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.
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 |
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.
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.
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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