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)].
- Cardiac Failure [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.
Serious adverse reactions reported include anaphylactic shock [see Contraindications (4)], myelosuppression, gastrointestinal toxicity (diarrhea), fluid retention, hepatotoxicity and rash.
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 14.1 months (range: 0.3 to 24.7 months) and a median dose intensity of 391.8 mg/day.
Adverse reactions reported for greater than or equal to 20% of bosutinib patients with newly-diagnosed CML (N=268) were diarrhea (70%), nausea (35%), thrombocytopenia (35%), rash (34%), increased ALT (31%), abdominal pain (25%), and increased AST (23%) [see Clinical Studies (14.1)].
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.
| Adverse Reaction | Bosutinib 400 mg Chronic Phase CML N=268 | Imatinib 400 mg Chronic Phase CML N=265 | ||
|---|---|---|---|---|
| All Grades (%) | Grade 3/4 (%) | All Grades (%) | Grade 3/4 (%) | |
| Abbreviation: CML=Chronic myelogenous leukemia, N=number of patients. | ||||
| ||||
| Diarrhea | 70 | 8 | 34 | <1 |
| Nausea | 35 | 0 | 38 | 0 |
| Thrombocytopenia* | 35 | 14 | 20 | 6 |
| Rash† | 34 | 1 | 21 | 2 |
| Alanine aminotransferase increased | 31 | 19 | 6 | 2 |
| Abdominal pain‡ | 25 | 2 | 15 | <1 |
| Aspartate aminotransferase increased | 23 | 10 | 6 | 2 |
| Anemia§ | 19 | 3 | 19 | 5 |
| Headache | 19 | 1 | 13 | 1 |
| Fatigue¶ | 19 | <1 | 19 | 0 |
| Vomiting | 18 | 1 | 16 | 0 |
| Lipase increased# | 13 | 10 | 8 | 5 |
| Pyrexia | 13 | <1 | 8 | 0 |
| Respiratory tract infectionÞ | 12 | <1 | 12 | <1 |
| Neutropeniaß | 11 | 7 | 21 | 12 |
| Arthralgia | 11 | <1 | 13 | 0 |
| Asthenia | 11 | 0 | 6 | 0 |
| Appetite decreased | 10 | <1 | 6 | 0 |
In the randomized study in patients with newly-diagnosed CP CML, one patient in the group treated with BOSULIF experienced a Grade 3 QTc 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 Chronic Phase CML N=268 n (%) | Imatinib Chronic Phase CML N=265 n (%) | |
|---|---|---|
| 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. | ||
| Hematology Parameters | ||
| Platelet Count (Low) less than 50×109/L | 38 (14.2) | 17 (6.4) |
| Absolute Neutrophil Count less than 1×109/L | 24 (9.0) | 49 (18.5) |
| Hemoglobin (Low) less than 80 g/L | 19 (7.1) | 15 (5.7) |
| White Blood Cell Count (Low) less than 2×109/L | 15 (5.6) | 20 (7.5) |
| Biochemistry Parameters | ||
| SGPT/ALT greater than 5.0×ULN | 62 (23.1) | 7 (2.6) |
| SGOT/AST greater than 5.0×ULN | 32 (11.9) | 8 (3.0) |
| Lipase greater than 2×ULN | 35 (13.1) | 16 (6.0) |
| Phosphorus (Low) less than 0.6 mmol/L | 12 (4.5) | 45 (17.0) |
| Total Bilirubin greater than 3.0×ULN | 3 (1.1) | 2 (0.8) |
| Amylase greater than 2×ULN | 6 (2.2) | 4 (1.5) |
| Creatinine greater than 3.0×baseline; greater than 3.0×ULN | 0 | 2 (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)]. 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, and a median dose intensity of 442 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 and a median dose intensity of 442 mg/day.
- one hundred forty-three (143) patients with advanced phase 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 and 3 months, respectively. The median dose intensity was 425 mg/day, and 456 mg/day, in the AP CML and BP CML cohorts, respectively.
Adverse reactions of any toxicity grade reported for greater than or equal to 20% of patients in the safety population of the single-arm trial in patients with CP CML (N=546) who were resistant or intolerant to prior therapy were diarrhea (85%), nausea (47%), abdominal pain (42%), rash (42%), thrombocytopenia (40%), vomiting (37%), anemia (27%), fatigue (26%), pyrexia (23%), cough (22%), headache (21%), ALT (20%), and edema (20%) [see Clinical Studies (14.2)].
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.
| Chronic Phase CML N=403 | Advanced Phase CML N=143 | |||
|---|---|---|---|---|
| All Grades (%) | Grade 3/4 (%) | All Grades (%) | Grade 3/4 (%) | |
| Abbreviations: CML=chronic myelogenous leukemia; N=number of patients. | ||||
| Advanced Phase CML includes patients with Accelerated Phase and Blast Phase CML. | ||||
| ||||
| Diarrhea | 85 | 9 | 76 | 4 |
| Nausea | 47 | 1 | 48 | 2 |
| Abdominal Pain† | 42 | 2 | 31 | 6 |
| Rash‡ | 42 | 9 | 38 | 5 |
| Thrombocytopenia§ | 40 | 26 | 45 | 39 |
| Vomiting | 37 | 3 | 43 | 3 |
| Anemia¶ | 27 | 11 | 38 | 27 |
| Fatigue# | 26 | 2 | 21 | 5 |
| Pyrexia | 23 | <1 | 37 | 2 |
| Cough | 22 | 0 | 22 | 0 |
| Headache | 21 | <1 | 17 | 4 |
| Alanine aminotransferase increased | 20 | 8 | 10 | 5 |
| NeutropeniaÞ | 18 | 12 | 22 | 20 |
| Arthralgia | 17 | <1 | 14 | 0 |
| Aspartate aminotransferase increased | 16 | 3 | 11 | 3 |
| Edemaß | 20 | 1 | 17 | 2 |
| Respiratory tract infectionà | 15 | <1 | 10 | 0 |
| Decreased appetite | 14 | <1 | 13 | 0 |
| Back pain | 13 | <1 | 8 | 1 |
| Nasopharyngitis | 13 | 0 | 6 | 0 |
| Asthenia | 13 | 2 | 10 | <1 |
| Pleural effusion | 12 | 4 | 9 | 4 |
| Dyspnea | 12 | 2 | 20 | 6 |
| Pruritus | 12 | <1 | 7 | 0 |
| Dizziness | 11 | 0 | 13 | <1 |
| Leukopeniaè | 10 | 4 | 15 | 12 |
| Blood creatinine increased | 10 | <1 | 6 | <1 |
| Influenza | 10 | <1 | 3 | 0 |
| Chest painð | 7 | 1 | 12 | 1 |
In the single-arm study in patients with CML who were resistant or intolerant to prior therapy, 1 patient (0.2%) 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.
| Chronic Phase (CP) CML N=403 n (%) | Advanced Phase (AdvP) CML N=143 n (%) | All CP and AdvP CML N=546 n (%) | |
|---|---|---|---|
| Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; CML=chronic myelogenous leukemia; N/n=number of patients; SGPT=serum glutamate-pyruvate transaminase; SGOT=serum glutamate-oxaloacetate aminotransferase; ULN=upper limit of normal. | |||
| |||
| Hematology Parameters | |||
| Platelet Count (Low) less than 50×109/L | 105 (26) | 82 (57) | 187 (34) |
| Absolute Neutrophil Count less than 1×109/L | 65 (16) | 55 (39) | 120 (22) |
| Hemoglobin (Low) less than 80 g/L | 51 (13) | 54 (38) | 105 (19) |
| Biochemistry Parameters | |||
| SGPT/ALT greater than 5.0×ULN | 43 (11) | 8 (6) | 51 (9) |
| SGOT/AST greater than 5.0×ULN | 19 (5) | 5 (4) | 24 (4) |
| Lipase greater than 2×ULN | 42 (10) | 9 (6) | 51 (9) |
| Phosphorus (Low) less than 0.6 mmol/L | 30 (7) | 10 (7) | 40 (7) |
| Total Bilirubin greater than 3.0×ULN | 3 (1) | 4 (3) | 7 (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 1272 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: less than 0.01% - Febrile neutropenia, Granulocytopenia
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
Vascular Disorders: 1% and less than 10% - Hypertension
Gastrointestinal Disorders: 1% and less than 10% - Gastritis; 0.1% and less than 1% - Pancreatitis (includes Pancreatitis, Pancreatitis acute), Gastrointestinal hemorrhage (includes Anal hemorrhage, Gastric hemorrhage, Gastrointestinal hemorrhage, Intestinal hemorrhage, Lower gastrointestinal hemorrhage, Rectal hemorrhage)
General Disorders and Administrative Site Conditions: 1% and less than 10% - Pain
Hepatobiliary Disorders: 1% and less than 10% - Hepatotoxicity (includes Hepatotoxicity, Hepatitis, Hepatitis toxic, Liver disorder), Hepatic function abnormal (includes Hepatic function abnormal, Liver function test abnormal, Transaminases increased); 0.1% and less than 1% - Liver injury (includes Liver injury, Drug-induced liver injury)
Immune System Disorders: 0.1% and less than 1% - Anaphylactic shock, Drug hypersensitivity
Infections and Infestations: 1% and less than 10% - pneumonia (includes pneumonia, atypical pneumonia), influenza, bronchitis
Investigations: 1% and less than 10% - Electrocardiogram QT prolonged (includes Electrocardiogram QT prolonged, Long QT syndrome), Blood bilirubin increased (includes Blood bilirubin increased, Hyperbilirubinaemia), Blood creatine phosphokinase increased, Amylase increased, GGT increased
Metabolism and Nutrition Disorders: 1% and less than 10% - Hypophosphatemia (includes Hypophosphatemia, Blood phosphorus decreased), Hyperkalemia (includes Hyperkalemia, Blood potassium increased), 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, Acute renal failure, Renal failure
Respiratory, Thoracic and Mediastinal Disorders: 0.1% and less than 1% - Acute pulmonary edema, Respiratory failure, Pulmonary hypertension
Skin and Subcutaneous Disorders: 0.1% and less than 1% - Erythema multiforme
6.2 Post-Marketing 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