The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:
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 most common adverse reactions, in ≥20% of adults with newly diagnosed CP Ph+ CML or CP, AP, or BP Ph+ CML with resistance or intolerance to prior therapy (N=814) were diarrhea (80%), rash (44%), nausea (44%), abdominal pain (43%), vomiting (33%), fatigue (33%), hepatic dysfunction (33%), respiratory tract infection (25%), pyrexia (24%), and headache (21%).
The most common laboratory abnormalities that worsened from baseline in ≥20% of adults were creatinine increased (93%), hemoglobin decreased (90%), lymphocyte count decreased (72%), platelets decreased (69%), ALT increased (58%), calcium decreased (53%), white blood cell count decreased (52%), absolute neutrophils count decreased (50%), AST increased (50%), glucose increased (46%), phosphorus decreased (44%), urate increased (41%), alkaline phosphatase increased (40%), lipase increased (36%), creatine kinase increased (29%), and amylase increased (24%).
The most common adverse reactions, in ≥20% of pediatric patients (N=49) were diarrhea (82%), abdominal pain (73%), vomiting (55%), nausea (49%), rash (49%), fatigue (37%), hepatic dysfunction (37%), headache (35%), pyrexia (31%), decreased appetite (27%), and constipation (20%).
The most common laboratory abnormalities that worsened from baseline in ≥20% of pediatric patients were creatinine increased (92%), alanine aminotransferase increased (59%), white blood cell count decreased (53%), aspartate aminotransferase increased (51%), platelet count decreased (49%), glucose increased (41%), calcium decreased (31%), hemoglobin decreased (31%), neutrophil count decreased (31%), lymphocyte count decreased (29%), serum amylase increased (27%), and CPK increased (25%).
Adverse Reactions in Adult Patients With Newly-Diagnosed CP CML
The clinical trial randomized and treated 533 patients with newly-diagnosed CP CML to receive BOSULIF 400 mg daily or imatinib 400 mg daily as single agents (Newly-Diagnosed CP CML Study) [see Clinical Studies (14.1)]. The safety population (received at least 1 dose of BOSULIF) included:
Serious adverse reactions occurred in 22% of patients with newly-diagnosed CP CML who received bosutinib. Serious adverse reactions reported in >2% of patients included hepatic dysfunction (4.1%), pneumonia (3.4%), coronary artery disease (3.4%), and gastroenteritis (2.2%). Fatal adverse reactions occurred in 3 patients (1.1%) due to coronary artery disease (0.4%), cardiac failure acute (0.4%), and renal failure (0.4%).
Permanent discontinuation of bosutinib due to an adverse reaction occurred in 20% of patients with newly-diagnosed CP CML who received bosutinib. Adverse reactions which resulted in permanent discontinuation in > 2% of patients included hepatic dysfunction (9%).
Dose modifications (dose interruption or reductions) of bosutinib due to an adverse reaction occurred in 68% of patients with newly-diagnosed CP CML. Adverse reactions which required dose interruptions or reductions in >5% of patients included hepatic dysfunction (27%), thrombocytopenia (16%), diarrhea (16%), lipase increased (10%), neutropenia (7%), abdominal pain (6%), rash (5%).
The most common adverse reactions, in >20% of bosutinib-treated patients with newly-diagnosed CML (N=268) were diarrhea (75%), hepatic dysfunction (45%), rash (40%), abdominal pain (39%), nausea (37%), fatigue (33%), respiratory tract infection (27%), headache (22%), and vomiting (21%).
The most common laboratory abnormalities that worsened from baseline in ≥20% of patients were creatinine increased (94%), hemoglobin decreased (89%), lymphocyte count decreased (84%), ALT increased (68%), platelet count decreased (68%), glucose increased (57%), AST increased (56%), calcium decreased (55%), phosphorus decreased (54%), lipase increased (53%), white blood cell count decreased (50%), absolute neutrophil count decreased (42%), alkaline phosphatase increased (41%), creatine kinase increased (36%), and amylase increased (32%).
Table 7 identifies adverse reactions greater than or equal to 10% for All Grades and Grades 3 or 4 (3/4) for the Phase 3 CP CML safety population.
Bosutinib 400 mg Chronic Phase CML (N=268) | Imatinib 400 mg Chronic Phase CML (N=265) | ||||
---|---|---|---|---|---|
| |||||
System Organ Class | Preferred Term | All Grades | Grade 3/4 | All Grades | Grade 3/4 |
Gastrointestinal disorders | Diarrhea | 75 | 9 | 40 | 1 |
Abdominal pain† | 39 | 2 | 27 | 1 | |
Nausea | 37 | 0 | 42 | 0 | |
Vomiting | 21 | 1 | 20 | 0 | |
Constipation | 13 | 0 | 6 | 0 | |
Hepatobiliary disorders | Hepatic dysfunction‡ | 45 | 27 | 15 | 4 |
Skin and subcutaneous tissue disorders | Rash§ | 40 | 2 | 30 | 2 |
Pruritus | 11 | <1 | 4 | 0 | |
General disorders and administration-site conditions | Fatigue¶ | 33 | 1 | 30 | <1 |
Pyrexia | 17 | 1 | 11 | 0 | |
Edema# | 15 | 0 | 46 | 2 | |
Infections and infestations | Respiratory tract infectionÞ | 27 | 1 | 25 | <1 |
Nervous system disorders | Headache | 22 | 1 | 15 | 1 |
Musculoskeletal and connective tissue disorders | Arthralgia | 18 | 1 | 18 | <1 |
Back pain | 12 | <1 | 9 | <1 | |
Respiratory, thoracic, and mediastinal disorders | Cough | 11 | 0 | 10 | 0 |
Dyspnea | 11 | 1 | 6 | 1 | |
Metabolism and nutrition disorders | Decreased appetite | 11 | <1 | 6 | 0 |
Vascular disorders | Hypertensionß | 10 | 5 | 11 | 5 |
In the randomized study in patients with newly-diagnosed CP CML, one patient in the group treated with BOSULIF experienced a Grade 3 QTcF prolongation (>500 msec). Patients with uncontrolled or significant cardiovascular disease including QT interval prolongation were excluded by protocol.
Table 8 identifies the clinically relevant or severe Grade 3/4 laboratory test abnormalities for the Phase 3 newly-diagnosed CML safety population.
Bosutinib N=268 % | Imatinib N=265 % | |||
---|---|---|---|---|
All Grade | Grade 3–4 | All Grade | Grade 3–4 | |
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; CML=chronic myelogenous leukemia; SGPT=serum glutamic-pyruvic transaminase; SGOT=serum glutamic-oxaloacetic transaminase; N/n=number of patients; ULN=upper limit of normal. Graded using CTCAE v 4.03 | ||||
| ||||
Hematology Parameters | ||||
Platelet Count decreased | 68 | 14 | 60 | 6 |
Absolute Neutrophil Count decreased | 42 | 9 | 65 | 20 |
Hemoglobin decreased | 89 | 9 | 90 | 7 |
White Blood Cell Count decreased | 50 | 6 | 70 | 8 |
Lymphocyte Count decreased | 84 | 12 | 82 | 14 |
Biochemistry Parameters | ||||
SGPT/ALT increased | 68 | 26 | 28 | 3 |
SGOT/AST increased | 56 | 13 | 29 | 3.4 |
Lipase increased | 53 | 19 | 35 | 8 |
Phosphorus decreased | 54 | 9 | 69 | 21 |
Amylase increased | 32 | 3.4 | 18 | 2.3 |
Alkaline Phosphatase increased | 41 | 0 | 43 | 0.4 |
Calcium decreased | 55 | 1.5 | 57 | 1.1 |
Glucose increased | 57 | 3 | 65 | 3.4 |
Creatine Kinase increased | 36 | 3 | 65 | 5 |
Creatinine increased | 94 | 1.1 | 98 | 0.8 |
Adverse Reactions in Adult Patients With Imatinib-Resistant or -Intolerant Ph+ CP, AP, and BP CML
The single-arm clinical trial enrolled patients with Ph+ CP, AP, or BP CML and with resistance or intolerance to prior therapy [see Clinical Studies (14.2)]. The safety population (received at least 1 dose of BOSULIF) included 546 CML patients:
Serious adverse reactions occurred in 30% of patients in the safety population of the single-arm trial in patients with CML (N=546) who were resistant or intolerant to prior therapy. Serious adverse reactions reported in >2% of patients included pneumonia (7%), pleural effusion (6%), pyrexia (3.7%), coronary artery disease (3.5%), dyspnea (2.6%), rash (2.2%), thrombocytopenia (2%), abdominal pain (2%), and diarrhea (2%).
Fatal adverse reactions occurred in 12 patients (2.2%) due to coronary artery disease (0.9%), pneumonia (0.4%), respiratory failure (0.4%), gastrointestinal hemorrhage (0.2%), acute kidney injury (0.2%), and acute pulmonary edema (0.2%).
Permanent discontinuation of bosutinib due to an adverse reaction occurred in 22% of patients with CML who were resistant or intolerant to prior therapy. Adverse reactions which resulted in permanent discontinuation in >2% of patients included thrombocytopenia (6%), hepatic dysfunction (3.3%), and neutropenia (2%).
Dose modifications (dose interruption or reductions) of bosutinib due to an adverse reaction occurred in 66% of patients with CML who were resistant or intolerant to prior therapy. Adverse reactions which required dose interruptions or reductions in >5% of patients included thrombocytopenia (24%), diarrhea (14%), rash (13%), hepatic dysfunction (10%), neutropenia (9%), pleural effusion (8%), vomiting (7%), anemia (6%), and abdominal pain (6%).
The most common adverse reactions, in ≥20% of patients in the safety population of the single-arm trial in patients with CML (N=546) who were resistant or intolerant to prior therapy were diarrhea (83%), nausea (47%), rash (46%), abdominal pain (45%), vomiting (39%), fatigue (33%), pyrexia (28%), hepatic dysfunction (27%), respiratory tract infection (24%), cough (23%), and headache (21%).
The most common laboratory abnormalities that worsened from baseline in ≥20% were creatinine increased (93%), hemoglobin decreased (91%), lymphocyte decreased (80%), platelets decreased (69%), absolute neutrophil count (54%), ALT increased (53%), calcium decreased (53%), white blood cell count decreased (52%), urate increased (48%), AST increased (47%), phosphorus decreased (39%), alkaline phosphatase increased (39%), lipase increased (28%), magnesium increased (25%), potassium decreased (24%), potassium increased (23%). See Table 10 for Grade 3/4 laboratory abnormalities.
Table 9 identifies adverse reactions greater than or equal to 10% for All Grades and Grades 3 or 4 for the Phase 1/2 CML safety population based on long-term follow-up.
CP CML (N=403) | AdvP CML (N=143) | ||||
---|---|---|---|---|---|
System Organ Class | Preferred Term | All Grades % | Grade 3/4 % | All Grades % | Grade 3/4 % |
ADR Definition | |||||
| |||||
Gastrointestinal disorders | Diarrhea | 85 | 10 | 76 | 4 |
Abdominal pain† | 49 | 2 | 36 | 7 | |
Nausea | 47 | 1 | 48 | 2 | |
Vomiting | 38 | 3 | 43 | 3 | |
Constipation | 15 | <1 | 17 | 1 | |
Skin and subcutaneous tissue disorders | Rash‡ | 48 | 9 | 42 | 5 |
Pruritus | 12 | 1 | 7 | 0 | |
General disorders and administration-site conditions | Fatigue | 35 | 3 | 27 | 6 |
Pyrexia | 25 | 1 | 37 | 3 | |
Edema§ | 19 | <1 | 17 | 1 | |
Chest pain¶ | 8 | 1 | 12 | 1 | |
Hepatobiliary disorders | Hepatic dysfunction# | 29 | 11 | 21 | 10 |
Infections and infestations | Respiratory tract infectionÞ | 27 | <1 | 17 | 0 |
Influenzaß | 11 | 1 | 3 | 0 | |
Pneumoniaà | 10 | 4 | 18 | 12 | |
Respiratory, thoracic, and mediastinal disorders | Cough | 24 | 0 | 22 | 0 |
Pleural effusion | 14 | 4 | 9 | 4 | |
Dyspnea | 12 | 2 | 20 | 6 | |
Nervous system disorders | Headache | 21 | 1 | 18 | 4 |
Dizziness | 11 | 0 | 14 | 1 | |
Musculoskeletal and connective tissue disorders | Arthralgia | 19 | 1 | 15 | 0 |
Back pain | 14 | 1 | 8 | 1 | |
Metabolism and nutrition disorders | Decreased appetite | 14 | 1 | 14 | 0 |
Vascular disorders | Hypertensionè | 11 | 3 | 8 | 3 |
In the single-arm study in patients with CML who were resistant or intolerant to prior therapy, 2 patients (0.4%) experienced QTcF interval of greater than 500 milliseconds. Patients with uncontrolled or significant cardiovascular disease including QT interval prolongation were excluded by protocol.
Table 10 identifies the clinically relevant or severe Grade 3/4 laboratory test abnormalities for the safety population of the study in patients with CML who were resistant or intolerant to prior therapy based on long-term follow-up.
CP CML N=403 % | AdvP CML N=143 % | |||
---|---|---|---|---|
All grade | Grade 3/4 | All grade | Grade 3/4 | |
Abbreviations: AdvP=advanced phase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CML=chronic myelogenous leukemia; CP=chronic phase; N/n=number of patients; SGPT=serum glutamate-pyruvate transaminase; SGOT=serum glutamate-oxaloacetate aminotransferase; ULN=upper limit of normal. | ||||
| ||||
Hematology Parameters | ||||
Platelet Count decreased | 66 | 26 | 80 | 57 |
Absolute Neutrophil Count decreased | 50 | 16 | 66 | 39 |
Hemoglobin decreased | 89 | 13 | 97 | 38 |
Lymphocyte decreased | 79 | 14 | 82 | 21 |
White Blood Cell Count decreased | 51 | 7 | 57 | 27 |
Biochemistry Parameters | ||||
SGPT/ALT increased | 58 | 11 | 39 | 6 |
SGOT/AST increased | 50 | 5 | 37 | 3.5 |
Lipase increased | 32 | 12 | 19 | 6 |
Phosphorus decreased | 41 | 8 | 33 | 7 |
Total Bilirubin increased | 16 | 0.7 | 22 | 2.8 |
Creatinine increased | 95 | 3 | 87 | 1.4 |
Alkaline Phosphatase increased | 39 | 0 | 39 | 1.4 |
Glucose increased | 42 | 2.7 | 39 | 6 |
Sodium increased | 23 | 0.5 | 11 | 0 |
Sodium decreased | 18 | 2.2 | 27 | 6 |
Calcium decreased | 55 | 4.7 | 45 | 3.5 |
Urate increased | 49 | 6 | 43 | 6 |
Magnesium increased | 27 | 7 | 18 | 4.9 |
Potassium decreased | 22 | 1.7 | 29 | 4.9 |
Potassium increased | 25 | 2.7 | 19 | 2.1 |
Pediatric Patients with Newly-Diagnosed CP Ph+ CML or CP Ph+ CML that is Resistant or Intolerant to Prior Therapy
The safety of BOSULIF was evaluated in BCHILD, a single-arm trial for the treatment of pediatric patients aged 1 year and older with newly-diagnosed CP Ph+ CML or in patients with CP Ph+ CML who are resistant or intolerant to prior therapy [see Clinical Studies (14.3)]. Patients received BOSULIF (n = 49) 300 mg/m2 to 400 mg/m2 orally once daily until disease progression or unacceptable toxicity. The median time on treatment with BOSULIF was 12.2 months (range, 0.2 to 60.9 months). Among patients who received BOSULIF, 77.6% were exposed for 6 months or longer and 51% were exposed for one year or longer.
Permanent discontinuation of BOSULIF due to an adverse reaction occurred in 20% of patients. Adverse reactions which resulted in permanent discontinuation in 2 or more patients included ALT increased (6%), AST increased (4%), diarrhea (4%), fatigue (4%) and rash maculo-papular (4%).
The most common adverse reactions, in ≥20% of BOSULIF-treated pediatric patients were diarrhea, abdominal pain, vomiting, nausea, rash, fatigue, hepatic dysfunction, headache, pyrexia, decreased appetite, and constipation.
Table 11 summarizes the adverse reactions in BCHILD.
Adverse drug reactions are based on all-causality treatment-emergent adverse reactions. | |||
The commonality stratification is based on 'All Grades' under Bosutinib 400 mg column. | |||
'Grade 3/4 columns indicate maximum toxicity. | |||
| |||
System Organ Class | Preferred Term | BOSULIF Total % | |
All Grades | Grade 3/4 | ||
Gastrointestinal disorders | Diarrhea | 82 | 12 |
Abdominal pain* | 73 | 4 | |
Vomiting | 55 | 6 | |
Nausea | 49 | 2 | |
Constipation | 20 | 0 | |
Skin and subcutaneous tissue disorders | Rash† | 49 | 8 |
Hepatobiliary disorders | Hepatic dysfunction‡ | 37 | 14 |
General disorders and administration-site conditions | Fatigue§ | 37 | 4 |
Pyrexia | 31 | 4 | |
Nervous system disorders | Headache | 35 | 2 |
Metabolism and nutrition disorders | Decreased appetite | 27 | 2 |
Infections and infestations | Respiratory tract infection¶ | 12 | 2 |
The most common laboratory abnormalities that worsened from baseline in ≥20% of patients were creatinine increased, alanine aminotransferase increased, white blood cell count decreased, aspartate aminotransferase increased, platelet count decreased, glucose increased, calcium decreased, hemoglobin decreased, neutrophil count decreased, lymphocyte count decreased, serum amylase increased and CPK increased.
Table 12 summarizes laboratory test abnormalities in BCHILD.
Grades are defined using CTCAE V4.03. Based on CTCAE grading without regard to fasting status for 'Hyperglycemia' lab parameter. | ||
Includes data up to 28 days after last dose of study treatment. | ||
BOSULIF (N= 49) | ||
All Grade | Grade 3/4 | |
% | % | |
Creatinine increased | 92 | 0 |
Alanine aminotransferase increased | 59 | 14 |
White blood cell count decreased | 53 | 4 |
Aspartate aminotransferase increased | 51 | 6 |
Platelet count decreased | 49 | 18 |
Glucose increased | 41 | 0 |
Calcium decreased | 31 | 0 |
Hemoglobin decreased | 31 | 8 |
Neutrophil count decreased | 31 | 12 |
Lymphocyte count decreased | 29 | 2 |
Serum amylase increased | 27 | 4 |
CPK increased | 25 | 0 |
Additional Adverse Reactions From Multiple Clinical Trials
The following adverse reactions were reported in patients in clinical trials with BOSULIF (less than 10% of BOSULIF-treated patients). They represent an evaluation of the adverse reaction data from all 1372 patients with leukemia who received at least 1 dose of single-agent BOSULIF. These adverse reactions are presented by system organ class and are ranked by frequency. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category.
Blood and Lymphatic System Disorders: 0.1% and less than 1% - Febrile neutropenia
Cardiac Disorders: 1% and less than 10% - Cardiac ischemia (includes Acute coronary syndrome, Acute myocardial infarction, Angina pectoris, Angina unstable, Arteriosclerosis coronary artery, Coronary artery disease, Coronary artery occlusion, Coronary artery stenosis, Myocardial infarction, Myocardial ischemia, Troponin increased), Pericardial effusion, Cardiac failure (includes Cardiac failure, Cardiac failure acute, Cardiac failure chronic, Cardiac failure congestive, Cardiogenic shock, Cardiorenal syndrome, Ejection fraction decreased, Left ventricular failure); 0.1% and less than 1% - Pericarditis
Ear and Labyrinth Disorders: 1% and less than 10% - Tinnitus
Endocrine Disorders: 1% and less than 10% - Hypothyroidism; 0.1% and less than 1% - Hyperthyroidism
Gastrointestinal Disorders: 1% and less than 10% - Gastritis, Pancreatitis (includes Edematous pancreatitis, Pancreatic enzymes increased, Pancreatitis, Pancreatitis acute, Pancreatitis chronic), Gastrointestinal hemorrhage (includes Anal hemorrhage, Gastric hemorrhage, Gastrointestinal hemorrhage, Intestinal hemorrhage, Lower gastrointestinal hemorrhage, Rectal hemorrhage, Upper gastrointestinal hemorrhage)
General Disorders and Administrative Site Conditions: 1% and less than 10% - Pain
Immune System Disorders: 1% and less than 10% - Drug hypersensitivity; 0.1% and less than 1% - Anaphylactic shock
Infections and Infestations: 1% and less than 10% - Bronchitis
Investigations: 1% and less than 10% - Electrocardiogram QT prolonged (includes Electrocardiogram QT prolonged, Long QT syndrome)
Metabolism and Nutrition Disorders: 1% and less than 10% - Dehydration
Musculoskeletal and Connective Tissue Disorders: 1% and less than 10% - Myalgia
Nervous System Disorders: 1% and less than 10% - Dysgeusia
Renal and Urinary Disorders: 1% and less than 10% - Acute kidney injury, Renal impairment, Renal failure
Respiratory, Thoracic and Mediastinal Disorders: 1% and less than 10% - Pulmonary hypertension (includes Pulmonary hypertension, Pulmonary arterial hypertension, Pulmonary arterial pressure increased); 0.1% and less than 1% - Acute pulmonary edema (includes Acute pulmonary edema, Pulmonary edema), Interstitial lung disease, Respiratory failure
Skin and Subcutaneous Disorders: 0.1% and less than 1% - Erythema multiforme
The following additional adverse reactions have been identified during post-approval use of BOSULIF. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and Lymphatic System Disorders: Thrombotic microangiopathy
Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome
The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:
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 most common adverse reactions, in ≥20% of adults with newly diagnosed CP Ph+ CML or CP, AP, or BP Ph+ CML with resistance or intolerance to prior therapy (N=814) were diarrhea (80%), rash (44%), nausea (44%), abdominal pain (43%), vomiting (33%), fatigue (33%), hepatic dysfunction (33%), respiratory tract infection (25%), pyrexia (24%), and headache (21%).
The most common laboratory abnormalities that worsened from baseline in ≥20% of adults were creatinine increased (93%), hemoglobin decreased (90%), lymphocyte count decreased (72%), platelets decreased (69%), ALT increased (58%), calcium decreased (53%), white blood cell count decreased (52%), absolute neutrophils count decreased (50%), AST increased (50%), glucose increased (46%), phosphorus decreased (44%), urate increased (41%), alkaline phosphatase increased (40%), lipase increased (36%), creatine kinase increased (29%), and amylase increased (24%).
The most common adverse reactions, in ≥20% of pediatric patients (N=49) were diarrhea (82%), abdominal pain (73%), vomiting (55%), nausea (49%), rash (49%), fatigue (37%), hepatic dysfunction (37%), headache (35%), pyrexia (31%), decreased appetite (27%), and constipation (20%).
The most common laboratory abnormalities that worsened from baseline in ≥20% of pediatric patients were creatinine increased (92%), alanine aminotransferase increased (59%), white blood cell count decreased (53%), aspartate aminotransferase increased (51%), platelet count decreased (49%), glucose increased (41%), calcium decreased (31%), hemoglobin decreased (31%), neutrophil count decreased (31%), lymphocyte count decreased (29%), serum amylase increased (27%), and CPK increased (25%).
Adverse Reactions in Adult Patients With Newly-Diagnosed CP CML
The clinical trial randomized and treated 533 patients with newly-diagnosed CP CML to receive BOSULIF 400 mg daily or imatinib 400 mg daily as single agents (Newly-Diagnosed CP CML Study) [see Clinical Studies (14.1)]. The safety population (received at least 1 dose of BOSULIF) included:
Serious adverse reactions occurred in 22% of patients with newly-diagnosed CP CML who received bosutinib. Serious adverse reactions reported in >2% of patients included hepatic dysfunction (4.1%), pneumonia (3.4%), coronary artery disease (3.4%), and gastroenteritis (2.2%). Fatal adverse reactions occurred in 3 patients (1.1%) due to coronary artery disease (0.4%), cardiac failure acute (0.4%), and renal failure (0.4%).
Permanent discontinuation of bosutinib due to an adverse reaction occurred in 20% of patients with newly-diagnosed CP CML who received bosutinib. Adverse reactions which resulted in permanent discontinuation in > 2% of patients included hepatic dysfunction (9%).
Dose modifications (dose interruption or reductions) of bosutinib due to an adverse reaction occurred in 68% of patients with newly-diagnosed CP CML. Adverse reactions which required dose interruptions or reductions in >5% of patients included hepatic dysfunction (27%), thrombocytopenia (16%), diarrhea (16%), lipase increased (10%), neutropenia (7%), abdominal pain (6%), rash (5%).
The most common adverse reactions, in >20% of bosutinib-treated patients with newly-diagnosed CML (N=268) were diarrhea (75%), hepatic dysfunction (45%), rash (40%), abdominal pain (39%), nausea (37%), fatigue (33%), respiratory tract infection (27%), headache (22%), and vomiting (21%).
The most common laboratory abnormalities that worsened from baseline in ≥20% of patients were creatinine increased (94%), hemoglobin decreased (89%), lymphocyte count decreased (84%), ALT increased (68%), platelet count decreased (68%), glucose increased (57%), AST increased (56%), calcium decreased (55%), phosphorus decreased (54%), lipase increased (53%), white blood cell count decreased (50%), absolute neutrophil count decreased (42%), alkaline phosphatase increased (41%), creatine kinase increased (36%), and amylase increased (32%).
Table 7 identifies adverse reactions greater than or equal to 10% for All Grades and Grades 3 or 4 (3/4) for the Phase 3 CP CML safety population.
Bosutinib 400 mg Chronic Phase CML (N=268) | Imatinib 400 mg Chronic Phase CML (N=265) | ||||
---|---|---|---|---|---|
| |||||
System Organ Class | Preferred Term | All Grades | Grade 3/4 | All Grades | Grade 3/4 |
Gastrointestinal disorders | Diarrhea | 75 | 9 | 40 | 1 |
Abdominal pain† | 39 | 2 | 27 | 1 | |
Nausea | 37 | 0 | 42 | 0 | |
Vomiting | 21 | 1 | 20 | 0 | |
Constipation | 13 | 0 | 6 | 0 | |
Hepatobiliary disorders | Hepatic dysfunction‡ | 45 | 27 | 15 | 4 |
Skin and subcutaneous tissue disorders | Rash§ | 40 | 2 | 30 | 2 |
Pruritus | 11 | <1 | 4 | 0 | |
General disorders and administration-site conditions | Fatigue¶ | 33 | 1 | 30 | <1 |
Pyrexia | 17 | 1 | 11 | 0 | |
Edema# | 15 | 0 | 46 | 2 | |
Infections and infestations | Respiratory tract infectionÞ | 27 | 1 | 25 | <1 |
Nervous system disorders | Headache | 22 | 1 | 15 | 1 |
Musculoskeletal and connective tissue disorders | Arthralgia | 18 | 1 | 18 | <1 |
Back pain | 12 | <1 | 9 | <1 | |
Respiratory, thoracic, and mediastinal disorders | Cough | 11 | 0 | 10 | 0 |
Dyspnea | 11 | 1 | 6 | 1 | |
Metabolism and nutrition disorders | Decreased appetite | 11 | <1 | 6 | 0 |
Vascular disorders | Hypertensionß | 10 | 5 | 11 | 5 |
In the randomized study in patients with newly-diagnosed CP CML, one patient in the group treated with BOSULIF experienced a Grade 3 QTcF prolongation (>500 msec). Patients with uncontrolled or significant cardiovascular disease including QT interval prolongation were excluded by protocol.
Table 8 identifies the clinically relevant or severe Grade 3/4 laboratory test abnormalities for the Phase 3 newly-diagnosed CML safety population.
Bosutinib N=268 % | Imatinib N=265 % | |||
---|---|---|---|---|
All Grade | Grade 3–4 | All Grade | Grade 3–4 | |
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; CML=chronic myelogenous leukemia; SGPT=serum glutamic-pyruvic transaminase; SGOT=serum glutamic-oxaloacetic transaminase; N/n=number of patients; ULN=upper limit of normal. Graded using CTCAE v 4.03 | ||||
| ||||
Hematology Parameters | ||||
Platelet Count decreased | 68 | 14 | 60 | 6 |
Absolute Neutrophil Count decreased | 42 | 9 | 65 | 20 |
Hemoglobin decreased | 89 | 9 | 90 | 7 |
White Blood Cell Count decreased | 50 | 6 | 70 | 8 |
Lymphocyte Count decreased | 84 | 12 | 82 | 14 |
Biochemistry Parameters | ||||
SGPT/ALT increased | 68 | 26 | 28 | 3 |
SGOT/AST increased | 56 | 13 | 29 | 3.4 |
Lipase increased | 53 | 19 | 35 | 8 |
Phosphorus decreased | 54 | 9 | 69 | 21 |
Amylase increased | 32 | 3.4 | 18 | 2.3 |
Alkaline Phosphatase increased | 41 | 0 | 43 | 0.4 |
Calcium decreased | 55 | 1.5 | 57 | 1.1 |
Glucose increased | 57 | 3 | 65 | 3.4 |
Creatine Kinase increased | 36 | 3 | 65 | 5 |
Creatinine increased | 94 | 1.1 | 98 | 0.8 |
Adverse Reactions in Adult Patients With Imatinib-Resistant or -Intolerant Ph+ CP, AP, and BP CML
The single-arm clinical trial enrolled patients with Ph+ CP, AP, or BP CML and with resistance or intolerance to prior therapy [see Clinical Studies (14.2)]. The safety population (received at least 1 dose of BOSULIF) included 546 CML patients:
Serious adverse reactions occurred in 30% of patients in the safety population of the single-arm trial in patients with CML (N=546) who were resistant or intolerant to prior therapy. Serious adverse reactions reported in >2% of patients included pneumonia (7%), pleural effusion (6%), pyrexia (3.7%), coronary artery disease (3.5%), dyspnea (2.6%), rash (2.2%), thrombocytopenia (2%), abdominal pain (2%), and diarrhea (2%).
Fatal adverse reactions occurred in 12 patients (2.2%) due to coronary artery disease (0.9%), pneumonia (0.4%), respiratory failure (0.4%), gastrointestinal hemorrhage (0.2%), acute kidney injury (0.2%), and acute pulmonary edema (0.2%).
Permanent discontinuation of bosutinib due to an adverse reaction occurred in 22% of patients with CML who were resistant or intolerant to prior therapy. Adverse reactions which resulted in permanent discontinuation in >2% of patients included thrombocytopenia (6%), hepatic dysfunction (3.3%), and neutropenia (2%).
Dose modifications (dose interruption or reductions) of bosutinib due to an adverse reaction occurred in 66% of patients with CML who were resistant or intolerant to prior therapy. Adverse reactions which required dose interruptions or reductions in >5% of patients included thrombocytopenia (24%), diarrhea (14%), rash (13%), hepatic dysfunction (10%), neutropenia (9%), pleural effusion (8%), vomiting (7%), anemia (6%), and abdominal pain (6%).
The most common adverse reactions, in ≥20% of patients in the safety population of the single-arm trial in patients with CML (N=546) who were resistant or intolerant to prior therapy were diarrhea (83%), nausea (47%), rash (46%), abdominal pain (45%), vomiting (39%), fatigue (33%), pyrexia (28%), hepatic dysfunction (27%), respiratory tract infection (24%), cough (23%), and headache (21%).
The most common laboratory abnormalities that worsened from baseline in ≥20% were creatinine increased (93%), hemoglobin decreased (91%), lymphocyte decreased (80%), platelets decreased (69%), absolute neutrophil count (54%), ALT increased (53%), calcium decreased (53%), white blood cell count decreased (52%), urate increased (48%), AST increased (47%), phosphorus decreased (39%), alkaline phosphatase increased (39%), lipase increased (28%), magnesium increased (25%), potassium decreased (24%), potassium increased (23%). See Table 10 for Grade 3/4 laboratory abnormalities.
Table 9 identifies adverse reactions greater than or equal to 10% for All Grades and Grades 3 or 4 for the Phase 1/2 CML safety population based on long-term follow-up.
CP CML (N=403) | AdvP CML (N=143) | ||||
---|---|---|---|---|---|
System Organ Class | Preferred Term | All Grades % | Grade 3/4 % | All Grades % | Grade 3/4 % |
ADR Definition | |||||
| |||||
Gastrointestinal disorders | Diarrhea | 85 | 10 | 76 | 4 |
Abdominal pain† | 49 | 2 | 36 | 7 | |
Nausea | 47 | 1 | 48 | 2 | |
Vomiting | 38 | 3 | 43 | 3 | |
Constipation | 15 | <1 | 17 | 1 | |
Skin and subcutaneous tissue disorders | Rash‡ | 48 | 9 | 42 | 5 |
Pruritus | 12 | 1 | 7 | 0 | |
General disorders and administration-site conditions | Fatigue | 35 | 3 | 27 | 6 |
Pyrexia | 25 | 1 | 37 | 3 | |
Edema§ | 19 | <1 | 17 | 1 | |
Chest pain¶ | 8 | 1 | 12 | 1 | |
Hepatobiliary disorders | Hepatic dysfunction# | 29 | 11 | 21 | 10 |
Infections and infestations | Respiratory tract infectionÞ | 27 | <1 | 17 | 0 |
Influenzaß | 11 | 1 | 3 | 0 | |
Pneumoniaà | 10 | 4 | 18 | 12 | |
Respiratory, thoracic, and mediastinal disorders | Cough | 24 | 0 | 22 | 0 |
Pleural effusion | 14 | 4 | 9 | 4 | |
Dyspnea | 12 | 2 | 20 | 6 | |
Nervous system disorders | Headache | 21 | 1 | 18 | 4 |
Dizziness | 11 | 0 | 14 | 1 | |
Musculoskeletal and connective tissue disorders | Arthralgia | 19 | 1 | 15 | 0 |
Back pain | 14 | 1 | 8 | 1 | |
Metabolism and nutrition disorders | Decreased appetite | 14 | 1 | 14 | 0 |
Vascular disorders | Hypertensionè | 11 | 3 | 8 | 3 |
In the single-arm study in patients with CML who were resistant or intolerant to prior therapy, 2 patients (0.4%) experienced QTcF interval of greater than 500 milliseconds. Patients with uncontrolled or significant cardiovascular disease including QT interval prolongation were excluded by protocol.
Table 10 identifies the clinically relevant or severe Grade 3/4 laboratory test abnormalities for the safety population of the study in patients with CML who were resistant or intolerant to prior therapy based on long-term follow-up.
CP CML N=403 % | AdvP CML N=143 % | |||
---|---|---|---|---|
All grade | Grade 3/4 | All grade | Grade 3/4 | |
Abbreviations: AdvP=advanced phase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CML=chronic myelogenous leukemia; CP=chronic phase; N/n=number of patients; SGPT=serum glutamate-pyruvate transaminase; SGOT=serum glutamate-oxaloacetate aminotransferase; ULN=upper limit of normal. | ||||
| ||||
Hematology Parameters | ||||
Platelet Count decreased | 66 | 26 | 80 | 57 |
Absolute Neutrophil Count decreased | 50 | 16 | 66 | 39 |
Hemoglobin decreased | 89 | 13 | 97 | 38 |
Lymphocyte decreased | 79 | 14 | 82 | 21 |
White Blood Cell Count decreased | 51 | 7 | 57 | 27 |
Biochemistry Parameters | ||||
SGPT/ALT increased | 58 | 11 | 39 | 6 |
SGOT/AST increased | 50 | 5 | 37 | 3.5 |
Lipase increased | 32 | 12 | 19 | 6 |
Phosphorus decreased | 41 | 8 | 33 | 7 |
Total Bilirubin increased | 16 | 0.7 | 22 | 2.8 |
Creatinine increased | 95 | 3 | 87 | 1.4 |
Alkaline Phosphatase increased | 39 | 0 | 39 | 1.4 |
Glucose increased | 42 | 2.7 | 39 | 6 |
Sodium increased | 23 | 0.5 | 11 | 0 |
Sodium decreased | 18 | 2.2 | 27 | 6 |
Calcium decreased | 55 | 4.7 | 45 | 3.5 |
Urate increased | 49 | 6 | 43 | 6 |
Magnesium increased | 27 | 7 | 18 | 4.9 |
Potassium decreased | 22 | 1.7 | 29 | 4.9 |
Potassium increased | 25 | 2.7 | 19 | 2.1 |
Pediatric Patients with Newly-Diagnosed CP Ph+ CML or CP Ph+ CML that is Resistant or Intolerant to Prior Therapy
The safety of BOSULIF was evaluated in BCHILD, a single-arm trial for the treatment of pediatric patients aged 1 year and older with newly-diagnosed CP Ph+ CML or in patients with CP Ph+ CML who are resistant or intolerant to prior therapy [see Clinical Studies (14.3)]. Patients received BOSULIF (n = 49) 300 mg/m2 to 400 mg/m2 orally once daily until disease progression or unacceptable toxicity. The median time on treatment with BOSULIF was 12.2 months (range, 0.2 to 60.9 months). Among patients who received BOSULIF, 77.6% were exposed for 6 months or longer and 51% were exposed for one year or longer.
Permanent discontinuation of BOSULIF due to an adverse reaction occurred in 20% of patients. Adverse reactions which resulted in permanent discontinuation in 2 or more patients included ALT increased (6%), AST increased (4%), diarrhea (4%), fatigue (4%) and rash maculo-papular (4%).
The most common adverse reactions, in ≥20% of BOSULIF-treated pediatric patients were diarrhea, abdominal pain, vomiting, nausea, rash, fatigue, hepatic dysfunction, headache, pyrexia, decreased appetite, and constipation.
Table 11 summarizes the adverse reactions in BCHILD.
Adverse drug reactions are based on all-causality treatment-emergent adverse reactions. | |||
The commonality stratification is based on 'All Grades' under Bosutinib 400 mg column. | |||
'Grade 3/4 columns indicate maximum toxicity. | |||
| |||
System Organ Class | Preferred Term | BOSULIF Total % | |
All Grades | Grade 3/4 | ||
Gastrointestinal disorders | Diarrhea | 82 | 12 |
Abdominal pain* | 73 | 4 | |
Vomiting | 55 | 6 | |
Nausea | 49 | 2 | |
Constipation | 20 | 0 | |
Skin and subcutaneous tissue disorders | Rash† | 49 | 8 |
Hepatobiliary disorders | Hepatic dysfunction‡ | 37 | 14 |
General disorders and administration-site conditions | Fatigue§ | 37 | 4 |
Pyrexia | 31 | 4 | |
Nervous system disorders | Headache | 35 | 2 |
Metabolism and nutrition disorders | Decreased appetite | 27 | 2 |
Infections and infestations | Respiratory tract infection¶ | 12 | 2 |
The most common laboratory abnormalities that worsened from baseline in ≥20% of patients were creatinine increased, alanine aminotransferase increased, white blood cell count decreased, aspartate aminotransferase increased, platelet count decreased, glucose increased, calcium decreased, hemoglobin decreased, neutrophil count decreased, lymphocyte count decreased, serum amylase increased and CPK increased.
Table 12 summarizes laboratory test abnormalities in BCHILD.
Grades are defined using CTCAE V4.03. Based on CTCAE grading without regard to fasting status for 'Hyperglycemia' lab parameter. | ||
Includes data up to 28 days after last dose of study treatment. | ||
BOSULIF (N= 49) | ||
All Grade | Grade 3/4 | |
% | % | |
Creatinine increased | 92 | 0 |
Alanine aminotransferase increased | 59 | 14 |
White blood cell count decreased | 53 | 4 |
Aspartate aminotransferase increased | 51 | 6 |
Platelet count decreased | 49 | 18 |
Glucose increased | 41 | 0 |
Calcium decreased | 31 | 0 |
Hemoglobin decreased | 31 | 8 |
Neutrophil count decreased | 31 | 12 |
Lymphocyte count decreased | 29 | 2 |
Serum amylase increased | 27 | 4 |
CPK increased | 25 | 0 |
Additional Adverse Reactions From Multiple Clinical Trials
The following adverse reactions were reported in patients in clinical trials with BOSULIF (less than 10% of BOSULIF-treated patients). They represent an evaluation of the adverse reaction data from all 1372 patients with leukemia who received at least 1 dose of single-agent BOSULIF. These adverse reactions are presented by system organ class and are ranked by frequency. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category.
Blood and Lymphatic System Disorders: 0.1% and less than 1% - Febrile neutropenia
Cardiac Disorders: 1% and less than 10% - Cardiac ischemia (includes Acute coronary syndrome, Acute myocardial infarction, Angina pectoris, Angina unstable, Arteriosclerosis coronary artery, Coronary artery disease, Coronary artery occlusion, Coronary artery stenosis, Myocardial infarction, Myocardial ischemia, Troponin increased), Pericardial effusion, Cardiac failure (includes Cardiac failure, Cardiac failure acute, Cardiac failure chronic, Cardiac failure congestive, Cardiogenic shock, Cardiorenal syndrome, Ejection fraction decreased, Left ventricular failure); 0.1% and less than 1% - Pericarditis
Ear and Labyrinth Disorders: 1% and less than 10% - Tinnitus
Endocrine Disorders: 1% and less than 10% - Hypothyroidism; 0.1% and less than 1% - Hyperthyroidism
Gastrointestinal Disorders: 1% and less than 10% - Gastritis, Pancreatitis (includes Edematous pancreatitis, Pancreatic enzymes increased, Pancreatitis, Pancreatitis acute, Pancreatitis chronic), Gastrointestinal hemorrhage (includes Anal hemorrhage, Gastric hemorrhage, Gastrointestinal hemorrhage, Intestinal hemorrhage, Lower gastrointestinal hemorrhage, Rectal hemorrhage, Upper gastrointestinal hemorrhage)
General Disorders and Administrative Site Conditions: 1% and less than 10% - Pain
Immune System Disorders: 1% and less than 10% - Drug hypersensitivity; 0.1% and less than 1% - Anaphylactic shock
Infections and Infestations: 1% and less than 10% - Bronchitis
Investigations: 1% and less than 10% - Electrocardiogram QT prolonged (includes Electrocardiogram QT prolonged, Long QT syndrome)
Metabolism and Nutrition Disorders: 1% and less than 10% - Dehydration
Musculoskeletal and Connective Tissue Disorders: 1% and less than 10% - Myalgia
Nervous System Disorders: 1% and less than 10% - Dysgeusia
Renal and Urinary Disorders: 1% and less than 10% - Acute kidney injury, Renal impairment, Renal failure
Respiratory, Thoracic and Mediastinal Disorders: 1% and less than 10% - Pulmonary hypertension (includes Pulmonary hypertension, Pulmonary arterial hypertension, Pulmonary arterial pressure increased); 0.1% and less than 1% - Acute pulmonary edema (includes Acute pulmonary edema, Pulmonary edema), Interstitial lung disease, Respiratory failure
Skin and Subcutaneous Disorders: 0.1% and less than 1% - Erythema multiforme
The following additional adverse reactions have been identified during post-approval use of BOSULIF. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and Lymphatic System Disorders: Thrombotic microangiopathy
Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome
{{section_body_html_patient}}
Chat online with Pfizer Medical Information regarding your inquiry on a Pfizer medicine.
*Speak with a Pfizer Medical Information Professional regarding your medical inquiry. Available 9AM-5PM ET Monday to Friday; excluding holidays.
Submit a medical question for Pfizer prescription products.
Pfizer Safety
To report an adverse event related to the Pfizer-BioNTech COVID-19 Vaccine, and you are not part of a clinical trial* for this product, click the link below to submit your information:
Pfizer Safety Reporting Site*If you are involved in a clinical trial for this product, adverse events should be reported to your coordinating study site.
If you cannot use the above website, or would like to report an adverse event related to a different Pfizer product, please call Pfizer Safety at (800) 438-1985.
FDA Medwatch
You may also contact the U.S. Food and Drug Administration (FDA) directly to report adverse events or product quality concerns either online at www.fda.gov/medwatch or call (800) 822-7967.