VA Class:AN900
Topotecan, a semisynthetic derivative of camptothecin is an antineoplastic agent.1, 3, 5, 6, 7, 9, 10, 11, 13, 17, 24, 47, 57
Topotecan is used IV for the treatment of advanced ovarian cancer in patients with disease that has recurred or progressed following therapy with platinum-based (i.e., cisplatin, carboplatin) regimens.1, 34, 57 The current indication for use of IV topotecan is based principally on data from 2 clinical trials (including a multicenter, randomized study comparing topotecan with paclitaxel) in patients with advanced ovarian cancer.1, 28, 35, 36, 57 In these clinical trials, topotecan was administered at an initial dosage of 1.5 mg/m2 IV over 30 minutes once daily for 5 days (as tolerated) followed by 16 treatment-free days (total of 21 days per treatment course); dosage of topotecan in subsequent cycles was adjusted according to hematologic tolerance.1, 28, 36, 57
In a randomized trial of patients receiving IV topotecan versus paclitaxel (175 mg/m2 IV over 3 hours once every 21 days), respectively, the overall response rate (21 versus 14%), the median response duration (25.9 versus 21.6 weeks), and the median survival duration (63 versus 53 weeks) were similar.1, 36, 57 In patients receiving topotecan, the median time to response was longer (7.6 versus 6 weeks), but median time to disease progression was prolonged (18.9 versus 14.7 weeks), compared with patients receiving paclitaxel.1, 36, 57 Patients with disease that did not respond to, or progressed during, the initially assigned therapy were allowed to subsequently receive the alternative therapy.1, 36, 57 Among 61 patients receiving topotecan following initial therapy with paclitaxel, 8 patients (13%) had an objective response (all partial responses); among 49 patients receiving paclitaxel following initial therapy with topotecan, 5 patients (10%) had an objective response (2 complete responses, 3 partial responses).1, 57 Hematologic toxicity, including grade 4 neutropenia, grade 4 thrombocytopenia, and grade 3 or 4 anemia, occurred more frequently during topotecan therapy.36, 57 In a separate analysis of a subset of patients with disease resistant to platinum-containing therapy (defined as tumor progression during therapy or relapse within 6 months following completion of therapy), treatment with topotecan or paclitaxel was associated with an overall response rate of 12 or 7%, respectively; all responses were partial responses except for 1 complete response in a patient receiving topotecan.1, 57
In an open-label trial, responses were observed in 14% of patients receiving IV topotecan as second-line therapy for resistant or recurrent ovarian cancer following treatment with a platinum-containing regimen.1, 57 The median duration of response in these patients was 22 weeks (range: 4.6-41.9 weeks), the median time to disease progression was 11.3 weeks (range: 0.7-72.1 weeks), and the median survival was 67.9 weeks (range: 1.4-112.9 weeks).1, 57
Topotecan is used orally and IV as second-line therapy for treatment-sensitive small cell lung cancer.1, 34, 39, 40, 46, 47, 57 The current indication for use of oral topotecan monotherapy is based principally on data from a randomized, open-label, multicenter phase 3 trial comparing oral topotecan and best supportive care with best supportive care alone in 141 patients with recurrent small cell lung cancer.46, 47, 49, 50 Eligible patients included those who achieved a complete or partial response to first-line chemotherapy, those who were not considered suitable for further IV chemotherapy (i.e., those with resistant disease based on short disease-free interval, presence of comorbidities, or those who refused additional parenteral chemotherapy), and patients who had relapsed at least 45 days after the completion of a prior chemotherapy regimen (i.e., to ensure adequate bone marrow recovery).46, 47, 49, 50 The median treatment-free interval after first-line therapy for patients randomized to oral topotecan and best supportive care or best supportive care alone was 84 or 90 days, respectively.46 Patients randomized to oral topotecan received a dosage of 2.3 mg/m2 daily on days 1-5 of a 21-day cycle; patients received a median of 4 cycles (range: 1-10).46, 47, 49, 50 Based on an intent-to-treat analysis, an improvement in median overall survival (i.e., all-cause mortality) was observed in patients receiving topotecan and best supportive care (25.9 weeks) compared with those receiving best supportive care alone (13.9 weeks);46, 47, 49, 50 6-month survival rates also improved in patients receiving oral topotecan (49%) compared with those receiving best supportive care alone (26%).46, 50 An improvement in median survival also was reported in poor-risk patients receiving oral topotecan including those with chemoresistant disease (defined by a disease-free interval of 60 days or less) or with an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less.46 In the oral topotecan group, partial response and stabilization of disease were achieved in 7 and 44% of patients, respectively.46, 49, 50 Responses from patient questionnaires also indicated a slower decline in health-related quality of life measures (performed at 3-month intervals) in patients receiving oral topotecan;46, 49, 50 control of symptoms such as dyspnea, sleep interference, and fatigue was greater with use of oral topotecan and best supportive care compared with best supportive care alone.46, 49
In the group receiving oral topotecan, grade 3/4 cytopenias, including neutropenia, thrombocytopenia, and anemia, were reported in 61, 37, and 25% of patients, respectively.46, 47, 49, 50 Severe (grade 3/4) diarrhea also was reported in 5% of patients receiving the drug.46, 47, 50
Safety and efficacy of oral topotecan have been compared directly with IV topotecan as second-line therapy in a randomized, open-label, phase 3 study of 309 patients with recurrent, treatment-sensitive small cell lung cancer.48 Eligible patients included those with disease recurrence at least 90 days following completion of first-line chemotherapy.48 Patients were randomized to receive either oral topotecan (2.3 mg/m2 daily) or IV topotecan (1.5 mg/m2 over 30 minutes daily) on days 1-5 of a 21-day cycle; patients received a median of 4 cycles.48 Overall response was similar between the two treatment groups with rates of 18.3 and 21.9% reported for oral and IV topotecan, respectively.48 Similar improvement in median survival time also was reported for patients receiving oral topotecan (33 weeks) compared with IV topotecan (35 weeks).48 However, the trial was not adequately powered to demonstrate an improvement in survival outcome for one particular regimen.48
In this study, the incidence of grade 3 neutropenia was similar in both treatment groups; however, grade 4 neutropenia was reported more frequently (64 versus 47%) in patients receiving IV compared with oral topotecan, respectively.48 Antibiotic usage also was slightly higher in patients receiving IV topotecan compared with those receiving oral therapy.48 In addition, granulocyte colony-stimulating factor (G-CSF, filgrastim) was used in a higher percentage (25 versus 16%) of patients receiving oral than IV topotecan, respectively.48 Diarrhea was a frequently reported adverse event with oral topotecan; grade 3/4 diarrhea occurred in 7.9 compared with 2.7% of patients receiving oral or IV topotecan, respectively.48 In patients reporting diarrhea with oral topotecan, the symptoms were characterized as self-limiting or manageable with standard antidiarrhea treatment (e.g., loperamide).48
Some experts state that use of oral topotecan is a reasonable alternative for patients with recurrent small cell lung cancer who cannot tolerate the IV formulation of the drug.48, 49, 50
In the clinical studies submitted to support the labeled indication of IV topotecan for use in small cell lung cancer, treatment-sensitive small cell lung cancer was defined as disease initially responding to first-line chemotherapy with subsequent relapse no sooner than 60-90 days following completion of first-line therapy.1, 40, 57
The current indication for use of IV topotecan in recurrent small cell lung cancer is based principally on data from a randomized, multicenter, phase 3 trial and 3 uncontrolled, phase 2 studies.1, 40, 41, 57 Results from a large randomized trial indicate that IV topotecan used as a single agent is as effective as combination chemotherapy with cyclophosphamide, doxorubicin, and vincristine (CAV) for the treatment of recurrent small cell lung cancer.40 In this trial, 211 patients with small cell lung cancer that relapsed at least 60 days following completion of first-line chemotherapy were randomized to receive either IV topotecan (1.5 mg/m2 IV over 30 minutes daily on days 1-5) or combination chemotherapy with CAV (sequential administration of cyclophosphamide 1000 mg/m2, doxorubicin 45 mg/m2, and vincristine 2 mg on day 1) on a 21-day cycle; in patients experiencing an objective response, therapy was continued until disease progression or unacceptable toxicity occurred, or for at least 6 courses past the maximal response.1, 40, 57 About 80% of the patients receiving IV topotecan or CAV had received a platinum-containing agent and etoposide, with or without other agents, as initial treatment for small cell lung cancer.1, 40, 57 The overall response rate was similar in patients receiving IV topotecan (24.3%, all partial responses) or CAV (18.3%, 1% complete responses).1, 40, 57 Among patients receiving IV topotecan or CAV, respectively, the median time to progression (13.3 versus 12.3 weeks) and the median survival duration (25 versus 24.7 weeks) also were comparable.1, 40, 57 IV topotecan was more effective than CAV for palliation of symptoms, including dyspnea, anorexia, hoarseness, fatigue, and interference with daily activity.1, 40, 57
Grade 4 neutropenia was reported in about 70% of patients receiving either IV topotecan or CAV1, 40, 57 but occurred more frequently in treatment courses with CAV (51.4%) versus IV topotecan (37.8%).40 IV topotecan was associated with a higher incidence of grade 4 thrombocytopenia (29 versus 5%) and grade 3 or 4 anemia (42 versus 20%) than combination chemotherapy with CAV.1, 40, 57 Cardiac toxicity with reduction in left ventricular ejection fraction occurred more frequently in patients receiving CAV than in those receiving IV topotecan (17.1 versus 7.7%, respectively).40
In 3 uncontrolled phase 2 studies of IV topotecan for the treatment of recurrent or progressive small cell lung cancer, objective response rates ranged from 11-31% in patients with treatment-sensitive disease (defined as progression of disease at least 90 days following completion of therapy) and from 2-7% in patients with refractory disease (defined as progression of disease during, or within 90 days of completion of, first-line therapy).1, 57
Topotecan is used IV in combination with cisplatin for the treatment of stage IVB, recurrent or persistent cervical cancer that is not amenable to curative treatment with surgery and/or radiation therapy.1, 57
The current indication for use of IV topotecan in combination with cisplatin for advanced cervical cancer is based on the results of a randomized trial in which patients received cisplatin alone, topotecan and cisplatin, or methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC).1, 42 Following 4 deaths related to treatment, the MVAC arm of the trial was closed, and the data for these patients were excluded from this analysis.1, 42 In the remaining arms, treatment consisted of combination therapy with topotecan 0.75 mg/m2 IV over 30 minutes for 3 consecutive days starting on day 1 of a 21-day course plus cisplatin 50 mg/m2 on day 1; or cisplatin alone (same cisplatin dosage as in combination regimen).1, 42 About half (56%) of the patients in each arm had received previous treatment with cisplatin (alone or with other agents) as first-line therapy.1, 42, 57
Among 293 patients receiving either IV topotecan and cisplatin or cisplatin alone for advanced cervical cancer, median survival was prolonged (9.4 versus 6.5 months, hazard ratio: 0.76) for patients receiving the combination regimen.1, 42, 57 Despite greater hematologic toxicity among patients receiving combination therapy, quality of life scores were similar in patients receiving topotecan and cisplatin or cisplatin alone.43 Adverse dermatologic effects, infection/febrile neutropenia, cardiovascular and hepatic toxicity, and stomatitis/pharyngitis were more frequent in patients receiving combination therapy with topotecan and cisplatin compared with cisplatin alone.1, 42, 57
Reconstitution and Administration
Topotecan hydrochloride capsules are administered orally and may be taken with or without food.47, 58 The capsules should be swallowed whole and should not be crushed, chewed, divided, or opened.47, 58 If vomiting occurs following administration of oral topotecan, a replacement dose should not be administered.47, 58
Topotecan hydrochloride for injection concentrate is administered by IV infusion only.1, 2, 3, 33, 57 Care should be taken to avoid extravasation of the drug; inadvertent extravasation of topotecan has been associated with mild local reactions such as erythema and bruising.1, 57
Commercially available topotecan hydrochloride for injection concentrate must be diluted prior to IV administration.33 The drug is reconstituted by adding 4 mL of sterile water for injection to the vial labeled as containing 4 mg of topotecan in order to provide a solution containing 1 mg/mL of topotecan.1, 3, 57 The calculated daily dose of topotecan is then diluted in a suitable volume (e.g., 50-250 mL) of 5% dextrose or 0.9% sodium chloride injection and infused IV over a period of 30 minutes.1, 3, 6, 12, 16, 22, 33, 57 The manufacturer states that solutions of topotecan hydrochloride should be prepared immediately before use since the lyophilized drug does not contain a preservative.1, 33, 57
Topotecan hydrochloride for injection concentrate should be inspected visually for particulate matter in the vial and again in the syringe when transferring the drug solution to prepare admixtures of the drug.33 As with all parenteral products, diluted solutions of the drug should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.33
The manufacturer recommends that procedures for proper handling and disposal of antineoplastic drugs (e.g., use of protective clothing and gloves, preparation of drug solutions under a vertical laminar flow hood) be used to avoid exposure to topotecan during preparation of IV solutions.1, 22, 57 If topotecan hydrochloride or a solution of the drug comes in contact with the skin or mucous membranes, the skin should be washed immediately and thoroughly with soap and water or the mucosa should be flushed with copious amounts of water.1, 22, 57
Dosage of oral and IV topotecan hydrochloride is expressed in terms of topotecan.1, 22, 47, 57 Dosage of the drug must be individualized based on body surface area and patient tolerance.1, 2, 57
For the treatment of metastatic cancer of the ovary in patients with disease that has recurred or progressed following therapy with platinum-based (i.e., cisplatin, carboplatin) regimens, the recommended initial dose of topotecan is 1.5 mg/m2 infused IV over a period of 30 minutes; this dose is administered daily for 5 consecutive days followed by a 16-day rest period for a 21-day treatment course.1, 2, 3, 6, 7, 11, 14, 16, 17, 24, 57 In patients without progression of disease, the manufacturer recommends a minimum of 4 courses of topotecan therapy (provided that intolerable toxicity does not develop) because median time to response was 9-12 weeks in 3 clinical trials in patients with metastatic ovarian cancer, and response may not be achieved if therapy with the drug is discontinued prematurely.1, 2, 33, 57
When used orally for the treatment of recurrent small cell lung cancer following initial response to chemotherapy, the recommended initial dosage of topotecan is 2.3 mg/m2 administered once daily for 5 consecutive days followed by a 16-day rest period for a 21-day treatment course.46, 47 The calculated daily dosage should be rounded to the nearest 0.25 mg, and the minimum number of capsules containing 0.25 and 1 mg should be prescribed.47 The same number of 0. 25-mg and 1-mg capsules should be administered for each of the 5 dosing days.47 Although the manufacturer does not recommend a specific number of cycles for the treatment of small cell lung cancer, at least 4 treatment cycles of oral topotecan were used in a controlled clinical trial.46
When used IV for the treatment of recurrent small cell lung cancer following initial response to chemotherapy, the recommended initial dosage of topotecan is 1.5 mg/m2 infused over a period of 30 minutes; this dosage is administered daily for 5 consecutive days followed by a 16-day rest period for a 21-day treatment course.1, 40, 57 In patients without progression of disease, the manufacturer recommends a minimum of 4 courses of IV topotecan therapy (provided that intolerable toxicity does not develop) because median time to response was 5-7 weeks in 4 small clinical trials in patients with small cell lung cancer, and response may not be achieved if therapy with the drug is discontinued prematurely.1, 57
For the treatment of stage IVB, recurrent or persistent cervical cancer that is not amenable to curative treatment with surgery and/or radiation therapy, the recommended dose of topotecan is 0.75 mg/m2 infused IV over a period of 30 minutes; this dose is administered daily for 3 consecutive days (days 1-3) and on day 1 is followed by IV cisplatin 50 mg/m2 for each 21-day course.1, 57
Dosage Modification for Toxicity
The dose-limiting toxicity of topotecan therapy is myelosuppression.1, 2, 3, 4, 5, 6, 7, 8, 11, 12, 13, 14, 16, 17, 19, 24, 27, 28, 34, 47, 57 Because neutropenia occurs frequently during topotecan therapy and may be severe and potentially fatal, it is essential that bone marrow function be monitored through evaluation of peripheral blood cell counts before and during topotecan therapy.1, 2, 3, 5, 6, 7, 11, 12, 14, 16, 47, 57
Before the initial course of therapy with either oral or IV topotecan, patients must have a baseline neutrophil count of at least 1500/mm3 and a platelet count of at least 100,000/mm3.1, 2, 47, 57 Bone marrow reserves should be evaluated frequently during topotecan therapy using peripheral blood cell counts, and subsequent courses of therapy should be withheld until the neutrophil count exceeds 1000/mm3, platelet count exceeds 100,000/mm3, and hemoglobin concentration is at least 9 g/dL (with transfusion if necessary).1, 2, 47, 57
If severe neutropenia (defined by National Cancer Institute [NCI] Common Toxicity Criteria as grade 4, (i.e., an absolute neutrophil count [ANC] less than 500/mm3)15 occurs with any course of oral topotecan therapy for small cell lung cancer and is associated with fever or infection or has a duration of 7 days or longer, or if moderate neutropenia (i.e., ANC 500-1000/mm3) persists beyond day 21 of a treatment course, the dosage of topotecan in subsequent courses should be reduced by 0.4 mg/m2 daily (to 1.9 mg/m2).47
If the platelet count falls below 25,000/mm3 during any course of oral topotecan therapy, the dosage of topotecan should be reduced by 0.4 mg/m2 daily (to 1.9 mg/m2) in subsequent courses.47
If grade 3 or 4 diarrhea occurs during any course of oral topotecan therapy, the dosage of topotecan in subsequent courses should be reduced by 0.4 mg/m2 daily (to 1.9 mg/m2).47 The manufacturer states that the same dosage modification for oral topotecan also may be necessary in patients reporting mild diarrhea (grade 2) during therapy.47 (See Warnings: GI Effects.)
If severe neutropenia (defined by NCI Common Toxicity Criteria as grade 4, (i.e., ANC less than 500/mm3)15 occurs with any course of IV topotecan monotherapy of ovarian or small cell lung cancer, the dose of topotecan in subsequent courses should be reduced by 0.25 mg/m2 (to 1.25 mg/m2); alternatively, G-CSF (filgrastim) may be administered following the subsequent course.1, 12, 14, 16, 57 If severe neutropenia occurs in a treatment course and therapy with filgrastim is preferred to reduction of IV topotecan dosage in the subsequent course, filgrastim should be initiated 24 hours after the final dose of IV topotecan in the subsequent treatment course (i.e., beginning on day 6 of the 21-day treatment course) since concurrent therapy with filgrastim and IV topotecan can increase the severity and duration of neutropenia.1, 2, 12, 14, 16, 33, 57
If the platelet count falls below 25,000/mm3 with any course of IV topotecan monotherapy, the dose of topotecan in subsequent courses should be reduced by 0.25 mg/m2 (to 1.25 mg/m2).1, 57
Myelosuppression may be greater when IV topotecan is used in combination with other cytotoxic agents, and dose reduction may be necessary.1 (See Drug Interactions: Antineoplastic Agents.) If severe febrile neutropenia (i.e., ANC less than 1000/mm3 with temperature of 38°C) occurs when IV topotecan is being used in combination with cisplatin for treatment of cervical cancer, the dose of topotecan should be reduced by 20% to 0.6 mg/m2 for subsequent courses of therapy.1, 57 Similarly, if the platelet count falls below 25,000/mm3, the dose of IV topotecan should be reduced by 20% to 0.6 mg/m2.1, 57 If severe febrile neutropenia occurs in a treatment course and therapy with filgrastim is preferred to reduction of topotecan dosage in the subsequent course, filgrastim should be initiated 24 hours after the final dose of topotecan in the subsequent treatment course (i.e., beginning on day 4 of the 21-day treatment course).1, 57 If febrile neutropenia occurs despite the use of filgrastim, the dose of IV topotecan should be further reduced by 20% to 0.45 mg/m2 for subsequent courses of therapy.1 For administration and hydration guidelines for cisplatin and for recommendations for dosage reduction for cisplatin in the event of hematologic toxicity, see the manufacturer's labeling for cisplatin.1, 57
Dosage in Renal and Hepatic Impairment
In patients with impaired renal function receiving oral or IV topotecan monotherapy, the dosage of topotecan must be modified in response to the degree of renal impairment.1, 2, 6, 29, 30, 47, 57
For patients receiving oral topotecan for treatment of small cell lung cancer, dosage adjustment is not recommended for patients with creatinine clearance of 50-80 mL/minute; however, for patients with creatinine clearance of 30-49 mL/minute, the dosage of oral topotecan should be reduced to 1.8 mg/m2 daily (rounded to the nearest 0.25 mg).47 The manufacturer states that insufficient data are available to provide a dosage recommendation for oral topotecan in patients with creatinine clearance less than 30 mL/minute.47
For patients receiving IV topotecan, no dosage adjustment is recommended for patients with creatinine clearance of 40-60 mL/minute; however the dosage of IV topotecan should be reduced to 0.75 mg/m2 in patients with creatinine clearance of 20-39 mL/minute.1, 2, 24, 30, 57 The manufacturer states that insufficient data are available to provide a dosage recommendation for IV topotecan in patients with creatinine clearance less than 19 mL/minute.1, 2, 57
In patients with cervical cancer, therapy with IV topotecan and cisplatin should be initiated only in those with serum creatinine concentrations of 1.5 mg/dL or less.1, 57 In the clinical trial, cisplatin therapy was discontinued in patients with a serum creatinine concentration exceeding 1.5 mg/dL.1, 57 No data are available regarding the safety or efficacy of continued therapy with topotecan following discontinuance of cisplatin therapy in patients with cervical cancer.1, 57
In geriatric patients, no adjustments in either oral or IV topotecan dosage appear to be required other than those related to decreases in renal function with age.1, 29, 47 Because geriatric patients are more likely to have decreased renal function and because patients with renal impairment may be at increased risk of topotecan-induced toxicity, care should be taken in dosage selection for patients in this age group and renal function should be monitored.1, 47, 57
Clinically important alterations in the pharmacokinetics of oral or IV topotecan in patients with impaired hepatic function (i.e., plasma bilirubin greater than 1.5 to less than 15 mg/dL) have not been observed to date, and the manufacturer makes no specific recommendations for dosage modification in such patients.1, 2, 6, 26, 29, 47, 57
The data on adverse effects are based on the experience of 682 patients with lung cancer (recurrent small cell lung cancer and non-small cell lung cancer) receiving at least one dose of oral topotecan in clinical studies.47 Among patients receiving oral topotecan for lung cancer, the treatment-related death rate was 5.7%.47 In addition, safety data are reported based on the experience of 879 patients receiving IV topotecan 1.5 mg/m2 daily for 5 days for metastatic ovarian cancer (453 patients) or recurrent or progressive small cell lung cancer (426 patients) and 140 patients receiving IV topotecan 0.75 mg/m2 daily for 3 consecutive days with cisplatin 50 mg/m2 on day 1 for advanced cervical cancer.1, 57 Among patients receiving IV topotecan for ovarian cancer, the treatment-related death rate was 1%.1, 57 Among patients receiving IV topotecan for small cell lung cancer, the treatment-related death rate was 5%.1, 57
Hematologic Effects and Infectious Complications
Hematologic toxicity generally occurs in all patients receiving oral or IV topotecan.1, 47, 57 Myelosuppression, mainly neutropenia, may be severe in patients receiving topotecan, and can result in infection and death.1, 47, 57 Topotecan-induced neutropenia is not cumulative over time.1, 47, 57 Pancytopenia also has been reported with topotecan.1, 47, 57
Leukopenia is the dose-limiting toxicity of topotecan, and the white blood cell count decreases with increasing dosage or increasing area under the concentration-time curve (AUC) of topotecan.1, 47, 51, 57 For orally administered topotecan, an association between topotecan AUC on day 1 and observed myelosuppression has been established.47, 51 The AUC of the pharmacologically active form of the drug, topotecan lactone (i.e., over a treatment course), also may correlate with the level of hematologic toxicity (i.e., leukopenia).51 Among patients receiving oral topotecan for lung cancer (recurrent small cell lung cancer and non-small cell lung cancer), leukopenia (less than 3000 cells/mm3) occurred in 86% of patients and grade 4 leukopenia (less than 1000 cells/mm3) was reported in 15% of patients.47
Among patients receiving IV topotecan for ovarian cancer or small cell lung cancer, leukopenia (less than 3000 cells/mm3) occurred in 97% and grade 4 leukopenia (less than 1000 cells/mm3) occurred in 32% of patients.1, 57 Following the first cycle of topotecan 1.5 mg/m2 IV for 5 days, an 80-90% decrease in white blood cell count typically is observed at nadir.1, 57
Among patients receiving oral topotecan for lung cancer (recurrent small cell lung cancer and non-small cell lung cancer), neutropenia occurred in 83% and grade 3 and 4 neutropenia (less than 500 cells/mm3) occurred in 24 and 32% of patients, respectively.47 Grade 4 neutropenia was most common during the first course of therapy (20% of patients) and occurred for a median duration of 7 days.47 Febrile neutropenic episodes were reported in 4% of patients; fatal sepsis occurred in 1% of patients receiving oral topotecan in clinical trials.47
Among patients receiving IV topotecan for ovarian cancer or small cell lung cancer, neutropenia (less than 1500 cells/mm3) occurred in 97% and grade 4 neutropenia (less than 500 cells/mm3) occurred in 78% of patients.1, 57 Grade 4 neutropenia was common during the first course of therapy (60% of patients).1, 57 Grade 4 neutropenia occurred in 39% of all treatment courses for a median duration of 7 days.1 The nadir neutrophil count was reached at a median of 12 days.1, 57 Intravenous topotecan-induced sepsis or febrile neutropenia occurred in 23% of patients; fatal sepsis occurred in 1% of patients receiving IV topotecan in clinical trials.57 Among patients receiving IV topotecan and cisplatin for cervical cancer, neutropenia (less than 2000 cells/mm3) occurred in 89%, grade 3 neutropenia (less than 1000 cells/mm3 to 500 cells/mm3) occurred in 26%, and grade 4 neutropenia (less than 500 cells/mm3) occurred in 48% of patients.1, 57 Infection or febrile neutropenia occurred in 28% of such patients and was grade 3 in 15% and grade 4 in 4% of patients.1, 57
Among patients receiving oral topotecan for lung cancer (recurrent small cell lung cancer and non-small cell lung cancer), thrombocytopenia occurred in 81%; grade 4 thrombocytopenia (less than 10,000 cells/mm3) occurred in 6% of patients for a median duration of 3 days.47
Among patients receiving IV topotecan for ovarian cancer or small cell lung cancer, thrombocytopenia (less than 75,000 cells/mm3) occurred in 69% and grade 4 thrombocytopenia (less than 25,000 cells/mm3) occurred in 27% of patients.1, 57 Grade 4 thrombocytopenia occurred in 9% of all treatment courses for a median duration of 5 days.1, 57 The nadir platelet count was reached at a median of 15 days.1, 57 Platelet transfusions were administered to 15% of patients in 4% of treatment courses with IV topotecan.1, 57 Among patients receiving IV topotecan and cisplatin for cervical cancer, thrombocytopenia (less than 130,000 cells/mm3) occurred in 74%, grade 3 thrombocytopenia (less than 50,000 cells/mm3 to 10,000 cells/mm3) occurred in 26%, and grade 4 thrombocytopenia (less than 10,000 cells/mm3) occurred in 7% of patients.1, 57
Among patients receiving oral topotecan for lung cancer (recurrent small cell lung cancer and non-small cell lung cancer), anemia occurred in 98% and grade 3 or 4 anemia (hemoglobin less than 8 g/dL) occurred in 25% of patients.47
Among patients receiving IV topotecan for ovarian cancer or small cell lung cancer, anemia (hemoglobin less than 10 g/dL) occurred in 89% and grade 3 or 4 anemia (hemoglobin less than 8 g/dL) occurred in 37% of patients.1, 57 Grade 3 or 4 anemia occurred in 14% of all treatment courses.1 The nadir erythrocyte count was reached at a median of 15 days.1, 57 Red blood cell transfusions were administered to 52% of patients in 22% of treatment courses with topotecan.1, 57 Among patients receiving IV topotecan and cisplatin for cervical cancer, anemia (hemoglobin less than 12 g/dL) occurred in 94%, grade 3 anemia (less than 8 g/dL to 6.5 g/dL) occurred in 34%, and grade 4 anemia (less than 6.5 g/dL) occurred in 6% of patients.1, 57
Neutropenic colitis (typhlitis), a sequela of drug-induced neutropenia, has been reported with oral and IV topotecan and can be fatal.47, 57 Cases of neutropenic colitis have occurred in patients receiving IV topotecan as part of some combination chemotherapy regimens†, in patients with acute leukemia†, or in pediatric patients†.52, 53, 54, 55, 56
The possibility of neutropenic colitis should be considered in patients who develop fever, neutropenia, and abdominal pain during topotecan therapy.47, 57 (See Cautions: GI Effects.)
Diarrhea (sometimes severe and requiring hospitalization) has been reported with oral topotecan.46, 47, 51 Topotecan-related diarrhea is associated with substantial morbidity and in some cases, may be life-threatening.47 Among patients with recurrent small cell lung cancer receiving oral topotecan in a controlled clinical trial, diarrhea occurred in 14% of patients with 5% of these patients reporting grade 3/4 diarrhea.47 The median time to onset for grade 2 diarrhea (or worse) in this study was 9 days.47 Data pooled from 4 lung cancer trials (in patients with small cell lung cancer or non-small cell lung cancer) demonstrated a 22% incidence of diarrhea with 4.4% of patients reporting grade 3/4 diarrhea.47 In these trials, the incidence of diarrhea was 28% in patients 65 years of age or older compared with 19% in patients younger than 65 years of a grade 3/4 diarrhea also was reported more frequently in patients 65 years of age or older (8%) compared with those younger than 65 years of age (3%).47 In another study comparing oral and IV topotecan regimens, the incidence of diarrhea was higher (36 versus 20%) in patients receiving oral topotecan.48, 50
Diarrhea may occur at the same time as neutropenia and its sequelae.47 (See Cautions: Neutropenic Colitis.) Severe diarrhea was temporally associated with the onset of severe neutropenia (e.g., occurring within 5 days) in 5% of patients receiving oral topotecan in clinical trials.47
Among patients receiving oral topotecan for small cell lung cancer in a clinical trial, nausea or vomiting occurred in 27 or 19% of patients, respectively.47
Among patients receiving IV topotecan for ovarian cancer or small cell lung cancer, adverse GI effects included nausea (64%), vomiting (45%), diarrhea (32%), constipation (29%), abdominal pain (22%), and stomatitis (18%).1, 57 Grade 3 or 4 abdominal pain occurred in 6% of patients receiving topotecan for ovarian cancer and in 2% of patients receiving the drug for small cell lung cancer.1 Anorexia was reported in 19% of patients.1, 57 Grade 3 or 4 intestinal obstruction was reported in 5% of patients in a clinical trial receiving topotecan for advanced ovarian cancer.1, 57
Among patients receiving IV topotecan and cisplatin for cervical cancer, adverse GI effects included nausea in 55%, vomiting in 40%, and stomatitis/pharyngitis in 6% of patients.1, 57 Unspecified other GI disorders were reported in 63% of patients.1, 57
Interstitial lung disease (sometimes fatal) has been reported during postmarketing experience with IV topotecan.47, 57 Risk factors for developing interstitial lung disease include pulmonary fibrosis, lung cancer, exposure to thoracic radiation, use of drugs known to cause pulmonary toxicity, use of colony-stimulating factors (i.e., hematopoietic growth factors), and a history of interstitial lung disease.47, 57 Patients should be monitored for symptoms suggestive of interstitial lung disease, including cough, fever, dyspnea, and/or hypoxia.47, 57 If a new diagnosis of interstitial lung disease is confirmed, the manufacturer states that topotecan therapy should be discontinued.47, 57
Dyspnea was reported in 22% and coughing in 15% of patients receiving IV topotecan for ovarian cancer or small cell lung cancer.1, 57 Grade 3 or 4 dyspnea occurred in 6% of patients receiving IV topotecan for ovarian cancer and in 9% of patients receiving the drug for small cell lung cancer.1, 57 Grade 3 or 4 pneumonia was reported in 8% of patients receiving IV topotecan for recurrent or progressive small cell lung cancer in a clinical trial.1, 57 Among patients receiving IV topotecan and cisplatin for cervical cancer, adverse respiratory effects occurred in 17% of patients.1, 57
Among patients receiving oral topotecan for small cell lung cancer in a clinical trial, alopecia occurred in 10% of patients.47
Among patients receiving IV topotecan for ovarian cancer or small cell lung cancer, adverse dermatologic effects such as alopecia (49%) and rash (16%), including pruritus, erythematous rash, urticaria, dermatitis, bullous eruption, and maculopapular rash have been reported.1, 57 Total alopecia (grade 2) occurred in 31% of patients receiving IV topotecan for ovarian cancer or small cell lung cancer.1
Among patients receiving IV topotecan and cisplatin for cervical cancer, adverse dermatologic effects occurred in 48% of patients.1, 57
Severe dermatitis or pruritus has occurred rarely in patients receiving IV topotecan.1, 47, 57
Headache was reported in 18% of patients and paresthesia, generally mild, was reported in 7% of patients receiving IV topotecan for ovarian cancer or small cell lung cancer.1, 57
Among patients receiving IV topotecan and cisplatin for cervical cancer, adverse nervous system effects occurred in 38% of patients, including neuropathy in 3% of patients.57
Among patients receiving IV topotecan and cisplatin for cervical cancer, adverse genitourinary effects occurred in 36% of patients.1, 57
Among patients receiving IV topotecan and cisplatin for cervical cancer, adverse cardiovascular effects occurred in 25% of patients.1, 57 Hemorrhage was reported in 15% and coagulation in 6% of such patients.1, 57 Severe bleeding (associated with thrombocytopenia) has occurred rarely in patients receiving IV topotecan.1, 57
Transient elevations in serum aminotransferase concentrations (grade 1 in 8%, grade 3 or 4 in 4%) occurred in patients receiving IV topotecan for ovarian cancer or small cell lung cancer.1, 57 Grade 3 or 4 elevations in serum bilirubin concentrations occurred in less than 2% of such patients.1, 57
Among patients receiving IV topotecan and cisplatin for cervical cancer, adverse hepatic effects occurred in 24% of patients.1, 57
Grade 3 or 4 arthralgia was reported in 1% of patients receiving IV topotecan for advanced ovarian cancer in a clinical trial.1
Among patients receiving IV topotecan and cisplatin for cervical cancer, adverse musculoskeletal effects occurred in 14% of patients.1, 57
Anaphylactoid reactions and angioedema have occurred rarely in patients receiving IV topotecan.1, 47, 57 Allergic manifestations have been reported.1, 47, 57
Erythema and bruising, generally mild, have occurred following inadvertent extravasation of IV topotecan.1, 57
Among patients receiving oral topotecan for small cell lung cancer in a clinical trial, fatigue was reported in 11% and asthenia was reported in 3% of patients.47
Among patients receiving IV topotecan for ovarian cancer or small cell lung cancer, other adverse effects included fatigue in 29%, pyrexia in 28%, asthenia in 25%, and pain (including body pain, back pain, and skeletal pain) in 23% of patients.1, 57 Grade 3 or 4 chest pain and malaise each was reported in 2% of patients receiving IV topotecan for advanced ovarian cancer in a clinical trial.1
Among patients receiving IV topotecan and cisplatin for cervical cancer, adverse constitutional effects, including fatigue, lethargy, malaise, asthenia, fever without neutropenia, rigors, chills, sweating, and weight change (gain or loss) occurred in 69%, pain in 59%, and adverse metabolic or laboratory effects in 39% of patients.1, 57 Other adverse effects reported in patients receiving topotecan and cisplatin for cervical cancer were allergic/immunologic or endocrine effects in 6%, sexual/reproductive effects in 5%, and ocular effects in 5% of patients.1, 57
Precautions and Contraindications
Topotecan should be used IV under the supervision of a qualified clinician experienced in therapy with antineoplastic agents.1 Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.1
Patients should be advised to use caution when driving or operating machinery if they experience symptoms of asthenia or fatigue, which can occur with the use of chemotherapeutic agents, including topotecan.1, 57, 58
Myelosuppression, principally neutropenia, is the dose-limiting toxicity of topotecan, and use of the drug is contraindicated in patients with severe myelosuppression.1, 47, 57 Oral and IV topotecan therapy should not be initiated in patients with baseline neutrophil counts less than 1500/mm3 or platelet counts less than 100,000/mm3.1, 47, 57 Frequent monitoring of peripheral blood cell counts is required during topotecan therapy.1, 47, 57 Patients should be informed that topotecan may decrease blood cell counts and that frequent blood tests will be performed to monitor for the development of bone marrow suppression.47, 57 Patients also should be advised to contact their clinician if fever, other signs of infection (e.g., chills, cough, burning pain on urination), or bleeding develops during therapy.47, 57
Patients should be advised of the risk of potentially severe diarrhea with oral topotecan.47 Patients also should be informed about diarrhea prevention and/or proactive management of early signs and symptoms of diarrhea and instructed to contact their clinician if severe diarrhea develops, including symptoms of diarrhea 3 or more times a day, with fever, and/or with abdominal pain or cramps.47, 58 If diarrhea occurs, clinicians are advised to aggressively manage the condition in accordance with published clinical guidelines.47 Aggressive management of diarrhea may include the use of antidiarrhea agents and anti-infectives, changes in fluid intake and diet, and/or hospitalization.47
Topotecan can cause fetal toxicity when administered to pregnant women.1, 47, 57 If the drug is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.1, 47, 57 The manufacturer states that use of oral topotecan is contraindicated in pregnant and nursing women.47 (See Cautions: Pregnancy and Lactation.)
Topotecan also is contraindicated in patients with a known history of hypersensitivity reactions to the drug or any component of the formulation.1, 47, 57
Safety and efficacy of topotecan in children have not been established.1, 47, 57
Because elimination of oral and IV topotecan may be prolonged in patients with renal impairment and geriatric patients may have decreased renal function, the risk of adverse effects may be greater in such patients.1, 47, 57 Careful dosage selection and monitoring of renal function are advised in geriatric patients receiving topotecan.1, 47, 57
Among 682 patients receiving oral topotecan for thoracic cancer, 33% were 65 years of age or older and 5% were 75 years of age or older.47 In clinical trials, diarrhea was reported more frequently (28 versus 19%) with the use of oral topotecan in patients 65 years of age or older than in those younger than 65 years of age.47
Among 879 patients receiving IV topotecan for metastatic ovarian cancer or recurrent or progressive small cell lung cancer, 32% were 65 years of age or older and 4% were 75 years of age or older.1, 57 Among 140 patients receiving IV topotecan and cisplatin for cervical cancer, 6% were 65 years of age or older and 3% were 75 years of age or older.1, 57 Although no overall differences in safety and efficacy were observed between geriatric and younger patients receiving IV topotecan, the possibility that some geriatric patients may exhibit increased sensitivity to IV topotecan cannot be ruled out.1, 57
Topotecan is mutagenic.1, 47, 57 Topotecan exhibited mutagenic activity in L5178Y mouse lymphoma cells.1, 47, 57 Topotecan was clastogenic to cultured human lymphocytes (with and without metabolic activation) and mouse bone marrow.1, 47, 57 Topotecan did not demonstrate mutagenic activity in bacterial cells.1, 47, 57
Although studies to determine the carcinogenic potential of topotecan have not been performed to date, the drug is known to be genotoxic to mammalian cells and is a probable carcinogen.1, 47, 57
Topotecan can cause fetal toxicity when administered to pregnant women.1, 47, 57 The manufacturer states that use of oral topotecan is contraindicated in pregnant women.47
Reproduction studies in rabbits receiving an IV topotecan dosage of 0.1 mg/kg daily (approximately equivalent to the IV clinical dose in humans on a mg/m2 basis) on gestation days 6-20 revealed evidence of maternal toxicity, embryolethality, and reduced fetal body weight.1, 47, 57 Reproduction studies in rats receiving an IV topotecan dosage of 0.23 mg/kg daily (approximately equivalent to the IV clinical dose in humans on a mg/m2 basis) for 14 days before mating through gestation day 6 showed fetal resorption, microphthalmia, preimplant loss, and mild maternal toxicity.1, 47, 57 The offspring of rats receiving an IV topotecan dosage of 0.1 mg/kg daily (approximately equivalent to half the IV clinical dose in humans on a mg/m2 basis) on gestation days 6-17 experienced an increase in postimplantation mortality and total fetal malformations.1, 47, 57 The most frequent malformations affected the eye (microphthalmia, anophthalmia, rosette formation of the retina, coloboma of the retina, ectopic orbit), brain (dilated lateral and third ventricles), skull, and vertebrae.1, 47, 57
There are no adequate and well-controlled studies to date using topotecan in pregnant women.1, 47, 57 If topotecan is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.1, 47, 57 Women of childbearing potential should be advised to use effective contraceptive measures to avoid becoming pregnant during therapy with topotecan.1, 47, 57
In lactating rats receiving IV topotecan at a dosage of 4.72 mg/m2, high concentrations of the drug (i.e., up to 48 times higher than plasma concentrations) were distributed into milk.47, 57 It is not known whether topotecan is distributed into human milk.1, 47, 57 The manufacturer states that use of oral topotecan is contraindicated in nursing women.47 Because of the potential for serious adverse reactions to topotecan in nursing infants, nursing should be discontinued during therapy.1, 47, 57
Drugs Metabolized by Hepatic Microsomal Enzymes
In vitro drug interaction studies show no evidence that topotecan affects substrates of cytochrome P-450 (CYP) isoenzymes, including CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E, CYP3A, or CYP4A; however, in vivo drug interaction studies evaluating the effects of topotecan on CYP isoenzymes have not been performed to date.47, 57 In vitro data also indicate that dihydropyrimidine dehydrogenase (DPD) enzyme activity is not affected by topotecan.47, 57
Drugs that Inhibit Efflux Transport Systems
Topotecan is a substrate of the efflux transporters P -glycoprotein (Pgp, ABCB1) and ABCG2 (breast cancer resistance protein [BCRP]).47 Concomitant use of elacridar (not commercially available in the US), an inhibitor of both P -glycoprotein and ABCG2 transporters, with oral topotecan resulted in a 2.5-fold increase in the area under the plasma concentration-time curve (AUC) for both topotecan lactone, the pharmcologically active form of the drug, and total topotecan.47 Concomitant use of oral topotecan with inhibitors of P -glycoprotein (e.g., cyclosporine, ketoconazole, ritonavir, saquinavir) also resulted in substantial increases in topotecan exposure.47 In one study, concomitant use of cyclosporine administered within 4 hours of an oral dose of topotecan resulted in a 2- to 3-fold increase in the AUCs of both topotecan lactone and total topotecan.47 The manufacturer states that concomitant use of oral topotecan with Pgp inhibitors should be avoided.47 If topotecan is used concomitantly with a Pgp (ABCB1) and/or an ABCG2 inhibitor, careful monitoring for signs of toxicity should be performed.47
Concurrent administration of granulocyte colony-stimulating factor (G-CSF) can prolong the duration of neutropenia associated with IV topotecan therapy.1, 57 If G-CSF (filgrastim) is to be used concomitantly, therapy should be initiated 24 hours after the final dose of IV topotecan (i.e., beginning on day 6 of the 21-day treatment course for monotherapy or beginning on day 4 of the 21-day treatment course for combination therapy with IV topotecan and cisplatin).1, 57
The severity of drug-induced myelosuppression may be increased when IV topotecan is used in combination with other cytotoxic agents, and dosage reduction may be necessary.1, 57 Severe myelotoxicity, in some cases resulting in fatalities from sepsis, has occurred during combined therapy with IV topotecan and other antineoplastic agents (e.g., cisplatin, paclitaxel).1, 2, 25, 29, 31, 57 A sequence-dependent interaction has been reported when IV topotecan is administered concomitantly with cisplatin; lower doses of each drug were required with administration of cisplatin on day 1 of the topotecan dosing schedule compared with administration of cisplatin on day 5 of the topotecan dosing schedule.1, 57
Concurrent administration of ranitidine did not result in any change to the pharmacokinetics of oral topotecan.47
Limited information is available on the acute toxicity of topotecan.1, 57 Overdosage of oral or IV topotecan would be expected to cause bone marrow suppression.1, 47, 57 A patient who erroneously received a single IV dose of 35 mg/m2 rather than the intended dose of 17.5 mg/m2 experienced severe neutropenia (nadir of 320/mm3) 14 days later followed by recovery without incident.1, 57 The LD10 of IV topotecan in mice is 75 mg/m2.1 There is no known specific antidote for overdosage with topotecan.1, 47, 57 If acute overdosage occurs with oral or IV topotecan, patients should be observed closely for bone marrow suppression and supportive measures, including prophylactic use of granulocyte colony-stimulating factor (G-CSF) and/or antibiotic therapy should be considered.47, 57
Topotecan, a semisynthetic derivative of camptothecin, is an antineoplastic agent.1, 3, 5, 6, 7, 9, 10, 11, 13, 17, 24, 47, 57 Topotecan is a type I DNA topoisomerase inhibitor.1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 17, 47, 48, 57 DNA topoisomerases (i.e., types I and II) are enzymes in the cell nucleus that regulate DNA topology (3-dimensional conformation)7 and facilitate nuclear processes such as DNA replication, recombination, and repair.1, 6, 7, 8, 9, 13, 17, 21, 57 During these processes, type I DNA topoisomerase creates transient (reversible) single-stranded breaks in double-stranded DNA, allowing intact single DNA strands to pass through the break and relieve the topologic constraints (e.g., torsional strain) inherent in supercoiled DNA.1, 3, 4, 7, 8, 9, 11, 13, 17, 21, 57 The 3'-DNA terminus of the broken DNA strand binds covalently with the topoisomerase enzyme to form a catalytic intermediate, termed a cleavable complex.1, 4, 5, 7, 8, 9, 11, 13, 17, 21, 57 After the DNA is sufficiently relaxed and the strand passage reaction is complete, DNA topoisomerase reattaches the broken DNA strands to form the chemically unaltered topoisomers that allow transcription to proceed.8, 9, 11, 13, 17, 21
Topotecan and other type I topoisomerase inhibitors are believed to exert their cytotoxic effects during the S-phase of DNA synthesis through an interaction with the DNA-DNA topoisomerase cleavable complex.1, 2, 3, 5, 7, 8, 9, 11, 13, 17, 21, 23, 24, 46, 47 The cleavable complex is bound and stabilized by topotecan, preventing the topoisomerase from religating the single-strand breaks.2, 3, 5, 7, 8, 11, 13, 17, 21, 23, 47, 57 The ternary complex of topotecan, DNA, and DNA topoisomerase interferes with the moving replication fork, inducing replication arrest and lethal double-stranded breaks in DNA.1, 2, 4, 7, 8, 9, 10, 11, 13, 17, 21, 23, 47, 57 This DNA damage is not efficiently repaired and apparently leads to apoptosis (programmed cell death).9, 23, 57
Following oral administration, topotecan is rapidly absorbed with peak plasma concentrations occurring within 1-2 hours.47 Oral bioavailability of topotecan is approximately 40%.47 Administration of a high-fat meal with oral topotecan did not affect the extent of absorption, but delayed the time to achieve maximum serum concentrations for both total topotecan (from 3-4 hours) and topotecan lactone, its pharmacologically active form (from 1.5-3 hours).47 Oral topotecan may be given without regard to food.47
Area under the plasma concentration-time curve (AUC) is approximately proportional to dose following oral or IV administration of topotecan.1, 47, 57 IV topotecan exhibits multiexponential pharmacokinetics.1, 57
Following oral or IV administration, about 35% of the drug is bound to plasma proteins.1, 47, 57 It is not known whether topotecan is distributed into human milk.1, 47, 57
At a pH of 4 or less, the lactone moiety of topotecan undergoes hydrolysis to create the pharmacologically active form of the drug; this process is reversible and, at physiologic pH, the drug is present mostly in ring-opened hydroxy form.1, 47, 57 Topotecan is metabolized in the liver to N -desmethyl topotecan.1, 47, 57
Following oral administration, about 57% of topotecan (administered daily for 5 days) is excreted in urine as unchanged drug (20%) and as the N -desmethyl metabolite (2%).47 Approximately 33% of the oral dose of topotecan was eliminated in feces as total topotecan and approximately 2% as N -desmethyl topotecan.47
Following IV administration, about 74% of a topotecan dose is excreted, mostly unchanged in urine (51%) and feces (18%) within 9 days; excretion of N -desmethyl topotecan in urine is approximately 3% and in feces is approximately 2%.1, 57 O -Glucuronide metabolites of topotecan and N -desmethyl topotecan also have been detected in urine following oral and IV (less than 2% of the administered IV dose) administration of the drug.1, 47, 57
Topotecan has a terminal half-life of 3-6 hours following oral administration47 and 2-3 hours following IV administration of the drug.1, 57
No substantial gender-related differences in pharmacokinetics were reported in patients receiving oral topotecan.47 The average plasma clearance of IV topotecan was 24% higher in males than in females, mainly because of difference in body size.1, 57
Following oral administration, exposure to topotecan lactone was 10 or 20% higher in patients with mild (creatinine clearance of 50-80 mL/minute) or moderate renal impairment (creatinine clearance of 30-49 mL/minute), respectively, than in patients with normal renal function.47 The manufacturer states that no apparent differences in pharmacokinetics were observed in geriatric patients with creatinine clearance of 60 mL/minute or more receiving oral topotecan.47 Dosage adjustment of oral topotecan is not required for patients with mild renal impairment; however, in patients with moderate renal impairment, reduction to a level that is predicted to adjust the AUC to within the normal range is recommended.47 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)
In patients with impaired renal function, the clearance of IV topotecan is reduced and half-life may be prolonged.1, 30, 57 In patients with creatinine clearance of 40-60 mL/minute, plasma clearance of IV topotecan was decreased by approximately 67% compared with patients having normal renal function.57 In patients with creatinine clearance of 20-39 mL/minute, plasma clearance was reduced to about 34% of control values and half-life was increased to approximately 5 hours.57 Dosage reduction is recommended in patients with impaired renal function according to the degree of renal impairment.1, 30, 57 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)
Following oral administration, substantial differences in the pharmacokinetics of topotecan were not observed in patients based on measurement of hepatic function (e.g., serum bilirubin or transaminase concentrations).47 In patients with impaired hepatic function (i.e., serum bilirubin concentrations of 1.7-15 mg/dL), the clearance of IV topotecan was reduced by approximately 67% compared with patients having normal hepatic function, and half-life was slightly prolonged (from 2 to 2.5 hours).57 However, the usual recommended dosage of IV topotecan was tolerated in such patients with hepatic impairment.1, 57
Topotecan, a semisynthetic derivative of camptothecin, is an antineoplastic agent.1, 3, 5, 6, 7, 9, 10, 11, 13, 17, 24, 47, 57 Camptothecins are alkaloids with antitumor activity that are extracted from plants such as Camptotheca acuminata .1, 3, 4, 6, 7, 9, 10, 11, 13, 17 Topotecan is a type I DNA topoisomerase inhibitor.1, 47, 57 Topotecan is soluble in water.1, 47, 57
Commercially available capsules contain topotecan hydrochloride equivalent to 0.25 or 1 mg of topotecan as free base.47
Commercially available topotecan for injection concentrate is a sterile lyophilized, buffered, light yellow to greenish powder.1, 57 Each single-dose vial contains topotecan hydrochloride equivalent to 4 mg of topotecan as free base.1, 57 Hydrochloric acid and/or sodium hydroxide may be used to adjust the pH to 2.5-3.5.1, 57
Reconstituted solutions of IV topotecan are yellow to yellow-green.1, 57
Commercially available topotecan capsules should be stored at 2-8°C.47 Bottles containing topotecan capsules should be stored in their original containers (i.e., outer cartons) and protected from light and heat.47, 58
Commercially available topotecan for injection concentrate should be stored in unopened vials at 20-25°C and retained in the original package for protection from light.1, 57 When stored under recommended conditions, unopened vials of commercially available topotecan for injection concentrate are stable until the date indicated on the package.1, 57
Following reconstitution of vials of topotecan hydrochloride, solutions of the drug are stable for up to 24 hours when stored at controlled room temperature (approximately 20-25°C) in ambient light.1, 22, 57 When topotecan is further diluted to concentrations of 10 or 500 mcg/mL in Viaflex IV bags containing 5% dextrose or 0.9% sodium chloride injection, such solutions reportedly are stable for up to 4 days when stored at room temperature.25 However, the manufacturer states that diluted solutions of topotecan for IV infusion should be administered within 24 hours because of microbiologic considerations.22, 33
Additional Information
For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 0.25 mg (of topotecan) | ||
1 mg (of topotecan) | Hycamtin® | GlaxoSmithKline | ||
Parenteral | For injection concentrate, for IV infusion only | 4 mg (of topotecan) | Hycamtin® | GlaxoSmithKline |
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