ADVERSE REACTIONS
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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Ovarian Cancer and Small Cell Lung Cancer:
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 1 lists the principal hematologic adverse reactions and Table 2 lists non-hematologic adverse reactions occurring in at least 15% of patients.
Table 1. Hematologic Adverse Reactions Experienced in ≥15% Ovarian Cancer and Small Cell Lung Cancer Patients Receiving HYCAMTIN
Hematologic Adverse Reaction
|
Patients
(n = 879)
% Incidence
|
Neutropenia
|
|
<1,500 cells/mm3
|
97
|
<500 cells/mm3
|
78
|
Leukopenia
|
|
<3,000 cells/mm3
|
97
|
<1,000 cells/mm3
|
32
|
Thrombocytopenia
|
|
<75,000/mm3
|
69
|
<25,000/mm3
|
27
|
Anemia
|
|
<10 g/dL
|
89
|
<8 g/dL
|
37
|
Table 2. Non-hematologic Adverse Reactions Experienced by ≥15% of Ovarian Cancer and Small Cell Lung Cancer Patients Receiving HYCAMTIN
Non-hematologic
Adverse Reaction
|
Percentage of Patients With Adverse Reaction (879 Patients)
|
All Grades
|
Grade 3
|
Grade 4
|
Infections and infestations
|
|
|
|
Sepsis or pyrexia/infection with neutropenia a
|
43
|
NR
|
23
|
Metabolism and nutrition disorders
|
|
|
|
Anorexia
|
19
|
2
|
<1
|
Nervous system disorders
|
|
|
|
Headache
|
18
|
1
|
<1
|
Respiratory, thoracic, and mediastinal disorders
|
|
|
|
Dyspnea
|
22
|
5
|
3
|
Coughing
|
15
|
1
|
0
|
Gastrointestinal disorders
|
|
|
|
Nausea
|
64
|
7
|
1
|
Vomiting
|
45
|
4
|
1
|
Diarrhea
|
32
|
3
|
1
|
Constipation
|
29
|
2
|
1
|
Abdominal pain
|
22
|
2
|
2
|
Stomatitis
|
18
|
1
|
<1
|
Skin and subcutaneous tissue disorders
|
|
|
|
Alopecia
|
49
|
NA
|
NA
|
Rashb
|
16
|
1
|
0
|
General disorders and administrative site conditions
|
|
|
|
Fatigue
|
29
|
5
|
0
|
Pyrexia
|
28
|
1
|
<1
|
Painc
|
23
|
2
|
1
|
Asthenia
|
25
|
4
|
2
|
NA = Not applicable.
NR = Not reported separately.
a Does not include Grade 1 sepsis or pyrexia.
b Rash also includes pruritus, rash erythematous, urticaria, dermatitis, bullous eruption, and maculopapular rash.
c Pain includes body pain, back pain, and skeletal pain.
Nervous System Disorders:
Paresthesia occurred in 7% of patients but was generally Grade 1.
Hepatobiliary Disorders:
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.
Table 3 shows the Grade 3/4 hematologic and major non-hematologic adverse reactions in the topotecan/paclitaxel comparator trial in ovarian cancer.
Table 3. Adverse Reactions Experienced by ≥5% of Ovarian Cancer Patients Randomized to Receive HYCAMTIN or Paclitaxel
Adverse Reaction
|
HYCAMTIN
(n = 112)
|
Paclitaxel
(n = 114)
|
Hematologic Grade 3/4
|
%
|
%
|
Grade 4 neutropenia (<500 cells/mm3)
|
80
|
21
|
Grade 3/4 anemia (Hgb <8 g/dL)
|
41
|
6
|
Grade 4 thrombocytopenia (<25,000 plts/mm3)
|
27
|
3
|
Pyrexia/Grade 4 neutropenia
|
23
|
4
|
Non-hematologic Grade 3/4
|
%
|
%
|
Infections and infestations
|
|
|
Documented sepsisa
|
5
|
2
|
Respiratory, thoracic, and mediastinal disorders
|
|
|
Dyspnea
|
6
|
5
|
Gastrointestinal disorders
|
|
|
Abdominal pain
|
5
|
4
|
Constipation
|
5
|
0
|
Diarrhea
|
6
|
1
|
Intestinal obstruction
|
5
|
4
|
Nausea
|
10
|
2
|
Vomiting
|
10
|
3
|
General disorders and administrative site conditions
|
|
|
Fatigue
|
7
|
6
|
Asthenia
|
5
|
3
|
Painb
|
5
|
7
|
a Death related to sepsis occurred in 2% of patients receiving HYCAMTIN and 0% of patients receiving paclitaxel.
b Pain includes body pain, skeletal pain, and back pain.
Table 4 shows the Grade 3/4 hematologic and major non-hematologic adverse reactions in the topotecan/CAV (cyclophosphamide‑doxorubicin‑vincristine) comparator trial in small cell lung cancer.
Table 4. Adverse Reactions Experienced by ≥5% of Small Cell Lung Cancer Patients Randomized to Receive HYCAMTIN or CAV
Adverse Reaction
|
HYCAMTIN
(n = 107)
|
CAV
|
(n = 104)
|
Hematologic Grade 3/4
|
%
|
%
|
Grade 4 neutropenia
(<500 cells/mm3)
|
70
|
72
|
Grade 3/4 anemia
(Hgb <8 g/dL)
|
42
|
20
|
Grade 4 thrombocytopenia
(<25,000 plts/mm3)
|
29
|
5
|
Pyrexia/Grade 4 neutropenia
|
28
|
26
|
Non-hematologic Grade 3/4
|
%
|
%
|
Infections and infestations
|
|
|
Documented sepsisa
|
5
|
5
|
Respiratory, thoracic, and mediastinal disorders
|
|
|
Dyspnea
|
9
|
14
|
Pneumonia
|
8
|
6
|
Gastrointestinal disorders
|
|
|
Abdominal pain
|
6
|
4
|
Nausea
|
8
|
6
|
General disorders and administrative site conditions
|
|
|
Fatigue
|
6
|
10
|
Asthenia
|
9
|
7
|
Painb
|
5
|
7
|
a Death related to sepsis occurred in 3% of patients receiving HYCAMTIN, and 1% of patients receiving CAV.
b Pain includes body pain, skeletal pain, and back pain.
Cervical Cancer:
In the comparative trial with HYCAMTIN plus cisplatin versus cisplatin in patients with cervical cancer, the most common dose-limiting adverse reaction was myelosuppression. Table 5 shows the hematologic adverse reactions and Table 6 shows the non-hematologic adverse reactions in patients with cervical cancer.
Table 5. Hematologic Adverse Reactions in Patients with Cervical Cancer Treated with HYCAMTIN Plus Cisplatin or Cisplatin Monotherapya
Hematologic Adverse Reaction
|
HYCAMTIN Plus Cisplatin
(n = 140)
|
Cisplatin
(n = 144)
|
Anemia
|
|
|
All Grades (Hgb <12 g/dL)
|
131 (94%)
|
130 (90%)
|
Grade 3 (Hgb <8-6.5 g/dL)
|
47 (34%)
|
28 (19%)
|
Grade 4 (Hgb <6.5 g/dL)
|
9 (6%)
|
5 (3%)
|
Leukopenia
|
|
|
All Grades (<3,800 cells/mm3)
|
128 (91%)
|
43 (30%)
|
Grade 3 (<2,000-1,000 cells/mm3)
|
58 (41%)
|
1 (1%)
|
Grade 4 (<1,000 cells/mm3)
|
35 (25%)
|
0 (0%)
|
Neutropenia
|
|
|
All Grades (<2,000 cells/mm3)
|
125 (89%)
|
28 (19%)
|
Grade 3 (<1,000-500 cells/mm3)
|
36 (26%)
|
1 (1%)
|
Grade 4 (<500 cells/mm3)
|
67 (48%)
|
1 (1%)
|
Thrombocytopenia
|
|
|
All Grades (<130,000 cells/mm3)
|
104 (74%)
|
21 (15%)
|
Grade 3 (<50,000-10,000 cells/mm3)
|
36 (26%)
|
5 (3%)
|
Grade 4 (<10,000 cells/mm3)
|
10 (7%)
|
0 (0%)
|
a Includes patients who were eligible and treated.
Table 6. Non-hematologic Adverse Reactions Experienced by ≥5% of Patients with Cervical Cancer Treated with HYCAMTIN Plus Cisplatin or Cisplatin Monotherapya
Adverse Reaction
|
HYCAMTIN Plus Cisplatin
|
Cisplatin
|
(n = 140)
|
(n = 144)
|
All Gradesb
|
Grade 3
|
Grade 4
|
All Gradesb
|
Grade 3
|
Grade 4
|
General disorders and administrative site conditions
|
|
|
|
|
|
|
Constitutionalc
|
96 (69%)
|
11 (8%)
|
0
|
89 (62%)
|
17 (12%)
|
0
|
Paind
|
82 (59%)
|
28 (20%)
|
3 (2%)
|
72 (50%)
|
18 (13%)
|
5 (3%)
|
Gastrointestinal disorders
|
|
|
|
|
|
|
Vomiting
|
56 (40%)
|
20 (14%)
|
2 (1%)
|
53 (37%)
|
13 (9%)
|
0
|
Nausea
|
77 (55%)
|
18 (13%)
|
2 (1%)
|
79 (55%)
|
13 (9%)
|
0
|
Stomatitis-pharyngitis
|
8 (6%)
|
1 (<1%)
|
0
|
0
|
0
|
0
|
Other
|
88 (63%)
|
16 (11%)
|
4 (3%)
|
80 (56%)
|
12 (8%)
|
3 (2%)
|
Dermatology
|
67 (48%)
|
1 (<1%)
|
0
|
29 (20%)
|
0
|
0
|
Metabolic-Laboratory
|
55 (39%)
|
13 (9%)
|
7 (5%)
|
44 (31%)
|
14 (10%)
|
1 (<1%)
|
Genitourinary
|
51 (36%)
|
9 (6%)
|
9 (6%)
|
49 (34%)
|
7 (5%)
|
7 (5%)
|
Nervous system disorders
|
|
|
|
|
|
|
Neuropathy
|
4 (3%)
|
1 (<1%)
|
0
|
3 (2%)
|
1 (<1%)
|
0
|
Other
|
49 (35%)
|
3 (2%)
|
1 (<1%)
|
43 (30%)
|
7 (5%)
|
2 (1%)
|
Infection-febrile neutropenia
|
39 (28%)
|
21 (15%)
|
5 (4%)
|
26 (18%)
|
11 (8%)
|
0
|
Cardiovascular
|
35 (25%)
|
7 (5%)
|
6 (4%)
|
22 (15%)
|
8 (6%)
|
3 (2%)
|
Hepatic
|
34 (24%)
|
5 (4%)
|
2 (1%)
|
23 (16%)
|
2 (1%)
|
0
|
Pulmonary
|
24 (17%)
|
4 (3%)
|
0
|
23 (16%)
|
5 (3%)
|
3 (2%)
|
Vascular disorders
|
|
|
|
|
|
|
Hemorrhage
|
21 (15%)
|
8 (6%)
|
1 (<1%)
|
20 (14%)
|
3 (2%)
|
1 (<1%)
|
Coagulation
|
8 (6%)
|
4 (3%)
|
3 (2%)
|
10 (7%)
|
7 (5%)
|
0
|
Musculoskeletal
|
19 (14%)
|
3 (2%)
|
0
|
7 (5%)
|
1 (<1%)
|
1 (<1%)
|
Allergy-Immunology
|
8 (6%)
|
2 (1%)
|
1 (<1%)
|
4 (3%)
|
0
|
1 (<1%)
|
Endocrine
|
8 (6%)
|
0
|
0
|
4 (3%)
|
2 (1%)
|
0
|
Sexual reproduction function
|
7 (5%)
|
0
|
0
|
10 (7%)
|
1 (<1%)
|
0
|
Ocular-visual
|
7 (5%)
|
0
|
0
|
7 (5%)
|
1 (<1%)
|
0
|
Data were collected using NCI Common Toxicity Criteria, v. 2.0.
a Includes patients who were eligible and treated.
b Grades 1 through 4 only. There were 3 patients who experienced Grade 5 deaths with investigator-designated attribution. One was a Grade 5 hemorrhage in which the drug-related thrombocytopenia aggravated the event. A second patient experienced bowel obstruction, cardiac arrest, pleural effusion and respiratory failure which were not treatment related but probably aggravated by treatment. A third patient experienced a pulmonary embolism and adult respiratory distress syndrome; the latter was indirectly treatment-related.
c Constitutional includes fatigue (lethargy, malaise, asthenia), fever (in the absence of neutropenia), rigors, chills, sweating, and weight gain or loss.
d Pain includes abdominal pain or cramping, arthralgia, bone pain, chest pain (non-cardiac and non-pleuritic), dysmenorrhea, dyspareunia, earache, headache, hepatic pain, myalgia, neuropathic pain, pain due to radiation, pelvic pain, pleuritic pain, rectal or perirectal pain, and tumor pain.
Postmarketing Experience
In addition to adverse reactions reported from clinical trials or listed in other sections of the prescribing information, the following reactions have been identified during postmarketing use of HYCAMTIN. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to HYCAMTIN.
Blood and Lymphatic System Disorders:
Severe bleeding (in association with thrombocytopenia) [see Warnings and Precautions].
Immune System Disorders:
Allergic manifestations, anaphylactoid reactions.
Gastrointestinal Disorders:
Abdominal pain potentially associated with neutropenic colitis [see Warnings and Precautions].
Pulmonary Disorders:
Interstitial lung disease [see Warnings and Precautions].
Skin and Subcutaneous Tissue Disorders:
Angioedema, severe dermatitis, severe pruritus.
General Disorders and Administration Site Conditions:
Inadvertent extravasation [see Warnings and Precautions].
|
REPORTS OF SUSPECTED HYCAMTIN SIDE EFFECTS / ADVERSE REACTIONS
Below is a sample of reports where side effects / adverse reactions may be related to Hycamtin. The information is not vetted and should not be considered as verified clinical evidence.
Possible Hycamtin side effects / adverse reactions in 15 year old male
Reported by a consumer/non-health professional from United States on 2011-10-04
Patient: 15 year old male
Reactions: Death
Adverse event resulted in: death
Suspect drug(s):
Hycamtin
Possible Hycamtin side effects / adverse reactions in 63 year old female
Reported by a health professional (non-physician/pharmacist) from United States on 2011-10-07
Patient: 63 year old female
Reactions: Small Cell Lung Cancer Stage Unspecified
Adverse event resulted in: death, life threatening event, hospitalization, disablity
Suspect drug(s):
Hycamtin
Other drugs received by patient: Promethazine; Xopenex; Flexeril; Estradiol; Zofran; Nexium; Asmanex Twisthaler; Marinol; Prozac; Codeine Sulfate; Proair HFA; Hydrocodone Bitartrate
Possible Hycamtin side effects / adverse reactions in 49 year old female
Reported by a health professional (non-physician/pharmacist) from France on 2011-10-18
Patient: 49 year old female
Reactions: Thrombocytosis
Adverse event resulted in: hospitalization
Suspect drug(s):
Solu-Medrol
Dosage: unk %, unk
Indication: Premedication
Start date: 2011-09-06
End date: 2011-09-11
Emend
Dosage: unk
Indication: Premedication
Start date: 2011-09-06
End date: 2011-09-11
Plitican
Dosage: unk
Indication: Premedication
Start date: 2011-09-06
Ketoprofen
Dosage: unk
Administration route: Oral
Cisplatin
Dosage: unk
Indication: Cervix Carcinoma
Start date: 2011-09-07
End date: 2011-09-08
Acetaminophen
Dosage: unk
Administration route: Oral
Hycamtin
Dosage: unk %, unk
Indication: Cervix Carcinoma
Start date: 2011-09-07
End date: 2011-09-09
Tramadol HCL
Dosage: 100 mg, 3x/day
Administration route: Oral
Start date: 2011-09-06
|