Paclitaxel (Page 5 of 9)

Information for Patients

(See Patient Information Leaflet).

ADVERSE REACTIONS

Pooled Analysis of Adverse Event Experiences from Single-Agent Studies

Data in the following table are based on the experience of 812 patients (493 with ovarian carcinoma and 319 with breast carcinoma) enrolled in 10 studies who received single-agent paclitaxel injection. Two hundred and seventy-five patients were treated in 8, Phase 2 studies with paclitaxel doses ranging from 135 to 300 mg/m2 administered over 24 hours (in 4 of these studies, G-CSF was administered as hematopoietic support). Three hundred and one patients were treated in the randomized Phase 3 ovarian carcinoma study which compared 2 doses (135 or 175 mg/m2) and 2 schedules (3 or 24 hours) of paclitaxel.

Two hundred and thirty-six patients with breast carcinoma received paclitaxel (135 or 175 mg/m2) administered over 3 hours in a controlled study.

TABLE 10. SUMMARYa OF ADVERSE EVENTS IN PATIENTS WITH SOLID TUMORS RECEIVING SINGLE-AGENT PACLITAXEL

Percent of Patients

(n=812)

Bone Marrow

— Neutropenia <2,000/mm3

<500/mm3

— Leukopenia <4,000/mm3

<1,000/mm3

— Thrombocytopenia <100,000/mm3

<50,000/mm3

— Anemia <11 g/dL

<8 g/dL

— Infections

— Bleeding

— Red Cell Transfusions

— Platelet Transfusions

90

52

90

17

20

7

78

16

30

14

25

2

Hypersensitivity Reactionb

— All

— Severe

41

2

Cardiovascular

— Vital Sign Changesc

— Bradycardia (n=537)

— Hypotension (n=532)

— Significant Cardiovascular Events

3

12

1

Abnormal ECG

— All Pts

— Pts with normal baseline (n=559)

23

14

Peripheral Neuropathy

— Any symptoms

— Severe symptoms

60

3

Myalgia/Arthralgia

— Any symptoms

— Severe symptoms

60

8

Gastrointestinal

— Nausea and vomiting

— Diarrhea

— Mucositis

52

38

31

Alopecia

87

Hepatic (Pts with normal baseline and on study data)

— Bilirubin elevations (n=765)

— Alkaline phosphatase elevations (n=575)

— AST (SGOT) elevations (n=591)

7

22

19

Injection Site Reaction

13

a Based on worst course analysis.

b All patients received premedication.

c During the first 3 hours of infusion.

† Severe events are defined as at least Grade III toxicity.

None of the observed toxicities were clearly influenced by age.

Disease-Specific Adverse Event Experiences

First-Line Ovary in Combination

For the 1,084 patients who were evaluable for safety in the Phase 3 first-line ovary combination therapy studies, TABLE 11 shows the incidence of important adverse events. For both studies, the analysis of safety was based on all courses of therapy (6 courses for the GOG-111 study and up to 9 courses for the Intergroup study).

TABLE 11. FREQUENCYa OF IMPORTANT ADVERSE EVENTS IN THE PHASE 3 FIRST-LINE OVARIAN CARCINOMASTUDIES

Intergroup

GOG-111

T175/3b

c75c

(n=339)

C750c

c75c (n=336)

T135/24b

c75c (n=196)

C750c

c75c (n=213)

Bone Marrow

—Neutropenia <2,000/mm3

91d

95d

96

92

<500/mm3

33d

43d

81d

58d

—Thrombocytopenia <100,000/mm3e

21d

33d

26

30

<50,000/mm3

3d

7d

10

9

—Anemia <11 g/dLf

96

97

88

86

<8 g/dL

3 d

8 d

13

9

—Infections

25

27

21

15

—Febrile Neutropenia

7

15d

4 d

Hypersensitivity Reaction

—All

11 d

6d

8 d,g

1 d,g

—Severe

1

1

3 d,g

d,g

Neurotoxicityh

—Any symptoms

87d

52d

25

20

—Severe symptoms†

21d

2d

3d

d

Nausea and Vomiting

—Any symptoms

88

93

65

69

—Severe symptoms

18

2

10

11

Myalgia/Arthralgia

—Any symptoms

60d

27d

9d

2d

—Severe symptoms

6d

1d

1

Diarrhea

—Any symptoms

37d

29d

16d

8d

—Severe symptoms

Asthenia

2

3

4

1

—Any symptoms

—Severe symptoms

NC

NC

NC

NC

17d

1

10d

1

Alopecia

—Any symptoms

96d

89d

55d

37d

—Severe symptoms

51d

21d

6

8

a Based on worst course analysis.

b Paclitaxel (T) dose in mg/m2 /infusion duration in hours.

c Cyclophosphamide (C) or

cisplatin (c) dose in mg/m2.

d p<0.05 by Fisher exact test.

e <130,000/mm3 in the Intergroup study.

f <12 g/dL in the Intergroup study.

g All patients received premedication.

h In the GOG-111 study, neurotoxicity was collected as peripheral neuropathy and in the Intergroup study, neurotoxicity was collected as either neuromotor or neurosensory symptoms.

Severe events are defined as at least Grade III toxicity.

NC Not Collected

Second-Line Ovary

For the 403 patients who received single-agent paclitaxel injection in the Phase 3 second-line ovarian carcinoma study, the following table shows the incidence of important adverse events.

Table 12. Frequencya of Important Adverse Events in the Phase 3 Second-Line Ovarian Carcinoma Study

Percent of Patients

175/3b

(n=95)

175/24b

(n=105)

135/3b

(n=98)

135/24b

(n=105)

Bone Marrow

— Neutropenia <2,000/mm3

<500/mm3

— Thrombocytopenia <100,000/mm3

<50,000/mm3

— Anemia <11 g/dL

<8 g/dL

— Infections

78

27

4

1

84

11

26

98

75

18

7

90

12

29

78

14

8

2

68

6

20

98

67

6

1

88

10

18

Hypersensitivity Reactionc

— All

— Severe

41

2

45

0

38

2

45

1

Peripheral Neuropathy

— Any symptoms

— Severe symptoms

63

1

60

2

55

0

42

0

Mucositis

— Any symptoms

— Severe symptoms

17

0

35

3

21

0

25

2

a Based on worst course analysis.

b Paclitaxel dose in mg/m2 /infusion duration in hours

c All patients received premedication.

Severe events are defined as at least Grade III toxicity.

Myelosuppression was dose and schedule related, with the schedule effect being more prominent. The development of severe hypersensitivity reactions (HSRs) was rare; 1% of the patients and 0.2% of the courses overall. There was no apparent dose or schedule effect seen for the HSRs. Peripheral neuropathy was clearly dose related, but schedule did not appear to affect the incidence.

Adjuvant Breast

For the Phase 3 adjuvant breast carcinoma study, the following table shows the incidence of important severe adverse events for the 3121 patients (total population) who were evaluable for safety as well as for a group of 325 patients (early population) who, per the study protocol, were monitored more intensively than other patients.

Table 13. Frequencya of Important Severeb Adverse Events in the Phase 3 Adjuvant Breast Carcinoma Study

Percent of Patients

Early Population

Total Population

ACc

(n=166)

ACc

followed

by Td

(n=159)

ACc

(n=1551)

ACc

followed

by Td

(n=1570)

Bone Marrow

— Neutropenia <500/mm3

— Thrombocytopenia <50,000/mm3

— Anemia <8 g/dL

— Infections

— Fever Without Infection

79

27

17

6

76

25

21

14

3

48

11

8

5

<1

50

11

8

6

1

Hypersensitivity Reactionf

1

4

1

2

Cardiovascular Events

1

2

1

2

Neuromotor Toxicity

1

1

<1

1

Neurosensory Toxicity

3

<1

3

Myalgia/Arthralgia

2

<1

2

Nausea/Vomiting

13

18

8

9

Mucositis

13

4

6

5

a Based on worst course analysis.

b Severe events are defined as at least Grade III toxicity.

c Patients received 600 mg/m2 cyclophosphamide and doxorubicin (AC) at doses of either 60 mg/m2 , 75 mg/m2 , or 90 mg/m2 (with prophylactic G-CSF support and ciprofloxacin), every 3 weeks for 4 courses.

d Paclitaxel (T) following 4 courses of AC at a dose of 175 mg/m2 /3 hours every 3 weeks for 4 courses.

e The incidence of febrile neutropenia was not reported in this study.

f All patients were to receive premedication.

The incidence of an adverse event for the total population likely represents an underestimation of the actual incidence given that safety data were collected differently based on enrollment cohort. However, since safety data were collected consistently across regimens, the safety of the sequential addition of paclitaxel following AC therapy may be compared with AC therapy alone. Compared to patients who received AC alone, patients who received AC followed by paclitaxel experienced more Grade III/IV neurosensory toxicity, more Grade III/IV myalgia/arthralgia, more Grade III/IV neurologic pain (5% vs 1%), more Grade III/IV flu- like symptoms (5% vs 3%), and more Grade III/IV hyperglycemia (3% vs 1%). During the additional 4 courses of treatment with paclitaxel, 2 deaths (0.1%) were attributed to treatment. During paclitaxel treatment, Grade IV neutropenia was reported for 15% of patients, Grade II/III neurosensory toxicity for 15%, Grade II/III myalgias for 23%, and alopecia for 46%.

The incidences of severe hematologic toxicities, infections, mucositis, and cardiovascular events increased with higher doses of doxorubicin.

Breast Cancer After Failure of Initial Chemotherapy

For the 458 patients who received single-agent paclitaxel in the Phase 3 breast carcinoma study, the following table shows the incidence of important adverse events by treatment arm (each arm was administered by a 3-hour infusion).

Table 14. Frequencya of Important Adverse Events in the Phase 3 Study of Breast Cancer after Failure of Initial Chemotherapy or Within 6 Months of Adjuvant Chemotherapy

Percent of Patients

175/3b

(n=229)

135/3b

(n=229)

Bone Marrow

— Neutropenia <2,000/mm3

<500/mm3

— Thrombocytopenia <100,000/mm3

<50,000/mm3

— Anemia <11 g/dL

<8 g/dL

— Infections

— Febrile Neutropenia

90

28

11

3

55

4

23

2

81

19

7

2

47

2

15

2

Hypersensitivity Reactionc

— All

— Severe

36

0

31

<1

Peripheral Neuropathy

— Any symptoms

— Severe symptoms

70

7

46

3

Mucositis

— Any symptoms

— Severe symptoms

23

3

17

<1

a Based on worst course analysis.

b Paclitaxel dose in mg/m2 /infusion duration in hours.

c All patients received premedication.

Severe events are defined as at least Grade III Toxicity.

Myelosuppression and peripheral neuropathy were dose related. There was one severe hypersensitivity reaction (HSR) observed at the dose of 135 mg/m2.

First-Line NSCLC in Combination

In the study conducted by the Eastern Cooperative Oncology Group (ECOG), patients were randomized to either paclitaxel (T) 135 mg/m2 as a 24-hour infusion in combination with cisplatin (c) 75 mg/m2 , paclitaxel (T) 250 mg/m2 as a 24-hour infusion in combination with cisplatin (c) 75 mg/m2 with G-CSF support, or cisplatin (c) 75 mg/m2 on day 1, followed by etoposide (VP) 100 mg/m2 on days 1, 2, and 3 (control).

The following table shows the incidence of important adverse events.

Table 15. Frequencya of Important Adverse Events in the Phase 3 Study for First-Line NSCLC

Percent of Patients

T135/24b

c75

(n=195)

T250/24c c75

(n=197)

VP100d c75

(n=196)

Bone Marrow

— Neutropenia <2,000/mm3

<500/mm3

— Thrombocytopenia <normal

<50,000/mm3

— Anemia <normal

<8 g/dL

— Infections

89

74e

48

6

94

22

38

86

65

68

12

96

19

31

84

55

62

16

95

28

35

Hypersensitivity Reactionf

— All

— Severe

16

1

27

4e

13

1

Arthralgia/Myalgia

— Any symptoms

— Severe symptoms

21e

3

42e

11

9

1

Nausea/Vomiting

— Any symptoms

— Severe symptoms

85

27

87

29

81

22

Mucositis

— Any symptoms

— Severe symptoms

18

1

28

4

16

2

Neuromotor Toxicity

— Any symptoms

— Severe symptoms

37

6

47

12

44

7

Neurosensory Toxicity

— Any symptoms

— Severe symptoms

48

13

61

28e

25

8

Cardiovascular Events

— Any symptoms

— Severe symptoms

33

13

39

12

24

8

a Based on worst course analysis.

b Paclitaxel (T) dose in mg/m2 /infusion duration in hours; cisplatin (c) dose in mg/m2.

c Paclitaxel dose in mg/m2 /infusion duration in hours with G-CSF support; cisplatin dose in mg/m2.

d Etoposide (VP) dose in mg/m2 was administered IV on days 1, 2, and 3; cisplatin dose in mg/m2.

e p<0.05.

f All patients received premedication.

Severe events are defined as at least Grade III Toxicity.

Toxicity was generally more severe in the high-dose paclitaxel treatment arm (T250/c75) than in the low-dose paclitaxel arm(T135/c75). Compared to the cisplatin/etoposide arm, patients in the low-dose paclitaxel arm experienced more arthralgia/myalgia of any grade and more severe neutropenia. The incidence of febrile neutropenia was not reported in this study.

Kaposi’s Sarcoma

The following table shows the frequency of important adverse events in the 85 patients with KS treated with 2 different single-agent paclitaxel regimens.

Table 16. Frequencya of Important Adverse Events in the Aids-Related Kaposi’s Sarcoma Studies

Percent of Patients

Study CA139-174

Paclitaxel 135/3b

q 3 wk

(n=29)

Study CA139-281

Paclitaxel 100/3b

q 2 wk

(n=56)

Bone Marrow

— Neutropenia <2,000/mm3

<500/mm3

— Thrombocytopenia <100,000/mm3

<50,000/mm3

— Anemia <11 g/dL

<8 g/dL

— Febrile Neutropenia

100

76

52

17

86

34

55

95

35

27

5

73

25

9

Opportunistic Infection

— Any

— Cytomegalovirus

— Herpes Simplex

Pneumocystis carinii

M. avinum intracellulare

— Candidiasis, esophageal

— Cryptosporidiosis

— Cryptococcal meningitis

— Leukoencephalopathy

76

45

38

14

24

7

7

3

54

27

11

21

4

9

7

2

2

Hypersensitivity Reactionc

— All

14

9

Cardiovascular

— Hypotension

— Bradycardia

17

3

9

Peripheral Neuropathy

— Any

— Severe

79

10

46

2

Myalgia/Arthralgia

— Any

— Severe

93

14

48

16

Gastrointestinal

— Nausea and Vomiting

— Diarrhea

— Mucositis

69

90

45

70

73

20

Renal (creatinine elevation)

— Any

— Severe†

34

7

18

5

Discontinuation for drug toxicity

7

16

a Based on worst course analysis.

b Paclitaxel dose in mg/m2 /infusion duration in hours.

c All patients received premedication.

Severe events are defined as at least Grade III toxicity.

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