The safety of TIBSOVO® was evaluated in more than 200 patients with AML with an IDH1 mutation1
| Adverse reactions common to both the newly diagnosed and R/R settings reported in ≥10% (any grade) or ≥5% (Grade ≥3) of patients1 |
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|---|---|---|---|---|
|
TIBSOVO (500 mg daily) Newly diagnosed AML, N=28 |
TIBSOVO (500 mg daily) R/R AML, N=179 |
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|
Body system Adverse reaction |
All grades | Grade ≥3 | All grades | Grade ≥3 |
| Blood system and lymphatic system disorders | ||||
| Leukocytosis | 36% | 7% | 38% | 8% |
|
Differentiation syndromea |
25% | 11% | 19% | 13% |
| 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% |
| Investigations | ||||
| Electrocardiogram QT prolonged | 21% | 11% | 26% | 10% |
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 39% | 4% | 18% | 2% |
| Musculoskeletal and connective tissue disorders | ||||
| Arthralgia | 32% | 4% | 36% | 4% |
| Myalgia | 25% | 4% | 18% | 1% |
| Nervous system disorders | ||||
| Neuropathy | 14% | 0% | 12% | 1% |
| Headache | 11% | 0% | 16% | 0% |
| Respiratory, thoracic, and mediastinal disorders | ||||
| Dyspnea | 29% | 4% | 33% | 9% |
| Cough | 14% | 0% | 22% | <1% |
| Skin and subcutaneous tissue disorders | ||||
| Rash | 14% | 4% | 26% | 2% |
| 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 | ||||
| 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 |
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| 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 months)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 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% |
- 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
- 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
| 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 |
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% |
| 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%)
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%) |
Warnings and Precautions
Differentiation Syndrome: See Boxed WARNING. 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 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.
R/R, relapsed or refractory.
Reference: 1. TIBSOVO [package insert]. Cambridge, MA: Agios Pharmaceuticals, Inc.; 2019.
INDICATIONS
TIBSOVO is indicated for the treatment of acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test in:
- Adult patients with newly diagnosed AML who are ≥75 years old or who have comorbidities that preclude use of intensive induction chemotherapy.
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.
