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Safety profile

TIBSOVO® (ivosidenib tablets) has a well-characterized safety profile studied in more than 200 patients with IDH1-mutated AML1

Adverse reactions common to both the newly diagnosed and R/R settings
reported in ≥10% (any grade) or ≥5% (Grade ≥3) of patients1
TIBSOVO (500 mg daily)
Newly diagnosed AML, N=28 		TIBSOVO (500 mg daily)
R/R AML, N=179
Body system
Adverse reaction 		All grades Grade ≥3 All grades Grade ≥3
Gastrointestinal disorders
Diarrhea 61% 7% 34% 2%
Nausea 36% 7% 31% 1%
Abdominal pain 29% 4% 16% 1%
Constipation 21% 4% 20% 1%
Vomiting 21% 4% 18% 1%
Mucositis 21% 0% 28% 3%
General disorders and administration site conditions
Fatigue 50% 14% 39% 3%
Edema 43% 0% 32% 1%
Metabolism and nutrition disorders
Decreased appetite 39% 4% 18% 2%
Blood system and lymphatic system disorders
Leukocytosis 36% 7% 38% 8%
Differentiation
syndromea 		25% 11% 19% 13%
Musculoskeletal and connective tissue disorders
Arthralgia 32% 4% 36% 4%
Myalgia 25% 4% 18% 1%
Respiratory, thoracic, and mediastinal disorders
Dyspnea 29% 4% 33% 9%
Cough 14% 0% 22% <1%
Investigations
Electrocardiogram QT prolonged 21% 11% 26% 10%
Nervous system disorders
Neuropathy 14% 0% 12% 1%
Headache 11% 0% 16% 0%
Skin and subcutaneous tissue disorders
Rash 14% 4% 26% 2%
R/R, relapsed or refractory.

a 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.1
Adverse reactions common to both the newly diagnosed and R/R settings
reported in ≥10% (any grade) or ≥5% (Grade ≥3) of patients1
TIBSOVO (500 mg daily)
Newly diagnosed AML, N=28
Body system
Adverse reaction 		All grades Grade ≥3
Gastrointestinal disorders
Diarrhea 61% 7%
Nausea 36% 7%
Abdominal pain 29% 4%
Constipation 21% 4%
Vomiting 21% 4%
Mucositis 21% 0%
General disorders and administration site conditions
Fatigue 50% 14%
Edema 43% 0%
Metabolism and nutrition disorders
Decreased appetite 39% 4%
Blood system and lymphatic system disorders
Leukocytosis 36% 7%
Differentiation
syndromea 		25% 11%
Musculoskeletal and connective tissue disorders
Arthralgia 32% 4%
Myalgia 25% 4%
Respiratory, thoracic, and mediastinal disorders
Dyspnea 29% 4%
Cough 14% 0%
Investigations
Electrocardiogram QT prolonged 21% 11%
Nervous system disorders
Neuropathy 14% 0%
Headache 11% 0%
Skin and subcutaneous tissue disorders
Rash 14% 4%
TIBSOVO (500 mg daily)
R/R AML, N=179
Body system
Adverse reaction 		All grades Grade ≥3
Gastrointestinal disorders
Diarrhea 34% 2%
Nausea 31% 1%
Abdominal pain 16% 1%
Constipation 20% 1%
Vomiting 18% 1%
Mucositis 28% 3%
General disorders and administration site conditions
Fatigue 39% 3%
Edema 32% 1%
Metabolism and nutrition disorders
Decreased appetite 18% 2%
Blood system and lymphatic system disorders
Leukocytosis 38% 8%
Differentiation
syndromea 		19% 13%
Musculoskeletal and connective tissue disorders
Arthralgia 36% 4%
Myalgia 18% 1%
Respiratory, thoracic, and mediastinal disorders
Dyspnea 33% 9%
Cough 22% <1%
Investigations
Electrocardiogram QT prolonged 26% 10%
Nervous system disorders
Neuropathy 12% 1%
Headache 16% 0%
Skin and subcutaneous tissue disorders
Rash 26% 2%
R/R, relapsed or refractory.

a 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.1

Additional adverse reactions in the newly diagnosed setting

Additional adverse reactions in the newly diagnosed setting reported in ≥10% (any grade) or ≥5% (Grade ≥3) of patients1
TIBSOVO (500 mg daily)
Newly diagnosed AML, N=28
Adverse reaction All grades Grade ≥3
Dizziness 21% 0%
Pruritus 14% 4%
Dyspepsia 11% 0%
Weight decreased 11% 0%
  • Common (≥5%) serious adverse events included differentiation syndrome (18%), electrocardiogram QT prolonged (7%), and fatigue (7%). There was one case of posterior reversible encephalopathy syndrome (PRES)1
  • Median duration of exposure to TIBSOVO: 4.3 months (range, 0.3-40.9)1
    • 10 patients (36%) were exposed to TIBSOVO for ≥6 months and 6 patients (21%) for ≥1 year

Additional adverse reactions in the R/R setting

Additional adverse reactions in the R/R setting reported in ≥10% (any grade) or ≥5% (Grade ≥3) of patients1
TIBSOVO (500 mg daily)
R/R AML, N=179
Adverse reaction All grades Grade ≥3
Pyrexia 23% 1%
Chest pain 16% 3%
Pleural effusion 13% 3%
Hypotension 12% 4%
Tumor lysis syndrome 8% 6%
R/R, relapsed or refractory.
  • Serious adverse reactions (≥5%) were differentiation syndrome (10%), leukocytosis (10%), and electrocardiogram QT prolonged (7%). There was one case of progressive multifocal leukoencephalopathy (PML)1
  • Median duration of exposure to TIBSOVO: 3.9 months (range, 0.1-39.5)1
    • 65 patients (36%) were exposed to TIBSOVO for ≥6 months and 16 patients (9%) for ≥1 year

Laboratory abnormalities reported in patients who received TIBSOVO1

Laboratory abnormalities common to both the newly diagnosed and R/R settings reported in ≥10% (any grade) or ≥5% (Grade ≥3) of patients1,b
TIBSOVO (500 mg daily)
Newly diagnosed AML, N=28 		TIBSOVO (500 mg daily)
R/R AML, N=179
Parameter All grades Grade ≥3 All grades Grade ≥3
Hemoglobin decreased 54% 43% 60% 46%
Alkaline phosphatase increased 46% 0% 27% 1%
Potassium decreased 43% 11% 31% 6%
Sodium decreased 39% 4% 39% 4%
Uric acid increased 29% 4% 32% 6%
Aspartate aminotransferase increased 29% 4% 27% 1%
Creatinine increased 29% 0% 23% 1%
Magnesium decreased 25% 0% 38% 0%
Phosphate decreased 21% 7% 25% 8%
Alanine aminotransferase increased 14% 4% 15% 1%
R/R, relapsed or refractory.
bLaboratory abnormality was defined as new or worsened by at least one grade from baseline or if baseline is unknown.1
Most common (≥10%) or ≥5% (Grade ≥3) new or worsening laboratory abnormalities reported in patients1,b
TIBSOVO (500 mg daily)
Newly diagnosed AML, N=28
Parameter All grades Grade ≥3
Hemoglobin decreased 54% 43%
Alkaline phosphatase increased 46% 0%
Potassium decreased 43% 11%
Sodium decreased 39% 4%
Uric acid increased 29% 4%
Aspartate aminotransferase increased 29% 4%
Creatinine increased 29% 0%
Magnesium decreased 25% 0%
Phosphate decreased 21% 7%
Alanine aminotransferase increased 14% 4%
TIBSOVO (500 mg daily)
R/R AML, N=179
Parameter All grades Grade ≥3
Hemoglobin decreased 60% 46%
Alkaline phosphatase increased 27% 1%
Potassium decreased 31% 6%
Sodium decreased 39% 4%
Uric acid increased 32% 6%
Aspartate aminotransferase increased 27% 1%
Creatinine increased 23% 1%
Magnesium decreased 38% 0%
Phosphate decreased 25% 8%
Alanine aminotransferase increased 15% 1%
R/R, relapsed or refractory.
bLaboratory abnormality is defined as new or worsened by at least one grade from baseline, or if baseline is unknown.1

Additional laboratory abnormalities reported in ≥10% (any grade) or ≥5% (Grade ≥3) of patients1:

  • In patients with newly diagnosed AML: calcium decreased (all grades, 25%; Grade ≥3, 4%)
  • In patients with R/R AML: bilirubin increased (all grades, 16%; Grade ≥3, 1%)
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Dose modification

Dose modifications seen with TIBSOVO1

Newly diagnosed AML, N=28 R/R AML, N=179
Adverse reactions that led to permanent discontinuation Diarrhea (4%), PRES (4%) Guillain-Barré syndrome (1%), rash (1%), stomatitis (1%), creatinine increased (1%)
Most common adverse reactions that led to dose interruption Electrocardiogram QT prolonged (14%), differentiation syndrome (11%) Electrocardiogram QT prolonged (7%), differentiation syndrome (3%), leukocytosis (3%), dyspnea (3%)
Adverse reactions that led to dose reduction Electrocardiogram QT prolonged (7%) 3% of patients required a dose reduction due to an adverse reaction

- Adverse reactions leading to dose reduction included electrocardiogram QT prolonged (1%), diarrhea (1%), nausea (1%), decreased hemoglobin (1%), increased transaminases (1%)
PRES, posterior reversible encephalopathy syndrome.
Newly diagnosed AML, N=28
Adverse reactions that led to permanent discontinuation Diarrhea (4%), PRES (4%)
Most common adverse reactions that led to dose interruption Electrocardiogram QT prolonged (14%), differentiation syndrome (11%)
Adverse reactions that led to dose reduction Electrocardiogram QT prolonged (7%)
R/R AML, N=179
Adverse reactions that led to permanent discontinuation Guillain-Barré syndrome (1%), rash (1%), stomatitis (1%), creatinine increased (1%)
Most common adverse reactions that led to dose interruption Electrocardiogram QT prolonged (7%), differentiation syndrome (3%), leukocytosis (3%), dyspnea (3%)
Adverse reactions that led to dose reduction 3% of patients required a dose reduction due to an adverse reaction

Adverse reactions leading to dose reduction included electrocardiogram QT prolonged (1%), diarrhea (1%), nausea (1%), decreased hemoglobin (1%), increased transaminases (1%)
PRES, posterior reversible encephalopathy syndrome.
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TIBSOVO is not myelosuppressive and is associated with a low rate of severe cytopenias2,3

Warnings and Precautions

Differentiation Syndrome in AML: In the clinical trial, 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. 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 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. 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.

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. 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.

QTc Interval Prolongation: Patients treated with TIBSOVO can develop QT (QTc) prolongation and ventricular arrhythmias. One patient developed ventricular fibrillation attributed to TIBSOVO. Concomitant use of TIBSOVO 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. Conduct monitoring of electrocardiograms (ECGs) and electrolytes. In patients with congenital long QTc syndrome, congestive heart failure, or electrolyte abnormalities, or in those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary.

Interrupt TIBSOVO if QTc increases to greater than 480 msec and less than 500 msec. Interrupt and reduce TIBSOVO if QTc increases to greater than 500 msec. Permanently discontinue TIBSOVO in patients who develop QTc interval prolongation with signs or symptoms of life- threatening arrhythmia.

Guillain-Barré Syndrome: Guillain-Barré syndrome can develop in patients treated with TIBSOVO. Monitor patients taking TIBSOVO 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 TIBSOVO in patients who are diagnosed with Guillain-Barré syndrome.

Learn about TIBSOVO dosing

References: 1. Tibsovo. Package insert. Servier Pharmaceuticals LLC; 2021. 2. Roboz GJ, DiNardo CD, Stein EM, et al. Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. Blood. 2020;135(7):463-471. doi: 10.1182/blood.2019002140 3. DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 2018;378(25):2386-2398. doi: 10.1056/NEJMoa1716984

 
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Indications

TIBSOVO is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of adult patients with a susceptible IDH1 mutation as detected by an FDA-approved test with:

  • Adult patients with newly-diagnosed Acute Myeloid Leukemia (AML) who are ≥75 years old or who have comorbidities that preclude use of intensive induction chemotherapy.
  • Adult patients with relapsed or refractory AML.

IMPORTANT SAFETY INFORMATION

WARNING: DIFFERENTIATION SYNDROME IN AML
Patients treated with TIBSOVO 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.

WARNINGS AND PRECAUTIONS

Differentiation Syndrome in AML: In the clinical trial, 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. 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 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. 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.

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. 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.

QTc Interval Prolongation: Patients treated with TIBSOVO can develop QT (QTc) prolongation and ventricular arrhythmias. One patient developed ventricular fibrillation attributed to TIBSOVO. Concomitant use of TIBSOVO 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. Conduct monitoring of electrocardiograms (ECGs) and electrolytes. In patients with congenital long QTc syndrome, congestive heart failure, or electrolyte abnormalities, or in those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary.

Interrupt TIBSOVO if QTc increases to greater than 480 msec and less than 500 msec. Interrupt and reduce TIBSOVO if QTc increases to greater than 500 msec. Permanently discontinue TIBSOVO in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.

Guillain-Barré Syndrome: Guillain-Barré syndrome can develop in patients treated with TIBSOVO. Monitor patients taking TIBSOVO 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 TIBSOVO in patients who are diagnosed with Guillain-Barré syndrome.

ADVERSE REACTIONS

  • In patients with AML, the most common adverse reactions including laboratory abnormalities (≥20%) were hemoglobin decreased (60%), fatigue (43%), arthralgia (39%), calcium decreased (39%), sodium decreased (39%), leukocytosis (38%), diarrhea (37%), magnesium decreased (36%), edema (34%), nausea (33%), dyspnea (32%), uric acid increased (32%), potassium decreased (32%), alkaline phosphatase increased (30%), mucositis (28%), aspartate aminotransferase increased (27%), phosphatase decreased (25%), electrocardiogram QT prolonged (24%), rash (24%), creatinine increased (24%), cough (23%), decreased appetite (22%), myalgia (21%), constipation (20%), and pyrexia (20%).
  • In patients with newly diagnosed AML, the most frequently reported Grade ≥3 adverse reactions (≥5%) were fatigue (14%), differentiation syndrome (11%), electrocardiogram QT prolonged (11%), diarrhea (7%), nausea (7%), and leukocytosis (7%). Serious adverse reactions (≥5%) were differentiation syndrome (18%), electrocardiogram QT prolonged (7%), and fatigue (7%). There was one case of posterior reversible encephalopathy syndrome (PRES).
  • In patients with relapsed or refractory AML, the most frequently reported Grade ≥3 adverse reactions (≥5%) were differentiation syndrome (13%), electrocardiogram QT prolonged (10%), dyspnea (9%), leukocytosis (8%), and tumor lysis syndrome (6%). Serious adverse reactions (≥5%) were differentiation syndrome (10%), leukocytosis (10%), and electrocardiogram QT prolonged (7%). There was one case of progressive multifocal leukoencephalopathy (PML).

DRUG INTERACTIONS

Strong or Moderate CYP3A4 Inhibitors: Reduce TIBSOVO dose with strong CYP3A4 inhibitors. Monitor patients for increased risk of QTc interval prolongation.

Strong CYP3A4 Inducers: Avoid concomitant use with TIBSOVO.

Sensitive CYP3A4 Substrates: Avoid concomitant use with TIBSOVO.

QTc Prolonging Drugs: Avoid concomitant use with TIBSOVO. If co-administration is unavoidable, monitor patients for increased risk of QTc interval prolongation.

LACTATION

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 at least 1 month after the last dose.

Please see Full Prescribing Information, including BOXED WARNING for AML patients.

 

INDICATIONS

TIBSOVO is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of adult patients with a susceptible IDH1 mutation as detected by an FDA-approved test with:

  • Adult patients with newly-diagnosed Acute Myeloid Leukemia (AML) who are ≥75 years old or who have comorbidities that preclude use of intensive induction chemotherapy.
  • Adult patients with relapsed or refractory AML.
Indications & Important Safety Information

IMPORTANT SAFETY INFORMATION

WARNING: DIFFERENTIATION SYNDROME IN AML

Patients treated with TIBSOVO 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.

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