BOSULIF® Adverse Reactions

(bosutinib)

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 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:

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 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.

Table 7: Adverse Reactions (10% or Greater) in Patients With Newly-Diagnosed CML in Bosutinib 400 mg Study*
Bosutinib 400 mg
Chronic Phase CML
(N=268)
Imatinib 400 mg
Chronic Phase CML
(N=265)
*
Based on a Minimum of 57 Months of Follow-up.
Adverse drug reactions are based on all-causality treatment-emergent adverse events.
The commonality stratification is based on 'All Grades' under Total column.
'Grade 3', 'Grade 4' columns indicate maximum toxicity.
Abdominal pain includes the following preferred terms: Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Dyspepsia, Epigastric discomfort, Gastrointestinal pain.
Hepatic dysfunction includes the preferred terms: Alanine aminotransferase increased, Aspartate aminotransferase, Aspartate aminotransferase increased, Bilirubin conjugated increased, Blood alkaline phosphatase increased, Blood bilirubin increased, Drug-induced liver injury, Gamma-glutamyltransferase increased, Hepatic enzyme increased, Hepatic steatosis, Hepatitis, Hepatitis toxic, Hepatocellular injury, Hepatotoxicity, Hyperbilirubinemia, Jaundice, Liver disorder, Liver function test increased, Ocular icterus, Transaminases increased.
§
Rash includes the following preferred terms: Acne, Blister, Dermatitis, Dermatitis acneiform, Dermatitis bullous, Dermatitis exfoliative generalized, Drug reaction with eosinophilia and systemic symptoms, Dyshidrotic eczema, Eczema, Eczema asteatotic, Erythema, Erythema nodosum, Genital rash, Lichen planus, Perivascular dermatitis, Photosensitivity reaction, Psoriasis, Rash, Rash erythematous, Rash macular, Rash maculo-papular, Rash papular, Rash pruritic, Rash pustular, Rash vesicular, Seborrhoeic keratosis, Skin discoloration, Skin exfoliation, Skin hypopigmentation, Skin irritation, Skin lesion, Stasis dermatitis.
Fatigue includes the following preferred terms: Asthenia, Fatigue, Malaise.
#
Edema includes the following preferred terms: Eye edema, Eyelid edema, Face edema, Edema, Edema peripheral, Orbital edema, Periorbital edema, Periorbital swelling, Peripheral swelling, Swelling, Swelling face, Swelling of eyelid, Swollen tongue.
Þ
Respiratory tract infection includes the following preferred terms: Nasopharyngitis, Respiratory tract congestion, Respiratory tract infection, Respiratory tract infection viral, Upper respiratory tract infection.
ß
Hypertension* includes the preferred terms: Blood pressure systolic increased, Hypertension, Hypertensive crisis, Hypertensive heart disease, Retinopathy hypertensive.

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.

Table 8: Select Laboratory Abnormalities (>20%) That Worsened From Baseline in Patients with Newly-Diagnosed CML in Bosutinib 400 mg Study*
Bosutinib
N=268
%
Imatinib
N=265
%
All GradeGrade 3–4All GradeGrade 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
*
Based on a Minimum of 57 Months of Follow-up.

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:

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 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.

Table 9: Adverse Reactions (10% or Greater) in Patients With CML Who Were Resistant or Intolerant to Prior Therapy in Single-Arm Trial*
CP CML
(N=403)
AdvP CML
(N=143)
System Organ ClassPreferred TermAll Grades
%
Grade 3/4
%
All Grades
%
Grade 3/4
%
ADR Definition
*
Based on a Minimum of 105 Months of Follow-up.
Adverse drug reactions are based on all-causality treatment-emergent adverse events.
The commonality stratification is based on 'All Grades' under Total column.
'Grade 3', 'Grade 4' columns indicate maximum toxicity.
Abdominal pain includes the following preferred terms: Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Dyspepsia, Epigastric discomfort, Gastrointestinal pain, Hepatic pain.
Rash includes the following preferred terms: Acarodermatitis, Acne, Angular cheilitis, Blister, Dermatitis, Dermatitis acneiform, Dermatitis psoriasiform, Drug eruption, Eczema, Eczema asteatotic, Erythema, Erythema annulare, Exfoliative rash, Lichenoid keratosis, Palmar erythema, Photosensitivity reaction, Pigmentation disorder, Psoriasis, Pyoderma gangrenosum, Pyogenic granuloma, Rash, Rash erythematous, Rash generalised, Rash macular, Rash maculo-papular, Rash pruritic, Rash pustular, Seborrhoeic dermatitis, Seborrhoeic keratosis, Skin depigmentation, Skin discoloration, Skin disorder, Skin exfoliation, Skin hyperpigmentation, Skin hypopigmentation, Skin irritation, Skin lesion, Skin plaque, Skin toxicity, Stasis dermatitis.
§
Edema includes the following preferred terms: Eye edema, Eyelid edema, Face edema, Generalized edema, Localized edema, Edema, Edema peripheral, Penile edema, Periorbital edema, Periorbital swelling, Peripheral swelling, Scrotal edema, Scrotal swelling, Swelling, Swelling face, Swelling of eyelid, Testicular edema, Tongue edema.
Chest pain includes the following preferred terms: Chest discomfort, Chest pain.
#
Hepatic dysfunction includes the following preferred terms: Alanine aminotransferase increased, Aspartate aminotransferase increased, Bilirubin conjugated increased, Blood alkaline phosphatase increased, Blood bilirubin increased, Blood bilirubin unconjugated increased, Gamma-glutamyltransferase increased, Hepatic enzyme increased, Hepatic function abnormal, Hepatic steatosis, Hepatitis toxic, Hepatomegaly, Hepatotoxicity, Hyperbilirubinemia, Liver disorder, Liver function test abnormal, Liver function test increased, Transaminases increased.
Þ
Respiratory tract infection includes the following preferred terms: Nasopharyngitis, Respiratory tract congestion, Respiratory tract infection, Respiratory tract infection viral, Upper respiratory tract infection, Viral upper respiratory tract infection.
ß
Influenza includes the following preferred terms: H1N1 influenza, Influenza.
à
Pneumonia includes the following preferred terms: Atypical pneumonia, Lower respiratory tract congestion, Lower respiratory tract infection, Pneumonia, Pneumonia aspiration, Pneumonia bacterial, Pneumonia fungal, Pneumonia necrotising, Pneumonia streptococcal.
è
Hypertension* includes the following preferred terms: Blood pressure increased, Blood pressure systolic increased, Essential hypertension, Hypertension, Hypertensive crisis, Retinopathy hypertensive.
* ADR identified post-marketing.

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.

Table 10: Number (%) of Patients With Clinically Relevant All Grade 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*
CP CML
N=403
%
AdvP CML
N=143
%
All gradeGrade 3/4All gradeGrade 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.
*
Based on a Minimum of 105 Months of Follow-up.

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.

Table 11: Adverse Reactions (10% or Greater) in Pediatric Patients with Newly Diagnosed CP Ph+ CML or CP Ph+ CML Resistant or Intolerant to Prior Therapy Who Received BOSULIF 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.
*
Abdominal pain includes the following preferred terms: Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Dyspepsia, Epigastric discomfort, Gastrointestinal pain, Hepatic pain.
Rash includes the following preferred terms: Acarodermatitis, Acne, Angular cheilitis, Blister, Dermatitis, Dermatitis acneiform, Dermatitis bullous, Dermatitis exfoliative generalized, Dermatitis psoriasiform, Drug eruption, Drug reaction with eosinophilia and systemic symptoms, Dyshidrotic eczema, Eczema, Eczema asteatotic, Erythema, Erythema annulare, Erythema nodosum, Exfoliative rash, Genital rash, Lichen planus, Lichenoid keratosis, Palmar erythema, Palmar-plantar erythrodysesthesia syndrome, Perivascular dermatitis, Photosensitivity reaction, Pigmentation disorder, Pruritus allergic, Psoriasis, Punctate keratitis, Pyoderma gangrenosum, Pyogenic granuloma, Rash, Rash erythematous, Rash generalized, Rash macular, Rash maculo-papular, Rash papular, Rash pruritic, Rash pustular, Rash vesicular, Seborrheic dermatitis, Seborrhoeic keratosis, Skin depigmentation, Skin discoloration, Skin disorder, Skin exfoliation, Skin hyperpigmentation, Skin hypopigmentation, Skin irritation, Skin lesion, Skin plaque, Skin reaction, Skin toxicity, Stasis dermatitis.
Hepatic dysfunction includes the following preferred terms: Alanine aminotransferase abnormal, Alanine aminotransferase increased, Aspartate aminotransferase, Aspartate aminotransferase increased, Bilirubin conjugated increased, Blood alkaline phosphatase increased, Blood bilirubin increased, Blood bilirubin unconjugated increased, Gamma-glutamyltransferase increased, Hepatic enzyme increased, Hepatomegaly, Hepatosplenomegaly, Hyperbilirubinaemia, Jaundice, Liver function test abnormal, Liver function test increased, Ocular icterus, Transaminases increased, Hepatic function abnormal, Drug-induced liver injury, Hepatic steatosis, Hepatitis, Hepatitis toxic, Hepatobiliary disease, Hepatocellular injury, Hepatotoxicity, Liver disorder, Liver injury.
§
Fatigue includes the following preferred terms: Asthenia, Fatigue, Malaise.
Respiratory tract infection includes the following preferred terms: Nasopharyngitis, Respiratory tract congestion, Respiratory tract infection, Respiratory tract infection viral, Upper respiratory tract congestion, Upper respiratory tract infection, Upper respiratory tract inflammation, Viral upper respiratory tract infection.

System Organ Class

Preferred Term

BOSULIF Total
(N=49)

%

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.

Table 12: Laboratory Abnormalities (≥ 20%) That Worsened From Baseline in Pediatric Patients with Newly-Diagnosed CP Ph+ CML or CP Ph+ CML Resistant or Intolerant to Prior Therapy Who Received BOSULIF 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 Disorders0.1% 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), Interstitial lung disease, 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

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Adverse Reactions

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 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:

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 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.

Table 7: Adverse Reactions (10% or Greater) in Patients With Newly-Diagnosed CML in Bosutinib 400 mg Study*
Bosutinib 400 mg
Chronic Phase CML
(N=268)
Imatinib 400 mg
Chronic Phase CML
(N=265)
*
Based on a Minimum of 57 Months of Follow-up.
Adverse drug reactions are based on all-causality treatment-emergent adverse events.
The commonality stratification is based on 'All Grades' under Total column.
'Grade 3', 'Grade 4' columns indicate maximum toxicity.
Abdominal pain includes the following preferred terms: Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Dyspepsia, Epigastric discomfort, Gastrointestinal pain.
Hepatic dysfunction includes the preferred terms: Alanine aminotransferase increased, Aspartate aminotransferase, Aspartate aminotransferase increased, Bilirubin conjugated increased, Blood alkaline phosphatase increased, Blood bilirubin increased, Drug-induced liver injury, Gamma-glutamyltransferase increased, Hepatic enzyme increased, Hepatic steatosis, Hepatitis, Hepatitis toxic, Hepatocellular injury, Hepatotoxicity, Hyperbilirubinemia, Jaundice, Liver disorder, Liver function test increased, Ocular icterus, Transaminases increased.
§
Rash includes the following preferred terms: Acne, Blister, Dermatitis, Dermatitis acneiform, Dermatitis bullous, Dermatitis exfoliative generalized, Drug reaction with eosinophilia and systemic symptoms, Dyshidrotic eczema, Eczema, Eczema asteatotic, Erythema, Erythema nodosum, Genital rash, Lichen planus, Perivascular dermatitis, Photosensitivity reaction, Psoriasis, Rash, Rash erythematous, Rash macular, Rash maculo-papular, Rash papular, Rash pruritic, Rash pustular, Rash vesicular, Seborrhoeic keratosis, Skin discoloration, Skin exfoliation, Skin hypopigmentation, Skin irritation, Skin lesion, Stasis dermatitis.
Fatigue includes the following preferred terms: Asthenia, Fatigue, Malaise.
#
Edema includes the following preferred terms: Eye edema, Eyelid edema, Face edema, Edema, Edema peripheral, Orbital edema, Periorbital edema, Periorbital swelling, Peripheral swelling, Swelling, Swelling face, Swelling of eyelid, Swollen tongue.
Þ
Respiratory tract infection includes the following preferred terms: Nasopharyngitis, Respiratory tract congestion, Respiratory tract infection, Respiratory tract infection viral, Upper respiratory tract infection.
ß
Hypertension* includes the preferred terms: Blood pressure systolic increased, Hypertension, Hypertensive crisis, Hypertensive heart disease, Retinopathy hypertensive.

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.

Table 8: Select Laboratory Abnormalities (>20%) That Worsened From Baseline in Patients with Newly-Diagnosed CML in Bosutinib 400 mg Study*
Bosutinib
N=268
%
Imatinib
N=265
%
All GradeGrade 3–4All GradeGrade 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
*
Based on a Minimum of 57 Months of Follow-up.

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:

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 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.

Table 9: Adverse Reactions (10% or Greater) in Patients With CML Who Were Resistant or Intolerant to Prior Therapy in Single-Arm Trial*
CP CML
(N=403)
AdvP CML
(N=143)
System Organ ClassPreferred TermAll Grades
%
Grade 3/4
%
All Grades
%
Grade 3/4
%
ADR Definition
*
Based on a Minimum of 105 Months of Follow-up.
Adverse drug reactions are based on all-causality treatment-emergent adverse events.
The commonality stratification is based on 'All Grades' under Total column.
'Grade 3', 'Grade 4' columns indicate maximum toxicity.
Abdominal pain includes the following preferred terms: Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Dyspepsia, Epigastric discomfort, Gastrointestinal pain, Hepatic pain.
Rash includes the following preferred terms: Acarodermatitis, Acne, Angular cheilitis, Blister, Dermatitis, Dermatitis acneiform, Dermatitis psoriasiform, Drug eruption, Eczema, Eczema asteatotic, Erythema, Erythema annulare, Exfoliative rash, Lichenoid keratosis, Palmar erythema, Photosensitivity reaction, Pigmentation disorder, Psoriasis, Pyoderma gangrenosum, Pyogenic granuloma, Rash, Rash erythematous, Rash generalised, Rash macular, Rash maculo-papular, Rash pruritic, Rash pustular, Seborrhoeic dermatitis, Seborrhoeic keratosis, Skin depigmentation, Skin discoloration, Skin disorder, Skin exfoliation, Skin hyperpigmentation, Skin hypopigmentation, Skin irritation, Skin lesion, Skin plaque, Skin toxicity, Stasis dermatitis.
§
Edema includes the following preferred terms: Eye edema, Eyelid edema, Face edema, Generalized edema, Localized edema, Edema, Edema peripheral, Penile edema, Periorbital edema, Periorbital swelling, Peripheral swelling, Scrotal edema, Scrotal swelling, Swelling, Swelling face, Swelling of eyelid, Testicular edema, Tongue edema.
Chest pain includes the following preferred terms: Chest discomfort, Chest pain.
#
Hepatic dysfunction includes the following preferred terms: Alanine aminotransferase increased, Aspartate aminotransferase increased, Bilirubin conjugated increased, Blood alkaline phosphatase increased, Blood bilirubin increased, Blood bilirubin unconjugated increased, Gamma-glutamyltransferase increased, Hepatic enzyme increased, Hepatic function abnormal, Hepatic steatosis, Hepatitis toxic, Hepatomegaly, Hepatotoxicity, Hyperbilirubinemia, Liver disorder, Liver function test abnormal, Liver function test increased, Transaminases increased.
Þ
Respiratory tract infection includes the following preferred terms: Nasopharyngitis, Respiratory tract congestion, Respiratory tract infection, Respiratory tract infection viral, Upper respiratory tract infection, Viral upper respiratory tract infection.
ß
Influenza includes the following preferred terms: H1N1 influenza, Influenza.
à
Pneumonia includes the following preferred terms: Atypical pneumonia, Lower respiratory tract congestion, Lower respiratory tract infection, Pneumonia, Pneumonia aspiration, Pneumonia bacterial, Pneumonia fungal, Pneumonia necrotising, Pneumonia streptococcal.
è
Hypertension* includes the following preferred terms: Blood pressure increased, Blood pressure systolic increased, Essential hypertension, Hypertension, Hypertensive crisis, Retinopathy hypertensive.
* ADR identified post-marketing.

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.

Table 10: Number (%) of Patients With Clinically Relevant All Grade 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*
CP CML
N=403
%
AdvP CML
N=143
%
All gradeGrade 3/4All gradeGrade 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.
*
Based on a Minimum of 105 Months of Follow-up.

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.

Table 11: Adverse Reactions (10% or Greater) in Pediatric Patients with Newly Diagnosed CP Ph+ CML or CP Ph+ CML Resistant or Intolerant to Prior Therapy Who Received BOSULIF 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.
*
Abdominal pain includes the following preferred terms: Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Dyspepsia, Epigastric discomfort, Gastrointestinal pain, Hepatic pain.
Rash includes the following preferred terms: Acarodermatitis, Acne, Angular cheilitis, Blister, Dermatitis, Dermatitis acneiform, Dermatitis bullous, Dermatitis exfoliative generalized, Dermatitis psoriasiform, Drug eruption, Drug reaction with eosinophilia and systemic symptoms, Dyshidrotic eczema, Eczema, Eczema asteatotic, Erythema, Erythema annulare, Erythema nodosum, Exfoliative rash, Genital rash, Lichen planus, Lichenoid keratosis, Palmar erythema, Palmar-plantar erythrodysesthesia syndrome, Perivascular dermatitis, Photosensitivity reaction, Pigmentation disorder, Pruritus allergic, Psoriasis, Punctate keratitis, Pyoderma gangrenosum, Pyogenic granuloma, Rash, Rash erythematous, Rash generalized, Rash macular, Rash maculo-papular, Rash papular, Rash pruritic, Rash pustular, Rash vesicular, Seborrheic dermatitis, Seborrhoeic keratosis, Skin depigmentation, Skin discoloration, Skin disorder, Skin exfoliation, Skin hyperpigmentation, Skin hypopigmentation, Skin irritation, Skin lesion, Skin plaque, Skin reaction, Skin toxicity, Stasis dermatitis.
Hepatic dysfunction includes the following preferred terms: Alanine aminotransferase abnormal, Alanine aminotransferase increased, Aspartate aminotransferase, Aspartate aminotransferase increased, Bilirubin conjugated increased, Blood alkaline phosphatase increased, Blood bilirubin increased, Blood bilirubin unconjugated increased, Gamma-glutamyltransferase increased, Hepatic enzyme increased, Hepatomegaly, Hepatosplenomegaly, Hyperbilirubinaemia, Jaundice, Liver function test abnormal, Liver function test increased, Ocular icterus, Transaminases increased, Hepatic function abnormal, Drug-induced liver injury, Hepatic steatosis, Hepatitis, Hepatitis toxic, Hepatobiliary disease, Hepatocellular injury, Hepatotoxicity, Liver disorder, Liver injury.
§
Fatigue includes the following preferred terms: Asthenia, Fatigue, Malaise.
Respiratory tract infection includes the following preferred terms: Nasopharyngitis, Respiratory tract congestion, Respiratory tract infection, Respiratory tract infection viral, Upper respiratory tract congestion, Upper respiratory tract infection, Upper respiratory tract inflammation, Viral upper respiratory tract infection.

System Organ Class

Preferred Term

BOSULIF Total
(N=49)

%

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.

Table 12: Laboratory Abnormalities (≥ 20%) That Worsened From Baseline in Pediatric Patients with Newly-Diagnosed CP Ph+ CML or CP Ph+ CML Resistant or Intolerant to Prior Therapy Who Received BOSULIF 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 Disorders0.1% 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), Interstitial lung disease, 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

Medication Guide

Health Professional Information

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