BOSULIF (bosutinib) tablet Adverse Reactions

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Adverse Drug Reaction Overview

The safety information provided in this section represents an assessment of the adverse reactions from 1521 patients who received at least 1 oral dose of single-agent BOSULIF in newly diagnosed Ph+ CP CML, CML resistant or intolerant to prior therapy, other Ph+ leukemias, and advanced malignant solid tumors.

Serious adverse reactions reported include anaphylactic shock (see CONTRAINDICATIONS), myelosuppression, gastrointestinal toxicity (diarrhea), fluid retention, hepatotoxicity and rash.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Newly Diagnosed Chronic Phase Ph+ CML

A total of 268 patients newly-diagnosed with CP CML received at least 1 dose of single-agent bosutinib 400 mg in a randomized Phase 3 clinical study. After a minimum of 12 months of follow-up, the median duration of therapy was 14.1 months (range: 0.3 to 24.7 months); the median dose intensity was 391.8 mg/day.

The most frequent adverse reactions reported for ≥20% of patients in the bosutinib treatment group were diarrhoea (70.1% of patients), nausea (35.1%), ALT increased (30.6%), thrombocytopenia (35.1%), abdominal pain (25.3%), and AST increased (22.8%).

The Grade 3 or Grade 4 adverse reactions reported for ≥5% of patients in the bosutinib treatment group were alanine aminotransferase increased (19.0%), lipase increased (9.7%), aspartate aminotransferase increased (9.7%), thrombocytopenia (9.0%), diarrhoea (7.8%), neutropenia (6.0%), and platelet count decreased (5.6%).

Table 1 below presents adverse reactions (all causality) of any toxicity and grades 3/4 very commonly reported (frequencies ≥10%) in the Phase 3 safety population.

Table 1: Newly-Diagnosed CML Patient Receiving BOSULIF 400 mg Reporting Very Common (≥10%) Frequencies Adverse Reactions by All Grades and Grades 3 or 4 for the Phase 3 Safety Population
 
Note: Classifications of adverse events are based on the Medical Dictionary for Regulatory Activities
 
Abbreviations: CML=Chronic myelogenous leukemia; N=number of patients.
 
Thrombocytopenia includes the following preferred terms: Platelet count decreased, Thrombocytopenia.
 
Anemia includes the following preferred terms: Anemia, Hemoglobin decreased.
 
Neutropenia includes the following preferred terms: Neutropenia, Neutrophil count decreased.
 
Abdominal pain includes the following preferred terms: Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Gastrointestinal pain.
 
Fatigue includes the following preferred terms: Fatigue, Malaise.
 
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.
 
Lipase increased includes the following preferred terms: Hyperlipasaemia, Lipase increased
 
Rash includes the following preferred terms: Rash, Rash generalized, Rash macular, Rash maculo-papular, Rash papular, Rash pruritic.

Bosutinib 400 mg

Newly Diagnosed Chronic Phase CML

N=268

Imatinib 400 mg

Chronic Phase CML

N=265

System Organ Class

All

Grades (%)

Grade 3/4

(%)

All Grades (%)

Grade 3/4

(%)

Preferred Term

Any Adverse Events

96

51

93

36

Blood and lymphatic system disorders

Thrombocytopenia

35

14

20

6

Anemia

19

3

19

5

Neutropenia

11

7

21

12

Gastrointestinal disorders

Diarrhea

70

8

34

<1

Nausea

35

0

38

0

Abdominal pain

25

2

15

<1

Vomiting

18

1

16

0

General disorders and administration site conditions

Fatigue

19

<1

19

0

Pyrexia

13

<1

8

0

Asthenia

11

0

6

0

Infections and infestations

Respiratory tract infection

12

<1

12

<1

Investigations

ALT increased

31

19

6

2

AST increased

23

10

6

2

Lipase increased

13

10

8

5

Metabolism and nutrition disorders

Appetite decreased

10

<1

6

0

Musculoskeletal and connective tissue disorders

Arthralgia

11

<1

13

0

Nervous system disorders

Headache

19

1

13

1

Skin and subcutaneous disorders

Rash

26

1

18

2

Table 2 below presents adverse reactions (all causality) of any toxicity and grades 3/4 commonly reported (frequencies ≥ 1% to <10%) in the Phase 3 safety population.

Table 2: Newly-Diagnosed CML Patient Receiving BOSULIF 400 mg Reporting Common (≥ 1% to <10%) Frequencies Adverse Reactions by All Grades and Grades 3 or 4 for the Phase 3 Safety Population
 
Note: Classifications of adverse events are based on the Medical Dictionary for Regulatory Activities
 
Abbreviations: CML=Chronic myelogenous leukemia; N=number of patients.
 
Totals for the No. of Subjects at a higher level are not necessarily the sum of those at the lower levels since a subject may report two or more different adverse events within the higher level category. SOC for some preferred terms does not follow MedDRA classification.
 
The commonality stratification is based on 'All Grade' under Total column.
 
'Grade 3', 'Grade 4' columns indicate maximum toxicity.
 
Amylase increased includes the following preferred terms: Amylase increased, Hyperamylasaemia.
 
Blood bilirubin increased includes the following preferred terms: Blood bilirubin increased, Hyperbilirubinaemia.
 
Chest pain includes the following preferred terms: Chest discomfort, Chest pain
 
Electrocardiogram QT prolonged includes the following MedDRA SMQ: Torsade de pointes/QT prolongation (Narrow)
 
Hepatic function abnormal includes the following preferred terms: Hepatic function abnormal, Hyper transaminasaemia, Liver function test abnormal, Liver function test increased, Transaminases increased
 
Hepatotoxicity includes the following preferred terms: Hepatitis, Hepatitis acute, Hepatitis cholestatic, Hepatitis toxic,Hepatotoxicity, Liver disorder
 
Hyperkalaemia includes the following preferred terms: Blood potassium increased, Hyperkalaemia
 
Hypertension* includes the following high level term and preferred terms: HLT- Accelerated and malignant hypertension, PT- Bloodpressure ambulatory increased, Blood pressure diastolic increased, Blood pressure increased, Blood pressure systolic increased, Diastolic Hypertension, Essential Hypertension, Hypertension, LabileHypertension, Systolic Hypertension
 
Hypophosphataemia includes the following preferred terms: Blood phosphorus decreased, Hypophosphataemia
 
Leukopenia includes the following preferred terms: Leukopenia, White blood cell count decreased
 
Oedema includes the following preferred terms: Face oedema, Localised Oedema, Oedema, Oedema peripheral
 
Pneumonia includes the following preferred terms: Atypical pneumonia, Pneumonia

 

Bosutinib 400 mg

Newly Diagnosed Chronic Phase CML

N=268

Imatinib 400 mg

Newly Diagnosed Chronic Phase CML

N=265

System Organ Class

All Grades (%)

Grade 3/4

(%)

All Grades (%)

Grade 3/4

(%)

Preferred Term

Any Adverse Events

96

51

93

36

Blood and lymphatic system disorders

Leukopenia

6

1

11

3

Ear and labyrinth disorders

Tinnitus

2

0

<1

0

Gastrointestinal disorders

Gastritis

1

0

1

<1

General disorders and administration site conditions

Oedema

6

0

17

<1

Chest Pain

3

0

3

0

Pain

1

0

3

0

Hepatobiliary disorders

Hepatic function abnormal

3

2

1

1

Hepatotoxicity

3

2

<1

0

Infections and infestations

Nasopharyngitis

10

<1

9

0

Bronchitis

3

0

2

<1

Influenza

3

0

3

<1

Pneumonia

3

<1

2

<1

Investigations

Blood bilirubin increased

6

<1

3

<1

Blood creatinine increased

6

0

6

<1

Amylase increased

5

1

3

1

Blood creatine phosphokinase increased

3

<1

8

2

Gamma-glutamyl

transferase increased

2

<1

<1

<1

Electrocardiogram QT prolonged

1

<1

3

<1

Metabolism and nutrition disorders

Hypophosphataemia

2

<1

6

3

Hyperkalaemia

1

<1

2

0

Musculoskeletal and connective tissue disorders

Back pain

8

<1

7

<1

Myalgia

3

<1

15

1

Nervous system disorders

Dizziness

7

0

7

0

Dysgeusia

1

0

3

0

Respiratory, thoracic and mediastinal disorders

Dyspnoea

9

<1

4

<1

Cough

8

0

7

0

Pleural effusion

2

0

2

0

Skin and subcutaneous disorders

Pruritus

9

0

2

0

Acne

2

0

0

0

Urticaria

2

0

1

0

Vascular disorders

Hypertension

5

2

6

2

In the phase 3 study in patients newly diagnosed with CP CML treated with bosutinib 400 mg, the median time of onset for diarrhea (all grades) in the bosutinib treatment group was 3 days, and the median duration of an event was 3 days. The median time of onset for either ALT or AST elevations (all grades) observed was 32 and 43 days, respectively, and the median duration was 20 and 15 days, respectively.

Chronic Phase (CP), Accelerated Phase (AP) and Blast Phase (BP) CML and ALL Patients Resistant or Intolerant to Previous TKIs Treatment

The single-arm Phase 1/2 clinical study enrolled a total of 571 patients with Ph+ chronic (n=284), accelerated (n=79), or blast (n=64) phase chronic myelogenous leukemia (CML) and 24  patients with Ph+ acute lymphoblastic leukemia (ALL) who were resistant or intolerant to prior TKI therapy. The safety population (received at least 1 dose of BOSULIF) included 570  patients.

With the ≥ 4 years of follow up, the majority of BOSULIF-treated patients (99.5%) experienced at least one adverse event. The most common (incidence ≥ 30%) were diarrhea (81.6%), nausea (47.0%), thrombocytopenia (41.4%), vomiting (39.1%), abdominal pain (38.4%), rash (32.8%), and anemia (30.2%).

Overall, 77.9% of patients experienced severe, Grade 3 and 4 adverse events, and 44.2% of patients experienced serious adverse events (SAEs). The most common SAEs (>2% of subjects overall) were pneumonia (4.9%), pleural effusion (4.7%), pyrexia (3.3%), thrombocytopenia (2.5%), dyspnea (2.3%), disease progression, and diarrhea (2.1% each).

Overall, 134 (24%) of patients permanently discontinued bosutinib due to treatment-emerged adverse events (TEAEs). The most common TEAEs leading to discontinuation (≥ 2% of subjects overall) were thrombocytopenia (5.3%) and ALT increased (2.1%). Overall, 65.3% of subjects had at least one dose interruption due to adverse events. The most common TEAEs (≥ 4% of subjects) resulting in dose interruption were thrombocytopenia (21.6%), diarrhea (11.6%), rash (9.8%), neutropenia (8.1%), vomiting and pleural effusion (6.0% each), ALT increased (7.0%), AST increased (5.1%), and anemia (4.2%). Overall, 49% of subjects had ≥1 dose reduction due to TEAEs. The most common TEAEs (≥ 4% of subjects) resulting in reductions in bosutinib dose were thrombocytopenia (13.5%), rash (5.4%), and diarrhea (4.7%).

Table 3 below presents adverse reactions (all causality) of any toxicity and grades 3/4 very commonly reported (frequencies ≥10%) in the Phase 1/2 safety population.

Table 3: CML Patients Receiving BOSULIF Reporting Very Common (≥10%) Frequencies Adverse Reactions by All Grades and Grades 3 or 4 for the Phase 1/2 Safety Population
 
* CP = Chronic Phase; AP = Accelerated Phase; BP = Blast Phase
 
(a) Totals for the No. of Subjects at a higher level are not necessarily the sum of those at the lower levels since asubject may report two or more different adverse events within the higher level category. SOC for some preferred terms does not follow Meddra classification.
 
Classifications of adverse events are based on the Medical Dictionary for Regulatory Activities (MedDRA).
 
The commonality stratification is based on 'All Grade' under Total column.
 
'Grade 3', 'Grade 4' column indicate maximum toxicity.
 
Abdominal pain includes the following preferred terms: Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Gastrointestinal pain.
 
Anaemia includes the following preferred terms: Anaemia, Haemoglobin decreased.
 
Chest pain includes the following preferred terms: Chest discomfort, Chest pain.
 
Fatigue includes the following preferred terms: Fatigue, Malaise.
 
Leukopenia includes the following preferred terms: Leukopenia, White blood cell count decreased.
 
Neutropenia includes the following preferred terms: Neutropenia, Neutrophil count decreased.
 
Oedema includes the following preferred terms: Face oedema, Localised Oedema, Oedema, Oedema peripheral.
 
Rash includes the following preferred terms: Rash, Rash generalised, Rash macular, Rash maculo-papular, , Rash pruritic.
 
Thrombocytopenia includes the following preferred terms: Platelet count decreased, Thrombocytopenia.

CP* CML
Imatinib Resistant or Intolerant
N=284

CP* CML
Resistant or Intolerant ≥2 TKIs
N=119

AP* CML

Resistant or Intolerant to at least Imatinib
N=79

BP* CML

Resistant or Intolerant to at least Imatinib

N=64

System Organ Class

All Grades (%)

Grade 3/4

(%)

All Grades

(%)

Grade 3/4

(%)

All Grades

(%)

Grade 3/4

(%)

All Grades

(%)

Grade 3/4

(%)

Preferred Term


Any Adverse Event

100

69

100

61

100

82

97

70

Blood and lymphatic system disorders

Thrombocytopenia

42

25

38

26

53

44

34

33

Anaemia

29

13

20

7

46

33

30

20

Neutropenia

16

10

21

16

19

18

25

23

Leukopenia

13

5

4

<1

13

6

19

19

Gastrointestinal disorders

Diarrhoea

86

10

83

9

85

4

64

5

Nausea

46

2

48

<1

46

3

50

2

Abdominal pain

45

2

36

<1

34

5

27

8

Vomiting

37

4

38

<1

44

4

41

3

General disorders and administration site conditions

Pyrexia

27

1

15

0

35

1

39

3

Fatigue

27

2

23

2

22

5

20

5

Oedema

15

<1

13

0

14

0

14

2

Asthenia

15

2

8

0

14

1

6

0

Chest pain

8

2

6

0

15

3

8

0

Infections and infestations

Respiratory tract infection

14

<1

15

<1

15

0

5

0

Nasopharyngitis

13

0

11

0

9

0

2

0

Influenza

10

<1

10

0

6

0

0

0

Pneumonia

5

4

4

0

14

11

16

9

Investigations

ALT increased

22

8

15

6

14

8

6

2

AST decreased

20

4

8

3

15

5

6

0

Blood creatinine increased

9

<1

13

0

8

1

5

0

Metabolism and nutrition disorders

Decreased appetite

15

<1

13

<1

9

0

19

0

Musculoskeletal and connective tissue disorders

Arthralgia

17

1

18

<1

15

0

13

0

Back pain

13

<1

12

3

10

1

6

2

Nervous system disorders

Headache

19

0

27

3

15

3

20

6

Dizziness

9

0

15

0

14

1

13

0

Respiratory, thoracic and mediastinal disorders

Cough

23

0

21

0

30

0

13

0

Dyspnoea

12

2

12

2

20

9

19

3

Pleural effusion

11

3

17

5

13

5

5

3

Skin and subcutaneous disorders

Rash

37

9

30

4

35

4

31

5

Pruritus

10

<1

17

<1

8

0

6

0

Table 4 below presents adverse reactions (all causality) of any toxicity and grades 3/4 commonly reported (frequencies ≥ 1% to <10%) in the Phase 1/2 safety population.

Table 4: CML Patients Receiving BOSULIF Reporting Common (≥ 1% to <10%) Frequencies Adverse Reactions by All Grades and Grades 3 or 4 for the Phase 1/2 Safety Population
 
* CP = Chronic Phase; AP = Accelerated Phase; BP = Blast Phase
 
Totals for the No. of Subjects at a higher level are not necessarily the sum of those at the lower levels since a subject may report two or more different adverse events within the higher level category. SOC for some preferred terms does not follow MedDRA classification.
 
Classifications of adverse events are based on the Medical Dictionary for Regulatory Activities (MedDRA).
 
The commonality stratification is based on 'All Grade' under Total column.
 
'Grade 3', 'Grade 4' columns indicate maximum toxicity.
 
Amylase increased includes the following preferred terms: Amylase increased, Hyperamylasaemia.
 
Blood bilirubin increased includes the following preferred terms: Blood bilirubin increased, Hyperbilirubinaemia.
 
Electrocardiogram QT prolonged includes the following Electrocardiogram QT prolonged, Long QT syndrome
 
Gastrointestinal haemorrhage includes the following preferred terms: Anal haemorrhage, Gastrointestinal haemorrhage, Intestinal haemorrhage, Lower gastrointestinal haemorrhage, Rectal haemorrhage.
 
Hepatotoxicity includes the following preferred terms:, Hepatitis toxic, Hepatotoxicity, Liver disorder.
 
Hyperkalaemia includes the following preferred terms: Blood potassium increased, Hyperkalaemia .
 
Hypophosphataemia includes the following preferred terms: Blood phosphorus decreased, Hypophosphataemia.
 
Lipase increased includes the following preferred terms: Hyperlipasaemia, Lipase increased.
 
Pancreatitis acute includes the following preferred terms: Pancreatitis, Pancreatitis acute.
 
Pneumonia includes the following preferred terms: Atypical pneumonia, Pneumonia.
 
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.
 

CP* CML
Imatinib Resistant or Intolerant
N=284

CP* CML
Resistant or Intolerant ≥2 TKIs
N=119

AP* CML

Resistant or Intolerant to at least Imatinib
N=79

BP* CML

Resistant or Intolerant to at least Imatinib

N=64

System Organ Class

All Grades (%)

Grade 3/4

(%)

All Grades

(%)

Grade 3/4

(%)

All Grades

(%)

Grade 3/4

(%)

All Grades

(%)

Grade 3/4

(%)

Preferred Term


Any Adverse Event

100

69

100

61

100

82

97

70

Blood and lymphatic system disorders

Febrile Neutropenia

0

0

2

2

1

1

5

3

Cardiac disorders

Pericardial effusion

3

1

6

3

6

1

2

0

Pericarditis

<1

0

<1

<1

1

1

0

0

Ear and labyrinth disorders

Tinnitus

1

0

3

0

0

0

0

0

Gastrointestinal disorders

Gastritis

4

<1

3

<1

4

0

3

2

Gastrointestinal haemorrhage

2

<1

3

0

1

1

5

3

Acute pancreatitis

1

1

0

0

3

3

0

0

General disorders and administration site conditions

Pain

7

<1

6

0

8

1

8

3

Hepatobiliary disorders

Hepatotoxicity

4

1

3

3

0

0

3

0

Hepatic function abnormal

3

2

2

0

1

0

3

0

Immune system disorders

Drug hypersensitivity

<1

<1

4

2

1

0

2

0

Infections and infestations

Bronchitis

6

<1

5.0

<1

8

0

0

0

Investigations

Lipase increased

10

7

7

4

8

2.5

5

3

Amylase increased

5

2

5

0

1

0

5

2

Blood creatine phosphokinase increased

5

2

2

0

4

0

0

0

Blood bilirubin increased

4

0

2

<1

3

0

9

8

Gamma-glutamyl

transferase increased

2

<1

3

<1

3

0

0

0

Electrocardiogram QT prolonged

1

<1

0

0

0

0

2

0

Metabolism and nutrition disorders

Hypophosphataemia

6

2

4

0

6

4

6

3

Hyperkalaemia

3

1

5

<1

5

1

5

0

Dehydration

2

0

2

0

4

1

6

0

Musculoskeletal and connective tissue disorders

Myalgia

8

0

4

<1

9

0

9

2

Nervous system disorders

Dysgeusia

2

0

3

0

3

0

2

0

Renal and urinary disorders

Renal failure

2

<1

3

2

6

0

2

2

Acute kidney injury

2

1

0

0

1

1

5

3

Renal impairment

2

<1

0

0

1

0

0

0

Respiratory, thoracic and mediastinal disorders

Pulmonary hypertension

1

<1

<1

0

0

0

0

0

Respiratory failure

<1

<1

0

0

1

1

5

3

Skin and subcutaneous disorders

Acne

4

0

<1

0

3

0

2

0

Urticaria

2

0

3

<1

3

0

2

2

Exfoliative rash

1

0

0

0

1

0

0

0

Drug eruption

<1

<1

0

0

3

0

0

0

In the single-arm Phase 1/2 clinical study, the median time of onset for diarrhea (all grades) was 2 days and the median duration per event was 2 days. Based on adverse reactions reported, the median time of onset for either ALT or AST (all grades) elevations was 29 and 30 days, respectively, and the median duration for each was 18 days.

ECG Findings

In the Phase 1/ 2 clinical study, 1 patient (0.2%) experienced QTcF (corrected QT by the Fridericia method) intervals of greater than 500 ms. Seven (1.2%) of the patients experienced QTcF increases from baseline exceeding 60 ms. Patients with uncontrolled or significant cardiovascular disease, including QT interval prolongation, at baseline were excluded by protocol criteria from the clinical trials.

In the phase 3 study in patients newly diagnosed with CP CML treated with 400 mg, there was 1 patient in the bosutinib treatment group and 0 patients in the imatinib treatment group who experienced corrected QT by the Fridericia method (QTcF) interval of greater than 500 msec.

In a Phase 3 study of newly diagnosed Ph+ CP CML patients treated with 500 mg, 2 patients (0.8%) experienced QTcF interval greater than 500 ms in the BOSULIF treatment arm. Patients with uncontrolled or significant cardiovascular disease including QT interval prolongation were excluded from enrolling in this clinical study. In this study population, BOSULIF was associated with statistically significant decreases from baseline in heart rate of approximately 4 bpm at months 2 and 3.

Tabulated Summary of Adverse Reactions

The following adverse reactions in Table 5 were reported in patients in pooled clinical studies with BOSULIF. They represent an evaluation of the adverse reaction data from 1521 patients who received at least 1 dose of single-agent BOSULIF in newly diagnosed Ph+ CP CML, CML resistant or intolerant to prior therapy, other Ph+ leukemias, and advanced malignant solid tumors. These adverse reactions are presented by system organ class and by frequency. Frequency categories are defined as: very common (≥10%), common (≥1% to <10%), uncommon (≥0.1% to <1%), rare (≥0.01% to <0.1%), very rare (<0.01%), not known (cannot be estimated from the available data).

Table 5: Adverse Reactions for BOSULIF Pooled Safety (Newly diagnosed Ph+ CP CML, CML resistant or intolerant to prior therapy, other Ph+ leukemias, and advanced malignant solid tumors) N= 1521
 
Note: Preferred Terms shown in parenthesis were grouped to determine a more accurate frequency.
Infections and infestations
Very common respiratory tract infection (including upper respiratory tract infection, lower respiratory tract infection, viral upper respiratory tract infection, respiratory tract infection viral ), nasopharyngitis
Common pneumonia (including pneumonia, atypical pneumonia), influenza, bronchitis
Blood and lymphatic system disorders
Very common thrombocytopenia (including platelet count decreased), anemia (including Hemoglobin decreased), neutropenia (including neutrophil count decreased)
Common leucopenia (including white blood cell count decreased)
Uncommon febrile neutropenia, granulocytopenia
Immune system disorders
Uncommon anaphylactic shock, drug hypersensitivity
Metabolism and nutrition disorders
Very common decreased appetite
Common

hyperkalemia (including blood potassium increased), hypophosphatemia (including blood phosphorus decreased), dehydration

Nervous system disorders
Very common headache, dizziness
Common dysgeusia
Ear and labyrinth disorders
Common tinnitus
Cardiac disorders
Common pericardial effusion
Uncommon pericarditis
Vascular disorders
Common hypertension (including blood pressure increased, blood pressure systolic increased, essential hypertension, hypertensive crisis)
Respiratory, thoracic and mediastinal disorders
Very common dyspnea
Common pleural effusion
Uncommon acute pulmonary edema, respiratory failure, pulmonary hypertension
Gastrointestinal disorders
Very common diarrhea, vomiting, abdominal pain (including upper abdominal pain, lower abdominal pain, abdominal discomfort, abdominal tenderness, gastrointestinal pain), nausea
Common gastritis, gastrointestinal hemorrhage (including anal hemorrhage, gastric hemorrhage, upper gastrointestinal hemorrhage, lower gastrointestinal hemorrhage, rectal hemorrhage)
Uncommon

acute pancreatitis

Hepatobiliary disorders
Common hepatotoxicity (including toxic hepatitis, cytolytic hepatitis, liver disorder), abnormal hepatic function (including liver function test abnormal, liver function test increased, transaminsases increased)
Uncommon liver injury (including drug-induced liver injury)
Skin and subcutaneous tissue disorders
Very common rash (including maculopapular rash, pruritic rash, generalized rash, papular rash, macular rash)
Common urticaria, pruritus, acne
Uncommon

erythema multiforme, exfoliative rash, drug eruption

Musculoskeletal and connective tissue disorders
Very common arthralgia, back pain
Common myalgia
Renal and urinary disorders
Common acute renal failure, acute kidney injury, renal failure, renal impairment
General disorders and administration site conditions
Very common fatigue (including malaise), pyrexia, edema (including face edema, localized edema, peripheral edema ), asthenia
Common chest pain (including chest discomfort), pain
Investigations
Very common increased alanine aminotransferase, increased aspartate aminotransferase, increased lipase (including hyperlipasaemia)
Common increased blood amylase, increased gamma-glutamyltransferase, increased blood creatine phosphokinase, increased blood bilirubin (including hyperbilirubinemia), electrocardiogram QT prolonged (including long QT symdrome, ventricular tachycardia), increased blood creatinine

All treatment-emergent adverse events that were reported in BOSULIF pooled clinical studies, regardless of causality and frequency, are listed in Table 6 below.

Abnormal Hematologic and Clinical Chemistry Findings

Table 6 presents potential clinically relevant or severe abnormalities of routine hematological, or biochemistry laboratory values in the study patient population who received at least one dose of BOSULIF in the Phase 1/2 study.

Table 6. Percent of Patients with Potential Clinically Relevant or Severe Grade 3/4 Laboratory Test Abnormalities in the Phase 1/2 Clinical Study
*
CP = Chronic Phase; AP = Accelerated Phase; BP = Blast Phase

CP* CML
Imatinib- Resistant or Intolerant
N=284

CP* CML
Resistant or Intolerant ≥2 TKIs
N=119

AP* CML, BP* CML
Resistant or Intolerant to at least Imatinib
N=143

Hematology parameters % % %
Platelet Count <50 X 109/L 26 26 57
Absolute Neutrophil Count <1 X109/L

15 18 38
Hemoglobin (Low) <80 g/L 14 8 38
Biochemistry parameters
SGPT/ALT >5.0 X ULN 12 8 6
SGOT/AST >5.0 X ULN 5 3 3
Lipase >2 X ULN 12 8 6
Phosphorus (Low) <0.6 mmol/L 9 3 7
Total Bilirubin (High) >3xULN 0 2 3

Table 7 presents potential clinically relevant or severe abnormalities of routine hematological, or biochemistry laboratory values in the study patient population who received at least one dose of BOSULIF in the Phase 3 study.

Table 7. Percent of Patients with Potential Clinically Relevant or Severe Grade 3/4 Laboratory Test Abnormalities in the Phase 3 Clinical Study

Bosutinib 400 mg
Newly Diagnosed Chronic Phase CML
N=268

Hematology parameters %
Platelet Count <50 X 109/L 14
Absolute Neutrophil Count <1 X109/L

9
Hemoglobin (Low) <80 g/L 7
Biochemistry parameters
SGPT/ALT >5.0 X ULN 23
SGOT/AST >5.0 X ULN 12
Lipase >2 X ULN 13
Phosphorus (Low) <0.6 mmol/L 4.5
Total Bilirubin (High) >3xULN 1

Table 8 presents the median (90% CI) change in eGFR from baseline over time in patients with a baseline creatinine value in the Phase 1/2 study (see CLINICAL TRIALS).

Table 8: On-treatment eGFR Change from Baseline Over Time In Patients in the Phase 1/2 study

Time Point

(months)

Total

(N=569)

eGRF (mL/min/1.73 m2)
Median Change
(90% CI)

Baseline 569 NA
3 429 -5.29 (-6.26, -4.02)
12 290 -7.55 (-8.29, -4.89)
24 210 -8.54 (-10.07, -6.55)
36 185 -10.92 (-12.92, -8.62)
48 167 -10.51 (-13.57, -9.20)

Table 9 presents the median (90% CI) change in eGFR from baseline over time in patients with a baseline creatinine value in the Phase 3 study (see CLINICAL TRIALS).

Table 9: On-treatment eGFR Change from Baseline Over Time In Patients in the Phase 3 study

Time Point

(months)

Total

(N=268)

eGRF (mL/min/1.73 m2)
Median Change
(90% CI)

Baseline 267 NA
3 247 -4.9 (-6.9, -2.4)
12 216 -11.1 (-12.9, -9.2)