ADVERSE REACTIONS
Data in the following section are based on the combined experience of 453 patients with metastatic ovarian carcinoma, and 426 patients with small cell lung cancer treated with HYCAMTIN. Table 4 lists the principal hematologic toxicities, and Table 5 lists non-hematologic toxicities occurring in at least 15% of patients.
Table 4. Summary of Hematologic Adverse Events in Patients Receiving HYCAMTIN
| Hematologic Adverse Event |
Patients
n = 879 % Incidence |
Courses
n = 4124 % Incidence |
|
Neutropenia
|
|
|
|
<1,500 cells/mm3 |
97
|
81
|
|
<500 cells/mm3 |
78
|
39
|
|
Leukopenia
|
|
|
|
<3,000 cells/mm3 |
97
|
80
|
|
<1,000 cells/mm3 |
32
|
11
|
|
Thrombocytopenia
|
|
|
|
<75,000 cells/mm3 |
69
|
42
|
|
<25,000 cells/mm3 |
27
|
9
|
|
Anemia
|
|
|
|
<10 g/dL
|
89
|
71
|
|
<8 g/dL
|
37
|
14
|
|
Sepsis or fever/infection with grade 4 neutropenia
|
23
|
7
|
|
Platelet transfusions
|
15
|
4
|
|
RBC transfusions
|
52
|
22
|
|
Table 5. Summary of Non-hematologic Adverse Events in Patients Receiving HYCAMTIN
| Non-hematologic Adverse Event |
All Grades % Incidence |
Grade 3 % Incidence |
Grade 4 % Incidence |
|
|
n = 879 Patients |
n = 4124 Courses |
n = 879 Patients |
n = 4124 Courses |
n = 879 Patients |
n = 4124 Courses |
| Gastrointestinal |
|
|
|
|
|
|
|
Nausea
|
64
|
42
|
7
|
2
|
1
|
<1
|
|
Vomiting
|
45
|
22
|
4
|
1
|
1
|
<1
|
|
Diarrhea
|
32
|
14
|
3
|
1
|
1
|
<1
|
|
Constipation
|
29
|
15
|
2
|
1
|
1
|
<1
|
|
Abdominal pain
|
22
|
10
|
2
|
1
|
2
|
<1
|
|
Stomatitis
|
18
|
8
|
1
|
<1
|
<1
|
<1
|
|
Anorexia
|
19
|
9
|
2
|
1
|
<1
|
<1
|
| Body as a Whole |
|
|
|
|
|
|
|
Fatigue
|
29
|
22
|
5
|
2
|
0
|
0
|
|
Fever
|
28
|
11
|
1
|
<1
|
<1
|
<1
|
|
Pain *
|
23
|
11
|
2
|
1
|
1
|
<1
|
|
Asthenia
|
25
|
13
|
4
|
1
|
2
|
<1
|
| Skin/Appendages |
|
|
|
|
|
|
|
Alopecia
|
49
|
54
|
NA
|
NA
|
NA
|
NA
|
|
Rash # |
16
|
6
|
1
|
<1
|
0
|
0
|
| Respiratory System |
|
|
|
|
|
|
|
Dyspnea
|
22
|
11
|
5
|
2
|
3
|
1
|
|
Coughing
|
15
|
7
|
1
|
<1
|
0
|
0
|
| CNS/Peripheral Nervous System |
|
|
|
|
|
|
|
Headache
|
18
|
7
|
1
|
<1
|
<1
|
0
|
|
* Pain includes body pain, back pain, and skeletal pain.
|
| #Rash also includes pruritus, rash erythematous, urticaria, dermatitis, bullous eruption, and maculopapular rash.
|
|
Premedications were not routinely used in these clinical studies. Hematologic: (See WARNINGS.)
Gastrointestinal: The incidence of nausea was 64% (8% grade 3/4), and vomiting occurred in 45% (6% grade 3/4) of patients (see Table 5). The prophylactic use of antiemetics was not routine in patients treated with HYCAMTIN. Thirty-two percent of patients had diarrhea (4% grade 3/4), 29% constipation (2% grade 3/4), and 22% had abdominal pain (4% grade 3/4). Grade 3/4 abdominal pain was 6% in ovarian cancer patients and 2% in small cell lung cancer patients. Skin/Appendages: Total alopecia (grade 2) occurred in 31% of patients. Central and Peripheral Nervous System: Headache (18% of patients) was the most frequently reported neurologic toxicity. Paresthesia occurred in 7% of patients but was generally grade 1.
Liver/Biliary: Grade 1 transient elevations in hepatic enzymes occurred in 8% of patients. Greater elevations, grade 3/4, occurred in 4%. Grade 3/4 elevated bilirubin occurred in <2% of patients. Respiratory: The incidence of grade 3/4 dyspnea was 4% in ovarian cancer patients and 12% in small cell lung cancer patients.
Table 6 shows the grade 3/4 hematologic and major non-hematologic adverse events in the topotecan/paclitaxel comparator trial in ovarian cancer.
Table 6. Comparative Toxicity Profiles for Ovarian Cancer Patients Randomized to Receive HYCAMTIN or Paclitaxel
| Adverse Event |
HYCAMTIN |
Paclitaxel |
|
|
Patients |
Courses |
Patients |
Courses |
|
|
n = 112 |
n = 597 |
n = 114 |
n = 589 |
| Hematologic Grade 3/4 |
% |
% |
% |
% |
Grade 4 neutropenia
(<500 cells/mL)
|
80
|
36
|
21
|
9
|
Grade 3/4 anemia
(Hgb < 8 g/dL)
|
41
|
16
|
6
|
2
|
Grade 4 thrombocytopenia
(<25,000 plts/mL)
|
27
|
10
|
3
|
<1
|
|
Fever/Grade 4 neutropenia
|
23
|
6
|
4
|
1
|
|
Documented sepsis
|
5
|
1
|
2
|
<1
|
|
Death related to sepsis
|
2
|
NA
|
0
|
NA
|
| Non-hematologic Grade 3/4 |
| Gastrointestinal |
|
|
|
|
|
Abdominal pain
|
5
|
1
|
4
|
1
|
|
Constipation
|
5
|
1
|
0
|
0
|
|
Diarrhea
|
6
|
2
|
1
|
<1
|
|
Intestinal obstruction
|
5
|
1
|
4
|
1
|
|
Nausea
|
10
|
3
|
2
|
<1
|
|
Stomatitis
|
1
|
<1
|
1
|
<1
|
|
Vomiting
|
10
|
2
|
3
|
<1
|
| Constitutional |
|
|
|
|
|
Anorexia
|
4
|
1
|
0
|
0
|
|
Dyspnea
|
6
|
2
|
5
|
1
|
|
Fatigue
|
7
|
2
|
6
|
2
|
|
Malaise
|
2
|
<1
|
2
|
<1
|
| Neuromuscular |
|
|
|
|
|
Arthralgia
|
1
|
<1
|
3
|
<1
|
|
Asthenia
|
5
|
2
|
3
|
1
|
|
Chest pain
|
2
|
<1
|
1
|
<1
|
|
Headache
|
1
|
<1
|
2
|
1
|
|
Myalgia
|
0
|
0
|
3
|
2
|
|
Pain *
|
5
|
1
|
7
|
2
|
| Skin/Appendages |
|
|
|
|
|
Rash # |
0
|
0
|
1
|
<1
|
| Liver/Biliary |
|
|
|
|
|
Increased hepatic enzymes & |
1
|
<1
|
1
|
<1
|
|
*Pain includes body pain, skeletal pain, and back pain.
|
| #Rash also includes pruritus, rash erythematous, urticaria, dermatitis, bullous eruption, and maculopapular rash.
|
| &Increased hepatic enzymes includes increased SGOT/AST, increased SGPT/ALT, and increased hepatic enzymes.
|
|
Premedications were not routinely used in patients randomized to HYCAMTIN, whereas patients receiving paclitaxel received routine pretreatment with corticosteroids, diphenhydramine, and histamine receptor type 2 blockers.
Table 7 shows the grade 3/4 hematologic and major non-hematologic adverse events in the topotecan/CAV comparator trial in small cell lung cancer.
Table 7. Comparative Toxicity Profiles for Small Cell Lung Cancer Patients Randomized to Receive HYCAMTIN or CAV
| Adverse Event |
HYCAMTIN |
CAV |
|
|
Patients |
Courses |
Patients |
Courses |
|
|
n = 107 |
n = 446 |
n = 104 |
n = 359 |
| Hematologic Grade 3/4 |
% |
% |
% |
% |
Grade 4 neutropenia
(<500 cells/mL)
|
70
|
38
|
72
|
51
|
Grade 3/4 anemia
(Hgb < 8 g/dL)
|
42
|
18
|
20
|
7
|
Grade 4 thrombocytopenia
(<25,000 plts/mL)
|
29
|
10
|
5
|
1
|
|
Fever/Grade 4 neutropenia
|
28
|
9
|
26
|
13
|
|
Documented sepsis
|
5
|
1
|
5
|
1
|
|
Death related to sepsis
|
3
|
NA
|
1
|
NA
|
| Non-hematologic Grade 3/4 |
| Gastrointestinal |
|
|
|
|
|
Abdominal pain
|
6
|
1
|
4
|
2
|
|
Constipation
|
1
|
<1
|
0
|
0
|
|
Diarrhea
|
1
|
<1
|
0
|
0
|
|
Nausea
|
8
|
2
|
6
|
2
|
|
Stomatitis
|
2
|
<1
|
1
|
<1
|
|
Vomiting
|
3
|
<1
|
3
|
1
|
| Constitutional |
|
|
|
|
|
Anorexia
|
3
|
1
|
4
|
2
|
|
Dyspnea
|
9
|
5
|
14
|
7
|
|
Fatigue
|
6
|
4
|
10
|
3
|
| Neuromuscular |
|
|
|
|
|
Asthenia
|
9
|
4
|
7
|
2
|
|
Headache
|
0
|
0
|
2
|
<1
|
|
Pain *
|
5
|
2
|
7
|
4
|
| Respiratory System |
|
|
|
|
|
Coughing
|
2
|
1
|
0
|
0
|
|
Pneumonia
|
8
|
2
|
6
|
2
|
| Skin/Appendages |
|
|
|
|
|
Rash # |
1
|
<1
|
1
|
<1
|
| Liver/Biliary |
|
|
|
|
|
Increased hepatic enzymes & |
1
|
<1
|
0
|
0
|
|
*Pain includes body pain, skeletal pain, and back pain.
|
| #Rash also includes pruritus, rash erythematous, urticaria, dermatitis, bullous eruption, and maculopapular rash.
|
| &Increased hepatic enzymes includes increased SGOT/AST, increased SGPT/ALT, and increased hepatic enzymes.
|
|
Premedications were not routinely used in patients randomized to HYCAMTIN, whereas patients receiving CAV received routine pretreatment with corticosteroids, diphenhydramine, and histamine receptor type 2 blockers. Postmarketing Reports of Adverse Events: Reports of adverse events in patients taking HYCAMTIN received after market introduction, which are not listed above, include the following: Hematologic: Rare: Severe bleeding (in association with thrombocytopenia).
Skin/Appendages: Rare: Severe dermatitis, severe pruritus.
Body as a Whole: Infrequent: Allergic manifestations; rare: Anaphylactoid reactions, angioedema.
|
