Click here to view next page of this article Topotecan HydrochlorideIndications: Carcinoma, bronchogenic; Carcinoma, ovary
DESCRIPTION: Topotecan HCl is a semi-synthetic derivative of camptothecin and is an anti-tumor drug with topoisomerase I-inhibitory activity. Hycamtin for injection is supplied as a sterile lyophilized, buffered, light yellow to greenish powder available in single-dose vials. Each vial contains topotecan HCl equivalent.
Topotecan HCl was studied in two clinical trials of 223 patients given topotecan with metastatic ovarian carcinoma. All patients had disease that had recurred on, or was unresponsive to, a platinum-containing regimen. Patients in these two studies received an initial dose of 1.5 mg/m2 given. One study was a randomized trial of 112 patients treated with topotecan HCl (1.5 mg/m2/day × 5 days starting on day 1 of a 21-day course) and 114 patients treated with paclitaxel (175 mg/m2 over 3 hours on day 1 of a 21-day course). All patients had recurrent ovarian cancer after a platinum-containing regimen or had not responded to at least one prior platinum-containing regimen. Patients who did not respond to the study therapy, or who progressed, could be given the alternative treatment. Response rates, response duration, and time to progression are shown. The median time to response was 7.6 weeks (range 3.1-21.7) with topotecan HCl compared to 6.0 weeks (range 2.4-18.1) with paclitaxel. Consequently, the efficacy of topotecan HCl may not be achieved if patients are withdrawn from treatment prematurely. In the crossover phase, 8 of 61 (13%) patients who received topotecan HCl after paclitaxel had a partial response and 5 of 49 (10%) patients who received paclitaxel after topotecan HCl had a response (two complete responses). Topotecan HCl was active in ovarian cancer patients who had developed resistance to platinum-containing therapy, defined as tumor progression while on, or tumor relapse within 6 months after completion. Topotecan HCl was also studied in an open-label, non-comparative trial in 111 patients with recurrent ovarian cancer after treatment with a platinum-containing regimen, or who had not responded to one prior platinum-containing regimen. The response rate was 14% (95% CI=7-20%). The median duration of response was 22 weeks (range 4.6-41.9 weeks). The time to progression was 11.3 weeks (range 0.7-72.1 weeks). The median survival was 67.9 weeks (range 1.4-112.9 weeks). Small Cell Lung Cancer Topotecan HCl was studied in 426 patients with recurrent or progressive small cell lung cancer in one randomized, comparative study and in three single arm studies. Randomized Comparative Study In a randomized, comparative, Phase 3 trial, 107 patients were treated with topotecan HCl (1.5 mg/m2/day × 5 days starting on day 1 of a 21-day course) and 104 patients were treated with CAV (1000 mg/m2 cyclophosphamide, 45 mg/m2 doxorubicin, 2 mg vincristine administered sequentially on day 1 of a 21-day course).
Topotecan HCl was also studied in three open-label, non-comparative trials in a total of 319 patients with recurrent or progressive small cell lung cancer after treatment with first-line chemotherapy. In all three studies, patients were stratified as either sensitive (responders who then subsequently progressed 90 days after completion of first-line therapy) or refractory (no response to first-line chemotherapy or who responded to first-line therapy and then progressed within 90 days of completing first-line therapy). Response rates ranged from 11-31% for sensitive patients and 2-7% for refractory patients. Median time to progression and median survival were similar in all three studies and the comparative study. INDICATIONS AND USAGE: Topotecan HCl is indicated for the treatment of:
CONTRAINDICATIONS: Topotecan HCl is contraindicated in patients who have a history of hypersensitivity reactions to topotecan or to any of its ingredients. Topotecan HCl should not be used in patients who are pregnant or breast-feeding, or those with severe bone marrow depression. 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 topotecan HCl and 4% for CAV. Monitoring of Bone Marrow Function: Topotecan HCl should only be administered in patients with adequate bone marrow reserves, including baseline neutrophil count of at least 1500 cells/mm3 and platelet count at least 100,000/mm3. Frequent monitoring of peripheral blood cell counts should be instituted during treatment with topotecan HCl. Patients should not be treated with subsequent course of topotecan HCl until neutrophils recover to >1000 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 topotecan HCl is used in combination with cisplatin. Pregnancy: Topotecan HCl 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. 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 topotecan HCl. Gastrointestinal: The incidence of nausea was 64% (8% grade 3/4) and vomiting occurred in 45% (6% grade 3/4) of patients. The prophylactic use of antiemetics was not routine in patients treated with topotecan HCl. 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.
Prior to administration of the first course of topotecan HCl, patients must have a baseline neutrophil count of >1500 cells/mm3 and a platelet count of >100,000 cells/mm3. The recommended dose of topotecan HCl is 1.5 mg/m2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on day 1 of a 21-day course. In the absence of tumor progression, a minimum of four courses is recommended. |
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