage of ivosidenib and/or inhibition of IDH1 mutation activity is expected at ivosidenib concentrations sustainable at the recommended dosage; most common ivosidenib-susceptible IDH1 mutations are R132C or R132H substitution mutations.

• In vitro, inhibits IDH1 with R132C, R132H, R132G, R132L, or R132S mutation at much lower concentrations than IDH1 wild-type enzymes.

• Decreased 2-hydroxyglutarate levels and induced myeloid cell differentiation in vitro and in mice bearing tumor xenografts that expressed IDH1 mutation.

• Decreased 2-hydroxyglutarate levels, reduced blast cell counts, and increased percentages of mature myeloid cells in patients with AML that expressed IDH1 mutation.

Advice to Patients

• Importance of instructing patients to read the manufacturer’s patient information (medication guide).

• Importance of advising patients to swallow ivosidenib tablets whole and not to chew, crush, or split the tablets. Importance of avoiding high-fat meals while taking the drug.

• Importance of advising patients to take ivosidenib as directed by their clinician and at approximately the same time each day.

• If a dose of ivosidenib is missed by ≤12 hours, importance of administering the missed dose on the same day as soon as it is remembered and taking the next dose at the regularly scheduled time on the following day. If a dose is vomited, importance of administering the next dose at the regularly scheduled time; an additional dose should not be administered to replace the vomited dose. Advise patients not to take 2 doses within a 12-hour period.

• Risk of developing differentiation syndrome. Importance of informing clinician immediately if manifestations of differentiation syndrome (e.g., pyrexia, cough, difficulty breathing, rash, decreased urination, hypotension, rapid weight gain, peripheral edema) occur.

• Risk of tumor lysis syndrome. Importance of monitoring blood chemistry and maintaining adequate hydration during ivosidenib therapy.

• Risk of QT interval prolongation. Importance of informing clinician if manifestations of QT interval prolongation (e.g., feelings of dizziness, lightheadedness, faintness) occur. Importance of monitoring ECGs and serum electrolytes during therapy.

• Risk of Guillain-Barré syndrome. Importance of informing clinician if manifestations of Guillain-Barré syndrome (e.g., weakness or tingling sensation in legs, arms, or upper body; unilateral or bilateral numbness and pain; altered sensory function; burning or prickling sensation; difficulty breathing) occur.

• Risk of diarrhea, nausea, vomiting, mucositis, constipation, decreased appetite, or abdominal pain. Importance of contacting clinician if any of these adverse reactions occur.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Apprise patient of potential hazard to the fetus if used during pregnancy.

• Importance of advising women to avoid breast-feeding during therapy and for ≥1 month after the last dose.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of ivosidenib is restricted. Contact manufacturer for additional information.

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Frequently asked questions

• What is Tibsovo used to treat?

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