Ivosidenib (Monograph)

Brand name: Tibsovo
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Jun 10, 2024. Written by ASHP.

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Introduction

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

Uses for Ivosidenib

Acute Myeloid Leukemia (AML)

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

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

Ivosidenib with or without azacitidine is generally recommended as one of several regimens that can be considered for treatment of newly diagnosed AML in older adults or adults with significant comorbidities.

Treatment of adult patients with relapsed or refractory AML with susceptible IDH1 mutation.

The National Cancer Institute (NCI) states there is no standard treatment regimen for relapsed or refractory AML; patients who are unable or unwilling to undergo intensive therapy may be candidates for reduced-intensity therapies, including ivosidenib.

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.

Relapsed or Refractory Myelodysplastic Syndromes (MDS)

Treatment of adult patients with relapsed or refractory MDS with a susceptible IDH1 mutation.

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 the treatment of MDS.

Locally Advanced or Metastatic Cholangiocarcinoma

Treatment of adult patients with previously treated, locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation.

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 cholangiocarcinoma.

Glioma

Based on current evidence, ivosidenib for the treatment of IDH mutant glioma^{† [off-label]} has Level 3 (low strength/quality) evidence supporting its use. Currently available data include phase 1 and retrospective studies and case series. However, based on these data, ivosidenib may have a potential role in patients with nonenhancing, IDH-mutated glioma as an alternative regimen in select patients.

Ivosidenib Dosage and Administration

General

Pretreatment Screening

• Confirm presence of IDH1 mutation (peripheral blood or bone marrow) prior to initiation of therapy.

• Perform an ECG.

• Perform CBC counts and blood chemistries for patients with AML or MDS.

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 for patients with AML or MDS.

• Monitor serum CK concentrations once weekly for the first month of therapy for patients with AML or MDS.

• 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).

• Monitor electrolyte levels as clinically indicated.

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

• Monitor for signs or symptoms of differentiation syndrome (e.g., noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, hypotension); if suspected, initiate corticosteroid therapy and hemodynamic monitoring as appropriate.

Administration

Oral Administration

Administer orally once daily at approximately the same time each day without regard to meals; however, avoid high-fat meals.

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

If a dose is vomited, do not administer replacement dose; wait until next scheduled dose is due. If a dose is missed or not taken at the usual time, administer dose as soon as possible and at least 12 hours prior to next scheduled dose. Return to normal schedule the following day. Do not administer 2 doses within 12 hours.

Dosage

Adults

AML

Newly Diagnosed AML (Monotherapy)

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.

Newly Diagnosed AML (Combination)

Oral

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

Start ivosidenib administration on Cycle 1 Day 1 in combination with azacitidine 75 mg/m² Sub-Q or IV once daily on Days 1–7 (or Days 1–5 and 8–9) of each 28-day cycle. Refer to azacitidine Prescribing Information for additional dosing information.

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.

Relapsed or Refractory MDS

Oral

500 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs. For patients without disease progression or unacceptable toxicity, continue ivosidenib for a minimum of 6 months to allow time for clinical response.

Locally Advanced or Metastatic Cholangiocarcinoma

Oral

500 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Glioma

Oral

500 mg once daily for the treatment of IDH mutant glioma^{† [off-label]}.

Dosage Modification for Toxicity

Differentiation Syndrome

Oral

If severe signs or symptoms of differentiation syndrome (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.

Noninfectious Leukocytosis

Oral

If noninfectious leukocytosis (WBC >25,000/mm³ or an absolute increase in total WBC >15,000/mm³) persists despite initiation of hydroxyurea therapy, withhold ivosidenib. Upon resolution of leukocytosis, resume therapy at 500 mg daily.

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. Monitor ECG at least weekly for 2 weeks following resolution of QT_c prolongation.

If QT_c interval >500 msec, 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 in Patients with AML Receiving Monotherapy or MDS

Oral

If grade 3 or greater adverse reaction occurs during ivosidenib monotherapy for AML or MDS, 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.

Other Toxicity in Patients with AML Receiving Combination Therapy with Azacitidine and in Patients with Cholangiocarcinoma

Oral

If grade 3 or greater adverse reaction occurs during ivosidenib therapy in combination with azacitidine for AML or during therapy for cholangiocarcinoma, withhold ivosidenib. When toxicity improves to grade 1 or less, or baseline, resume ivosidenib at a reduced dosage of 500 mg daily (grade 3 toxicity) or 250 mg daily (grade 4 toxicity). If grade 3 or greater adverse reaction recurs a second time, reduce dosage to 250 mg daily until toxicity resolves, then resume 500 mg daily.

If grade 3 toxicity recurs a third time or grade 4 toxicity recurs, discontinue ivosidenib.

Special Populations

Hepatic Impairment

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

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.

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.

Cautions for Ivosidenib

Contraindications

• None.

Warnings/Precautions

Warnings

Differentiation Syndrome in Acute Myeloid Leukemia and Myelodysplastic Syndrome

Differentiation syndrome associated with IDH1 inhibitor therapy (e.g., ivosidenib) reported; symptoms include 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. Observed as early as 1 day to 3 months after initiation of ivosidenib (see Boxed Warning).

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; 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.

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. 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. 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. 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

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.

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).

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

Common Adverse Effects

Common adverse reactions including laboratory abnormalities (≥25%) in patients with AML are decreased leukocytes, diarrhea, decreased hemoglobin, decreased platelets, increased glucose, fatigue, increased alkaline phosphatase, edema, decreased potassium, nausea, vomiting, decreased phosphate, decreased appetite, decreased sodium, leukocytosis, decreased magnesium, increased aspartate aminotransferase, arthralgia, dyspnea, increased uric acid, abdominal pain, increased creatinine, mucositis, rash, QT prolongation, differentiation syndrome, decreased calcium, decreased neutrophils, and myalgia.

Common adverse reactions including laboratory abnormalities (≥25%) in patients with relapsed or refractory MDS are increased creatinine, decreased hemoglobin, arthralgia, decreased albumin, increased aspartate aminotransferase, fatigue, diarrhea, cough, decreased sodium, mucositis, decreased appetite, myalgia, decreased phosphate, pruritus, and rash.

Common adverse reactions (≥15%) in patients with cholangiocarcinoma are fatigue, nausea, abdominal pain, diarrhea, cough, decreased appetite, ascites, vomiting, anemia, and rash. Common laboratory abnormalities (≥10%) in patients with cholangiocarcinoma are decreased hemoglobin, increased aspartate aminotransferase, and increased bilirubin.

Drug Interactions

Principally metabolized by CYP3A4.

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).

Potent CYP3A4 inducers: Possible decreased ivosidenib exposure. Avoid concomitant use.

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.

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.

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 2 to 3 hours.

Steady-state concentrations are achieved within 14 days of once-daily dosing; systemic accumulation observed (approximately 1.2- to 1.9-fold increases in peak plasma concentration and AUC).

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

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.

Special Populations

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

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

129, 58, 98, and 96 hours in patients with cholangiocarcinoma, relapsed or refractory AML, newly diagnosed AML in combination with azacitidine, and relapsed or refractory MDS, respectively.

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 (excursions permitted between 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 and in mouse models of intra-hepatic cholangiocarcinoma.

• 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

• Instuct patients to read the manufacturer’s patient information (medication guide).

• Advise patients to swallow ivosidenib tablets whole and not to chew, crush, or split the tablets. Avoid high-fat meals while taking the drug.

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

• If a dose is missed by ≤12 hours, advise patients to administer the missed dose on the same day as soon as it is remembered and to take the next dose at the regularly scheduled time on the following day. If a dose is vomited, administer 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 (in patients with AML and MDS). Advise patients to inform their 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. Advise patients of the importance of monitoring blood chemistry and maintaining adequate hydration during ivosidenib therapy.

• Risk of QT interval prolongation. Advise patients to inform their clinician if manifestations of QT interval prolongation (e.g., feelings of dizziness, lightheadedness, faintness) occur. Inform patients that ECGs and serum electrolytes must be monitored during therapy.

• Risk of Guillain-Barré syndrome. Advise patients to inform their 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 adverse GI effects. Advise patients to inform their clinician if diarrhea, nausea, vomiting, mucositis, constipation, decreased appetite, or abdominal pain occurs.

• Advise women to inform their 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.

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

• Advise patients to inform their clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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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