TIBSOVO SIDE EFFECTS
- Generic Name: ivosidenib tablets
- Brand Name: Tibsovo
- Drug Class: IDH1 Inhibitors
SIDE EFFECTS
The following clinically significant adverse reactions are described elsewhere in the labeling:
- Differentiation Syndrome
- QTc Interval Prolongation
- Guillain-Barre Syndrome
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.
The safety of TIBSOVO as a single agent at 500 mg daily was evaluated in 213 patients with AML in Study AG120-C-001. The median age of TIBSOVO treated patients was 68 (range 18-87) with 68% ≥ 65 years, 51% male, 66% White, 6% Black or African American, 3% Asian, 0.5% Native Hawaiian or other Pacific Islander, 0.5% American Indian or Alaska Native, and 24% other/not provided. Among the 213 patients who received TIBSOVO, 37% were exposed for 6 months or longer and 14% were exposed for 12 months or longer. The most common adverse reactions including laboratory abnormalities in ≥ 20% of 213 patients who received TIBSOVO were hemoglobin decreased, fatigue, arthralgia, calcium decreased, sodium decreased, leukocytosis, diarrhea, magnesium decreased, edema, nausea, dyspnea, uric acid increased, potassium decreased, alkaline phosphatase increased, mucositis, aspartate aminotransferase increased, phosphatase decreased, electrocardiogram QT prolonged, rash, creatinine increased, cough, decreased appetite, myalgia, constipation, and pyrexia.
Newly-Diagnosed AML
The safety profile of single-agent TIBSOVO was studied in 28 adults with newly-diagnosed AML treated with 500 mg daily. 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%), electrocardiogram QT prolonged (7%), and fatigue (7%). There was one case of posterior reversible encephalopathy syndrome (PRES).
Common (≥ 10%) adverse reactions leading to dose interruption included electrocardiogram QT prolonged (14%) and differentiation syndrome (11%). Two (7%) patients required a dose reduction due to electrocardiogram QT prolonged. One patient each required permanent discontinuation due to diarrhea and PRES.
The most common adverse reactions reported in the trial are shown in Table 1.
Table 1: Adverse Reactions Reported in ≥ 10% (Any Grade) or ≥ 5% (Grade ≥ 3) of Patients with Newly-Diagnosed AML
| Body System Adverse Reaction |
TIBSOVO (500 mg daily) N=28 |
|
| All Grades n (%) |
Grade ≥ 3 n (%) |
|
| Blood System and Lymphatic System Disorders | ||
| Leukocytosis1 | 10 (36) | 2 (7) |
| Differentiation Syndrome2 | 7 (25) | 3 (11) |
| Gastrointestinal Disorders | ||
| Diarrhea | 17 (61) | 2 (7) |
| Nausea | 10 (36) | 2 (7) |
| Abdominal pain3 | 8 (29) | 1 (4) |
| Constipation | 6 (21) | 1 (4) |
| Vomiting | 6 (21) | 1 (4) |
| Mucositis4 | 6 (21) | 0 |
| Dyspepsia | 3 (11) | 0 |
| General Disorders and Administration Site Conditions | ||
| Fatigue5 | 14 (50) | 4 (14) |
| Edema6 | 12 (43) | 0 |
| Investigations | ||
| Electrocardiogram QT prolonged | 6 (21) | 3 (11) |
| Weight decreased | 3 (11) | 0 |
| Metabolism and Nutrition Disorders | ||
| Decreased appetite | 11 (39) | 1 (4) |
| Musculoskeletal and Connective Tissue Disorders | ||
| Arthralgia7 | 9 (32) | 1 (4) |
| Myalgia8 | 7 (25) | 1 (4) |
| Nervous System Disorders | ||
| Dizziness | 6 (21) | 0 |
| Neuropathy9 | 4 (14) | 0 |
| Headache | 3 (11) | 0 |
| Respiratory, Thoracic and Mediastinal Disorders | ||
| Dyspnea10 | 8 (29) | 1 (4) |
| Cough11 | 4 (14) | 0 |
| Skin and Subcutaneous Tissue Disorders | ||
| Pruritis | 4 (14) | 1 (4) |
| Rash12 | 4 (14) | 1 (4) |
| 1 Grouped term includes leukocytosis, hyperleukocytosis, and increased white blood cell count. 2 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. 3 Grouped term includes abdominal pain, upper abdominal pain, abdominal discomfort, and abdominal tenderness. 4 Grouped term includes aphthous ulcer, esophageal pain, esophagitis, gingival pain, gingivitis, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal pain, proctalgia, and stomatitis. 5 Grouped term includes asthenia and fatigue. 6 Grouped term includes edema, face edema, fluid overload, fluid retention, hypervolemia, peripheral edema, and swelling face. 7 Grouped term includes arthralgia, back pain, musculoskeletal stiffness, neck pain, and pain in extremity. 8 Grouped term includes myalgia, muscular weakness, musculoskeletal pain, musculoskeletal chest pain, musculoskeletal discomfort, and myalgia intercostal. 9 Grouped term includes burning sensation, lumbosacral plexopathy, neuropathy peripheral, paresthesia, and peripheral motor neuropathy. 10 Grouped term includes dyspnea, dyspnea exertional, hypoxia, and respiratory failure. 11 Grouped term includes cough, productive cough, and upper airway cough syndrome. 12 Grouped term includes dermatitis acneiform, dermatitis, rash, rash maculo-papular, urticaria, rash erythematous, rash macular, rash pruritic, rash generalized, rash papular, skin exfoliation, and skin ulcer. |
||
Changes in selected post-baseline laboratory values that were observed in patients with newly diagnosed AML are shown in Table 2.
Table 2: Most Common (≥ 10%) or ≥ 5% (Grade ≥ 3) New or Worsening Laboratory Abnormalities Reported in Patients with Newly-Diagnosed AML1
| Parameter | TIBSOVO (500 mg daily) N=28 |
|
| All Grades n (%) |
Grade ≥ 3 n (%) |
|
| Hemoglobin decreased | 15 (54) | 12 (43) |
| Alkaline phosphatase increased | 13 (46) | 0 |
| Potassium decreased | 12 (43) | 3 (11) |
| Sodium decreased | 11 (39) | 1 (4) |
| Uric acid increased | 8 (29) | 1 (4) |
| Aspartate aminotransferase increased | 8 (29) | 1 (4) |
| Creatinine increased | 8 (29) | 0 |
| Magnesium decreased | 7 (25) | 0 |
| Calcium decreased | 7 (25) | 1 (4) |
| Phosphate decreased | 6 (21) | 2 (7) |
| Alanine aminotransferase increased | 4 (14) | 1 (4) |
| 1Laboratory abnormality is defined as new or worsened by at least one grade from baseline, or if baseline is unknown. | ||
Relapsed Or Refractory AML
The safety profile of single-agent TIBSOVO was studied in 179 adults with relapsed or refractory AML treated with 500 mg daily [see Clinical Studies].
The median duration of exposure to TIBSOVO was 3.9 months (range 0.1 to 39.5 months). Sixty-five patients (36%) were exposed to TIBSOVO for at least 6 months and 16 patients (9%) were exposed for at least 1 year.
Serious adverse reactions (≥ 5%) were differentiation syndrome (10%), leukocytosis (10%), and electrocardiogram QT prolonged (7%). There was one case of progressive multifocal leukoencephalopathy (PML).
The most common adverse reactions leading to dose interruption were electrocardiogram QT prolonged (7%), differentiation syndrome (3%), leukocytosis (3%) and dyspnea (3%). Five out of 179 patients (3%) required a dose reduction due to an adverse reaction. Adverse reactions leading to a dose reduction included electrocardiogram QT prolonged (1%), diarrhea (1%), nausea (1%), decreased hemoglobin (1%), and increased transaminases (1%). Adverse reactions leading to permanent discontinuation included Guillain-Barre syndrome (1%), rash (1%), stomatitis (1%), and creatinine increased (1%).
The most common adverse reactions reported in the trial are shown in Table 3.
Table 3: Adverse Reactions Reported in ≥ 10% (Any Grade) or ≥ 5% (Grade ≥ 3) of Patients with Relapsed or Refractory AML
| Body System Adverse Reaction |
TIBSOVO (500 mg daily) N=179 |
|
| All Grades n (%) |
Grade ≥ 3 n (%) |
|
| Blood System and Lymphatic System Disorders | ||
| Leukocytosis1 | 68 (38) | 15 (8) |
| Differentiation Syndrome2 | 34 (19) | 23 (13) |
| Gastrointestinal Disorders | ||
| Diarrhea | 60 (34) | 4 (2) |
| Nausea | 56 (31) | 1 (1) |
| Mucositis3 | 51 (28) | 6 (3) |
| Constipation | 35 (20) | 1 (1) |
| Vomiting4 | 32 (18) | 2 (1) |
| Abdominal pain5 | 29 (16) | 2 (1) |
| General Disorders and Administration Site Conditions | ||
| Fatigue6 | 69 (39) | 6 (3) |
| Edema7 | 57 (32) | 2 (1) |
| Pyrexia | 41 (23) | 2 (1) |
| Chest pain8 | 29 (16) | 5 (3) |
| Investigations | ||
| Electrocardiogram QT prolonged | 46 (26) | 18 (10) |
| Metabolism and Nutrition Disorders | ||
| Decreased appetite | 33 (18) | 3 (2) |
| Tumor lysis syndrome | 14 (8) | 11 (6) |
| Musculoskeletal and Connective Tissue Disorders | ||
| Arthralgia9 | 64 (36) | 8 (4) |
| Myalgia10 | 33 (18) | 1 (1) |
| Nervous System Disorders | ||
| Headache | 28 (16) | 0 |
| Neuropathy11 | 21 (12) | 2 (1) |
| Respiratory, Thoracic and Mediastinal Disorders | ||
| Cough12 | 40 (22) | 1 (<1) |
| Dyspnea13 | 59 (33) | 16 (9) |
| Pleural effusion | 23 (13) | 5 (3) |
| Skin and Subcutaneous Tissue Disorders | ||
| Rash14 | 46 (26) | 4 (2) |
| Vascular Disorders | ||
| Hypotension15 | 22 (12) | 7 (4) |
| 1 Grouped term includes leukocytosis, hyperleukocytosis, and increased white blood cell count. 2 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. 3 Grouped term includes aphthous ulcer, esophageal pain, esophagitis, gingival pain, gingivitis, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal pain, proctalgia, and stomatitis. 4 Grouped term includes vomiting and retching. 5 Grouped term includes abdominal pain, upper abdominal pain, abdominal discomfort, and abdominal tenderness. 6 Grouped term includes asthenia and fatigue. 7 Grouped term includes peripheral edema, edema, fluid overload, fluid retention, and face edema. 8 Grouped term includes angina pectoris, chest pain, chest discomfort, and non-cardiac chest pain. 9 Grouped term includes arthralgia, back pain, musculoskeletal stiffness, neck pain, and pain in extremity. 10 Grouped term includes myalgia, muscular weakness, musculoskeletal pain, musculoskeletal chest pain, musculoskeletal discomfort, and myalgia intercostal. 11 Grouped term includes ataxia, burning sensation, gait disturbance, Guillain-Barre syndrome, neuropathy peripheral, paresthesia, peripheral sensory neuropathy, peripheral motor neuropathy, and sensory disturbance. 12 Grouped term includes cough, productive cough, and upper airway cough syndrome. 13 Grouped term includes dyspnea, respiratory failure, hypoxia, and dyspnea exertional. 14 Grouped term includes dermatitis acneiform, dermatitis, rash, rash maculo-papular, urticaria, rash erythematous, rash macular, rash pruritic, rash generalized, rash papular, skin exfoliation, and skin ulcer. 15 Grouped term includes hypotension and orthostatic hypotension. |
||
Changes in selected post-baseline laboratory values that were observed in patients with relapsed or refractory AML are shown in Table 4.
Table 4: Most Common (≥ 10%) or ≥ 5% (Grade ≥ 3) New or Worsening Laboratory Abnormalities Reported in Patients with Relapsed or Refractory AML1
| Parameter | TIBSOVO (500 mg daily) N=179 |
|
| All Grades n (%) |
Grade ≥ 3 n (%) |
|
| Hemoglobin decreased | 108 (60) | 83 (46) |
| Sodium decreased | 69 (39) | 8 (4) |
| Magnesium decreased | 68 (38) | 0 |
| Uric acid increased | 57 (32) | 11 (6) |
| Potassium decreased | 55 (31) | 11 (6) |
| Alkaline phosphatase increased | 49 (27) | 1 (1) |
| Aspartate aminotransferase increased | 49 (27) | 1 (1) |
| Phosphate decreased | 45 (25) | 15 (8) |
| Creatinine increased | 42 (23) | 2 (1) |
| Alanine aminotransferase increased | 26 (15) | 2 (1) |
| Bilirubin increased | 28 (16) | 1 (1) |
| 1Laboratory abnormality is defined as new or worsened by at least one grade from baseline, or if baseline is unknown. | ||
SRC: NLM .