gemcitabine injection powder 2GM Adverse Reactions

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

•
Hypersensitivity [see Contraindications (4)]
•
Schedule-Dependent Toxicity [see Warnings and Precautions (5.1)]
•
Myelosuppression [see Warnings and Precautions (5.2)]
•
Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.3)]
•
Pulmonary Toxicity and Respiratory Failure [see Warnings and Precautions (5.4)]
•
Hemolytic Uremic Syndrome [see Warnings and Precautions (5.5)]
•
Hepatic Toxicity [see Warnings and Precautions (5.6)]
•
Exacerbation of Radiation Therapy Toxicity [see Warnings and Precautions (5.8)]
•
Capillary Leak Syndrome [see Warnings and Precautions (5.9)]
•
Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.10)]

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.

Single Agent

The data described below reflect exposure to gemcitabine as a single agent administered at doses between 800 mg/m2 to 1,250 mg/m2 intravenously over 30 minutes once weekly in 979 patients with various malignancies. The most common (≥20%) adverse reactions of single agent gemcitabine are nausea/vomiting, anemia, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), neutropenia, increased alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea, and edema. The most common (≥5%) Grade 3 or 4 adverse reactions were neutropenia, nausea/vomiting, increased ALT, increased alkaline phosphatase, anemia, increased AST, and thrombocytopenia. Approximately 10% of the 979 patients discontinued gemcitabine due to adverse reactions. Adverse reactions resulting in discontinuation of gemcitabine in 2% of 979 patients were cardiovascular adverse reactions (myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension) and adverse reactions resulting in discontinuation of gemcitabine in <1% of 979 patients were anemia, thrombocytopenia, hepatic dysfunction, renal dysfunction, nausea/vomiting, fever, rash, dyspnea, hemorrhage, infection, stomatitis, somnolence, flu-like syndrome, and edema.

Tables 5 and 6 present the incidence of selected adverse reactions and laboratory abnormalities reported in patients with various malignancies receiving single agent gemcitabine across 5 clinical trials. Additional clinically significant adverse reactions are provided following Table 6.

Table 5: Selected Adverse Reactions Occurring in ≥10% of Patients Receiving Single Agent Gemcitabine*
Adverse Reactions†Gemcitabine‡
All Grades
(%)		Grade 3
(%)		Grade 4
(%)
*
Grade based on criteria from the World Health Organization (WHO).
†
For approximately 60% of patients, non-laboratory adverse reactions were graded only if assessed to be possibly drug-related.
‡
N=699–974; all patients with laboratory or non-laboratory data.

Nausea and Vomiting

69

13

1

Fever

41

2

0

Rash

30

<1

0

Dyspnea

23

3

<1

Diarrhea

19

1

0

Hemorrhage

17

<1

<1

Infection

16

1

<1

Alopecia

15

<1

0

Stomatitis

11

<1

0

Somnolence

11

<1

<1

Paresthesias

10

<1

0

Table 6: Selected Laboratory Abnormalities Occurring in Patients Receiving Single Agent Gemcitabine*
Laboratory Abnormality†Gemcitabine‡
All Grades
(%)		Grade 3
(%)		Grade 4
(%)
*
Grade based on criteria from the WHO.
†
Regardless of causality.
‡
N=699–974; all patients with laboratory or non-laboratory data.

Hematologic

  Anemia

68

7

1

  Neutropenia

63

19

6

  Thrombocytopenia

24

4

1

Hepatic

  Increased ALT

68

8

2

  Increased AST

67

6

2

  Increased Alkaline

55

7

2

  Phosphatase

  Hyperbilirubinemia

13

2

<1

Renal

  Proteinuria

45

<1

0

  Hematuria

35

<1

0

  Increased BUN

16

0

0

  Increased Creatinine

8

<1

0

Additional adverse reactions include the following:

•
Transfusion requirements: Red blood cell transfusions (19%); platelet transfusions (<1%)
•
Edema: Edema (13%), peripheral edema (20%), generalized edema (<1%)
•
Flu-like symptoms: Fever, asthenia, anorexia, headache, cough, chills, myalgia, asthenia insomnia, rhinitis, sweating and/or malaise (19%)
•
Infection: Sepsis (<1%)
•
Extravasation: Injection-site reactions (4%)
•
Allergic: Bronchospasm (<2%); anaphylactoid reactions

Ovarian Cancer

Tables 7 and 8 presents the incidence of selected adverse reactions and laboratory abnormalities, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine with carboplatin arm, reported in a randomized trial (Study 1) of gemcitabine with carboplatin (n=175) compared to carboplatin alone (n=174) for the second-line treatment of ovarian cancer in women with disease that had relapsed more than 6 months following first-line platinum-based chemotherapy [see Clinical Studies (14.1)]. Additional clinically significant adverse reactions, occurring in <10% of patients, are provided following Table 8.

The proportion of patients with dose adjustments for carboplatin (1.8% versus 3.8%), doses of carboplatin omitted (0.2% versus 0) and discontinuing treatment for adverse reactions (11% versus 10%), were similar between arms. Dose adjustment for gemcitabine occurred in 10% of patients and gemcitabine dose was omitted in 14% of patients in the gemcitabine/carboplatin arm.

Table 7: Adverse Reactions Occurring in >10% of Patients Receiving Gemcitabine with Carboplatin and at Higher Incidence than in Patients Receiving Single Agent Carboplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3–4)] in Study 1*
Adverse Reactions†Gemcitabine/Carboplatin
(N=175)		Carboplatin
(N=174)
All Grades
(%)		Grade 3
(%)		Grade 4
(%)		All Grades
(%)		Grade 3
(%)		Grade 4
(%)
*
Grade based on National Cancer Institute CTC Version 2.0.
†
Regardless of causality.

Nausea

69

6

0

61

3

0

Alopecia

49

0

0

17

0

0

Vomiting

46

6

0

36

2

<1

Constipation

42

6

1

37

3

0

Fatigue

40

3

<1

32

5

0

Diarrhea

25

3

0

14

<1

0

Stomatitis/Pharyngitis

22

<1

0

13

0

0

Hematopoietic growth factors were administered more frequently in the gemcitabine-containing arm: leukocyte growth factor (24% and 10%) and erythropoiesis-stimulating agent (7% and 3.9%).

The following clinically relevant Grade 3 and 4 adverse reactions occurred more frequently in the gemcitabine with carboplatin arm: dyspnea (3.4% versus 2.9%), febrile neutropenia (1.1% versus 0), hemorrhagic event (2.3% versus 1.1 %), motor neuropathy (1.1% versus 0.6%), and rash/desquamation (0.6% versus 0).

Table 8: Laboratory Abnormalities Occurring in Patients Receiving Gemcitabine with Carboplatin and at Higher Incidence than in Patients Receiving Single Agent Carboplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3–4)] in Study 1*
Laboratory Abnormality†Gemcitabine/Carboplatin
(N=175)		Carboplatin
(N=174)
All Grades
(%)		Grade 3
(%)		Grade 4
(%)		All Grades
(%)		Grade 3
(%)		Grade 4
(%)
*
Grade based on National Cancer Institute CTC Version 2.0.
†
Regardless of causality.
‡
Percent of patients receiving transfusions. Transfusions are not CTC-graded events. Blood transfusions included both packed red blood cells and whole blood.

Hematologic

Neutropenia

90

42

29

58

11

1

Anemia

86

22

6

75

9

2

Thrombocytopenia

78

30

5

57

10

1

RBC Transfusions‡

38

-

-

15

-

-

Platelet Transfusions‡

9

-

-

3

-

-

Hematopoietic growth factors were administered more frequently in the gemcitabine-containing arm: leukocyte growth factor (24% and 10%) and erythropoiesis-stimulating agent (7% and 3.9%).

The following clinically relevant Grade 3 and 4 adverse reactions occurred more frequently in the gemcitabine with carboplatin arm: dyspnea (3.4% versus 2.9%), febrile neutropenia (1.1% versus 0), hemorrhagic event (2.3% versus 1.1 %), motor neuropathy (1.1% versus 0.6%), and rash/desquamation (0.6% versus 0).

Breast Cancer

Tables 9 and 10 presents the incidence of selected adverse reactions and laboratory abnormalities, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine with paclitaxel arm, reported in a randomized trial (Study 2) of gemcitabine with paclitaxel (n=262) compared to paclitaxel alone (n=259) for the first-line treatment of metastatic breast cancer (MBC) in women who received anthracycline-containing chemotherapy in the adjuvant/neo-adjuvant setting or for whom anthracyclines were contraindicated [see Clinical Studies (14.2)]. Additional clinically significant adverse reactions, occurring in <10% of patients, are provided following Table 10.

The requirement for dose reduction of paclitaxel were higher for patients in the gemcitabine/paclitaxel arm (5% versus 2%). The number of paclitaxel doses omitted (<1%), the proportion of patients discontinuing treatment for adverse reactions (7% versus 5%) and the number of treatment-related deaths (1 patient in each arm) were similar between the two arms.

Table 9: Selected Adverse Reactions Occurring in Patients Receiving Gemcitabine with Paclitaxel and at Higher Incidence than in Patients Receiving Single Agent Paclitaxel [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3–4)] in Study 2*
Adverse Reactions†Gemcitabine/Paclitaxel
(N=262)		Paclitaxel
(N=259)
All Grades
(%)		Grade 3
(%)		Grade 4
(%)		All Grades
(%)		Grade 3
(%)		Grade 4
(%)
*
Grade based on National Cancer Institute CTC Version 2.0.
†
Non-laboratory events were graded only if assessed to be possibly drug-related.

Alopecia

90

14

4

92

19

3

Neuropathy-Sensory

64

5

<1

58

3

0

Nausea

50

1

0

31

2

0

Fatigue

40

6

<1

28

1

<1

Vomiting

29

2

0

15

2

0

Diarrhea

20

3

0

13

2

0

Anorexia

17

0

0

12

<1

0

Neuropathy-Motor

15

2

<1

10

<1

0

Stomatitis/Pharyngitis

13

1

<1

8

<1

0

Fever

13

<1

0

3

0

0

Rash/Desquamation

11

<1

<1

5

0

0

Febrile Neutropenia

6

5

<1

2

1

0

Table 10: Selected Laboratory Abnormalities Occurring in >10% of Patients Receiving Gemcitabine with Paclitaxel and at a Higher Incidence than Patients Receiving Single Agent Paclitaxel [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3–4)] in Study 2*
Laboratory Abnormality†Gemcitabine / Paclitaxel
(N=262)		Paclitaxel
(N=259)
All Grades
(%)		Grade 3
(%)		Grade 4
(%)		All Grades
(%)		Grade 3
(%)		Grade 4
(%)
*
Grade based on National Cancer Institute CTC Version 2.0.
†
Regardless of causality.

Hematologic

  Anemia

69

6

1

51

3

<1

  Neutropenia

69

31

17

31

4

7

  Thrombocytopenia

26

5

<1

7

<1

<1

Hepatobiliary

  Increased ALT

18

5

<1

6

<1

0

  Increased AST

16

2

0

5

<1

0

Clinically relevant Grade 3 or 4 dyspnea occurred with a higher incidence in the gemcitabine with paclitaxel arm compared with the paclitaxel arm (1.9% versus 0).

Non-Small Cell Lung Cancer

Tables 11 and 12 presents the incidence of selected adverse reactions and laboratory abnormalities occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine with cisplatin arm, reported in a randomized trial (Study 3) of gemcitabine with cisplatin (n=260) administered in 28-day cycles as compared to cisplatin alone (n=262) in patients receiving first-line treatment for locally advanced or metastatic NSCLC [see Clinical Studies (14.3)].

Patients randomized to gemcitabine with cisplatin received a median of 4 cycles of treatment and those randomized to cisplatin alone received a median of 2 cycles of treatment. In this trial, the requirement for dose adjustments (>90% versus 16%), discontinuation of treatment for adverse reactions (15% versus 8%), and the proportion of patients hospitalized (36% versus 23%) were all higher for patients receiving gemcitabine with cisplatin compared to those receiving cisplatin alone. The incidence of febrile neutropenia (3% versus <1%), sepsis (4% versus 1%), Grade 3 cardiac dysrhythmias (3% versus <1%) were all higher in the gemcitabine with cisplatin arm compared to the cisplatin alone arm. The two-drug combination was more myelosuppressive with 4 (1.5%) possibly treatment-related deaths, including 3 resulting from myelosuppression with infection and one case of renal failure associated with pancytopenia and infection. No deaths due to treatment were reported on the cisplatin arm.

Table 11: Selected Adverse Reactions Occurring in ≥10% of Patients Receiving Gemcitabine with Cisplatin and at Higher Incidence than in Patients Receiving Single Agent Cisplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3–4)] in Study 3*
Adverse Reactions†Gemcitabine/Cisplatin‡Cisplatin§
All Grades
(%)		Grade 3
(%)		Grade 4
(%)		All Grades
(%)		Grade 3
(%)		Grade 4
(%)
*
Grade based on National Cancer Institute Common Toxicity Criteria (CTC).
†
Non-laboratory events were graded only if assessed to be possibly drug-related.
‡
N=217–253; all gemcitabine/cisplatin patients with laboratory or non-laboratory data.
§
N=213–248; all cisplatin patients with laboratory or non-laboratory data.

Nausea

93

25

2

87

20

<1

Vomiting

78

11

12

71

10

9

Alopecia

53

1

0

33

0

0

Neuro Motor

35

12

0

15

3

0

Diarrhea

24

2

2

13

0

0

Neuro Sensory

23

1

0

18

1

0

Infection

18

3

2

12

1

0

Fever

16

0

0

5

0

0

Neuro Cortical

16

3

1

9

1

0

Neuro Mood

16

1

0

10

1

0

Local

15

0

0

6

0

0

Neuro Headache

14

0

0

7

0

0

Stomatitis

14

1

0

5

0

0

Hemorrhage

14

1

0

4

0

0

Hypotension

12

1

0

7

1

0

Rash

11

0

0

3

0

0

Table 12: Selected Laboratory Abnormalities Occurring in >10% of Patients Receiving Gemcitabine with Cisplatin and at Higher Incidence than in Patients Receiving Single Agent Cisplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3–4)] in Study 3*
Laboratory Abnormality†Gemcitabine/ Cisplatin‡Cisplatin§
All Grades
(%)		Grade 3
(%)		Grade 4
(%)		All Grades
(%)		Grade 3
(%)		Grade 4
(%)
*
Grade based on National Cancer Institute CTC.
†
Regardless of causality.
‡
N=217–253; all gemcitabine/cisplatin patients with laboratory or non-laboratory data.
§
N=213–248; all cisplatin patients with laboratory or non-laboratory data.
Percent of patients receiving transfusions. Percent transfusions are not CTC-graded events.

Hematologic

  Anemia

89

22

3

67

6

1

  Thrombocytopenia

85

25

25

13

3

1

  Neutropenia

79

22

35

20

3

1

  Lymphopenia

75

25

18

51

12

5

  RBC Transfusions

39

-

-

13

-

-

  Platelet Transfusions

21

-

-

<1

-

-

Hepatic

  Increased Transaminases

22

2

1

10

1

0

  Increased Alkaline

19

1

0

13

0

0

  Phosphatase

Renal

  Increased Creatinine

38

4

<1

31

2

<1

  Proteinuria

23

0

0

18

0

0

  Hematuria

15

0

0

13

0

0

Other Laboratory

  Hyperglycemia

30

4

0

23

3

0

  Hypomagnesemia

30

4

3

17

2

0

  Hypocalcemia

18

2

0

7

0

<1

Tables 13 and 14 presents the incidence of selected adverse reactions and laboratory abnormalities occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine with cisplatin arm, reported in a randomized trial (Study 4) of gemcitabine with cisplatin (n=69) administered in 21-day cycles as compared to etoposide with cisplatin (n=66) in patients receiving first-line treatment for locally advanced or metastatic NSCLC [see Clinical Studies (14.3)]. Additional clinically significant adverse reactions are provided following Table 14.

Patients in the gemcitabine/cisplatin (GC) arm received a median of 5 cycles and those in the etoposide/cisplatin (EC) arm received a median of 4 cycles. The majority of patients receiving more than one cycle of treatment required dose adjustments; 81% in the GC arm and 68% in the EC arm. The incidence of hospitalizations for adverse reactions was 22% in the GC arm and 27% in the EC arm. The proportion of patients who discontinued treatment for adverse reactions was higher in the GC arm (14% versus 8%). The proportion of patients who were hospitalized for febrile neutropenia was lower in the GC arm (7% versus 12%). There was one death attributed to treatment, a patient with febrile neutropenia and renal failure, which occurred in the GC arm.

Table 13: Selected Adverse Reactions in Patients Receiving Gemcitabine with Cisplatin in Study 4*
Adverse Reactions†Gemcitabine/Cisplatin‡Etoposide/Cisplatin§
All Grades
(%)		Grade 3
(%)		Grade 4
(%)		All Grades
(%)		Grade 3
(%)		Grade 4
(%)
*
Grade based on criteria from the WHO.
†
Non-laboratory events were graded only if assessed to be possibly drug-related. Pain data were not collected.
‡
N=67–69; all gemcitabine/cisplatin patients with laboratory or non-laboratory data.
§
N=57–63; all Etoposide/cisplatin patients with laboratory or non-laboratory data.
Flu-like syndrome and edema were not graded.

Nausea and Vomiting

96

35

4

86

19

7

Alopecia

77

13

0

92

51

0

Paresthesias

38

0

0

16

2

0

Infection

28

3

1

21

8

0

Stomatitis

20

4

0

18

2

0

Diarrhea

14

1

1

13

0

2

Edema

12

-

-

2

-

-

Rash

10

0

0

3

0

0

Hemorrhage

9

0

3

3

0

3

Fever

6

0

0

3

0

0

Somnolence

3

0

0

3

2

0

Flu-like Syndrome

3

-

-

0

-

-

Dyspnea

1

0

1

3

0

0

Table 14: Selected Laboratory Abnormalities Occurring in Patients Receiving Gemcitabine with Cisplatin in Study 4*
Laboratory Abnormality†Gemcitabine/Cisplatin‡Etoposide/Cisplatin§
All Grades
(%)		Grade 3
(%)		Grade 4
(%)		All Grades
(%)		Grade 3
(%)		Grade 4
(%)
*
Grade based on criteria from the WHO.
†
Regardless of causality.
‡
N=67–69; all gemcitabine/cisplatin patients with laboratory or non-laboratory data.
§
N=57–63; all etoposide/ cisplatin patients with laboratory or non-laboratory data.
WHO grading scale not applicable to proportion of patients with transfusions.

Hematologic

  Anemia

88

22

0

77

13

2

  Neutropenia

88

36

28

87

20

56

  Thrombocytopenia

81

39

16

45

8

5

  RBC Transfusions‡

29

-

-

21

-

-

  Platelet Transfusions

3

-

-

8

-

-

Hepatic

  Increased Alkaline

16

0

0

11

0

0

  Phosphatase

  Increased ALT

6

0

0

12

0

0

  Increased AST

3

0

0

11

0

0

Renal

  Hematuria

22

0

0

10

0

0

  Proteinuria

12

0

0

5

0

0

  Increased BUN

6

0

0

4

0

0

  Increased Creatinine

2

0

0

2

0

0

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of gemcitabine. 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: Thrombotic microangiopathy (TMA)
•
Cardiovascular: Congestive heart failure, myocardial infarction, arrhythmias, supraventricular arrhythmias
•
Vascular: Peripheral vasculitis, gangrene, capillary leak syndrome
•
Skin: Cellulitis; pseudocellulitis; severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP); desquamation and bullous skin eruptions
•
Hepatic: Hepatic failure, hepatic veno-occlusive disease
•
Pulmonary: Interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, adult respiratory distress syndrome (ARDS), pulmonary eosinophilia
•
Nervous System: Posterior reversible encephalopathy syndrome (PRES)

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Adverse Reactions

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

•
Hypersensitivity [see Contraindications (4)]
•
Schedule-Dependent Toxicity [see Warnings and Precautions (5.1)]
•
Myelosuppression [see Warnings and Precautions (5.2)]
•
Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.3)]
•
Pulmonary Toxicity and Respiratory Failure [see Warnings and Precautions (5.4)]
•
Hemolytic Uremic Syndrome [see Warnings and Precautions (5.5)]
•
Hepatic Toxicity [see Warnings and Precautions (5.6)]
•
Exacerbation of Radiation Therapy Toxicity [see Warnings and Precautions (5.8)]
•
Capillary Leak Syndrome [see Warnings and Precautions (5.9)]
•
Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.10)]

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.

Single Agent

The data described below reflect exposure to gemcitabine as a single agent administered at doses between 800 mg/m2 to 1,250 mg/m2 intravenously over 30 minutes once weekly in 979 patients with various malignancies. The most common (≥20%) adverse reactions of single agent gemcitabine are nausea/vomiting, anemia, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), neutropenia, increased alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea, and edema. The most common (≥5%) Grade 3 or 4 adverse reactions were neutropenia, nausea/vomiting, increased ALT, increased alkaline phosphatase, anemia, increased AST, and thrombocytopenia. Approximately 10% of the 979 patients discontinued gemcitabine due to adverse reactions. Adverse reactions resulting in discontinuation of gemcitabine in 2% of 979 patients were cardiovascular adverse reactions (myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension) and adverse reactions resulting in discontinuation of gemcitabine in <1% of 979 patients were anemia, thrombocytopenia, hepatic dysfunction, renal dysfunction, nausea/vomiting, fever, rash, dyspnea, hemorrhage, infection, stomatitis, somnolence, flu-like syndrome, and edema.

Tables 5 and 6 present the incidence of selected adverse reactions and laboratory abnormalities reported in patients with various malignancies receiving single agent gemcitabine across 5 clinical trials. Additional clinically significant adverse reactions are provided following Table 6.

Table 5: Selected Adverse Reactions Occurring in ≥10% of Patients Receiving Single Agent Gemcitabine*
Adverse Reactions†Gemcitabine‡
All Grades
(%)		Grade 3
(%)		Grade 4
(%)
*
Grade based on criteria from the World Health Organization (WHO).
†
For approximately 60% of patients, non-laboratory adverse reactions were graded only if assessed to be possibly drug-related.
‡
N=699–974; all patients with laboratory or non-laboratory data.

Nausea and Vomiting

69

13

1

Fever

41

2

0

Rash

30

<1

0

Dyspnea

23

3

<1

Diarrhea

19

1

0

Hemorrhage

17

<1

<1

Infection

16

1

<1

Alopecia

15

<1

0

Stomatitis

11

<1

0

Somnolence

11

<1

<1

Paresthesias

10

<1

0

Table 6: Selected Laboratory Abnormalities Occurring in Patients Receiving Single Agent Gemcitabine*
Laboratory Abnormality†Gemcitabine‡
All Grades
(%)		Grade 3
(%)		Grade 4
(%)
*
Grade based on criteria from the WHO.
†
Regardless of causality.
‡
N=699–974; all patients with laboratory or non-laboratory data.

Hematologic

  Anemia

68

7

1

  Neutropenia

63

19

6

  Thrombocytopenia

24

4

1

Hepatic

  Increased ALT

68

8

2

  Increased AST

67

6

2

  Increased Alkaline

55

7

2

  Phosphatase

  Hyperbilirubinemia

13

2

<1

Renal

  Proteinuria

45

<1

0

  Hematuria

35

<1

0

  Increased BUN

16

0

0

  Increased Creatinine

8

<1

0

Additional adverse reactions include the following:

•
Transfusion requirements: Red blood cell transfusions (19%); platelet transfusions (<1%)
•
Edema: Edema (13%), peripheral edema (20%), generalized edema (<1%)
•
Flu-like symptoms: Fever, asthenia, anorexia, headache, cough, chills, myalgia, asthenia insomnia, rhinitis, sweating and/or malaise (19%)
•
Infection: Sepsis (<1%)
•
Extravasation: Injection-site reactions (4%)
•
Allergic: Bronchospasm (<2%); anaphylactoid reactions

Ovarian Cancer

Tables 7 and 8 presents the incidence of selected adverse reactions and laboratory abnormalities, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine with carboplatin arm, reported in a randomized trial (Study 1) of gemcitabine with carboplatin (n=175) compared to carboplatin alone (n=174) for the second-line treatment of ovarian cancer in women with disease that had relapsed more than 6 months following first-line platinum-based chemotherapy [see Clinical Studies (14.1)]. Additional clinically significant adverse reactions, occurring in <10% of patients, are provided following Table 8.

The proportion of patients with dose adjustments for carboplatin (1.8% versus 3.8%), doses of carboplatin omitted (0.2% versus 0) and discontinuing treatment for adverse reactions (11% versus 10%), were similar between arms. Dose adjustment for gemcitabine occurred in 10% of patients and gemcitabine dose was omitted in 14% of patients in the gemcitabine/carboplatin arm.

Table 7: Adverse Reactions Occurring in >10% of Patients Receiving Gemcitabine with Carboplatin and at Higher Incidence than in Patients Receiving Single Agent Carboplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3–4)] in Study 1*
Adverse Reactions†Gemcitabine/Carboplatin
(N=175)		Carboplatin
(N=174)
All Grades
(%)		Grade 3
(%)		Grade 4
(%)		All Grades
(%)		Grade 3
(%)		Grade 4
(%)
*
Grade based on National Cancer Institute CTC Version 2.0.
†
Regardless of causality.

Nausea

69

6

0

61

3

0

Alopecia

49

0

0

17

0

0

Vomiting

46

6

0

36

2

<1

Constipation

42

6

1

37

3

0

Fatigue

40

3

<1

32

5

0

Diarrhea

25

3

0

14

<1

0

Stomatitis/Pharyngitis

22

<1

0

13

0

0

Hematopoietic growth factors were administered more frequently in the gemcitabine-containing arm: leukocyte growth factor (24% and 10%) and erythropoiesis-stimulating agent (7% and 3.9%).

The following clinically relevant Grade 3 and 4 adverse reactions occurred more frequently in the gemcitabine with carboplatin arm: dyspnea (3.4% versus 2.9%), febrile neutropenia (1.1% versus 0), hemorrhagic event (2.3% versus 1.1 %), motor neuropathy (1.1% versus 0.6%), and rash/desquamation (0.6% versus 0).

Table 8: Laboratory Abnormalities Occurring in Patients Receiving Gemcitabine with Carboplatin and at Higher Incidence than in Patients Receiving Single Agent Carboplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3–4)] in Study 1*
Laboratory Abnormality†Gemcitabine/Carboplatin
(N=175)		Carboplatin
(N=174)
All Grades
(%)		Grade 3
(%)		Grade 4
(%)		All Grades
(%)		Grade 3
(%)		Grade 4
(%)
*
Grade based on National Cancer Institute CTC Version 2.0.
†
Regardless of causality.
‡
Percent of patients receiving transfusions. Transfusions are not CTC-graded events. Blood transfusions included both packed red blood cells and whole blood.

Hematologic

Neutropenia

90

42

29

58

11

1

Anemia

86

22

6

75

9

2

Thrombocytopenia

78

30

5

57

10

1

RBC Transfusions‡

38

-

-

15

-

-

Platelet Transfusions‡

9

-

-

3

-

-

Hematopoietic growth factors were administered more frequently in the gemcitabine-containing arm: leukocyte growth factor (24% and 10%) and erythropoiesis-stimulating agent (7% and 3.9%).

The following clinically relevant Grade 3 and 4 adverse reactions occurred more frequently in the gemcitabine with carboplatin arm: dyspnea (3.4% versus 2.9%), febrile neutropenia (1.1% versus 0), hemorrhagic event (2.3% versus 1.1 %), motor neuropathy (1.1% versus 0.6%), and rash/desquamation (0.6% versus 0).

Breast Cancer

Tables 9 and 10 presents the incidence of selected adverse reactions and laboratory abnormalities, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine with paclitaxel arm, reported in a randomized trial (Study 2) of gemcitabine with paclitaxel (n=262) compared to paclitaxel alone (n=259) for the first-line treatment of metastatic breast cancer (MBC) in women who received anthracycline-containing chemotherapy in the adjuvant/neo-adjuvant setting or for whom anthracyclines were contraindicated [see Clinical Studies (14.2)]. Additional clinically significant adverse reactions, occurring in <10% of patients, are provided following Table 10.

The requirement for dose reduction of paclitaxel were higher for patients in the gemcitabine/paclitaxel arm (5% versus 2%). The number of paclitaxel doses omitted (<1%), the proportion of patients discontinuing treatment for adverse reactions (7% versus 5%) and the number of treatment-related deaths (1 patient in each arm) were similar between the two arms.

Table 9: Selected Adverse Reactions Occurring in Patients Receiving Gemcitabine with Paclitaxel and at Higher Incidence than in Patients Receiving Single Agent Paclitaxel [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3–4)] in Study 2*
Adverse Reactions†Gemcitabine/Paclitaxel
(N=262)		Paclitaxel
(N=259)
All Grades
(%)		Grade 3
(%)		Grade 4
(%)		All Grades
(%)		Grade 3
(%)		Grade 4
(%)
*
Grade based on National Cancer Institute CTC Version 2.0.
†
Non-laboratory events were graded only if assessed to be possibly drug-related.

Alopecia

90

14

4

92

19

3

Neuropathy-Sensory

64

5

<1

58

3

0

Nausea

50

1

0

31

2

0

Fatigue

40

6

<1

28

1

<1

Vomiting

29

2

0

15

2

0

Diarrhea

20

3

0

13

2

0

Anorexia

17

0

0

12

<1

0

Neuropathy-Motor

15

2

<1

10

<1

0

Stomatitis/Pharyngitis

13

1

<1

8

<1

0

Fever

13

<1

0

3

0

0

Rash/Desquamation

11

<1

<1

5

0

0

Febrile Neutropenia

6

5

<1

2

1

0

Table 10: Selected Laboratory Abnormalities Occurring in >10% of Patients Receiving Gemcitabine with Paclitaxel and at a Higher Incidence than Patients Receiving Single Agent Paclitaxel [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3–4)] in Study 2*
Laboratory Abnormality†Gemcitabine / Paclitaxel
(N=262)		Paclitaxel
(N=259)
All Grades
(%)		Grade 3
(%)		Grade 4
(%)		All Grades
(%)		Grade 3
(%)		Grade 4
(%)
*
Grade based on National Cancer Institute CTC Version 2.0.
†
Regardless of causality.

Hematologic

  Anemia

69

6

1

51

3

<1

  Neutropenia

69

31

17

31

4

7

  Thrombocytopenia

26

5

<1

7

<1

<1

Hepatobiliary

  Increased ALT

18

5

<1

6

<1

0

  Increased AST

16

2

0

5

<1

0

Clinically relevant Grade 3 or 4 dyspnea occurred with a higher incidence in the gemcitabine with paclitaxel arm compared with the paclitaxel arm (1.9% versus 0).

Non-Small Cell Lung Cancer

Tables 11 and 12 presents the incidence of selected adverse reactions and laboratory abnormalities occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine with cisplatin arm, reported in a randomized trial (Study 3) of gemcitabine with cisplatin (n=260) administered in 28-day cycles as compared to cisplatin alone (n=262) in patients receiving first-line treatment for locally advanced or metastatic NSCLC [see Clinical Studies (14.3)].

Patients randomized to gemcitabine with cisplatin received a median of 4 cycles of treatment and those randomized to cisplatin alone received a median of 2 cycles of treatment. In this trial, the requirement for dose adjustments (>90% versus 16%), discontinuation of treatment for adverse reactions (15% versus 8%), and the proportion of patients hospitalized (36% versus 23%) were all higher for patients receiving gemcitabine with cisplatin compared to those receiving cisplatin alone. The incidence of febrile neutropenia (3% versus <1%), sepsis (4% versus 1%), Grade 3 cardiac dysrhythmias (3% versus <1%) were all higher in the gemcitabine with cisplatin arm compared to the cisplatin alone arm. The two-drug combination was more myelosuppressive with 4 (1.5%) possibly treatment-related deaths, including 3 resulting from myelosuppression with infection and one case of renal failure associated with pancytopenia and infection. No deaths due to treatment were reported on the cisplatin arm.

Table 11: Selected Adverse Reactions Occurring in ≥10% of Patients Receiving Gemcitabine with Cisplatin and at Higher Incidence than in Patients Receiving Single Agent Cisplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3–4)] in Study 3*
Adverse Reactions†Gemcitabine/Cisplatin‡Cisplatin§
All Grades
(%)		Grade 3
(%)		Grade 4
(%)		All Grades
(%)		Grade 3
(%)		Grade 4
(%)
*
Grade based on National Cancer Institute Common Toxicity Criteria (CTC).
†
Non-laboratory events were graded only if assessed to be possibly drug-related.
‡
N=217–253; all gemcitabine/cisplatin patients with laboratory or non-laboratory data.
§
N=213–248; all cisplatin patients with laboratory or non-laboratory data.

Nausea

93

25

2

87

20

<1

Vomiting

78

11

12

71

10

9

Alopecia

53

1

0

33

0

0

Neuro Motor

35

12

0

15

3

0

Diarrhea

24

2

2

13

0

0

Neuro Sensory

23

1

0

18

1

0

Infection

18

3

2

12

1

0

Fever

16

0

0

5

0

0

Neuro Cortical

16

3

1

9

1

0

Neuro Mood

16

1

0

10

1

0

Local

15

0

0

6

0

0

Neuro Headache

14

0

0

7

0

0

Stomatitis

14

1

0

5

0

0

Hemorrhage

14

1

0

4

0

0

Hypotension

12

1

0

7

1

0

Rash

11

0

0

3

0

0

Table 12: Selected Laboratory Abnormalities Occurring in >10% of Patients Receiving Gemcitabine with Cisplatin and at Higher Incidence than in Patients Receiving Single Agent Cisplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3–4)] in Study 3*
Laboratory Abnormality†Gemcitabine/ Cisplatin‡Cisplatin§
All Grades
(%)		Grade 3
(%)		Grade 4
(%)		All Grades
(%)		Grade 3
(%)		Grade 4
(%)
*
Grade based on National Cancer Institute CTC.
†
Regardless of causality.
‡
N=217–253; all gemcitabine/cisplatin patients with laboratory or non-laboratory data.
§
N=213–248; all cisplatin patients with laboratory or non-laboratory data.
Percent of patients receiving transfusions. Percent transfusions are not CTC-graded events.

Hematologic

  Anemia

89

22

3

67

6

1

  Thrombocytopenia

85

25

25

13

3

1

  Neutropenia

79

22

35

20

3

1

  Lymphopenia

75

25

18

51

12

5

  RBC Transfusions

39

-

-

13

-

-

  Platelet Transfusions

21

-

-

<1

-

-

Hepatic

  Increased Transaminases

22

2

1

10

1

0

  Increased Alkaline

19

1

0

13

0

0

  Phosphatase

Renal

  Increased Creatinine

38

4

<1

31

2

<1

  Proteinuria

23

0

0

18

0

0

  Hematuria

15

0

0

13

0

0

Other Laboratory

  Hyperglycemia

30

4

0

23

3

0

  Hypomagnesemia

30

4

3

17

2

0

  Hypocalcemia

18

2

0

7

0

<1

Tables 13 and 14 presents the incidence of selected adverse reactions and laboratory abnormalities occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine with cisplatin arm, reported in a randomized trial (Study 4) of gemcitabine with cisplatin (n=69) administered in 21-day cycles as compared to etoposide with cisplatin (n=66) in patients receiving first-line treatment for locally advanced or metastatic NSCLC [see Clinical Studies (14.3)]. Additional clinically significant adverse reactions are provided following Table 14.

Patients in the gemcitabine/cisplatin (GC) arm received a median of 5 cycles and those in the etoposide/cisplatin (EC) arm received a median of 4 cycles. The majority of patients receiving more than one cycle of treatment required dose adjustments; 81% in the GC arm and 68% in the EC arm. The incidence of hospitalizations for adverse reactions was 22% in the GC arm and 27% in the EC arm. The proportion of patients who discontinued treatment for adverse reactions was higher in the GC arm (14% versus 8%). The proportion of patients who were hospitalized for febrile neutropenia was lower in the GC arm (7% versus 12%). There was one death attributed to treatment, a patient with febrile neutropenia and renal failure, which occurred in the GC arm.

Table 13: Selected Adverse Reactions in Patients Receiving Gemcitabine with Cisplatin in Study 4*
Adverse Reactions†Gemcitabine/Cisplatin‡Etoposide/Cisplatin§
All Grades
(%)		Grade 3
(%)		Grade 4
(%)		All Grades
(%)		Grade 3
(%)		Grade 4
(%)
*
Grade based on criteria from the WHO.
†
Non-laboratory events were graded only if assessed to be possibly drug-related. Pain data were not collected.
‡
N=67–69; all gemcitabine/cisplatin patients with laboratory or non-laboratory data.
§
N=57–63; all Etoposide/cisplatin patients with laboratory or non-laboratory data.
Flu-like syndrome and edema were not graded.

Nausea and Vomiting

96

35

4

86

19

7

Alopecia

77

13

0

92

51

0

Paresthesias

38

0

0

16

2

0

Infection

28

3

1

21

8

0

Stomatitis

20

4

0

18

2

0

Diarrhea

14

1

1

13

0

2

Edema

12

-

-

2

-

-

Rash

10

0

0

3

0

0

Hemorrhage

9

0

3

3

0

3

Fever

6

0

0

3

0

0

Somnolence

3

0

0

3

2

0

Flu-like Syndrome

3

-

-

0

-

-

Dyspnea

1

0

1

3

0

0

Table 14: Selected Laboratory Abnormalities Occurring in Patients Receiving Gemcitabine with Cisplatin in Study 4*
Laboratory Abnormality†Gemcitabine/Cisplatin‡Etoposide/Cisplatin§
All Grades
(%)		Grade 3
(%)		Grade 4
(%)		All Grades
(%)		Grade 3
(%)		Grade 4
(%)
*
Grade based on criteria from the WHO.
†
Regardless of causality.
‡
N=67–69; all gemcitabine/cisplatin patients with laboratory or non-laboratory data.
§
N=57–63; all etoposide/ cisplatin patients with laboratory or non-laboratory data.
WHO grading scale not applicable to proportion of patients with transfusions.

Hematologic

  Anemia

88

22

0

77

13

2

  Neutropenia

88

36

28

87

20

56

  Thrombocytopenia

81

39

16

45

8

5

  RBC Transfusions‡

29

-

-

21

-

-

  Platelet Transfusions

3

-

-

8

-

-

Hepatic

  Increased Alkaline

16

0

0

11

0

0

  Phosphatase

  Increased ALT

6

0

0

12

0

0

  Increased AST

3

0

0

11

0

0

Renal

  Hematuria

22

0

0

10

0

0

  Proteinuria

12

0

0

5

0

0

  Increased BUN

6

0

0

4

0

0

  Increased Creatinine

2

0

0

2

0

0

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of gemcitabine. 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: Thrombotic microangiopathy (TMA)
•
Cardiovascular: Congestive heart failure, myocardial infarction, arrhythmias, supraventricular arrhythmias
•
Vascular: Peripheral vasculitis, gangrene, capillary leak syndrome
•
Skin: Cellulitis; pseudocellulitis; severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP); desquamation and bullous skin eruptions
•
Hepatic: Hepatic failure, hepatic veno-occlusive disease
•
Pulmonary: Interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, adult respiratory distress syndrome (ARDS), pulmonary eosinophilia
•
Nervous System: Posterior reversible encephalopathy syndrome (PRES)
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