Can Ivosidenib cause fatigue?

ADVERSE REACTIONS 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. 9 (13) 3 (4) 6 (8) 4 (5) Musculoskeletal and connective tissue disorders Arthralgia Grouped term includes pain in extremity, arthralgia, back pain, musculoskeletal stiffness, cancer pain, and neck pain. 21 (30) 3 (4) 6 (8) 1 (1) Respiratory, thoracic and mediastinal disorders Dyspnea Grouped term includes dyspnea, dyspnea exertional, hypoxia, respiration failure. 14 (20) 2 (3) 11 (15) 4 (5) Nervous system disorders Headache 8 (11) 0 2 (3) 0 Table 3: Select Laboratory Abnormalities Laboratory abnormality is defined as new or worsened by at least one grade from baseline, or if baseline is unknown. , The denominator used to calculate percentages is the number of treated subjects who can be evaluated for CTCAE criteria for each parameter in each arm. (≥10%) That Worsened from Baseline in Patients with AML Who Received TIBSOVO + azacitidine in AG120-C-009 TIBSOVO + Azacitidine N=71 Placebo + Azacitidine N=73 Parameter All Grades n (%) Grade ≥ 3 n (%) All Grades n (%) Grade ≥ 3 n (%) Hematology Parameters Leukocytes decreased 46 (65) 39 (55) 47 (64) 42 (58) Platelets decreased 41 (58) 30 (42) 52 (71) 42 (58) Hemoglobin decreased 40 (56) 33 (46) 48 (66) 42 (58) Neutrophils decreased 18 (25) 16 (23) 25 (35) 23 (32) Lymphocytes increased 17 (24) 1 (1) 7 (10) 1 (1) Chemistry Parameters Glucose increased 40 (56) 9 (13) 34 (47) 8 (11) Phosphate decreased 29 (41) 7 (10) 25 (34) 9 (12) Aspartate Aminotransferase increased 26 (37) 0 17 (23) 0 Magnesium decreased 25 (35) 0 19 (26) 0 Alkaline Phosphatase increased 23 (32) 0 21 (29) 0 Potassium increased 17 (24) 2 (3) 9 (12) 1 (1) TIBSOVO Monotherapy The safety profile of single-agent TIBSOVO was studied in 28 adults with newly diagnosed AML treated with 500 mg daily [see Clinical Studies (14.1) ] . The median duration of exposure to TIBSOVO was 4.3 months (range 0.3 to 40.9 months). Ten patients (36%) were exposed to TIBSOVO for at least 6 months and 6 patients (21%) were exposed for at least 1 year. Common (≥ 5%) serious adverse reactions included differentiation syndrome (18%), e

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. 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 [See Dosage and Administration (2.3) ] . 5.3 Guillain-Barré Syndrome Guillain-Barré syndrome can develop in patients treated with TIBSOVO. Guillain-Barré syndrome occurred in 0.8% (2/265) of patients treated with TIBSOVO in study AG120-C-001 [see Adverse Reactions (6.1) ] . 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 [see Dosage and Administration (2.3) ].