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Ivosidenib Tablets





Patients treated with ivosidenib have experienced symptoms of differentiation syndrome, which can be fatal if not treated. 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 [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].



Ivosidenib is an inhibitor of isocitrate dehydrogenase 1 (IDH1) enzyme. The chemical name is (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. The chemical structure is:

Empirical formula: C28H22ClF3N6O3 - Molecular weight: 583.0 g/mol

Ivosidenib is practically insoluble in aqueous solutions between pH 1.2 and 7.4.

Ivosidenib is available as a film-coated 250 mg tablet for oral administration. Each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The tablet coating includes FD&C blue #2, hypromellose, lactose monohydrate, titanium dioxide, and triacetin.


2.1 Acute Myeloid Leukemia

Ivosidenib is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test [see Dosage and Administration (3.1), Clinical Pharmacology and Clinical Studies].


3.1 Patient Selection

Select patients for the treatment of AML with ivosidenib based on the presence of IDH1 mutations in the blood or bone marrow [see Clinical Studies]. Patients without IDH1 mutations at diagnosis should be retested at relapse because a mutation in IDH1 may emerge during treatment and at relapse. Information on FDA-approved tests for the detection of IDH1 mutations in AML is available at

3.2 Recommended Dosage

The recommended dose of ivosidenib is 500 mg taken orally once daily until disease progression or unacceptable toxicity. For patients without disease progression or unacceptable toxicity, treat for a minimum of 6 months to allow time for clinical response.

Administer ivosidenib with or without food. Do not administer ivosidenib with a high-fat meal because of an increase in ivosidenib concentration [see Warnings and Precautions (5.2) and Clinical Pharmacology]. Do not split or crush ivosidenib tablets. Administer ivosidenib tablets orally about the same time each day. If a dose of ivosidenib is vomited, do not administer a replacement dose; wait until the next scheduled dose is due. If a dose of ivosidenib is missed or not taken at the usual time, administer the dose as soon as possible and at least 12 hours prior to the next scheduled dose. Return to the normal schedule the following day. Do not administer 2 doses within 12 hours.

3.3 Monitoring and Dose Modifications for Toxicities

Assess blood counts and blood chemistries prior to the initiation of ivosidenib, at least once weekly for the first month, once every other week for the second month, and once monthly for the duration of therapy. Monitor blood creatine phosphokinase weekly for the first month of therapy. Monitor electrocardiograms (ECGs) at least once weekly for the first 3 weeks of therapy and then at least once monthly for the duration of therapy. Manage any abnormalities promptly [see Adverse Reactions (6.1)].

Interrupt dosing or reduce dose for toxicities. See Table 1 for dose modification guidelines.

Table 1. Recommended Dose Modifications for Ivosidenib

* Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening.

3.4 Dose Modification for Use with Strong CYP3A4 Inhibitors

If a strong CYP3A4 inhibitor must be coadministered, reduce the ivosidenib dose to 250 mg once daily. If the strong inhibitor is discontinued, increase the ivosidenib dose (after at least 5 half-lives of the strong CYP3A4 inhibitor) to the recommended dose of 500 mg once daily.




5.1 Differentiation Syndrome

In the clinical trial, 19% (34/179) of patients with relapsed or refractory AML treated with ivosidenib experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms of differentiation syndrome in patients treated with ivosidenib included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome and creatinine increased. Of the 34 patients who experienced differentiation syndrome, 27 (79%) recovered after treatment or after dose interruption of ivosidenib.

Differentiation syndrome occurred as early as 1 day and up to 3 months after ivosidenib initiation and has been observed with or without concomitant leukocytosis.

If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement [see Dosage and Administration (3.3)]. If concomitant noninfectious leukocytosis is observed, initiate treatment with hydroxyurea or leukapheresis, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid and/or hydroxyurea treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt ivosidenib until signs and symptoms are no longer severe [see Dosage and Administration (3.3)].

5.2 QTc Interval Prolongation

Patients treated with ivosidenib can develop QT (QTc) prolongation [see Clinical Pharmacology] and ventricular arrhythmias. Of the 258 patients treated with ivosidenib in the clinical trial, 9% were found to have a QTc interval greater than 500 msec and 14% of patients had an increase from baseline QTc greater than 60 msec. One patient developed ventricular fibrillation attributed to ivosidenib. The clinical trial excluded patients with baseline QTc of ≥ 450 msec (unless the QTc ≥ 450 msec was due to a pre-existing bundle branch block) or with a history of long QT syndrome or uncontrolled or significant cardiovascular disease.

Concomitant use of ivosidenib with drugs known to prolong the QTc interval (e.g., anti-arrhythmic medicines, fluoroquinolones, triazole anti-fungals, 5-HT3 receptor antagonists) and CYP3A4 inhibitors may increase the risk of QTc interval prolongation [see Drug Interactions (7.1), Clinical Pharmacology]. Conduct monitoring of electrocardiograms (ECGs) and electrolytes [see Dosage and Administration (3.3)].

In patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary.

Interrupt ivosidenib if QTc increases to greater than 480 msec and less than 500 msec. Interrupt and reduce ivosidenib if QTc increases to greater than 500 msec. Permanently discontinue ivosidenib in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia [see Dosage and Administration (3.3)].

5.3 Guillain-Barré Syndrome

Guillain-Barré syndrome occurred in < 1% (2/258) of patients treated with ivosidenib in the clinical study. Monitor patients taking ivosidenib for onset of new signs or symptoms of motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing. Permanently discontinue ivosidenib in patients who are diagnosed with Guillain-Barré syndrome [see Dosage and Administration (3.3)].


The following serious adverse reactions are described elsewhere in the labeling:

 Differentiation Syndrome [see Warnings and Precautions (5.1)]

 QTc Interval Prolongation [see Warnings and Precautions (5.2)]

 Guillain-Barré Syndrome [see Warnings and Precautions (5.3)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety profile of single-agent ivosidenib is based on experience in 179 adults with relapsed or refractory AML treated with 500 mg daily [see Clinical Studies]. The median duration of exposure to ivosidenib was 3.9 months (range 0.1 to 39.5 months). Sixty-five patients (36%) were exposed to ivosidenib for at least 6 months and 16 patients (9%) were exposed for at least 1 year.

Serious adverse reactions (≥ 5%) were differentiation syndrome (10%), leukocytosis (10%), and electrocardiogram QT prolonged (7%). There was one case of progressive multifocal leukoencephalopathy (PML).

The most common adverse reactions leading to dose interruption were electrocardiogram QT prolonged (7%), differentiation syndrome (3%), leukocytosis (3%) and dyspnea (3%). Five out of 179 patients (3%) required a dose reduction due to an adverse reaction. Adverse reactions leading to a dose reduction included electrocardiogram QT prolonged (1%), diarrhea (1%), nausea (1%), decreased hemoglobin (1%), and increased transaminases (1%). Adverse reactions leading to permanent discontinuation included Guillain-Barré syndrome (1%), rash (1%), stomatitis (1%), and creatinine increased (1%).

The most common adverse reactions (≥ 20%) of any grade were fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, nausea, mucositis, electrocardiogram QT prolonged, rash, pyrexia, cough, and constipation. Adverse reactions reported in the trial are shown in Table 2.

Table 2: Adverse Reactions Reported in ≥ 10% (Any Grade) or ≥ 5% (Grade ≥ 3) of Patients with Relapsed or Refractory AML

1 Grouped term includes leukocytosis, hyperleukocytosis, and increased white blood cell count.

2 Differentiation syndrome can be associated with other commonly reported events such as peripheral edema, leukocytosis, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonia, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and creatinine increased.

3 Grouped term includes aphthous ulcer, esophageal pain, esophagitis, gingival pain, gingivitis, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal pain, proctalgia, and stomatitis.

4 Grouped term includes vomiting and retching.

5 Grouped term includes abdominal pain, upper abdominal pain, abdominal discomfort, and abdominal tenderness.

6 Grouped term includes asthenia and fatigue.

7 Grouped term includes peripheral edema, edema, fluid overload, fluid retention, and face edema.

8 Grouped term includes angina pectoris, chest pain, chest discomfort, and non-cardiac chest pain.

9 Grouped term includes arthralgia, back pain, musculoskeletal stiffness, neck pain, and pain in extremity.

10 Grouped term includes myalgia, muscular weakness, musculoskeletal pain, musculoskeletal chest pain, musculoskeletal discomfort, and myalgia intercostal.

11 Grouped term includes ataxia, burning sensation, gait disturbance, Guillain-Barré syndrome, neuropathy peripheral, paresthesia, peripheral sensory neuropathy, peripheral motor neuropathy, and sensory disturbance.

12 Grouped term includes cough, productive cough, and upper airway cough syndrome.

13 Grouped term includes dyspnea, respiratory failure, hypoxia, and dyspnea exertional.

14 Grouped term includes dermatitis acneiform, dermatitis, rash, rash maculo-papular, urticaria, rash erythematous, rash macular, rash pruritic, rash generalized, rash papular, skin exfoliation, and skin ulcer.

15 Grouped term includes hypotension and orthostatic hypotension.

Changes in selected post-baseline laboratory values that were observed in patients with relapsed or refractory AML are shown in Table 3.

Table 3: Most Common (≥ 10%) or ≥ 5% (Grade ≥ 3) New or Worsening Laboratory Abnormalities Reported in Patients with Relapsed or Refractory AML1

1 Laboratory abnormality is defined as new or worsened by at least one grade from baseline, or if baseline is unknown.


7.1 Effect of Other Drugs on Ivosidenib

Strong or Moderate CYP3A4 Inhibitors

Clinical Impact

 Co-administration of ivosidenib with strong or moderate CYP3A4 inhibitors increased ivosidenib plasma concentrations [see Clinical Pharmacology].

 Increased ivosidenib plasma concentrations may increase the risk of QTc interval prolongation [see Warnings and Precautions (5.2)].

Prevention or Management

 Consider alternative therapies that are not strong or moderate CYP3A4 inhibitors during treatment with ivosidenib.

 If co-administration of a strong CYP3A4 inhibitor is unavoidable, reduce ivosidenib to 250 mg once daily [see Dosage and Administration (3.3)].

 Monitor patients for increased risk of QTc interval prolongation [see Warnings and Precautions (5.2)].

Strong CYP3A4 Inducers

Clinical Impact

 Co-administration of ivosidenib with strong CYP3A4 inducers decreased ivosidenib plasma concentrations [see Clinical Pharmacology].

Prevention or Management

 Avoid co-administration of strong CYP3A4 inducers with ivosidenib.

QTc Prolonging Drugs

Clinical Impact

 Co-administration of ivosidenib with QTc prolonging drugs may increase the risk of QTc interval prolongation [see Warnings and Precautions (5.2)].

Prevention or Management

 Avoid co-administration of QTc prolonging drugs with ivosidenib or replace with alternative therapies.

 If co-administration of a QTc prolonging drug is unavoidable, monitor patients for increased risk of QTc interval prolongation [see Warnings and Precautions (5.2)].

7.2 Effect of Ivosidenib on Other Drugs

Ivosidenib induces CYP3A4 and may induce CYP2C9. Co-administration will decrease concentrations of drugs that are sensitive CYP3A4 substrates and may decrease the concentrations of drugs that are sensitive CYP2C9 substrates [see Clinical Pharmacology]. Use alternative therapies that are not sensitive substrates of CYP3A4 and CYP2C9 during ivosidenib treatment. Do not administer ivosidenib with itraconazole or ketoconazole (CYP3A4 substrates) due to expected loss of antifungal efficacy. Co-administration of ivosidenib may decrease the concentrations of hormonal contraceptives, consider alternative methods of contraception in patients receiving ivosidenib. If co-administration of ivosidenib sensitive CYP3A4 substrates or CYP2C9 substrates is unavoidable, monitor patients for loss of therapeutic effect of these drugs.


8.1 Pregnancy

Risk Summary

Based on animal embryo-fetal toxicity studies, ivosidenib may cause fetal harm when administered to a pregnant woman. There are no available data on ivosidenib use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal embryo-fetal toxicity studies, oral administration of ivosidenib to pregnant rats and rabbits during organogenesis was associated with embryo-fetal mortality and alterations to growth starting at 2 times the steady state clinical exposure based on the AUC at the recommended human dose (see Data). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.


Animal Data

Ivosidenib administered to pregnant rats at a dose of 500 mg/kg/day during organogenesis (gestation days 6-17) was associated with adverse embryo-fetal effects including lower fetal weights, and skeletal variations. These effects occurred in rats at approximately 2 times the human exposure at the recommended dose of 500 mg daily.

In pregnant rabbits treated during organogenesis (gestation days 7-20), ivosidenib was maternally toxic at doses of 180 mg/kg/day (exposure approximately 3.9 times the human exposure at the recommended dose of 500 mg daily) and caused spontaneous abortions as well as decreased fetal weights, skeletal variations, and visceral variations.

8.2 Lactation

Risk Summary

There are no data on the presence of ivosidenib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with ivosidenib and for at least 1 month after the last dose.

8.4 Pediatric Use

The safety and effectiveness of ivosidenib in pediatric patients have not been established.

8.5 Geriatric Use

One hundred and twelve (63%) of the 179 patients with relapsed or refractory AML in the clinical study were 65 years of age or older and 40 patients (22%) were 75 years or older. No overall differences in effectiveness or safety were observed between patients 65 years and older and younger patients.


Ivosidenib is a small molecule inhibitor that targets the mutant isocitrate dehydrogenase 1 (IDH1) enzyme. Susceptible IDH1 mutations are defined as those leading to increased levels of 2-hydroxyglutarate (2-HG) in the leukemia cells and where efficacy is predicted by 1) clinically meaningful remissions with the recommended dose of ivosidenib and/or 2) inhibition of mutant IDH1 enzymatic activity at concentrations of ivosidenib sustainable at the recommended dosage according to validated methods. The most common of such mutations are R132H and R132C substitutions.

Ivosidenib was shown to inhibit selected IDH1 R132 mutants at much lower concentrations than wild-type IDH1 in vitro. Inhibition of the mutant IDH1 enzyme by ivosidenib led to decreased 2HG levels and induced myeloid differentiation in vitro and in vivo in mouse xenograft models of IDH1-mutated AML. In blood samples from patients with AML with mutated IDH1, ivosidenib decreased 2-HG levels ex-vivo, reduced blast counts, and increased percentages of mature myeloid cells.


Multiple doses of ivosidenib 500 mg daily were observed to decrease plasma 2-HG concentrations in patients with hematological malignancies to levels similar to those observed at baseline in healthy subjects. In bone marrow, 2-HG concentrations were reduced by >90%.

Cardiac Electrophysiology

A concentration-dependent QTc interval prolongation of approximately 16.1 msec (90% CI: 13.3, 18.9) was observed at the steady-state Cmax following a 500 mg daily dose based on an analysis of 171 patients with an IDH1 mutation, including 136 patients with relapsed or refractory AML, who received ivosidenib 500 mg daily [see Warnings and Precautions (5.1)]. Co-administration with moderate or strong CYP3A inhibitors is expected to further increase QTc interval prolongation from baseline.


The following ivosidenib pharmacokinetic parameters were observed following administration of ivosidenib 500 mg as a single dose or daily dose (for steady-state), unless otherwise specified.

The mean peak plasma concentration (Cmax) is 4,503 ng/mL [% coefficient of variation (%CV: 38)] after a single dose, and 6,551 ng/mL (%CV: 44) at steady-state. The steady-state area under the concentration time curve (AUC) is 117,348 ng·hr/mL (%CV: 50).

The AUC and Cmax of ivosidenib increase in a less than dose-proportional manner from 200 mg to 1,200 mg daily (0.4 to 2.4 times the approved recommended dosage). Accumulation ratios were approximately 1.9 for AUC and 1.5 for Cmax over one month. Steady-state plasma levels are reached within 14 days.


The median time to Cmax is approximately 3 hours.

Effect of Food

Following administration of a single dose in healthy subjects, a high-fat meal (approximately 900 to 1,000 calories, 500 to 600 fat calories, 250 carbohydrate calories and 150 protein calories) increased ivosidenib Cmax by 98% (90% CI: 79%, 119%) and AUCinf by approximately 25%.


The mean apparent volume of distribution of ivosidenib at steady-state is 234 L (%CV: 47). Protein binding of ivosidenib ranges from 92 to 96% in vitro.


Ivosidenib has a terminal half-life of 93 hours (%CV: 67) and an apparent clearance (CL/F) of 4.3 L/hour (%CV: 50).


Ivosidenib is the predominant component (>92%) of total radioactivity in plasma. Ivosidenib is primarily metabolized by CYP3A4 with minor contributions by N-dealkylation and hydrolytic pathways.


After a single oral administration of radiolabeled ivosidenib to healthy subjects, 77% of ivosidenib was eliminated in the feces (67% as unchanged) and 17% in the urine (10% as unchanged).

Specific Populations

No clinically meaningful effects on the pharmacokinetics of ivosidenib were observed based on age (18 years to 89 years), sex, race (White, Asian, Black or African American), body weight (38 to 150 kg), ECOG performance status, mild or moderate renal impairment (eGFR ≥30 mL/min/1.73m2, MDRD), or mild hepatic impairment (total bilirubin ≤ upper limit of normal [ULN] and aspartate aminotransferase [AST] > ULN or total bilirubin 1.0 to 1.5 times ULN and any AST).

The pharmacokinetics of ivosidenib in patients with severe renal impairment (eGFR <30 mL/min/1.73m2, MDRD), renal impairment requiring dialysis, moderate hepatic impairment (total bilirubin 1.5 to 3.0 times the ULN and any value for AST), or severe hepatic impairment (total bilirubin greater than 3.0 times the ULN and any value for AST) is unknown.

Drug Interaction Studies

Clinical Studies and Model-Based Approaches

Effect of Strong or Moderate CYP3A4 Inhibitors on Ivosidenib

Itraconazole was used as a strong CYP3A4 index inhibitor to evaluate the effect of CYP3A4 inhibition on the pharmacokinetics of ivosidenib single-dose in a drug-drug interaction study in healthy subjects. Co-administration of 250 mg ivosidenib with itraconazole (200 mg itraconazole once daily for 18 days) increased ivosidenib single-dose AUC to 269% of control (90% CI: 245%, 295%) with no change in Cmax. In regards to multiple-dosing, note that because ivosidenib induces the metabolism of CYP3A4 substrates following ivosidenib multiple dosing, itraconazole (a CYP3A4 substrate) is not recommended to be used concomitantly with ivosidenib in patients (see Effect of Ivosidenib on CYP3A4 Substrates).

Based on physiologically-based pharmacokinetic modeling, co-administration of 500 mg ivosidenib with the moderate CYP3A4 inhibitor fluconazole (dosed to steady-state) is predicted to increase ivosidenib single-dose AUC to 173% of control with no change in Cmax. In regards to multiple-dosing, co-administration with ivosidenib and fluconazole is predicted to increase ivosidenib steady-state Cmax to 152% of control and AUC to 190% of control [see Drug Interactions (7.1)].

Effect of Strong CYP3A4 Inducers on Ivosidenib

Co-administration of ivosidenib with a strong CYP3A4 inducer (600 mg rifampin once daily for 15 days) is predicted to decrease ivosidenib steady-state AUC by 33% [see Drug Interactions (7.1)].

Effect of Ivosidenib on CYP3A4 Substrates

Ivosidenib induces CYP3A4, including its own metabolism. Co-administration of ivosidenib with CYP3A4 substrates such as itraconazole is expected to decrease itraconazole steady-state AUC to a clinically relevant extent [see Drug Interactions (7.2)].

Effect of Gastric Acid Reducing Agents on Ivosidenib

Gastric acid reducing agents (e.g., proton pump inhibitors, H2-receptor antagonists, antacids) do not affect ivosidenib concentrations.

In vitro Studies

Metabolic Pathways

Ivosidenib may induce CYP2B6, CYP2C8, and CYP2C9 and therefore may affect the pharmacokinetics of sensitive substrates of these enzymes [see Drug Interactions (7.2)].

Drug Transporter Systems

Ivosidenib is a substrate for P-glycoprotein (P-gp). Ivosidenib is not a substrate for BCRP or hepatic transporters OATP1B1 and OATP1B3.

Ivosidenib does not inhibit BCRP, OATP1B1, OATP1B3, OAT1, and OCT2 at clinically relevant concentrations. Ivosidenib is an inhibitor of OAT3 and P-gp.


How Supplied:

TIBSOVO (ivosidenib) 250 mg tablet: Blue oval-shaped film-coated tablet debossed “IVO” on one side and “250” on the other side.

 60-count bottles of 250 mg tablets with a desiccant canister (NDC 71334-100-01)

Storage and Handling:

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Rx only

Rev 07/18