Tibsovo
ivosidenib · Tablet, Film Coated · Oral
Uses
1 INDICATIONS AND USAGE TIBSOVO is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for patients with a susceptible IDH1 mutation as detected by an FDA-approved test with: Newly Diagnosed Acute Myeloid Leukemia (AML) In combination with azacitidine or as monotherapy for the treatment of newly diagnosed AML in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy ( 1.1 ). Relapsed or refractory AML For the treatment of adult patients with relapsed or refractory AML ( 1.2 ). Relapsed or refractory Myelodysplastic Syndromes (MDS) For the treatment of adult patients with relapsed or refractory myelodysplastic syndromes ( 1.3 ). Locally Advanced or Metastatic Cholangiocarcinoma For the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma who have been previously treated ( 1.4 ). 1.1 Newly Diagnosed Acute Myeloid Leukemia TIBSOVO is indicated in combination with azacitidine or as monotherapy for the treatment of newly diagnosed acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy [see Dosage and Administration (2.1) , Clinical Pharmacology (12.1) and Clinical Studies (14.1) ]. 1.2 Relapsed or Refractory Acute Myeloid Leukemia TIBSOVO 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 (2.1) , Clinical Pharmacology (12.1) and Clinical Studies (14.2) ] . 1.3 Relapsed or Refractory Myelodysplastic Syndromes TIBSOVO is indicated for the treatment of adult patients with relapsed or refractory myelodysplastic syndromes (MDS) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test [see Dosage and Administration (2.1) , Clinical Pharmacology (12.1) and Clinical Studies (14.3) ] . 1.4 Locally Advanced or Metastatic Cholangiocarcinoma TIBSOVO is indicated for the treatment of adult patients with previously treated, locally advanced or metastatic cholangiocarcinoma with an isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test [see Dosage and Administration (2.1) , Clinical Pharmacology (12.1) , and Clinical Studies (14.4) ] .
Dosage and administration
500 mg orally once daily with or without food until disease progression or unacceptable toxicity ( 2.2 ). Avoid a high-fat meal. 2.1 Patient Selection Select patients for treatment with TIBSOVO based on the presence of IDH1 mutations [see Clinical Studies (14.1 , 14.2 , 14.3 , 14.4 )]. Information on FDA-approved tests for the detection of IDH1 mutations in AML, MDS, and cholangiocarcinoma is available at http://www.fda.gov/CompanionDiagnostics. 2.2 Recommended Dosage The recommended dosage of TIBSOVO is 500 mg taken orally once daily until disease progression or unacceptable toxicity [see Clinical Studies (14.1 , 14.2 , 14.3 , 14.4 )] . For patients with AML or MDS without disease progression or unacceptable toxicity, continue TIBSOVO for a minimum of 6 months to allow time for clinical response. Administer TIBSOVO with or without food. Do not administer TIBSOVO with a high-fat meal [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ]. Do not split, crush, or chew TIBSOVO tablets. Administer TIBSOVO tablets orally about the same time each day. If a dose of TIBSOVO is vomited, do not administer a replacement dose; wait until the next scheduled dose is due. If a dose of TIBSOVO 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. Newly Diagnosed AML (Combination Regimen) Start TIBSOVO administration on Cycle 1 Day 1 in combination with azacitidine 75 mg/m 2 subcutaneously or intravenously once daily on Days 1-7 (or Days 1-5 and 8-9) of each 28-day cycle [see Clinical Studies (14.1) ] . Refer to the Prescribing Information for azacitidine for additional dosing information. 2.3 Monitoring and Dosage Modifications for Toxicities Obtain an electrocardiogram (ECG) prior to treatment initiation. Monitor ECGs at least once weekly for the first 3 weeks of therapy and then at least once monthly for the duration of therapy [see Warnings and Precautions (5.2) ] . Manage any abnormalities promptly . Interrupt dosing or reduce dose for toxicities. See Table 1 for dosage modification guidelines. Table 1: Recommended Dosage Modifications for TIBSOVO Adverse Reactions Recommended Action Differentiation syndrome [see Warnings and Precautions (5.1) ] If differentiation syndrome is suspected, administer systemic corticosteroids and initiate hemodynamic monitoring until symptom resolution and for a minimum of 3 days . Interrupt TIBSOVO if severe signs and/or symptoms persist for more than 48 hours after initiation of systemic corticosteroids . Resume TIBSOVO when signs and symptoms improve to Grade 2 or lower. Noninfectious leukocytosis (white blood cell [WBC] count greater than 25 × 10 9 /L or an absolute increase in total WBC of greater than 15 × 10 9 /L from baseline) Initiate treatment with hydroxyurea, as per standard institutional practices, and leukapheresis if clinically indicated. Taper hydroxyurea only after leukocytosis improves or resolves. Interrupt TIBSOVO if leukocytosis is not improved with hydroxyurea, and then resume TIBSOVO at 500 mg daily when leukocytosis has resolved. QTc interval greater than 480 msec to 500 msec [see Warnings and Precautions (5.2) and Drug Interactions (7.1) ] Monitor and supplement electrolyte levels as clinically indicated. Review and adjust concomitant medications with known QTc interval-prolonging effects. Interrupt TIBSOVO. Restart TIBSOVO at 500 mg once daily after the QTc interval returns to less than or equal to 480 msec. Monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation. QTc interval greater than 500 msec [see Warnings and Precautions (5.2) and Drug Interactions (7.1) ] Monitor and supplement electrolyte levels as clinically indicated. Review and adjust concomitant medications with known QTc interval-prolonging effects . Interrupt TIBSOVO. Resume TIBSOVO at a reduced dose of 250 mg once daily when QTc interval returns to within 30 msec of baseline or less than or equal to 480 msec. Monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation. Consider re-escalating the dose of TIBSOVO to 500 mg daily if an alternative etiology for QTc prolongation can be identified. QTc interval prolongation with signs/symptoms of life-threatening arrhythmia [see Warnings and Precautions (5.2) ] Discontinue TIBSOVO permanently. Guillain-Barré syndrome [see Warnings and Precautions (5.3) ] Discontinue TIBSOVO permanently. Other Grade 3 Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening; grading based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. adverse reactions As monotherapy in AML and MDS : Interrupt TIBSOVO until toxicity resolves to Grade 2 or lower. Resume TIBSOVO at 250 mg once daily; may increase to 500 mg once daily if toxicities resolve to Grade 1 or lower. If Grade 3 or higher toxicity recurs, discontinue TIBSOVO. In cholangiocarcinoma, or in AML in combination with azacitidine : Interrupt TIBSOVO until toxicity resolves to Grade 1 or lower, or baseline, then resume at 500 mg daily (Grade 3 toxicity) or 250 mg daily (Grade 4 toxicity). If Grade 3 toxicity recurs (a second time), reduce TIBSOVO dose to 250 mg daily until the toxicity resolves, then resume 500 mg daily. If Grade 3 toxicity recurs (a third time), or Grade 4 toxicity recurs, discontinue TIBSOVO. Patients with AML or MDS Assess blood counts and blood chemistries prior to the initiation of TIBSOVO, 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. 2.4 Dosage Modification for Use with Strong CYP3A4 Inhibitors If a strong CYP3A4 inhibitor must be coadministered, reduce the TIBSOVO dose to 250 mg once daily.
Dosage forms and strengths
Tablets: 250 mg as a blue oval-shaped film-coated tablet debossed "IVO" on one side and "250" on the other side. Tablets: 250 mg ( 3 ).
Contraindications
None. None ( 4 ).
Warnings and precautions
5 WARNINGS AND PRECAUTIONS QTc Interval Prolongation : Monitor electrocardiograms and electrolytes. If QTc interval prolongation occurs, dose reduce or withhold, then resume dose or permanently discontinue TIBSOVO ( 2.3 , 5.2 ). Guillain-Barré Syndrome : Monitor patients for signs and symptoms of new motor and/or sensory findings. Permanently discontinue TIBSOVO in patients who are diagnosed with Guillain-Barré syndrome ( 2.3 , 5.3 ). 5.1 Differentiation Syndrome in AML and MDS Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal. Symptoms of differentiation syndrome in patients treated with TIBSOVO 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. In the combination study AG120-C-009, 15% (11/71) patients with newly diagnosed AML treated with TIBSOVO plus azacitidine experienced differentiation syndrome [see Adverse Reactions (6.1) ] . Of the 11 patients with newly diagnosed AML who experienced differentiation syndrome with TIBSOVO plus azacitidine 8 (73%) recovered. Differentiation syndrome occurred as early as 3 days after start of therapy and during the first month on treatment. In the monotherapy clinical trial AG120-C-001, 25% (7/28) of patients with newly diagnosed AML and 19% (34/179) of patients with relapsed or refractory AML treated with TIBSOVO experienced differentiation syndrome [see Adverse Reactions (6.1) ] . Of the 7 patients with newly diagnosed AML who experienced differentiation syndrome, 6 (86%) patients recovered. Of the 34 patients with relapsed or refractory AML who experienced differentiation syndrome, 27 (79%) patients recovered after treatment or after dose interruption of TIBSOVO. Differentiation syndrome occurred as early as 1 day and up to 3 months after TIBSOVO initiation and has been observed with or without concomitant leukocytosis. In the monotherapy clinical trial AG120-C-001, 11% (2/19) of patients with relapsed or refractory MDS treated with TIBSOVO experienced differentiation syndrome [see Adverse Reactions (6.1) ] . Of the 2 patients who experienced differentiation syndrome, both recovered after treatment or after dose interruption of TIBSOVO. Differentiation syndrome occurred as early as 1 day and up to 3 months after TIBSOVO 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 (2.3) ] . 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 TIBSOVO until signs and symptoms are no longer severe [see Dosage and Administration (2.3) ]. 5.2 QTc Interval Prolongation Patients treated with TIBSOVO can develop QT (QTc) prolongation and ventricular arrhythmias [see Clinical Pharmacology (12.2) ]. Of the 71 patients with newly diagnosed AML treated with TIBSOVO in combination with azacitidine in the clinical trial (Study AG120-C-009), 10 (14%) were found to have a heart-rate corrected QT interval (using Fridericia's method) (QTcF) greater than 500 msec and 15 out of 69 (22%) had an increase from baseline QTcF greater than 60 msec [see Adverse Reactions (6.1) ] . The clinical trial excluded patients with a QTcF ≥ 470 msec or other factors that increased the risk of QT prolongation or arrhythmic events (e.g. NYHA Class III or IV congestive heart failure, hypokalemia, family history of long QT interval syndrome). Of the 265 patients with hematological malignancies, including patients with AML and MDS, treated with TIBSOVO monotherapy in the clinical trial (AG120-C-001), 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 [see Adverse Reactions (6.1) ] . One patient developed ventricular fibrillation attributed to TIBSOVO. 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. Of the 123 patients with cholangiocarcinoma treated with TIBSOVO in the clinical trial (Study AG120-C-005), 2% were found to have a QTc interval greater than 500 msec and 5% of patients had an increase from baseline QTc greater than 60 msec [see Adverse Reactions (6.1) ] . The clinical trial excluded patients with a heart-rate corrected QT interval (using Fridericia's formula) (QTcF) ≥ 450 msec or other factors that increased the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome). Concomitant use of TIBSOVO with drugs known to prolong the QTc interval (e.g., anti-arrhythmic medicines, fluoroquinolones, triazole anti-fungals, 5-HT 3 receptor antagonists) and CYP3A4 inhibitors may increase the risk of QTc interval prolongation [see Drug Interactions (7.1) , Clinical Pharmacology (12.2) ]. Conduct monitoring of electrocardiograms (ECGs) and electrolytes [see Dosage and Administration (2.3) ] . 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.
Side effects
The following clinically significant adverse reactions are described elsewhere in the labeling: Differentiation Syndrome in AML and MDS [see Warnings and Precautions (5.1) ] QTc Interval Prolongation [see Warnings and Precautions (5.2) ] Guillain-Barré Syndrome [see Warnings and Precautions (5.3) ] The most common adverse reactions including laboratory abnormalities (≥ 25%) in patients with AML are leukocytes decreased, diarrhea, hemoglobin decreased, platelets decreased, glucose increased, fatigue, alkaline phosphatase increased, edema, potassium decreased, nausea, vomiting, phosphate decreased, decreased appetite, sodium decreased, leukocytosis, magnesium decreased, aspartate aminotransferase increased, arthralgia, dyspnea, uric acid increased, abdominal pain, creatinine increased, mucositis, rash, electrocardiogram QT prolonged, differentiation syndrome, calcium decreased, neutrophils decreased, and myalgia ( 6.1 ). The most common adverse reactions including laboratory abnormalities (≥25%) in patients with relapsed or refractory MDS are creatinine increased, hemoglobin decrease, arthralgia, albumin decreased, aspartate aminotransferase increased, fatigue, diarrhea, cough, sodium decreased, mucositis, decreased appetite, myalgia, phosphate decreased, pruritus, and rash ( 6.1 ). The most common adverse reactions (≥15%) in patients with cholangiocarcinoma are fatigue, nausea, abdominal pain, diarrhea, cough, decreased appetite, ascites, vomiting, anemia, and rash ( 6.1 ). The most common laboratory abnormalities (≥10%) in patients with cholangiocarcinoma are hemoglobin decreased, aspartate aminotransferase increased, and bilirubin increased ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Servier Pharmaceuticals at 1-800-807-6124 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. Acute Myeloid Leukemia In AML, the safety population reflects exposure to TIBSOVO at 500 mg daily in combination with azacitidine or as monotherapy in patients in Studies AG120-C-009 (N=71) and AG120-C-001 (N=213), respectively [see Clinical Studies (14.1 and 14.2) ] . In this safety population, the most common adverse reactions including laboratory abnormalities (≥ 25% in either trial) were leukocytes decreased, diarrhea, hemoglobin decreased, platelets decreased, glucose increased, fatigue, alkaline phosphatase increased, edema, potassium decreased, nausea, vomiting, phosphatase decreased, decreased appetite, sodium decreased, leukocytosis, magnesium decreased, aspartate aminotransferase increased, arthralgia, dyspnea, uric acid increased, abdominal pain, creatinine increased, mucositis, rash, electrocardiogram QT prolonged, differentiation syndrome, calcium decreased, neutrophils decreased, and myalgia. Newly Diagnosed AML TIBSOVO in Combination with Azacitidine The safety of TIBSOVO was evaluated in AML patients treated in combination with azacitidine, in Study AG120-C-009 [see Clinical Studies (14.1) ] . Patients received at least one dose of either TIBSOVO 500 mg daily (N=71) or placebo (N=73). Among patients who received TIBSOVO in combination with azacitidine, the median duration of exposure to TIBSOVO was 6 months (range 0 to 33 months). Thirty-four patients (48%) were exposed to TIBSOVO for at least 6 months and 22 patients (31%) were exposed for at least 1 year. Common (≥ 5%) serious adverse reactions in patients who received TIBSOVO in combination with azacitidine included differentiation syndrome (8%). Fatal adverse reactions occurred in 4% of patients who received TIBSOVO in combination with azacitidine, due to differentiation syndrome (3%) and one case of cerebral ischemia. Adverse reactions leading to discontinuation of TIBSOVO in ≥2% of patients were differentiation syndrome (3%) and pulmonary embolism (3%). The most common (>5%) adverse reactions leading to dose interruption of TIBSOVO were neutropenia (25%), electrocardiogram QT prolonged (7%), and thrombocytopenia (7%). Adverse reactions leading to dose reduction of TIBSOVO included electrocardiogram QT prolonged (8%), neutropenia (8%), and thrombocytopenia (1%). The most common adverse reactions and laboratory abnormalities observed in Study AG120-C-009 are shown in Tables 2 and 3. Table 2: Adverse Reactions (≥10%) in Patients with AML Who Received TIBSOVO + azacitidine with a Difference Between Arms of ≥ 2% Compared with Placebo + azacitidine in AG120-C-009 TIBSOVO + Azacitidine N=71 Placebo + Azacitidine N=73 Body System Adverse Reaction All Grades n (%) Grade ≥3 n (%) All Grades n (%) Grade ≥3 n (%) Gastrointestinal disorders Nausea 30 (42) 2 (3) 28 (38) 3 (4) Vomiting Grouped term includes vomiting and retching. 29 (41) 0 20 (27) 1 (1) Investigations Electrocardiogram QT prolonged 14 (20) 7 (10) 5 (7) 2 (3) Psychiatric Disorders Insomnia 13 (18) 1 (1) 9 (12) 0 Blood system and lymphatic system disorders Differentiation Syndrome 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. 11 (15) 7 (10) 6 (8) 6 (8) Leukocytosis Grouped term includes leukocytosis, white blood cell count increased. 9 (13) 0 1 (1) 0 Vascular disorders Hematoma Grouped term includes hematoma, eye hematoma, catheter site hematoma, oral mucosa hematoma, spontaneous hematoma, application site hematoma, injection site hematoma, periorbital hematoma. 11 (15) 0 3 (4) 0 Hypertension Grouped term includes blood pressure increased, essential hypertension, and hypertension.
Drug interactions
Strong or Moderate CYP3A4 Inhibitors: Reduce TIBSOVO dose with strong CYP3A4 inhibitors. Monitor patients for increased risk of QTc interval prolongation ( 2.4 , 5.2 , 7.1 , 12.3 ). Strong CYP3A4 Inducers: Avoid concomitant use with TIBSOVO ( 7.1 , 12.3 ). Sensitive CYP3A4 substrates: Avoid concomitant use with TIBSOVO ( 7.2 , 12.3 ). QTc Prolonging Drugs: Avoid concomitant use with TIBSOVO. If co-administration is unavoidable, monitor patients for increased risk of QTc interval prolongation ( 5.2 , 7.1 ). 7.1 Effect of Other Drugs on Ivosidenib Strong or Moderate CYP3A4 Inhibitors Clinical Impact Co-administration of TIBSOVO with strong or moderate CYP3A4 inhibitors increased ivosidenib plasma concentrations [see Clinical Pharmacology (12.3) ]. 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 TIBSOVO. If co-administration of a strong CYP3A4 inhibitor is unavoidable, reduce TIBSOVO to 250 mg once daily [see Dosage and Administration (2.3) ]. Monitor patients for increased risk of QTc interval prolongation [see Warnings and Precautions (5.2) ] . Strong CYP3A4 Inducers Clinical Impact Co-administration of TIBSOVO with strong CYP3A4 inducers decreased ivosidenib plasma concentrations [see Clinical Pharmacology (12.3) ]. Prevention or Management Avoid co-administration of strong CYP3A4 inducers with TIBSOVO. QTc Prolonging Drugs Clinical Impact Co-administration of TIBSOVO 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 TIBSOVO 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 concentrations of drugs that are sensitive CYP2C9 substrates [see Clinical Pharmacology (12.3) ] . Use alternative therapies that are not sensitive substrates of CYP3A4 and CYP2C9 during TIBSOVO treatment. If co-administration of TIBSOVO with sensitive CYP3A4 substrates or CYP2C9 substrates is unavoidable, monitor patients for loss of therapeutic effect of these drugs. Do not administer TIBSOVO with anti-fungal agents that are substrates of CYP3A4 due to expected loss of antifungal efficacy. Co-administration of TIBSOVO may decrease the concentrations of hormonal contraceptives, consider alternative methods of contraception in patients receiving TIBSOVO.
Use in specific populations
Lactation: Advise women not to breastfeed ( 8.2) . 8.1 Pregnancy Risk Summary Based on animal embryo-fetal toxicity studies, TIBSOVO may cause fetal harm when administered to a pregnant woman. There are no available data on TIBSOVO 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. Data 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 TIBSOVO and for 1 month after the last dose. 8.4 Pediatric Use The safety and effectiveness of TIBSOVO in pediatric patients have not been established. 8.5 Geriatric Use Of the 304 patients who received TIBSOVO in the clinical studies for AML and MDS, 75% were 65 years of age or older and 35% were 75 years or older. Of the 124 patients with cholangiocarcinoma treated with TIBSOVO in Study AG120-C-005, 37% were 65 years of age or older and 11% were 75 years or older. No overall differences in effectiveness or safety were observed between patients who were 65 years and older compared to younger patients. 8.6 Renal Impairment No modification of the starting dose is recommended for patients with mild or moderate renal impairment (eGFR ≥ 30 mL/min/1.73m 2 , MDRD). The pharmacokinetics and safety of ivosidenib in patients with severe renal impairment (eGFR < 30 mL/min/1.73m 2 , MDRD) or renal impairment requiring dialysis are unknown [see Clinical Pharmacology (12.3) ] . For patients with pre-existing severe renal impairment or who are requiring dialysis, consider the risks and potential benefits before initiating treatment with TIBSOVO. 8.7 Hepatic Impairment No modification of the starting dose is recommended for patients with mild or moderate (Child-Pugh A or B) hepatic impairment [see Clinical Pharmacology (12.3) ] . The pharmacokinetics and safety of ivosidenib in patients with severe hepatic impairment (Child-Pugh C) are unknown. For patients with pre-existing severe hepatic impairment, consider the risks and potential benefits before initiating treatment with TIBSOVO.
Pregnancy
8.1 Pregnancy Risk Summary Based on animal embryo-fetal toxicity studies, TIBSOVO may cause fetal harm when administered to a pregnant woman. There are no available data on TIBSOVO 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. Data 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.
Pediatric use
8.4 Pediatric Use The safety and effectiveness of TIBSOVO in pediatric patients have not been established.
Geriatric use
8.5 Geriatric Use Of the 304 patients who received TIBSOVO in the clinical studies for AML and MDS, 75% were 65 years of age or older and 35% were 75 years or older. Of the 124 patients with cholangiocarcinoma treated with TIBSOVO in Study AG120-C-005, 37% were 65 years of age or older and 11% were 75 years or older. No overall differences in effectiveness or safety were observed between patients who were 65 years and older compared to younger patients.
Description
(ivosidenib) is an inhibitor of isocitrate dehydrogenase 1 (IDH1) enzyme. The chemical name is (2 S )- N -{(1 S )-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: The molecular formula is C 28 H 22 ClF 3 N 6 O 3 and the molecular weight is 583.0 g/mol. Ivosidenib is practically insoluble in aqueous solutions between pH 1.2 and 7.4. TIBSOVO (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. Chemical Structure
Mechanism of action
12.1 Mechanism of Action Ivosidenib is a small molecule inhibitor that targets the mutant isocitrate dehydrogenase 1 (IDH1) enzyme. In patients with AML, 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 in patients with AML 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 2-HG 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. In a patient-derived xenograft intra-hepatic cholangiocarcinoma mouse model with IDH1 R132C, ivosidenib reduced 2-HG levels.
How supplied
How Supplied 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 72694-617-60) Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
Storage
Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
Patient information
Advise the patient to read the FDA-approved patient labeling (Medication Guide). Differentiation Syndrome in AML and MDS Advise patients being treated with TIBSOVO of the risks of developing differentiation syndrome as early as 1 day after start of therapy and during the first 3 months on treatment. Ask patients to immediately report any symptoms suggestive of differentiation syndrome, such as fever, cough or difficulty breathing, rash, decreased urinary output, low blood pressure, rapid weight gain, or swelling of their arms or legs, to their healthcare provider for further evaluation [see Boxed Warning and Warnings and Precautions (5.1) ] . QTc Interval Prolongation Inform patients of symptoms that may be indicative of significant QTc interval prolongation including dizziness, lightheadedness, and fainting. Advise patients to report these symptoms and the use of all medications to their healthcare provider [see Warnings and Precautions (5.2) ]. Guillain-Barré Syndrome Inform patients of symptoms that may be indicative of Guillain-Barré syndrome, including new signs or symptoms of motor and/or sensory neuropathy, such as weakness or tingling sensation in the legs, arms, or upper body, numbness and pain on one side or both sides of the body, changes to any sensory function, or burning or prickling sensation, or difficulty breathing. Advise patients to report these symptoms to their healthcare provider [see Warnings and Precautions (5.3) ]. Drug Interactions Advise patients to inform their healthcare providers of all concomitant medications, including over-the-counter medications, vitamins, and herbal products [see Drug Interactions (7) ]. Tumor Lysis Syndrome Advise patients on the risks of developing tumor lysis syndrome. Advise patients on the importance of maintaining high fluid intake, and the need for frequent monitoring of blood chemistry values [see Adverse Reactions (6.1) ] . Gastrointestinal Adverse Reactions Advise patients on the risks of experiencing gastrointestinal reactions such as diarrhea, nausea, mucositis, constipation, vomiting, decreased appetite, ascites and abdominal pain. Ask patients to report these events to their healthcare provider and advise patients how to manage them [see Adverse Reactions (6.1) ]. Lactation Advise women not to breastfeed during treatment with TIBSOVO and for 1 month after the last dose [see Use in Specific Populations (8.2) ]. Dosing and Storage Instructions Advise patients to swallow tablets whole and to not split, crush, or chew TIBSOVO tablets. Advise patients to avoid taking TIBSOVO with a high-fat meal. Instruct patients that if a dose of TIBSOVO is vomited, not to take an additional dose, and wait until the next scheduled dose is due. If a dose of TIBSOVO is missed or not taken at the usual time, instruct patients to take the dose as soon as possible unless the next dose is due within 12 hours. Patients can return to the normal schedule the following day. Store TIBSOVO at room temperature from 20°C to 25°C (68°F to 77°F). Advise patients not to remove the desiccant canister from the bottle.
Label text from the FDA structured product label by Servier Pharmaceutical LLC (revised Dec 22, 2025). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Ivosidenib in 1 product
Tibsovo NDC products (1)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 72694-617 | Ivosidenib 250 mg/1 Tablet, Film Coated | Servier Pharmaceutical LLC | NDA |
Frequently asked questions
What is Tibsovo used for?
1 INDICATIONS AND USAGE TIBSOVO is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for patients with a susceptible IDH1 mutation as detected by an FDA-approved test with: Newly Diagnosed Acute Myeloid Leukemia (AML) In combination with azacitidine or as monotherapy for the treatment of newly diagnosed AML in adults 75 years or older, or who have comorbidities that preclude use of…
What are the side effects of Tibsovo?
The following clinically significant adverse reactions are described elsewhere in the labeling: Differentiation Syndrome in AML and MDS [see Warnings and Precautions (5.1) ] QTc Interval Prolongation [see Warnings and Precautions (5.2) ] Guillain-Barré Syndrome [see Warnings and Precautions (5.3) ] The most common adverse reactions including laboratory abnormalities (≥ 25%) in patients with AML… See the full label for the complete list.
Who makes Tibsovo?
Tibsovo is listed by 1 labeler in the FDA NDC directory, including Servier Pharmaceutical LLC.