NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend ivosidenib (TIBSOVO®) in R/R AML with an IDH1 mutation1

The safety of TIBSOVO® was evaluated in a patient population with difficult-to-treat disease1

Adverse reactions reported in ≥10% (any grade) or ≥5% (Grade ≥3) of patients (N=179)1
Adverse reaction All grades ≥Grade 3
Fatigue 39% 3%
Leukocytosis 38% 8%
Arthralgia 36% 4%
Diarrhea 34% 2%
Dyspnea 33% 9%
Edema 32% 1%
Nausea 31% 1%
Mucositis 28% 3%
Electrocardiogram QT prolonged 26% 10%
Rash 26% 2%
Pyrexia 23% 1%
Cough 22% <1%
Constipation 20% 1%
Differentiation syndromea 19% 13%
Decreased appetite 18% 2%
Myalgia 18% 1%
Vomiting 18% 1%
Chest pain 16% 3%
Abdominal pain 16% 1%
Headache 16% 0%
Pleural effusion 13% 3%
Hypotension 12% 4%
Neuropathy 12% 1%
Tumor lysis syndrome 8% 6%
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.1
  • 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 months)1
Most common (≥10%) or ≥5% (Grade ≥3) new or worsening laboratory abnormalities reported in patients (N=179)1b
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%
Bilirubin increased 16% 1%
Alanine aminotransferase increased 15% 1%
bLaboratory abnormality is defined as new or worsened by at least one grade from baseline, or if baseline is unknown.1

Dose reductions and discontinuations seen with TIBSOVO (N=179)

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Adverse reactions leading to permanent discontinuation included Guillain-Barré syndrome (1%), rash (1%), stomatitis (1%), and creatinine increased (1%)1

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The most common adverse reactions leading to dose interruption were electrocardiogram QT prolonged (7%), differentiation syndrome (3%), leukocytosis (3%), and dyspnea (3%)1

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3% of patients (5/179) required a dose reduction due to an adverse reaction1

  • Adverse reactions leading to a dose reduction included electrocardiogram QT prolonged (1%), diarrhea (1%), nausea (1%), decreased hemoglobin (1%), and increased transaminases (1%)
Reference: 1. TIBSOVO [package insert]. Cambridge, MA: Agios Pharmaceuticals, Inc.; 2018.

Warnings and Precautions

Differentiation Syndrome: See Boxed WARNING. In the clinical trial, 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 34 patients who experienced differentiation syndrome, 27 (79%) 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, 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 occurred in <1% (2/258) of patients treated with TIBSOVO in the clinical study. 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.

 

INDICATION

TIBSOVO® (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.

Indication & Important Safety Information

IMPORTANT SAFETY INFORMATION

WARNING: DIFFERENTIATION SYNDROME

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.