6 ADVERSE REACTIONS
The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:
- Gastrointestinal toxicity [see Warnings and Precautions (5.1)].
- Myelosuppression [see Warnings and Precautions (5.2)].
- Hepatic toxicity [see Warnings and Precautions (5.3)].
- Cardiovascular toxicity [see Warnings and Precautions (5.4)]
- Fluid retention [see Warnings and Precautions (5.5)].
- Renal toxicity [see Warnings and Precautions (5.6)].
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.
The most common adverse reactions, in ≥20% of patients 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 patients 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%).
Adverse Reactions in 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:
- two hundred sixty-eight (268) patients with newly-diagnosed CP CML had a median duration of BOSULIF treatment of 55 months (range: 0.3 to 60 months) and a median dose intensity of 394 mg/day.
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 4 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 5 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 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:
- two hundred eighty-four (284) patients with CP CML previously treated with imatinib only who had a median duration of BOSULIF treatment of 26 months (range: 0.2 to 155 months), and a median dose intensity of 437 mg/day.
- one hundred nineteen (119) patients with CP CML previously treated with both imatinib and at least 1 additional tyrosine kinase inhibitor (TKI) who had a median duration of BOSULIF treatment of 9 months (range: 0.2 to 148 months) and a median dose intensity of 427 mg/day.
- one hundred forty-three (143) patients with advanced phase (AdvP) CML including 79 patients with AP CML and 64 patients with BP CML. In the patients with AP CML and BP CML, the median duration of BOSULIF treatment was 10 months (range: 0.1 to 140 months) and 3 months (range: 0.03 to 71 months), respectively. The median dose intensity was 406 mg/day, and 456 mg/day, in the AP CML and BP CML cohorts, respectively.
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 7 for Grade 3/4 laboratory abnormalities.
Table 6 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 7 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 |
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% - Pericardial effusion; 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), Respiratory failure
Skin and Subcutaneous Disorders: 0.1% and less than 1% - Erythema multiforme
6.2 Postmarketing Experience
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