WARNINGS
Bone marrow suppression (primarily neutropenia) is the dose-limiting toxicity of topotecan. Neutropenia is not cumulative over time. The following data on myelosuppression with topotecan is based on the combined experience of 879 patients with metastatic ovarian cancer or small cell lung cancer.
Neutropenia: Grade 4 neutropenia (<500 cells/mm3) was most common during course 1 of treatment (60% of patients) and occurred in 39% of all courses, with a median duration of 7 days. The nadir neutrophil count occurred at a median of 12 days. Therapy-related sepsis or febrile neutropenia occurred in 23% of patients, and sepsis was fatal in 1%.
Thrombocytopenia: Grade 4 thrombocytopenia (<25,000/mm3) occurred in 27% of patients and in 9% of courses, with a median duration of 5 days and platelet nadir at a median of 15 days. Platelet transfusions were given to 15% of patients in 4% of courses. Anemia: Grade 3/4 anemia (<8 g/dL) occurred in 37% of patients and in 14% of courses. Median nadir was at day 15. Transfusions were needed in 52% of patients in 22% of courses.
In ovarian cancer, the overall treatment-related death rate was 1%. In the comparative study in small cell lung cancer, however, the treatment-related death rates were 5% for HYCAMTIN and 4% for CAV. Monitoring of Bone Marrow Function: HYCAMTIN should be administered only in patients with adequate bone marrow reserves, including baseline neutrophil count of at least 1,500 cells/mm3 and platelet count at least 100,000/mm3. Frequent monitoring of peripheral blood cell counts should be instituted during treatment with HYCAMTIN. Patients should not be treated with subsequent courses of HYCAMTIN until neutrophils recover to >1,000 cells/mm3, platelets recover to >100,000 cells/mm3, and hemoglobin levels recover to 9.0 g/dL (with transfusion if necessary). Severe myelotoxicity has been reported when HYCAMTIN is used in combination with cisplatin (see Drug Interactions).
Pregnancy: HYCAMTIN may cause fetal harm when administered to a pregnant woman. The effects of topotecan on pregnant women have not been studied. If topotecan is used during a patient's pregnancy, or if a patient becomes pregnant while taking topotecan, she should be warned of the potential hazard to the fetus. Fecund women should be warned to avoid becoming pregnant. In rabbits, a dose of 0.10 mg/kg/day (about equal to the clinical dose on a mg/m2 basis) given on days 6 through 20 of gestation caused maternal toxicity, embryolethality, and reduced fetal body weight. In the rat, a dose of 0.23 mg/kg/day (about equal to the clinical dose on a mg/m2 basis) given for 14 days before mating through gestation day 6 caused fetal resorption, microphthalmia, pre-implant loss, and mild maternal toxicity. A dose of 0.10 mg/kg/day (about half the clinical dose on a mg/m2 basis) given to rats on days 6 through 17 of gestation caused an increase in post-implantation mortality. This dose also caused an increase in total fetal malformations. The most frequent malformations were of the eye (microphthalmia, anophthalmia, rosette formation of the retina, coloboma of the retina, ectopic orbit), brain (dilated lateral and third ventricles), skull, and vertebrae.
PRECAUTIONS
General: Inadvertent extravasation with HYCAMTIN has been associated only with mild local reactions such as erythema and bruising. Information for Patients: As with other chemotherapeutic agents, HYCAMTIN may cause asthenia or fatigue; if these symptoms occur, caution should be observed when driving or operating machinery. Hematology: Monitoring of bone marrow function is essential (see WARNINGS and DOSAGE AND ADMINISTRATION).
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity testing of topotecan has not been performed. Topotecan, however, is known to be genotoxic to mammalian cells and is a probable carcinogen. Topotecan was mutagenic to L5178Y mouse lymphoma cells and clastogenic to cultured human lymphocytes with and without metabolic activation. It was also clastogenic to mouse bone marrow. Topotecan did not cause mutations in bacterial cells. Drug Interactions: Concomitant administration of G-CSF can prolong the duration of neutropenia, so if G-CSF is to be used, it should not be initiated until day 6 of the course of therapy, 24 hours after completion of treatment with HYCAMTIN.
Myelosuppression was more severe when HYCAMTIN was given in combination with cisplatin in Phase 1 studies. In a reported study on concomitant administration of cisplatin 50 mg/m2 and HYCAMTIN at a dose of 1.25 mg/m2/day × 5 days, 1 of 3 patients had severe neutropenia for 12 days and a second patient died with neutropenic sepsis. There are no adequate data to define a safe and effective regimen for HYCAMTIN and cisplatin in combination.
Greater myelosuppression is also likely to be seen when HYCAMTIN is used in combination with other cytotoxic agents, thereby necessitating a dose reduction. However, when combining HYCAMTIN with platinum agents (e.g., cisplatin or carboplatin), a distinct sequence-dependent interaction on myelosuppression has been reported. Coadministration of a platinum agent on day 1 of HYCAMTIN dosing required lower doses of each agent compared to coadministration on day 5 of the HYCAMTIN dosing schedule.
Pregnancy: Pregnancy Category D. (See WARNINGS.)
Nursing Mothers: It is not known whether the drug is excreted in human milk. Breast-feeding should be discontinued when women are receiving HYCAMTIN (see CONTRAINDICATIONS).
Pediatric Use: Safety and effectiveness in pediatric patients have not been established. Geriatric Use: Of the 879 patients with metastatic ovarian cancer or small cell lung cancer in clinical studies of HYCAMTIN, 32% (n = 281) were 65 years of age and older, while 3.8% (n = 33) were 75 years of age and older. No overall differences in effectiveness or safety were observed between these patients and younger adult patients. Other reported clinical experience has not identified differences in responses between the elderly and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.
There were no apparent differences in the pharmacokinetics of topotecan in elderly patients, once the age-related decrease in renal function was considered (see CLINICAL PHARMACOLOGY).
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION).
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