Topotecan (Page 2 of 6)

5.2 Neutropenic Colitis

Topotecan-induced neutropenia can lead to neutropenic colitis. Fatalities due to neutropenic colitis have been reported in clinical trials with Topotecan Injection. In patients presenting with fever, neutropenia, and a compatible pattern of abdominal pain, consider the possibility of neutropenic colitis.

5.3 Interstitial Lung Disease

Topotecan Injection has been associated with reports of interstitial lung disease (ILD), some of which have been fatal [see Adverse Reactions ( 6.2) ]. Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer, thoracic exposure to radiation, and use of pneumotoxic drugs and/or colony stimulating factors. Monitor patients for pulmonary symptoms indicative of interstitial lung disease (e.g., cough, fever, dyspnea, and/or hypoxia), and discontinue Topotecan Injection if a new diagnosis of ILD is confirmed.

5.4 Pregnancy

Pregnancy Category D

Topotecan Injection can cause fetal harm when administered to a pregnant woman.

Topotecan caused embryolethality, fetotoxicity, and teratogenicity in rats and rabbits when administered during organogenesis. There are no adequate and well controlled studies of Topotecan Injection in pregnant women. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving Topotecan Injection, the patient should be apprised of the potential hazard to the fetus. [see Use in Specific Populations, Pregnancy ( 8.1) ]

5.5 Inadvertent Extravasation

Inadvertent extravasation with topotecan has been observed, most reactions have been mild but severe cases have been reported.

6 ADVERSE REACTIONS

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.

Small Cell Lung Cancer

Data in the following section are based on the combined experiences of the 879 patients studied, including 426 patients with small cell lung cancer treated with topotecan. Table 1lists the principle hematologic adverse reactions and Table 2lists non-hematologic adverse reactions occurring in at least 15% of patients.

Table 1. Hematologic Adverse Reactions Experienced in ≥15% of Patients, Including 426 Patients With Small Cell Lung Cancer, Receiving Topotecan
Hematologic Adverse Reaction

Patients

(n=879)

Neutropenia

<1,500 cells/mm 3

3

97

Leukopenia

<3,000 cells/mm 3

3

97

Thrombocytopenia

<75,000/mm 3

3

69

Anemia

<10 g/dL

89

Table 2. Non-hematologic Adverse Reactions Experienced by ≥15% of 879 Patients, Including 426 Patients With Small Cell Lung Cancer, Receiving Topotecan

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
Rash b 16 1 0
General disorders and administrative site conditions
Fatigue 29 5 0
Pyrexia 28 1 <1
Pain c 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/CAV comparator trial in small cell lung cancer.

Table 3. Adverse Reactions Experienced by ≥5% of Small Cell Lung Cancer Patients Randomized to Receive Topotecan or CAV

Adverse Reaction

Topotecan

CAV

Hematologic Grade 3/4 % %

Grade 4 neutropenia

3)
70 72

Grade 3/4 anemia

42 20

Grade 4 thrombocytopenia

3)
29 5
Pyrexia/Grade 4 neutropenia 28 26
Non-hematologic Grade 3/4 % %

Infections and infestations

a
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

Pain b 5 7

a Death related to sepsis occurred in 3% of patients receiving topotecan, and in 1% of patients receiving CAV

b Pain includes body pain, skeletal pain, and back pain.

Cervical Cancer

In the comparative trial with Topotecan Injection plus cisplatin versus cisplatin in patients with cervical cancer, the most common dose-limiting adverse reaction was myelosuppression. Table 4shows the hematologic adverse reactions and Table 5shows the non-hematologic adverse reactions in patients with cervical cancer.

Table 4. Hematologic Adverse Reactions in Patients with Cervical Cancer Treated with Topotecan Injection Plus Cisplatin or Cisplatin Monotherapy a
Hematologic Adverse Reaction

Topotecan Injection Plus Cisplatin

(n = 140)

Cisplatin

(n = 144)
Anemia
All grades (Hgb <12 g/dL) 131 (94%) 130 (90%)
Grade 3 (Hgb <8 to 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/mm 3) 128 (91%) 43 (30%)
Grade 3 (<2,000 to 1,000 cells/mm 3) 58 (41%) 1 (1%)
Grade 4 (<1,000 cells/mm 3) 35 (25%) 0 (0%)
Neutropenia
All grades (<2,000 cells/mm 3) 125 (89%) 28 (19%)
Grade 3 (<1,000 to 500 cells/mm 3) 36 (26%) 1 (1%)
Grade 4 (<500 cells/mm 3) 67 (48%) 1 (1%)
Thrombocytopenia
All grades (<130,000 cells/mm 3) 104 (74%) 21 (15%)
Grade 3 (<50,000 to 10,000 cells/mm 3) 36 (26%) 5 (3%)
Grade 4 (<10,000 cells/mm 3) 10 (7%) 0 (0%)

a Includes patients who were eligible and treated.

Table 5. Non-hematologic Adverse Reactions Experienced by ≥ 5% of Patients with Cervical Cancer Treated with Topotecan Injection Plus Cisplatin or Cisplatin Monotherapy a
Topotecan Injection Plus Cisplatin Cisplatin
(n = 140) (n = 144)
Adverse Reaction All Grades b Grade 3 Grade 4 All Grades b Grade 3 Grade 4
General disorders and administrative site conditions
Constitutional c 96 (69%) 11 (8%) 0 89 (62%) 17 (12%) 0
Pain d 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.

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