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TIBSOVO (ivosidenib tablets) has a well-characterized safety profile studied in more than 270 patients with mIDH1 AML1

TIBSOVO in combination with azacitidine for treatment of newly diagnosed, IC-ineligible mIDH1 AML

Adverse reactions (≥10%) in patients with AML who received TIBSOVO + azacitidine with a difference of ≥2% between arms compared with placebo + azacitidine1

TIBSOVO + azacitidine
(N=71) 		Placebo + azacitidine
(N=73)
Body system
Adverse reaction 		All grades Grade ≥3 All grades Grade ≥3
Gastrointestinal disorders
Nausea 42% 3% 38% 4%
Vomiting 41% 0 27% 1%
Investigations
Electrocardiogram QT prolonged 20% 10% 7% 3%
Psychiatric disorders
Insomnia 18% 1% 12% 0
Blood system and lymphatic system disorders
Differentiation
syndromea 		15% 10% 8% 8%
Leukocytosis 13% 0 1% 0
Vascular disorders
Hematoma 15% 0 4% 0
Hypertension 13% 4% 8% 5%
Musculoskeletal and connective tissue disorders
Arthralgia 30% 4% 8% 1%
Respiratory, thoracic, and mediastinal disorders
Dyspnea 20% 3% 15% 5%
Nervous system disorders
Headache 11% 0 3% 0
TIBSOVO + azacitidine
(N=71)
Body system
Adverse reaction 		All grades Grade ≥3
Gastrointestinal disorders
Nausea 42% 3%
Vomiting 41% 0
Investigations
Electrocardiogram QT prolonged 20% 10%
Psychiatric disorders
Insomnia 18% 1%
Blood system and lymphatic system disorders
Differentiation
syndromea 		15% 10%
Leukocytosis 13% 0
Vascular disorders
Hematoma 15% 0
Hypertension 13% 4%
Musculoskeletal and connective tissue disorders
Arthralgia 30% 4%
Respiratory, thoracic, and mediastinal disorders
Dyspnea 20% 3%
Nervous system disorders
Headache 11% 0
Placebo + azacitidine
(N=73)
Body system
Adverse reaction 		All grades Grade ≥3
Gastrointestinal disorders
Nausea 38% 4%
Vomiting 27% 1%
Investigations
Electrocardiogram QT prolonged 7% 3%
Psychiatric disorders
Insomnia 12% 0
Blood system and lymphatic system disorders
Differentiation
syndromea 		8% 8%
Leukocytosis 1% 0
Vascular disorders
Hematoma 4% 0
Hypertension 8% 5%
Musculoskeletal and connective tissue disorders
Arthralgia 8% 1%
Respiratory, thoracic, and mediastinal disorders
Dyspnea 15% 5%
Nervous system disorders
Headache 3% 0

aDifferentiation 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.

  • TIBSOVO + azacitidine was associated with a lower rate of infection of any grade compared with azacitidine (28% vs 49%)2

Select laboratory abnormalities (≥10%) that worsened from baseline in patients with newly diagnosed AML who received TIBSOVO + azacitidine1,b,c

TIBSOVO + azacitidine
(N=71)		 Placebo + azacitidine
(N=73)
Parameter All grades Grade ≥3 All grades Grade ≥3
Hematology parameters
Leukocytes decreased 65% 55% 64% 58%
Platelets decreased 58% 42% 71% 58%
Hemoglobin decreased 56% 46% 66% 58%
Neutrophils decreased 25% 23% 35% 32%
Lymphocytes increased 24% 1% 10% 1%
Chemistry parameters
Glucose increased 56% 13% 47% 11%
Phosphate decreased 41% 10% 34% 12%
Aspartate aminotransferase increased 37% 0 23% 0
Magnesium decreased 35% 0 26% 0
Alkaline phosphatase increased 32% 0 29% 0
Potassium increased 24% 3% 12% 1%
TIBSOVO + azacitidine
(N=71)
Parameter All grades Grade ≥3
Hematology parameters
Leukocytes decreased 65% 55%
Platelets decreased 58% 42%
Hemoglobin decreased 56% 46%
Neutrophils decreased 25% 23%
Lymphocytes increased 24% 1%
Chemistry parameters
Glucose increased 56% 13%
Phosphate decreased 41% 10%
Aspartate aminotransferase increased 37% 0
Magnesium decreased 35% 0
Alkaline phosphatase increased 32% 0
Potassium increased 24% 3%
Placebo + azacitidine
(N=73)
Parameter All grades Grade ≥3
Hematology parameters
Leukocytes decreased 64% 58%
Platelets decreased 71% 58%
Hemoglobin decreased 66% 58%
Neutrophils decreased 35% 32%
Lymphocytes increased 10% 1%
Chemistry parameters
Glucose increased 47% 11%
Phosphate decreased 34% 12%
Aspartate aminotransferase increased 23% 0
Magnesium decreased 26% 0
Alkaline phosphatase increased 29% 0
Potassium increased 12% 1%

bLaboratory abnormality was defined as new or worsened by at least one grade from baseline or if baseline was unknown.

cThe denominator used to calculate percentages is the number of treated subjects who can be evaluated for Common Terminology Criteria for Adverse Events (CTCAE) for each parameter in each arm.

  • TIBSOVO + azacitidine was associated with fewer severe cytopenias compared with azacitidine1,2
  • Median duration of exposure to TIBSOVO was 6 months (range, 0 to 33)1
    • 34 patients (48%) were exposed to TIBSOVO for at least 6 months
    • 22 patients (31%) were exposed to TIBSOVO for at least 1 year
  • Fatal adverse reactions occurred in 4% of patients due to differentiation syndrome (3%) and one case of cerebral ischemia1

TIBSOVO + azacitidine: Dose discontinuations, interruptions, and reductions

  • The rate of discontinuation due to adverse events in patients treated with TIBSOVO + azacitidine was comparable to that of placebo + azacitidine (26.8% vs 26.0%)3
  • Adverse reactions leading to permanent discontinuation of TIBSOVO in ≥2% of patients were differentiation syndrome (3%) and pulmonary embolism (3%)1
  • The most common (>5%) adverse reactions leading to dose interruption of TIBSOVO were neutropenia (25%), electrocardiogram QT prolonged (7%), and thrombocytopenia (7%)1
  • Adverse reactions leading to dose reduction of TIBSOVO included electrocardiogram QT prolonged (8%), neutropenia (8%), and thrombocytopenia (1%)1

IC, induction chemotherapy; mIDH1, mutated isocitrate dehydrogenase‑1.

Safety profile: TIBSOVO monotherapy in the newly diagnosed setting

Adverse reactions ≥10% (any grade) or ≥5% (Grade ≥3) reported in newly diagnosed patients who received TIBSOVO1

TIBSOVO for 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
Dyspepsia 11% 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
syndromed 		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%
Weight decreased 11% 0
Nervous system disorders
Dizziness 21% 0
Neuropathy 14% 0
Headache 11% 0
Skin and subcutaneous tissue disorders
Pruritus 14% 4%
Rash 14% 4%

dDifferentiation 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

Laboratory abnormalities ≥10% (any grade) or ≥5% (Grade ≥3) reported in newly diagnosed patients who received TIBSOVO1,e

  TiBSOVO for 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
Calcium decreased 25% 4%
Phosphate decreased 21% 7%
Alanine aminotransferase increased 14% 4%

eLaboratory abnormality was defined as new or worsened by at least one grade from baseline or if baseline was unknown.1

Dose modifications seen with TIBSOVO1

  • Adverse reactions leading to discontinuation of TIBSOVO were diarrhea (4%) and PRES (4%)
  • The most common (≥10%) adverse reactions leading to dose interruption of TIBSOVO were electrocardiogram QT prolonged (14%) and differentiation syndrome (11%)
  • Adverse reactions leading to dose reduction of TIBSOVO included electrocardiogram QT prolonged (7%)
TIBSOVO was associated with a low rate of severe cytopenias4,5

Safety profile: TIBSOVO monotherapy in the relapsed or refractory setting

Adverse reactions ≥10% (any grade) or ≥5% (Grade ≥3) reported in R/R patients who received TIBSOVO monotherapy1

  TIBSOVO for R/R AML
(N=179)
Body system
Adverse reaction 		All grades Grade ≥3
General disorders and administration site conditions
Fatigue 39% 3%
Edema 32% 1%
Pyrexia 23% 1%
Chest pain 16% 3%
Blood system and lymphatic system disorders
Leukocytosis 38% 8%
Differentiation syndromef 19% 13%
Musculoskeletal and connective tissue disorders
Arthralgia 36% 4%
Myalgia 18% 1%
Gastrointestinal disorders
Diarrhea 34% 2%
Nausea 31% 1%
Mucositis 28% 3%
Constipation 20% 1%
Vomiting 18% 1%
Abdominal pain 16% 1%
Respiratory, thoracic, and mediastinal disorders
Dyspnea 33% 9%
Cough 22% <1%
Pleural effusion 13% 3%
Investigations
Electrocardiogram QT prolonged 26% 10%
Skin and subcutaneous tissue disorders
Rash 26% 2%
Metabolism and nutrition disorders
Decreased appetite 18% 2%
Tumor lysis syndrome 8% 6%
Nervous system disorders
Headache 16% 0
Neuropathy 12% 1%
Vascular disorders
Hypotension 12% 4%

fDifferentiation 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.

Laboratory abnormalities ≥10% (any grade) or ≥5% (Grade ≥3) reported in R/R patients who received TIBSOVO monotherapy1,g

  TIBSOVO for R/R AML
(N=179)
Parameter All grades Grade ≥3
Hemoglobin decreased 60% 46%
Sodium decreased 39% 4%
Magnesium decreased 38% 0
Uric acid increased 32% 6%
Potassium decreased 31% 6%
Alkaline phosphatase increased 27% 1%
Aspartate aminotransferase increased 27% 1%
Phosphate decreased 25% 8%
Creatinine increased 23% 1%
Alanine aminotransferase increased 15% 1%
Bilirubin increased 16% 1%

gLaboratory abnormality was defined as new or worsened by at least one grade from baseline or if baseline was unknown.1

  • No patient permanently discontinued treatment with TIBSOVO due to the adverse events of differentiation syndrome, QT interval prolongation, or leukocytosis1,4
  • No hepatotoxicity effects were observed with TIBSOVO1,4
    • TIBSOVO does not require monitoring of liver function tests

Dose modifications seen with TIBSOVO in the R/R setting1

  • Adverse reactions leading to discontinuation of TIBSOVO were Guillain-Barré syndrome (1%), rash (1%), stomatitis (1%), and creatinine increased (1%)
  • The most common adverse reactions leading to dose interruption of TIBSOVO were electrocardiogram QT prolonged (7%), differentiation syndrome (3%), leukocytosis (3%), and dyspnea (3%)
  • Adverse reactions leading to dose reduction of TIBSOVO included electrocardiogram QT prolonged (1%), diarrhea (1%), nausea (1%), decreased hemoglobin (1%), and increased transaminases (1%)

PRES, posterior reversible encephalopathy syndrome; R/R, relapsed/refractory.

Warnings and Precautions

Differentiation Syndrome in AML: In the combination study AG120-C-009, 15% (11/71) of patients with newly diagnosed AML treated with TIBSOVO plus azacitidine experienced differentiation syndrome. 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. 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. 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. Concomitant use of TIBSOVO with drugs known to prolong the QTc interval (eg, 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; 2023. 2. Montesinos P, Recher C, Vives S, et al. Ivosidenib and azacitidine in IDH1-mutated acute myeloid leukemia. N Engl J Med. 2022;386(16):1519-1531. doi:10.1056/NEJMoa2117344 3. Data on file. Servier Pharmaceuticals LLC. 4. 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 5. 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

 

Indications

TIBSOVO is indicated for patients with a susceptible isocitrate dehydrogenase-1 (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

Relapsed or Refractory AML

  • For the treatment of 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. 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: 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.

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. Concomitant use of TIBSOVO with drugs known to prolong the QTc interval (eg, 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, electrolyte abnormalities, or 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 adverse reactions including laboratory abnormalities (≥25%) 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

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

Advise women not to breastfeed.

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

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INDICATIONS

TIBSOVO is indicated for patients with a susceptible isocitrate dehydrogenase-1 (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 the use of intensive induction chemotherapy
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. 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.