BESPONSA™ Adverse Reactions

(inotuzumab ozogamicin)

6. ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the label:

Hepatotoxicity, including hepatic VOD (also known as SOS) [see Warnings and Precautions (5.1)]
Increased risk of post-transplant non-relapse mortality [see Warnings and Precautions (5.2)]
Myelosuppression [see Warnings and Precautions (5.3)]
Infusion related reactions [see Warnings and Precautions (5.4)]
QT interval prolongation [see Warnings and Precautions (5.5)]

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.

Relapsed or Refractory B-cell Precursor ALL

Adult Patients

The safety of BESPONSA was evaluated in adult patients with relapsed or refractory B-cell precursor ALL in the INO-VATE ALL trial. The study was a randomized clinical study of BESPONSA (n=164) versus Investigator’s choice of chemotherapy (fludarabine + cytarabine + granulocyte colony-stimulating factor [FLAG], mitoxantrone + cytarabine [MXN/Ara-C], or high dose cytarabine [HIDAC]) (n=143) [see Clinical Studies (14)].

Of the 164 patients who received BESPONSA, the median age was 47 years (range: 18–78 years), 56% were male, 68% had received 1 prior treatment regimen for ALL, 31% had received 2 prior treatment regimens for ALL, 68% were White, 19% were Asian, and 2% were Black.

In patients who received BESPONSA, the median duration of treatment was 8.9 weeks (range: 0.1–26.4 weeks), with a median of 3 treatment cycles started in each patient. In patients who received Investigator's choice of chemotherapy, the median duration of treatment was 0.9 weeks (range: 0.1–15.6 weeks), with a median of 1 treatment cycle started in each patient.

In patients who received BESPONSA, the most common (≥ 20%) adverse reactions were thrombocytopenia, neutropenia, infection, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, transaminases increased, abdominal pain, gamma-glutamyltransferase increased, and hyperbilirubinemia.

In patients who received BESPONSA, the most common (≥ 2%) serious adverse reactions were infection, febrile neutropenia, hemorrhage, abdominal pain, pyrexia, VOD, and fatigue.

In patients who received BESPONSA, the most common (≥ 2%) adverse reactions reported as the reason for permanent discontinuation were infection (6%), thrombocytopenia (2%), hyperbilirubinemia (2%), transaminases increased (2%), and hemorrhage (2%); the most common (≥ 5%) adverse reactions reported as the reason for dosing interruption were neutropenia (17%), infection (10%), thrombocytopenia (10%), transaminases increased (6%), and febrile neutropenia (5%); and the most common (≥ 1%) adverse reactions reported as the reason for dose reduction were neutropenia (1%), thrombocytopenia (1%), and transaminases increased (1%).

VOD was reported in 23/164 patients (14%) who received BESPONSA during or following treatment or following a HSCT after completion of treatment [see Warnings and Precautions (5.1)].

Table 7 shows the adverse reactions with ≥ 10% incidence reported in patients with relapsed or refractory ALL who received BESPONSA or Investigator's choice of chemotherapy.

Table 7. Adverse Reactions With ≥ 10% Incidence* in Adult Patients With Relapsed or Refractory B-Cell Precursor ALL Who Received BESPONSA or Investigator's Choice of Chemotherapy (FLAG, MXN/Ara-C, or HIDAC)
Body System
  Adverse Reaction
BESPONSA
(N=164)
FLAG, MXN/Ara-C, or HIDAC
(N=143)
All Grades≥ Grade 3All Grades≥ Grade 3
%%%%
Adverse reactions included treatment-emergent all-causality events that commenced on or after Cycle 1 Day 1 within 42 days after the final dose of BESPONSA, but prior to the start of a new anticancer treatment (including HSCT).
Preferred terms were retrieved by applying the Medical Dictionary for Regulatory Activities (MedDRA) version 18.1.
Severity grade of adverse reactions were according to NCI CTCAE version 3.0.
Abbreviations: ALL=acute lymphoblastic leukemia; FLAG=fludarabine + cytarabine + granulocyte colony-stimulating factor; HIDAC=high dose cytarabine; HSCT=hematopoietic stem cell transplant; MXN/Ara-C=mitoxantrone + cytarabine; N=number of patients; NCI CTCAE=National Cancer Institute Common Toxicity Criteria for Adverse Events.
*
Only adverse reactions with ≥ 10% incidence in the BESPONSA arm are included.
19 patients randomized to FLAG, MXN/Ara-C, or HIDAC did not receive treatment.
Infection includes any reported preferred terms for BESPONSA retrieved in the System Organ Class Infections and infestations.
§
Thrombocytopenia includes the following reported preferred terms: Platelet count decreased and Thrombocytopenia.
Neutropenia includes the following reported preferred terms: Neutropenia and Neutrophil count decreased.
#
Anemia includes the following reported preferred terms: Anemia and Hemoglobin decreased.
Þ
Leukopenia includes the following reported preferred terms: Leukopenia, Monocytopenia, and White blood cell count decreased.
ß
Lymphopenia includes the following reported preferred terms: B-lymphocyte count decreased, Lymphocyte count decreased, and Lymphopenia.
à
Headache includes the following reported preferred terms: Headache, Migraine, and Sinus headache.
è
Hemorrhage includes reported preferred terms for BESPONSA retrieved in the Standard MedDRA Query (narrow) for Hemorrhage terms (excluding laboratory terms), resulting in the following preferred terms: Conjunctival hemorrhage, Contusion, Ecchymosis, Epistaxis, Eyelid bleeding, Gastrointestinal hemorrhage, Gastritis hemorrhagic, Gingival bleeding, Hematemesis, Hematochezia, Hematotympanum, Hematuria, Hemorrhage intracranial, Hemorrhage subcutaneous, Hemorrhoidal hemorrhage, Intra-abdominal hemorrhage, Lip hemorrhage, Lower gastrointestinal hemorrhage, Mesenteric hemorrhage, Metrorrhagia, Mouth hemorrhage, Muscle hemorrhage, Oral mucosa hematoma, Petechiae, Post-procedural hematoma, Rectal hemorrhage, Shock hemorrhagic, Subcutaneous hematoma, Subdural hematoma, Upper gastrointestinal hemorrhage, and Vaginal hemorrhage.
ð
Abdominal pain includes the following reported preferred terms: Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Esophageal pain, and Hepatic pain.
ø
Stomatitis includes the following reported preferred terms: Aphthous ulcer, Mucosal inflammation, Mouth ulceration, Oral pain, Oropharyngeal pain, and Stomatitis.
ý
Fatigue includes the following reported preferred terms: Asthenia and Fatigue.
£
Transaminases increased includes the following reported preferred terms: Aspartate aminotransferase increased, Alanine aminotransferase increased, Hepatocellular injury, and Hypertransaminasemia.

Infections

  Infection

48

28

76

54

Blood and lymphatic system disorders

  Thrombocytopenia§

51

42

61

59

  Neutropenia

49

48

45

43

  Anemia#

36

24

59

47

  LeukopeniaÞ

35

33

43

42

  Febrile neutropenia

26

26

53

53

  Lymphopeniaß

18

16

27

26

Metabolism and nutrition disorders

  Decreased appetite

12

1

13

2

Nervous system disorders

  Headacheà

28

2

27

1

Vascular disorders

  Hemorrhageè

33

5

28

5

Gastrointestinal disorders

  Nausea

31

2

46

0

  Abdominal painð

23

3

23

1

  Diarrhea

17

1

38

1

  Constipation

16

0

24

0

  Vomiting

15

1

24

0

  Stomatitisø

13

2

26

3

Hepatobiliary disorders

  Hyperbilirubinemia

21

5

17

6

General disorders and administration site conditions

  Fatigueý

35

5

25

3

  Pyrexia

32

3

42

6

  Chills

11

0

11

0

Investigations

  Transaminases increased£

26

7

13

5

  Gamma-glutamyltransferase increased

21

10

8

4

  Alkaline phosphatase increased

13

2

7

0

Additional adverse reactions (all grades) that were reported in less than 10% of patients treated with BESPONSA included: lipase increased (9%), abdominal distension (6%), amylase increased (5%), hyperuricemia (4%), ascites (4%), infusion related reaction (2%; includes the following: hypersensitivity and infusion related reaction), pancytopenia (2%; includes the following: bone marrow failure, febrile bone marrow aplasia, and pancytopenia), tumor lysis syndrome (2%), and electrocardiogram QT prolonged (1%).

Table 8 shows the clinically important laboratory abnormalities reported in patients with relapsed or refractory ALL who received BESPONSA or Investigator's choice of chemotherapy.

Table 8. Laboratory Abnormalities in Patients With Relapsed or Refractory B-Cell Precursor ALL Who Received BESPONSA or Investigator's Choice of Chemotherapy (FLAG, MXN/Ara-C, or HIDAC)
BESPONSAFLAG, MXN/Ara-C, or HIDAC
All GradesGrade 3/4All GradesGrade 3/4
Laboratory Abnormality*N%%N%%
Severity grade of laboratory abnormalities according to NCI CTCAE version 3.0.
Abbreviations: ALL=acute lymphoblastic leukemia; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; FLAG=fludarabine + cytarabine + granulocyte colony-stimulating factor; GGT=gamma-glutamyltransferase; HIDAC=high dose cytarabine; MXN/Ara-C=mitoxantrone + cytarabine; N=number of patients; NCI CTCAE=National Cancer Institute Common Toxicity Criteria for Adverse Events.
*
Laboratory abnormalities were summarized up to the end of treatment + 42 days but prior to the start of a new anti-cancer therapy.

Hematology

Platelet count decreased

161

98

76

142

100

99

Hemoglobin decreased

161

94

40

142

100

70

Leukocytes decreased

161

95

82

142

99

98

Neutrophil count decreased

160

94

86

130

93

88

Lymphocytes (absolute) decreased

160

93

71

127

97

91

Chemistry

GGT increased

148

67

18

111

68

17

AST increased

160

71

4

134

38

4

ALP increased

158

57

1

133

52

3

ALT increased

161

49

4

137

46

4

Blood bilirubin increased

161

36

5

138

35

6

Lipase increased

139

32

13

90

20

2

Hyperuricemia

158

16

3

122

11

0

Amylase increased

143

15

2

102

9

1

Pediatric Patients

The safety of BESPONSA in pediatric patients 1 year and older with relapsed or refractory CD22-positive B-cell precursor ALL was evaluated in a multicenter, single-arm, open-label study (ITCC-059) [see Clinical Studies (14)]. Patients (n=53) received the recommended dosage of BESPONSA [see Dosage and Administration (2.1)] or BESPONSA at an initial dose of 1.4 mg/m2/cycle (approximately 0.78 times the recommended initial dosage). Patients received BESPONSA for a median of 2 (range: 1-4) cycles. The median age of patients who received BESPONSA was 9 years (range: 1-17), with 68% male.

Serious adverse reactions occurred in 62% of patients who received BESPONSA. Serious adverse reactions in > 2% of patients included infection (21%), febrile neutropenia (17%), VOD (15%), hemorrhage (4%), pyrexia (6%) and multiorgan failure (2%). Fatal adverse reactions occurred in 8% of patients who received BESPONSA, including multiorgan failure, lung infection, sepsis, and encephalopathy.

Permanent discontinuation of BESPONSA due to an adverse reaction occurred in 21% of patients. Adverse reactions which resulted in permanent discontinuation of BESPONSA in 2 or more patients included ALT increased and platelet count decreased.

Dosage interruptions of BESPONSA due to an adverse reaction occurred in 11% of patients. Adverse reactions which required dosage interruption of BESPONSA in 6 patients included increased transaminases, febrile neutropenia, and headache.

The most common adverse reactions (≥ 20%), including laboratory abnormalities, were thrombocytopenia, pyrexia, anemia, vomiting, infection, hemorrhage, neutropenia, nausea, leukopenia, febrile neutropenia, increased transaminases, abdominal pain, and headache.

Table 9 summarizes the adverse reactions in ITCC-059.

Table 9. Adverse Reactions (≥ 5%) in Pediatric Patients (N=53) With CD22-Positive Relapsed or Refractory ALL in Study WI203581 (ITCC-059)
Severity grade of adverse reactions were according to NCI CTCAE version 4.03.
*
Includes other related terms.
Infection includes any reported preferred terms for system organ class infections and infestations resulting in the following preferred terms: Acinetobacter bacteremia, bacteremia, candida infection, Cytomegalovirus infection, device related infection, device related sepsis, encephalitis, infectious enterocolitis, fungal infection, herpes virus infection, herpes zoster, influenza, kidney infection, mucosal infection, otitis media, paronychia, pneumonia, pneumonia fungal, respiratory tract infection, rhinitis, sepsis, sinusitis, skin infection, stoma site infection, upper respiratory tract infection, urinary tract inflammation, urinary tract infection, vaginal infection.
Hemorrhage includes any reported PT terms within the hemorrhage terms (excl laboratory terms) (SMQ) narrow, resulting in the following preferred terms: catheter site hemorrhage, diarrhea hemorrhagic, epistaxis, gingival bleeding, hematemesis, hematoma, hematuria, hemoptysis, hemorrhage intracranial, hemorrhoidal hemorrhage, lip hemorrhage, mouth hemorrhage, oral blood blister, petechiae, purpura, thrombotic thrombocytopenic purpura, and upper gastrointestinal hemorrhage.
§
Infusion related reaction includes the following preferred terms: infusion-related reaction and hypersensitivity.

Body System

     Adverse Reaction

BESPONSA Monotherapy

(N=53)

All Grades

≥ Grade 3

%

%

General disorders and administration site conditions

     Pyrexia

49

4

     Edema*

19

0

     Fatigue*

17

0

     Pain

15

2

     Chills

8

0

Blood and lymphatic system disorders

     Anemia*

45

38

     Febrile neutropenia

28

28

Gastrointestinal disorders

     Vomiting

45

2

     Nausea

32

0

     Abdominal pain*

25

2

     Constipation

19

2

     Stomatitis*

17

6

     Diarrhea

11

0

Infections and infestations

     Infection

43

23

Vascular disorders

     Hemorrhage

42

6

     Hypotension

6

4

Nervous system disorders

     Headache*

21

0

Skin and subcutaneous tissue disorders

     Rash*

19

4

     Pruritis

9

0

     Hyperhidrosis

6

0

Musculoskeletal and connective tissue disorders

     Pain in extremity

19

2

     Back pain

6

0

     Neck pain

6

0

     Muscular weakness

6

0

Respiratory, thoracic and mediastinal disorders

     Cough

17

0

     Dyspnea

8

2

     Hypoxia

8

4

Hepatobiliary disorders

     Veno-occlusive disease*

15

13

     Hyperbilirubinemia*

9

8

Metabolism and nutrition disorders

     Decreased appetite

11

4

     Tumor lysis syndrome

11

11

Investigations

     Weight increased

8

2

Injury, poisoning and procedural complications

     Infusion related reaction§

8

0

Cardiac disorders

     Sinus tachycardia

6

2

Psychiatric disorders

     Anxiety

6

0

Table 10 summarizes select laboratory abnormalities in pediatric patients with CD22-positive relapsed/refractory ALL after receiving BESPONSA monotherapy in Study WI203581 (ITCC-059).

Table 10. Select Laboratory Abnormalities in Pediatric Patients with CD22-positive Relapsed/Refractory ALL after receiving BESPONSA Monotherapy in Study WI203581 (ITCC-059)
Severity grade of laboratory abnormalities according to NCI CTCAE version 4.03.
Abbreviations: N= number of subjects with valid post-baseline assessment; NCI CTCAE=National Cancer Institute Common Toxicity Criteria for Adverse Events.

Laboratory Abnormality

BESPONSA Monotherapy

All Grades

Grade 3/4

N

%

%

Hematology

Platelet count decreased

53

100

85

Neutrophil count decreased

53

98

96

White blood cell decreased

53

98

89

Hemoglobin decreased

53

96

42

Lymphocyte count decreased

52

87

73

Chemistry

AST increased

53

87

21

ALT increased

53

83

21

GGT increased

33

79

27

Blood bilirubin increased

53

30

9

ALP increased

53

28

0

Lipase increased

48

23

4

Serum amylase increased

49

14

0

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Adverse Reactions

6. ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the label:

Hepatotoxicity, including hepatic VOD (also known as SOS) [see Warnings and Precautions (5.1)]
Increased risk of post-transplant non-relapse mortality [see Warnings and Precautions (5.2)]
Myelosuppression [see Warnings and Precautions (5.3)]
Infusion related reactions [see Warnings and Precautions (5.4)]
QT interval prolongation [see Warnings and Precautions (5.5)]

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.

Relapsed or Refractory B-cell Precursor ALL

Adult Patients

The safety of BESPONSA was evaluated in adult patients with relapsed or refractory B-cell precursor ALL in the INO-VATE ALL trial. The study was a randomized clinical study of BESPONSA (n=164) versus Investigator’s choice of chemotherapy (fludarabine + cytarabine + granulocyte colony-stimulating factor [FLAG], mitoxantrone + cytarabine [MXN/Ara-C], or high dose cytarabine [HIDAC]) (n=143) [see Clinical Studies (14)].

Of the 164 patients who received BESPONSA, the median age was 47 years (range: 18–78 years), 56% were male, 68% had received 1 prior treatment regimen for ALL, 31% had received 2 prior treatment regimens for ALL, 68% were White, 19% were Asian, and 2% were Black.

In patients who received BESPONSA, the median duration of treatment was 8.9 weeks (range: 0.1–26.4 weeks), with a median of 3 treatment cycles started in each patient. In patients who received Investigator's choice of chemotherapy, the median duration of treatment was 0.9 weeks (range: 0.1–15.6 weeks), with a median of 1 treatment cycle started in each patient.

In patients who received BESPONSA, the most common (≥ 20%) adverse reactions were thrombocytopenia, neutropenia, infection, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, transaminases increased, abdominal pain, gamma-glutamyltransferase increased, and hyperbilirubinemia.

In patients who received BESPONSA, the most common (≥ 2%) serious adverse reactions were infection, febrile neutropenia, hemorrhage, abdominal pain, pyrexia, VOD, and fatigue.

In patients who received BESPONSA, the most common (≥ 2%) adverse reactions reported as the reason for permanent discontinuation were infection (6%), thrombocytopenia (2%), hyperbilirubinemia (2%), transaminases increased (2%), and hemorrhage (2%); the most common (≥ 5%) adverse reactions reported as the reason for dosing interruption were neutropenia (17%), infection (10%), thrombocytopenia (10%), transaminases increased (6%), and febrile neutropenia (5%); and the most common (≥ 1%) adverse reactions reported as the reason for dose reduction were neutropenia (1%), thrombocytopenia (1%), and transaminases increased (1%).

VOD was reported in 23/164 patients (14%) who received BESPONSA during or following treatment or following a HSCT after completion of treatment [see Warnings and Precautions (5.1)].

Table 7 shows the adverse reactions with ≥ 10% incidence reported in patients with relapsed or refractory ALL who received BESPONSA or Investigator's choice of chemotherapy.

Table 7. Adverse Reactions With ≥ 10% Incidence* in Adult Patients With Relapsed or Refractory B-Cell Precursor ALL Who Received BESPONSA or Investigator's Choice of Chemotherapy (FLAG, MXN/Ara-C, or HIDAC)
Body System
  Adverse Reaction
BESPONSA
(N=164)
FLAG, MXN/Ara-C, or HIDAC
(N=143)
All Grades≥ Grade 3All Grades≥ Grade 3
%%%%
Adverse reactions included treatment-emergent all-causality events that commenced on or after Cycle 1 Day 1 within 42 days after the final dose of BESPONSA, but prior to the start of a new anticancer treatment (including HSCT).
Preferred terms were retrieved by applying the Medical Dictionary for Regulatory Activities (MedDRA) version 18.1.
Severity grade of adverse reactions were according to NCI CTCAE version 3.0.
Abbreviations: ALL=acute lymphoblastic leukemia; FLAG=fludarabine + cytarabine + granulocyte colony-stimulating factor; HIDAC=high dose cytarabine; HSCT=hematopoietic stem cell transplant; MXN/Ara-C=mitoxantrone + cytarabine; N=number of patients; NCI CTCAE=National Cancer Institute Common Toxicity Criteria for Adverse Events.
*
Only adverse reactions with ≥ 10% incidence in the BESPONSA arm are included.
19 patients randomized to FLAG, MXN/Ara-C, or HIDAC did not receive treatment.
Infection includes any reported preferred terms for BESPONSA retrieved in the System Organ Class Infections and infestations.
§
Thrombocytopenia includes the following reported preferred terms: Platelet count decreased and Thrombocytopenia.
Neutropenia includes the following reported preferred terms: Neutropenia and Neutrophil count decreased.
#
Anemia includes the following reported preferred terms: Anemia and Hemoglobin decreased.
Þ
Leukopenia includes the following reported preferred terms: Leukopenia, Monocytopenia, and White blood cell count decreased.
ß
Lymphopenia includes the following reported preferred terms: B-lymphocyte count decreased, Lymphocyte count decreased, and Lymphopenia.
à
Headache includes the following reported preferred terms: Headache, Migraine, and Sinus headache.
è
Hemorrhage includes reported preferred terms for BESPONSA retrieved in the Standard MedDRA Query (narrow) for Hemorrhage terms (excluding laboratory terms), resulting in the following preferred terms: Conjunctival hemorrhage, Contusion, Ecchymosis, Epistaxis, Eyelid bleeding, Gastrointestinal hemorrhage, Gastritis hemorrhagic, Gingival bleeding, Hematemesis, Hematochezia, Hematotympanum, Hematuria, Hemorrhage intracranial, Hemorrhage subcutaneous, Hemorrhoidal hemorrhage, Intra-abdominal hemorrhage, Lip hemorrhage, Lower gastrointestinal hemorrhage, Mesenteric hemorrhage, Metrorrhagia, Mouth hemorrhage, Muscle hemorrhage, Oral mucosa hematoma, Petechiae, Post-procedural hematoma, Rectal hemorrhage, Shock hemorrhagic, Subcutaneous hematoma, Subdural hematoma, Upper gastrointestinal hemorrhage, and Vaginal hemorrhage.
ð
Abdominal pain includes the following reported preferred terms: Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Esophageal pain, and Hepatic pain.
ø
Stomatitis includes the following reported preferred terms: Aphthous ulcer, Mucosal inflammation, Mouth ulceration, Oral pain, Oropharyngeal pain, and Stomatitis.
ý
Fatigue includes the following reported preferred terms: Asthenia and Fatigue.
£
Transaminases increased includes the following reported preferred terms: Aspartate aminotransferase increased, Alanine aminotransferase increased, Hepatocellular injury, and Hypertransaminasemia.

Infections

  Infection

48

28

76

54

Blood and lymphatic system disorders

  Thrombocytopenia§

51

42

61

59

  Neutropenia

49

48

45

43

  Anemia#

36

24

59

47

  LeukopeniaÞ

35

33

43

42

  Febrile neutropenia

26

26

53

53

  Lymphopeniaß

18

16

27

26

Metabolism and nutrition disorders

  Decreased appetite

12

1

13

2

Nervous system disorders

  Headacheà

28

2

27

1

Vascular disorders

  Hemorrhageè

33

5

28

5

Gastrointestinal disorders

  Nausea

31

2

46

0

  Abdominal painð

23

3

23

1

  Diarrhea

17

1

38

1

  Constipation

16

0

24

0

  Vomiting

15

1

24

0

  Stomatitisø

13

2

26

3

Hepatobiliary disorders

  Hyperbilirubinemia

21

5

17

6

General disorders and administration site conditions

  Fatigueý

35

5

25

3

  Pyrexia

32

3

42

6

  Chills

11

0

11

0

Investigations

  Transaminases increased£

26

7

13

5

  Gamma-glutamyltransferase increased

21

10

8

4

  Alkaline phosphatase increased

13

2

7

0

Additional adverse reactions (all grades) that were reported in less than 10% of patients treated with BESPONSA included: lipase increased (9%), abdominal distension (6%), amylase increased (5%), hyperuricemia (4%), ascites (4%), infusion related reaction (2%; includes the following: hypersensitivity and infusion related reaction), pancytopenia (2%; includes the following: bone marrow failure, febrile bone marrow aplasia, and pancytopenia), tumor lysis syndrome (2%), and electrocardiogram QT prolonged (1%).

Table 8 shows the clinically important laboratory abnormalities reported in patients with relapsed or refractory ALL who received BESPONSA or Investigator's choice of chemotherapy.

Table 8. Laboratory Abnormalities in Patients With Relapsed or Refractory B-Cell Precursor ALL Who Received BESPONSA or Investigator's Choice of Chemotherapy (FLAG, MXN/Ara-C, or HIDAC)
BESPONSAFLAG, MXN/Ara-C, or HIDAC
All GradesGrade 3/4All GradesGrade 3/4
Laboratory Abnormality*N%%N%%
Severity grade of laboratory abnormalities according to NCI CTCAE version 3.0.
Abbreviations: ALL=acute lymphoblastic leukemia; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; FLAG=fludarabine + cytarabine + granulocyte colony-stimulating factor; GGT=gamma-glutamyltransferase; HIDAC=high dose cytarabine; MXN/Ara-C=mitoxantrone + cytarabine; N=number of patients; NCI CTCAE=National Cancer Institute Common Toxicity Criteria for Adverse Events.
*
Laboratory abnormalities were summarized up to the end of treatment + 42 days but prior to the start of a new anti-cancer therapy.

Hematology

Platelet count decreased

161

98

76

142

100

99

Hemoglobin decreased

161

94

40

142

100

70

Leukocytes decreased

161

95

82

142

99

98

Neutrophil count decreased

160

94

86

130

93

88

Lymphocytes (absolute) decreased

160

93

71

127

97

91

Chemistry

GGT increased

148

67

18

111

68

17

AST increased

160

71

4

134

38

4

ALP increased

158

57

1

133

52

3

ALT increased

161

49

4

137

46

4

Blood bilirubin increased

161

36

5

138

35

6

Lipase increased

139

32

13

90

20

2

Hyperuricemia

158

16

3

122

11

0

Amylase increased

143

15

2

102

9

1

Pediatric Patients

The safety of BESPONSA in pediatric patients 1 year and older with relapsed or refractory CD22-positive B-cell precursor ALL was evaluated in a multicenter, single-arm, open-label study (ITCC-059) [see Clinical Studies (14)]. Patients (n=53) received the recommended dosage of BESPONSA [see Dosage and Administration (2.1)] or BESPONSA at an initial dose of 1.4 mg/m2/cycle (approximately 0.78 times the recommended initial dosage). Patients received BESPONSA for a median of 2 (range: 1-4) cycles. The median age of patients who received BESPONSA was 9 years (range: 1-17), with 68% male.

Serious adverse reactions occurred in 62% of patients who received BESPONSA. Serious adverse reactions in > 2% of patients included infection (21%), febrile neutropenia (17%), VOD (15%), hemorrhage (4%), pyrexia (6%) and multiorgan failure (2%). Fatal adverse reactions occurred in 8% of patients who received BESPONSA, including multiorgan failure, lung infection, sepsis, and encephalopathy.

Permanent discontinuation of BESPONSA due to an adverse reaction occurred in 21% of patients. Adverse reactions which resulted in permanent discontinuation of BESPONSA in 2 or more patients included ALT increased and platelet count decreased.

Dosage interruptions of BESPONSA due to an adverse reaction occurred in 11% of patients. Adverse reactions which required dosage interruption of BESPONSA in 6 patients included increased transaminases, febrile neutropenia, and headache.

The most common adverse reactions (≥ 20%), including laboratory abnormalities, were thrombocytopenia, pyrexia, anemia, vomiting, infection, hemorrhage, neutropenia, nausea, leukopenia, febrile neutropenia, increased transaminases, abdominal pain, and headache.

Table 9 summarizes the adverse reactions in ITCC-059.

Table 9. Adverse Reactions (≥ 5%) in Pediatric Patients (N=53) With CD22-Positive Relapsed or Refractory ALL in Study WI203581 (ITCC-059)
Severity grade of adverse reactions were according to NCI CTCAE version 4.03.
*
Includes other related terms.
Infection includes any reported preferred terms for system organ class infections and infestations resulting in the following preferred terms: Acinetobacter bacteremia, bacteremia, candida infection, Cytomegalovirus infection, device related infection, device related sepsis, encephalitis, infectious enterocolitis, fungal infection, herpes virus infection, herpes zoster, influenza, kidney infection, mucosal infection, otitis media, paronychia, pneumonia, pneumonia fungal, respiratory tract infection, rhinitis, sepsis, sinusitis, skin infection, stoma site infection, upper respiratory tract infection, urinary tract inflammation, urinary tract infection, vaginal infection.
Hemorrhage includes any reported PT terms within the hemorrhage terms (excl laboratory terms) (SMQ) narrow, resulting in the following preferred terms: catheter site hemorrhage, diarrhea hemorrhagic, epistaxis, gingival bleeding, hematemesis, hematoma, hematuria, hemoptysis, hemorrhage intracranial, hemorrhoidal hemorrhage, lip hemorrhage, mouth hemorrhage, oral blood blister, petechiae, purpura, thrombotic thrombocytopenic purpura, and upper gastrointestinal hemorrhage.
§
Infusion related reaction includes the following preferred terms: infusion-related reaction and hypersensitivity.

Body System

     Adverse Reaction

BESPONSA Monotherapy

(N=53)

All Grades

≥ Grade 3

%

%

General disorders and administration site conditions

     Pyrexia

49

4

     Edema*

19

0

     Fatigue*

17

0

     Pain

15

2

     Chills

8

0

Blood and lymphatic system disorders

     Anemia*

45

38

     Febrile neutropenia

28

28

Gastrointestinal disorders

     Vomiting

45

2

     Nausea

32

0

     Abdominal pain*

25

2

     Constipation

19

2

     Stomatitis*

17

6

     Diarrhea

11

0

Infections and infestations

     Infection

43

23

Vascular disorders

     Hemorrhage

42

6

     Hypotension

6

4

Nervous system disorders

     Headache*

21

0

Skin and subcutaneous tissue disorders

     Rash*

19

4

     Pruritis

9

0

     Hyperhidrosis

6

0

Musculoskeletal and connective tissue disorders

     Pain in extremity

19

2

     Back pain

6

0

     Neck pain

6

0

     Muscular weakness

6

0

Respiratory, thoracic and mediastinal disorders

     Cough

17

0

     Dyspnea

8

2

     Hypoxia

8

4

Hepatobiliary disorders

     Veno-occlusive disease*

15

13

     Hyperbilirubinemia*

9

8

Metabolism and nutrition disorders

     Decreased appetite

11

4

     Tumor lysis syndrome

11

11

Investigations

     Weight increased

8

2

Injury, poisoning and procedural complications

     Infusion related reaction§

8

0

Cardiac disorders

     Sinus tachycardia

6

2

Psychiatric disorders

     Anxiety

6

0

Table 10 summarizes select laboratory abnormalities in pediatric patients with CD22-positive relapsed/refractory ALL after receiving BESPONSA monotherapy in Study WI203581 (ITCC-059).

Table 10. Select Laboratory Abnormalities in Pediatric Patients with CD22-positive Relapsed/Refractory ALL after receiving BESPONSA Monotherapy in Study WI203581 (ITCC-059)
Severity grade of laboratory abnormalities according to NCI CTCAE version 4.03.
Abbreviations: N= number of subjects with valid post-baseline assessment; NCI CTCAE=National Cancer Institute Common Toxicity Criteria for Adverse Events.

Laboratory Abnormality

BESPONSA Monotherapy

All Grades

Grade 3/4

N

%

%

Hematology

Platelet count decreased

53

100

85

Neutrophil count decreased

53

98

96

White blood cell decreased

53

98

89

Hemoglobin decreased

53

96

42

Lymphocyte count decreased

52

87

73

Chemistry

AST increased

53

87

21

ALT increased

53

83

21

GGT increased

33

79

27

Blood bilirubin increased

53

30

9

ALP increased

53

28

0

Lipase increased

48

23

4

Serum amylase increased

49

14

0

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