Mechanism of Action

Topoisomerase I relieves torsional strain in DNA by inducing reversible single strand breaks. Topotecan binds to the topoisomerase I-DNA complex and prevents religation of these single strand breaks. The cytotoxicity of topotecan is thought to be due to double strand DNA damage produced during DNA synthesis, when replication enzymes interact with the ternary complex formed by topotecan, topoisomerase I, and DNA. Mammalian cells cannot efficiently repair these double strand breaks.

Pharmacokinetics

The pharmacokinetics of topotecan have been evaluated in cancer patients following doses of 0.5 to 1.5 mg/m² administered as a 30-minute infusion. Topotecan exhibits multiexponential pharmacokinetics with a terminal half-life of 2 to 3 hours. Total exposure (AUC) is approximately dose-proportional. Binding of topotecan to plasma proteins is about 35%.

Metabolism and Elimination: Topotecan undergoes a reversible pH dependent hydrolysis of its lactone moiety; it is the lactone form that is pharmacologically active. At pH ≤4, the lactone is exclusively present, whereas the ring-opened hydroxy-acid form predominates at physiologic pH. In vitro studies in human liver microsomes indicate topotecan is metabolized to an N-demethylated metabolite. The mean metabolite:parent AUC ratio was about 3% for total topotecan and topotecan lactone following IV administration.

Renal clearance is an important determinant of topotecan elimination (see Special Populations: Renal Impairment).

In a mass balance/excretion study in 4 patients with solid tumors, the overall recovery of total topotecan and its N-desmethyl metabolite in urine and feces over 9 days averaged 73.4±2.3% of the administered IV dose. Mean values of 50.8±2.9% as total topotecan and 3.1±1.0% as N-desmethyl topotecan were excreted in the urine following IV administration. Fecal elimination of total topotecan accounted for 17.9±3.6% while fecal elimination of N-desmethyl topotecan was 1.7±0.6%. An O-glucuronidation metabolite of topotecan and N-desmethyl topotecan has been identified in the urine. These metabolites, topotecan-O-glucuronide and N-desmethyl topotecan-O-glucuronide, were less than 2% of the administered dose.

Special Populations

Gender: The overall mean topotecan plasma clearance in male patients was approximately 24% higher than that in female patients, largely reflecting difference in body size.

Geriatrics: Topotecan pharmacokinetics have not been specifically studied in an elderly population, but population pharmacokinetic analysis in female patients did not identify age as a significant factor. Decreased renal clearance, which is common in the elderly, is a more important determinant of topotecan clearance (see PRECAUTIONS and DOSAGE AND ADMINISTRATION in full Prescribing Information).

Race: The effect of race on topotecan pharmacokinetics has not been studied.

Renal Impairment: In patients with mild renal impairment (creatinine clearance of 40 to 60 mL/min), topotecan plasma clearance was decreased to about 67% of the value in patients with normal renal function. In patients with moderate renal impairment (Cl_cr of 20 to 39 mL/min), topotecan plasma clearance was reduced to about 34% of the value in control patients, with an increase in half-life. Mean half-life, estimated in 3 renally impaired patients, was about 5.0 hours. Dosage adjustment is recommended for these patients (see DOSAGE AND ADMINISTRATION).

Hepatic Impairment: Plasma clearance in patients with hepatic impairment (serum bilirubin levels between 1.7 and 15.0 mg/dL) was decreased to about 67% of the value in patients without hepatic impairment. Topotecan half-life increased slightly, from 2.0 hours to 2.5 hours, but these hepatically impaired patients tolerated the usual recommended topotecan dosage regimen (see DOSAGE AND ADMINISTRATION).

Drug Interactions: Pharmacokinetic studies of the interaction of topotecan with concomitantly administered medications have not been formally investigated. In vitro inhibition studies using marker substrates known to be metabolized by human P450 CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A, or CYP4A or dihydropyrimidine dehydrogenase indicate that the activities of these enzymes were not altered by topotecan. Enzyme inhibition by topotecan has not been evaluated in vivo.

Administration of cisplatin (60 or 75 mg/m² on day 1) before topotecan (0.75 mg/m²/day on days 1-5) in 9 patients with ovarian cancer had no significant effect on the C_max and AUC of total topotecan.

Topotecan had no effect on the pharmacokinetics of free platinum in 15 patients with ovarian cancer who were administered cisplatin 50 mg/m² (n=9) or 75 mg/m² (n=6) on day 2 after paclitaxel 110 mg/m² on day 1 before topotecan 0.3 mg/m² IV daily on days 2-6. Topotecan had no effect on dose-normalized (60 mg/m²) C_max values of free platinum in 13 patients with ovarian cancer who were administered 60 mg/m² (n=10) or 75 mg/m² (n=3) cisplatin on day 1 before topotecan 0.75 mg/m² IV daily on days 1-5.

No pharmacokinetic data are available following topotecan (0.75 mg/m²/day for 3 consecutive days) and cisplatin (50 mg/m²/day on day 1) in patients with cervical cancer.

Pharmacodynamics

The dose-limiting toxicity of topotecan is leukopenia. White blood cell count decreases with increasing topotecan dose or topotecan AUC. When topotecan is administered at a dose of 1.5 mg/m²/day for 5 days, an 80% to 90% decrease in white blood cell count at nadir is typically observed after the first cycle of therapy.

Important Safety Information

Indications

Hycamtin is indicated for the treatment of metastatic carcinoma of the ovary after failure of initial or subsequent chemotherapy.

Hycamtin is indicated for the treatment of small cell lung cancer sensitive disease after failure of first-line chemotherapy.*

*In clinical studies submitted to support approval, sensitive disease was defined as disease responding to chemotherapy but subsequently progressing ≥60 days (in the phase III study) or ≥90 days (in the phase II studies) after chemotherapy.

Hycamtin in combination with cisplatin is indicated for the treatment of histologically confirmed Stage IV-B, recurrent, or persistent carcinoma of the cervix which is not amenable to curative treatment with surgery and/or radiation therapy.

Contraindications

Hycamtin is contraindicated in patients who have a history of hypersensitivity reactions to topotecan or to any of its ingredients. Hycamtin should not be used in patients who are pregnant or breast-feeding, or those with severe bone marrow depression.

Warnings

Hycamtin should be used only in patients with adequate bone marrow reserves, including baseline neutrophil counts of at least 1,500 cells/mm³ and platelet counts of at least 100,000/mm³. Frequent monitoring of blood 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 5-day dosing of Hycamtin is used in combination with cisplatin.

Hycamtin may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with Hycamtin.

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 24 hours after completion of treatment with Hycamtin.

Myelosuppression was more severe when Hycamtin, at a dose of 1.25 mg/m²/day x 5 days, was given in combination with cisplatin at a dose of 50 mg/m² in phase I studies. In one study, 1 of 3 patients had severe neutropenia for 12 days, and a second patient died with neutropenic sepsis.

Dosing for Ovarian Cancer/Small Cell Lung Cancer

Prior to administration of the first course of Hycamtin, patients must have a baseline neutrophil count of >1,500 cells/mm³ and a platelet count of >100,000 cells/mm³. The recommended dose of Hycamtin 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 4 courses is recommended because tumor response may be delayed. The median time to response in 3 ovarian clinical trials was 9 to 12 weeks, and median time to response in 4 small cell lung cancer trials was 5 to 7 weeks.

In the event of severe neutropenia during any course, the dose should be reduced by 0.25 mg/m² (to 1.25 mg/m²) for subsequent courses. Doses should be similarly reduced if the platelet count falls below 25,000 cells/mm³. Alternatively, in the event of severe neutropenia, G-CSF may be administered following the subsequent course (before resorting to dose reduction) starting from 24 hours after completion of administration of Hycamtin.

Dosing for Cervical Cancer

Prior to administration of the first course of Hycamtin, patients must have a baseline absolute neutrophil count of >1,500 cells/mm³ and a platelet count of >100,000 cells/mm³. The recommended dose of Hycamtin is 0.75 mg/m² by intravenous infusion over 30 minutes daily on days 1, 2, and 3; followed by cisplatin 50 mg/m² by intravenous infusion on day 1 repeated every 21 days (a 21-day course).

Dosage adjustments for subsequent courses of a regimen of Hycamtin in combination with cisplatin are specific for each drug.

In the event of severe febrile neutropenia (defined as <1,000 cells/mm³ with temperature of 38.0°C or 100.4°F), the dose of Hycamtin should be reduced by 20% to 0.60 mg/m² for subsequent courses. Doses of Hycamtin should be similarly reduced (by 20% to 0.60 mg/m²) if the platelet count falls below 10,000 cells/mm³. Alternatively, in the event of severe febrile neutropenia, G-CSF may be administered following the subsequent course (before resorting to dose reduction) starting from day 4 of the course (24 hours after completion of topotecan administration). If febrile neutropenia occurs despite the use of G-CSF, the dose of Hycamtin should be reduced by another 20% to 0.45 mg/m² for subsequent courses.

Adverse Events for Ovarian Cancer/Small Cell Lung Cancer

The most common serious adverse event is myelosuppression.

Severe neutropenia, the dose-limiting toxicity for Hycamtin, occurred in 78% of 879 ovarian and small cell lung cancer patients treated. Other hematologic adverse events reported include severe leukopenia (32%), severe thrombocytopenia (27%), and severe anemia (37%).

Frequently reported nonhematologic adverse events associated with use of Hycamtin included nausea (64%), vomiting (45%), diarrhea (32%), alopecia (49%), fatigue (29%), and dyspnea (22%). Most nonhematologic toxicities were grade 1 or 2.

Adverse Events for Cervical Cancer

The most common serious adverse event is myelosuppression.

Frequently reported grade 3/4 adverse events associated with use of Hycamtin/cisplatin included neutropenia (74%), leukopenia (66%), anemia (40%), thrombocytopenia (33%), pain (22%), vomiting (15%), nausea (14%), other GI (14%), metabolic/laboratory (14%), and genitourinary (12%).

See manufacturer’s Prescribing Information for cisplatin administration and hydration guidelines, and for cisplatin dosage adjustment in the event of hematologic toxicity.

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