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BOSULIF® (bosutinib) Adverse Reactions

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:

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.

Table 4: Adverse Reactions (10% or Greater) in Patients With Newly-Diagnosed CML in Bosutinib 400 mg Study
Adverse ReactionBosutinib 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.
*
Thrombocytopenia includes the following preferred terms: Platelet count decreased, Thrombocytopenia.
Rash includes the following preferred terms: Acne, Dermatitis, Dermatitis acneiform, Dermatitis allergic, Dermatitis exfoliative, Drug reaction with eosinophilia and systemic symptoms, Photosensitivity reaction, Rash, Rash erythematous, Rash generalised, Rash macular, Rash maculo-papular, Rash papular, Rash pruritic, Urticaria.
Abdominal pain includes the following preferred terms: Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Gastrointestinal pain.
§
Anemia includes the following preferred terms: Anemia, Hemoglobin decreased
Fatigue includes the following preferred terms: Fatigue, Malaise.
#
Lipase increased includes the following preferred terms: Hyperlipasemia, Lipase increased.
Þ
Respiratory tract infection includes the following preferred terms: Lower respiratory tract infection, Respiratory tract infection, Respiratory tract infection viral, Upper respiratory tract infection, Viral upper respiratory tract infection.
ß
Neutropenia includes the following preferred terms: Neutropenia, Neutrophil count decreased.
Diarrhea70834<1
Nausea350380
Thrombocytopenia*3514206
Rash341212
Alanine aminotransferase increased311962
Abdominal pain25215<1
Aspartate aminotransferase increased231062
Anemia§193195
Headache191131
Fatigue19<1190
Vomiting181160
Lipase increased#131085
Pyrexia13<180
Respiratory tract infectionÞ12<112<1
Neutropeniaß1172112
Arthralgia11<1130
Asthenia11060
Appetite decreased10<160

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.

Table 5: Number (%) of Patients With Clinically Relevant or Grade 3/4 Laboratory Test Abnormalities in Patients With Newly-Diagnosed CML in Bosutinib 400 mg Study, 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/L38 (14.2)17 (6.4)
  Absolute Neutrophil Count less than 1×109/L24 (9.0)49 (18.5)
  Hemoglobin (Low) less than 80 g/L19 (7.1)15 (5.7)
  White Blood Cell Count (Low) less than 2×109/L15 (5.6)20 (7.5)
 
Biochemistry Parameters
  SGPT/ALT greater than 5.0×ULN62 (23.1)7 (2.6)
  SGOT/AST greater than 5.0×ULN32 (11.9)8 (3.0)
  Lipase greater than 2×ULN35 (13.1)16 (6.0)
  Phosphorus (Low) less than 0.6 mmol/L12 (4.5)45 (17.0)
  Total Bilirubin greater than 3.0×ULN3 (1.1)2 (0.8)
  Amylase greater than 2×ULN6 (2.2)4 (1.5)
  Creatinine greater than 3.0×baseline; greater than 3.0×ULN02 (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.

Table 6: Adverse Reactions (10% or Greater) in Patients With CML Who Were Resistant or Intolerant to Prior Therapy in Single-Arm Trial*
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.
*
Based on a Minimum of 48 Months of Follow-up.
Abdominal pain includes the following preferred terms: Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Gastrointestinal pain
Rash includes the following preferred terms: Acne, Dermatitis, Dermatitis acneiform, Dermatitis allergic, Drug eruption, Exfoliative rash, Photosensitivity reaction, Rash, Rash erythematous, Rash generalised, Rash macular, Rash maculo-papular, Rash papular, Rash pruritic, Urticaria
§
Thrombocytopenia includes the following preferred terms: Platelet count decreased, Thrombocytopenia
Anemia includes the following preferred terms: Anemia, Hemoglobin decreased.
#
Fatigue includes the following preferred terms: Fatigue, Malaise.
Þ
Neutropenia includes the following preferred terms: Neutropenia, Neutrophil count decreased
ß
Edema includes the following preferred terms containing: Edema, Edema peripheral, Face edema, Localized edema.
à
Respiratory tract infection includes the following preferred terms: Lower respiratory tract infection, Respiratory tract infection, Respiratory tract infection viral, Upper respiratory tract infection, Viral upper respiratory tract infection.
è
Leukopenia includes the following preferred terms: Leukopenia, White blood cell count decreased.
ð
Chest pain included the following preferred terms: Chest discomfort, Chest pain.
Diarrhea859764
Nausea471482
Abdominal Pain422316
Rash429385
Thrombocytopenia§40264539
Vomiting373433
Anemia27113827
Fatigue#262215
Pyrexia23<1372
Cough220220
Headache21<1174
Alanine aminotransferase increased208105
NeutropeniaÞ18122220
Arthralgia17<1140
Aspartate aminotransferase increased163113
Edemaß201172
Respiratory tract infectionà15<1100
Decreased appetite14<1130
Back pain13<181
Nasopharyngitis13060
Asthenia13210<1
Pleural effusion12494
Dyspnea122206
Pruritus12<170
Dizziness11013<1
Leukopeniaè1041512
Blood creatinine increased10<16<1
Influenza10<130
Chest painð71121

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.

Table 7: Number (%) of Patients With Clinically Relevant or Grade 3/4 Laboratory Test Abnormalities in the Safety Population of the Study of Patients With CML Who Were Resistant or Intolerant to Prior Therapy*
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.
*
Based on a Minimum of 48 Months of Follow-up.
Hematology Parameters
   Platelet Count (Low) less than 50×109/L105 (26)82 (57)187 (34)
  Absolute Neutrophil Count less than 1×109/L65 (16)55 (39)120 (22)
  Hemoglobin (Low) less than 80 g/L51 (13)54 (38)105 (19)
  
Biochemistry Parameters
  SGPT/ALT greater than 5.0×ULN43 (11)8 (6)51 (9)
  SGOT/AST greater than 5.0×ULN19 (5)5 (4)24 (4)
  Lipase greater than 2×ULN42 (10)9 (6)51 (9)
  Phosphorus (Low) less than 0.6 mmol/L30 (7)10 (7)40 (7)
  Total Bilirubin greater than 3.0×ULN3 (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

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