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Pronunciation: TOE-poe-TEE-kan HYE-droe-KLOR-ide
Class: DNA topoisomerase inhibitor
- Powder for injection 4 mg
- Capsules 0.25 mg
- Capsules 1 mg
Antitumor drug with topoisomerase I–inhibitory activity.
Topotecan AUC is approximately dose-proportional.
Following oral administration, C max is reached between 1 and 2 h. Oral bioavailability is approximately 40%.
Approximately 35% protein bound.
Topotecan undergoes a reversible, pH-dependent hydrolysis of its lactone moiety. The lactone form is pharmacologically active.
After IV administration, t ½ is 2 to 3 h. Approximately 51% as total topotecan and 3% as metabolite are excreted in urine.
After oral administration, the mean terminal t ½ is 3 to 6 h. Approximately 20% as total topotecan and 2% as metabolite are excreted in urine. Fecal elimination accounted for 33% of total topotecan and 1.5% as metabolite.
Special PopulationsRenal Function Impairment
After IV administration, with CrCl approximately 40 to 60 mL/min, plasma Cl decreased to about 67%. With CrCl approximately 20 to 39 mL/min, plasma Cl decreased to about 34%. After oral administration, the exposure to the active metabolite topotecan lactone was 10% and 20% higher in patients with mild and moderate renal function impairment, respectively, increasing the risk of toxic reactions. Dosage adjustment is recommended in these patients.Hepatic Function Impairment
After IV administration, plasma Cl is decreased to approximately 67% in patients with hepatic function impairment with bilirubin 1.7 to 15 mg/dL. After oral administration, the pharmacokinetics of total topotecan did not differ significantly based on serum bilirubin, ALT, or AST. After IV or oral administration, no dosage adjustment is necessary.Elderly
The risk of toxic reactions may be greater in patients with renal function impairment, which is common in elderly patients.Gender
Overall plasma Cl is about 24% higher in men than women. The pharmacokinetics of oral topotecan were not affected by gender.Race
Effect of race on the pharmacokinetics has not been determined.Age
The pharmacokinetics of oral topotecan were not affected by age.
Indications and UsageInjection
Metastatic carcinoma of the ovary after failure of initial or subsequent chemotherapy; small cell lung cancer–sensitive disease after failure of first-line chemotherapy; in combination with cisplatin for treatment of stage IV-B, recurrent, or persistent carcinoma of the cervix that is not amenable to surgery and/or radiation therapy.Oral
Treatment of relapsed small cell lung cancer in patients with a prior complete or partial response who are at least 45 days from the end of first-line chemotherapy.
Treatment of advanced non–small cell lung cancer in combination with paclitaxel.
Hypersensitivity to topotecan or any of its ingredients; pregnancy or breast-feeding; severe bone marrow depression.
Dosage and AdministrationCervical Cancer
IV 0.75 mg/m 2 daily infused over 30 min on days 1, 2, and 3, followed by IV cisplatin 50 mg/m 2 infused on day 1 repeated every 21 days (a 21-day course). Prior to the first course of treatment, the patient must have a baseline absolute neutrophil count (ANC) of more than 1,500 cells/mm 3 and a platelet count of more than 100,000 cells/mm 3 .Dosage Adjustment
In the event of severe febrile neutropenia (defined as less than 1,000 cells/mm 3 with a temperature of 100.4°F), reduce the topotecan dose to 0.6 mg/m 2 for subsequent courses. Similarly, reduce doses to 0.6 mg/m 2 if the platelet count falls below 10,000 cells/mm 3 . Alternatively, in the event of severe febrile neutropenia, filgrastim may be started on day 4 of each subsequent cycle; give the first filgrastim dose 24 h after the final topotecan dose. If febrile neutropenia occurs despite use of filgrastim, reduce the dose of topotecan to 0.45 mg/m 2 for subsequent courses.Ovarian or Small Cell Lung Cancer
IV 1.5 mg/m 2 /day over 30 min daily for 5 consecutive days starting on day 1 of a 21-day cycle. Tumor response may be delayed; administer at least 4 cycles, provided the tumor is not progressing. Before giving each dose, the patient should have ANC greater than 1,500 cells/mm 3 and a platelet count greater than 100,000 cells/mm 3 .Dosage Adjustment
If neutropenia develops (defined as ANC less than 1,500 cells/mm 3 ), reduce the dose to 1.25 mg/m 2 for subsequent doses. Alternately, a course of filgrastim may be started on day 6 of each subsequent cycle; give the first filgrastim dose 24 h after the final topotecan dose.Relapsed Small Cell Lung Cancer
PO 2.3 mg/m 2 once daily for 5 consecutive days repeated every 21 days. Round the calculated oral daily dose to the nearest 0.25 mg. Do not treat with subsequent courses of topotecan until neutrophils recover to more than 1,000 cell/mm 3 , platelets recover to more than 100,000 cells/mm 3 , and hemoglobin levels recover to at least 9 g/dL. Reduce the dose to 0.4 mg/m 2 /day for subsequent courses in patients who experience severe neutropenia (neutrophils less than 500 cells/mm 3 associated with fever of infection or lasting for 7 days or more) or neutropenia (neutrophils 500 to 1,000 cells/mm 3 lasting beyond day 21 of the treatment course). The dose should be similarly reduced if the platelet count falls below 25,000 cells/mm 3 .Renal Function Impairment
IV Dosage adjustment is recommended in patients with moderate renal function impairment (CrCl 20 to 39 mL/min); give 0.75 mg/m 2 /day. For CrCl less than 20 mL/min, reduce dose; specific recommendations are not available. Oral dosage adjustment to 1.8 mg/m 2 /day is recommended for moderate renal function impairment (CrCl 30 to 49 mL/min); specific recommendations are not available for severe renal function impairment.
- Oral dose may be taken without regard to meals.
- Oral dose must be swallowed whole and not chewed, crushed, or divided.
- If patient vomits after taking an oral dose, a replacement dose should not be taken.
Store unopened vials at 68° to 77°F in original container. Protect from light. Use reconstituted solution immediately or use within 24 h if stored at 68° to 77°F and in ambient lighting conditions. Discard solution if not used within 24 h.Oral capsule
Store at refrigerated at 36° to 46°F. Protect from light.
Drug InteractionsCarboplatin, cisplatin
Myelosuppression is more severe when topotecan is given in combination with carboplatin or cisplatin.Drugs that inhibit drug efflux transporters (eg, P-glycoprotein [eg, cyclosporine])
Topotecan exposure following oral administration was increased approximately 2.5-fold.Filgrastim
Coadministration can prolong the duration of neutropenia. If filgrastim is used, do not initiate until day 6 of the course of therapy, 24 h after completion of treatment with topotecan.Hydantoins (eg, phenytoin)
Topotecan plasma levels may be reduced, decreasing efficacy.
Laboratory Test Interactions
None well documented.
Fatigue (29%); pyrexia (28%); asthenia (25%); headache (18%); paresthesia (7%); malaise (2%).Oral
Fatigue (11%); pyrexia (7%); asthenia (3%).
Alopecia (49%); rash (16%); severe dermatitis, severe pruritus (postmarketing).Oral
Nausea (64%); vomiting (45%); diarrhea (32%); constipation (29%); abdominal pain (22%); anorexia (19%); stomatitis (18%); intestinal obstruction (5%).Oral
Nausea (27%); vomiting (19%); diarrhea (14%); anorexia (7%).
Neutropenia (less than 1,500 cells/mm 3 [97%], less than 500 cells/mm 3 [78%]); leukopenia (less than 3,000 cells/mm 3 [97%], less than 1,000 cells/mm 3 [32%]); anemia (less than 10 g/dL [89%], less than 8 g/dL [37%]); thrombocytopenia (less than 75,000/mm 3 [69%], less than 25,000/mm 3 [27%]); RBC transfusions (52%); sepsis (23%); platelet transfusions (15%); rare severe bleeding (postmarketing).Oral
Anemia (94%); neutropenia (91%); leukopenia (90%); thrombocytopenia (81%).
Elevated hepatic enzymes (8%).
Allergic manifestations, anaphylactic reactions, angioedema (postmarketing).
Dyspnea (22%); coughing (15%); pneumonia (8%).
Fever (28%); pain (23%); chest pain, malaise (2%).
Bone marrow suppression is the dose-limiting toxicity of topotecan. Administer only to patients with adequate bone marrow reserves, including baseline neutrophil counts of at least 1,500 cells/mm 3 and platelet counts of at least 100,000 cells/mm 3 .
Monitor bone marrow function.
Category D .
Undetermined. Discontinue breast-feeding.
Safety and efficacy not established.
Severe anemia (grade 3/4; less than 8 g/dL) occurred.
Severe diarrhea, requiring hospitalization, has been reported during treatment with oral topotecan.
Topotecan is an irritant; inadvertent extravasation may produce mild local reactions, such as erythema and bruising.
Grade 4 neutropenia (less than 500 cells/mm 3 ) was most common during course 1 of treatment.
Grade 4 thrombocytopenia (less than 25,000 cells/mm 3 ) occurred.
Bone marrow suppression.
- Advise patient, family, or caregiver that medication will be prepared and administered by health care provider in a health care setting.
- Review dosing schedule with patient, family, or caregiver.
- Advise patient, family, or caregiver that medication may cause hair loss but that this is reversible when therapy is stopped.
- Advise patient, family, or caregiver to immediately report any of the following to health care provider: chills, fever, or other signs of infection; pain, redness, or swelling at injection site; unusual bleeding or bruising.
- Advise patient, family, or caregiver to report any of the following to health care provider: persistent appetite loss, diarrhea, nausea, vomiting, persistent or worsening general body weakness.
- Caution patient that medication may cause weakness or fatigue and to use caution when driving or performing other tasks that require mental alertness or coordination.
- Caution women of childbearing potential to avoid becoming pregnant during therapy.
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