Hycamtin (Topotecan HCl)

HYCAMTIN™

SmithKline Beecham

Topotecan HCl

Antineoplastic

Action And Clinical Pharmacology: Topotecan inhibits topoisomerase-I, an enzyme that functions in DNA replication to relieve the torsional strain introduced ahead of the moving replication fork. Topotecan inhibits topoisomerase-I by stabilizing the covalent complex of enzyme and strand-cleaved DNA which is an intermediate of the catalytic mechanism, thereby inducing breaks in the protein-associated DNA single-strands, resulting in cell death.

Pharmacokinetics: Following i.v. administration of topotecan at doses of 0.5 to 1.5 mg/mas a 30-minute infusion daily for 5 days, topotecan demonstrated a clearance of 1 030 mL/min with a plasma half-life of 2 to 3 hours.

Comparison of pharmacokinetic parameters did not suggest any change in pharmacokinetics over the dosing period. AUC increased approximately in proportion to the increase in dose.

Distribution: Topotecan has a volume of distribution of 130 L. The binding of topotecan to plasma proteins is 35%. Topotecan is evenly distributed between blood cells and plasma.

Metabolism: Topotecan undergoes pH dependent hydrolysis, with the equilibrium favoring the ring-opened hydroxy-acid form at physiologic pH.

Excretion: The renal clearance of topotecan could not be measured in humans due to the effect of urine pH on interconversion, although measurement of total topotecan (the lactone ring and the ring-opened hydroxy acid) in urine suggests that a variable fraction of the dose (generally 20 to 60%) is excreted in urine. Topotecan has also been measured in human bile samples indicating that topotecan is excreted by both biliary and urinary routes in humans.

Pharmacodynamics: The dose-limiting toxicity for topotecan is leukopenia. The relationship between decreased white blood count and either topotecan or total topotecan AUC can be described by a sigmoid Emax model.

Pharmacokinetics in Special Populations: Renal Impairment: Plasma clearance of topotecan in patients with mild renal impairment (creatinine clearance [Clcr] of 40 to 60 mL/min) decreased to about 67% compared with control patients. Volume of distribution was slightly decreased and thus half-life only increased by 14%.

In patients with moderate renal impairment (Clcr of 20 to 39 mL/min), topotecan plasma clearance was reduced to 34% of the value in control patients. Volume of distribution also decreased by about 25%, which resulted in an increase in mean half-life from 1.9 to 4.9 hours. Total topotecan clearance also decreased by 57% in patients with moderate renal impairment and by 17% in patients with mild renal impairment. Based on clinical data and on total topotecan pharmacokinetics, no dosage adjustment is required for patients with mild renal impairment (Clcr 40 to 60 mL/min). Dosage adjustment to 0.75 mg/mis recommended for patients with moderate renal impairment. Topotecan is not recommended for patients with a creatinine clearance of
Hepatic Impairment: Based on clinical data and total topotecan pharmacokinetics, no dosage adjustment is required in patients with hepatic impairment (serum bilirubin
Children: The pharmacokinetics of topotecan were studied in 12 pediatric patients treated with topotecan at doses between 2 and 7.5 mg/mas a 24-hour continuous infusion. Mean plasma clearance was 28.3 L/h/mwith a range of 18.1 to 44.2 L/h/m These values are similar to plasma clearance values seen in adults (approximately 36 L/h/m who received 24-hour topotecan infusions.

Gender: At this time, topotecan is indicated for the treatment of ovarian cancer, therefore the gender specific effects of topotecan have not been elucidated.

Geriatrics: Topotecan pharmacokinetics have not been specifically investigated in elderly patients. However, a population pharmacokinetic analysis in female patients did not identify age as a significant factor. Renal clearance is likely to be a more important determinant of topotecan clearance than age in this patient population.

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

Clinical Studies: Topotecan was studied in 4 clinical trials of 452 patients with metastatic ovarian carcinoma.

Patients in these 4 studies received an initial dose of 1.5 mg/mgiven by i.v. infusion over 30 minutes for the first 5 consecutive days of a 21-day course.

In a randomized Phase III study, topotecan was compared with paclitaxel. This study treated 112 patients with topotecan (1.5 mg/mday for the first 5 consecutive days of a 21-day course) and 114 patients with paclitaxel (175 mg/mover 3 hours on day 1 of a 21-day course).

Patients receiving topotecan achieved a higher response rate (21 vs 14%, p=0.196) than those receiving paclitaxel; a longer duration of response (median of 26 vs 22 weeks, hazard ratio=0.778, p=0.476); a longer time to progression [median of 19 vs 15 weeks (hazard ratio=0.764, p=0.0718)]; and a longer estimated median survival (63 vs 53 weeks, hazard ratio=0.986, p=0.9315).

However, the median time to response was longer with topotecan compared to paclitaxel: median of 8 vs 6 weeks (hazard ratio=0.615, p=0.1465). Consequently there is a risk of underestimating the expected efficacy of topotecan if patients are withdrawn from treatment prematurely (see Dosage).

Patients who failed on the initial arm of this study were allowed to switch to the alternate treatment. Eight of 61 (13.1%) patients who received topotecan after paclitaxel responded. Five of 49 (10.2%) patients who received paclitaxel after topotecan responded.

Topotecan was active in patients who had developed resistance to platinum-containing therapy, defined as tumor progression while on, or tumor relapse within 6 months after completion of, a platinum-containing regimen. One complete and 7 partial responses were seen in 60 patients, for a response rate of 13%. In the same study, there were no complete responders and only 4 partial responders on the paclitaxel arm, for a response rate of 7%.

Topotecan remained active in patients who did not respond to or eventually failed paclitaxel, as shown by the responders in this trial and the trial in platinum and paclitaxel failures (see below).

The safety profile for paclitaxel in this study was consistent with the product’s monograph; the safety profile for topotecan in this study was consistent with that observed in all 452 patients from the 4 ovarian clinical trials (see Adverse Effects).

The 3 additional studies were open-labeled and noncomparative in design. The first of these enrolled 111 patients who had failed 1 prior platinum-containing regimen. The response rate was 14% (95% CI:=7.9 to 20.9%). The median duration of response was 16 weeks (range: 4.6 to 41.9 weeks). The time to progression was 11 weeks (range: 0.7 to 72.1 weeks). The median survival was 52 weeks (range: 1.4 to 72.3 weeks).

A second open study enrolled 139 patients who had failed 1 (62 patients) or 2 (77 patients) prior regimens containing platinum and paclitaxel. The response rates in this study for evaluable patients were 12.9% and 16.9%, respectively. Median response duration was 18.1 weeks. Median time to progression was 12 weeks (range: 0.6 to 52.7 weeks). Median survival was 51.3 weeks for patients failing first-line therapy.

The third open study enrolled 30 patients who had failed 1 or 2 prior platinum-containing regimens. The response rate was 13% (95% CI:=3.8 to 30.7%). The median duration of response was 28 weeks (range: 16 to 59 weeks).

Indications And Clinical Uses: For the treatment of patients with metastatic carcinoma of the ovary after failure of initial or subsequent therapy.

Contra-Indications: Patients who have a history of hypersensitivity reactions to topotecan or to any of its other ingredients.

Pregnancy and Lactation: Should not be used in patients who are pregnant or breast-feeding.

Topotecan is contraindicated in patients who already have severe bone marrow depression prior to starting first course, as evidenced by baseline neutrophils.

Manufacturers’ Warnings In Clinical States: Topotecan should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Bone marrow suppression, primarily neutropenia, is the dose-limiting toxicity. Therapy with topotecan should not be given to patients with baseline neutrophil counts of 1 500 cells/mmor less. In order to monitor the occurrence of bone marrow suppression, frequent peripheral blood cell counts should be performed on all patients receiving topotecan.

Hematology: Bone marrow suppression (primarily neutropenia) is the dose-limiting toxicity. The nadir for neutrophil count occurred at a median of 11 days, and the nadir for platelet and hemoglobin counts occurred at a median of 15 days. The median duration of Grade 4 neutropenia was 7 days, and of thrombocytopenia was 5 days. The median duration of Grade 3/4 anemia was 7 days. (All grading scales reported are based on National Cancer Institute criteria.) Topotecan should only be administered in patients with adequate bone marrow reserves including baseline neutrophil counts of at least 1 500 cells/mmand platelet count at least 100 000/mm Frequent monitoring of blood counts should be instituted during treatment with topotecan.

There are no adequate data to define a safe and effective regimen for topotecan and cisplatin in combination. See Precautions.

Pregnancy: Topotecan may cause fetal harm when administered to a pregnant woman. Topotecan was shown to cause embryonic and fetal lethality when given to rats and rabbits at doses less than the human clinical i.v. dose (1.5 mg/m. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with topotecan.

Lactation: It is not known whether the drug is excreted in human milk. Breast-feeding should be discontinued when women are receiving topotecan (see Contraindications).

Children: Safety and effectiveness in pediatric patients have not been established.

Precautions: General: Inadvertent extravasation with topotecan has been associated only with mild local reactions such as erythema (and bruising).

Drug Interactions: Myelosuppression was more severe when topotecan was given in combination with cisplatin in Phase I studies. There are no adequate data to define a safe and effective regimen for topotecan and cisplatin in combination.

Concomitant administration of G-CSF can prolong the duration of neutropenia. If G-CSF is to be used, it should not be initiated until day 6 of the course of therapy (the day after completion of treatment with topotecan).

Hematology: Topotecan should not be administered to patients with baseline neutrophil counts of less than 1 500 cells/mm To monitor the occurrence of myelotoxicity, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving topotecan. Patients should not be retreated with subsequent courses of topotecan until neutrophils recover to a level >1 000 cells/mm platelets recover to a level >100 000 cells/mmand hemoglobin recovers to 9 g/dL, using transfusion if necessary.

Carcinogenesis, Mutagenesis, Impairment of Fertility: The carcinogenic potential of topotecan has not been studied (see Warnings, Pregnancy).

Topotecan has been shown to be genotoxic to mammalian cells (mouse lymphoma cells and human lymphocytes) in vitro, and mouse bone marrow cells in vivo, but is not mutagenic in bacterial cells (S. typhimurium and E. coli).

Pregnancy: (See Warnings.) Topotecan was shown to cause embryo-fetal lethality when given to rats (0.59 mg/m and rabbits (1.25 mg/m. At maternally toxic doses (0.59 mg/m, topotecan caused malformations, primarily of the eye, brain, skull and vertebrae.

Adverse Reactions: Data in the following section are based on the experience of 452 patients with metastatic ovarian carcinoma treated with topotecan in Phase II/III studies.

Hematologic: Neutropenia (reversible and noncumulative over time) was the major dose-limiting toxicity.

Therapy-related sepsis associated with death occurred in 0.7% of patients. There were no episodes of serious bleeding. Severe anemia (Grade 3/4) occurred in 16% of courses. Median platelet and hemoglobin nadirs occurred on day 15 of treatment.

Gastrointestinal: Prophylactic antiemetic use was not routine in patients treated with topotecan. Gastrointestinal effects were usually mild at the recommended dose level. Severe (Grade 3 or 4) nausea, vomiting, diarrhea and stomatitis incidence was 6, 4.5, 3.4 and 2% respectively. A small incidence (approximately 8%) of mild abdominal pain was also reported among patients.

Skin/Appendages: Total alopecia (Grade 2) occurred in 42% of patients.

Central and Peripheral Nervous Systems: Headache (19%) was the most frequently reported neurologic toxicity. Paresthesia were generally Grade 1 (8%).

Liver/Biliary: Grade 1 transient elevations in liver enzymes (5%);

Respiratory: Dyspnea (19%); Grade 3/4 dyspnea (3%).

Note: All grading scales are based on National Cancer Institute criteria.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There is no known antidote for overdosage with topotecan. The primary anticipated complication of overdosage would consist of bone marrow suppression. In a phase I study, one patient was incorrectly dosed at 35 mg/mduring course 9 of therapy and experienced hematologic toxicity associated with this increased dose.

The LD10 Rate in mice receiving single i.v. infusions of topotecan was 74.85 mg/m(95% Cl: 47.22 to 97.41).

Dosage And Administration: Prior to administration of the first course of topotecan, patients must have a baseline neutrophil count of >1 500 cells/mmand a platelet count of >100 000 cells/mm

The recommended dose is 1.5 mg/mby i.v. infusion over 30 minutes daily for 5 consecutive days, starting on day 1 of a 21-day course. A minimum of 4 courses is recommended because median time to response in three clinical trials was 9 to 12 weeks. In the event of severe neutropenia, the dose should be reduced by 0.25 mg/mfor subsequent courses. As an alternative, G-CSF may be administered before reducing the dose, starting from day 6 of the course (the day after completion of topotecan administration). Routine premedication for the prevention of nonhematological adverse events is not required.

Hepatic Impairment: No dosage adjustment is required for treating patients with hepatic impairment.

Renally Impaired Patients: No dosage adjustment is required for patients with mild renal impairment (Clcr 40 to 60 mL/min). Dosage adjustment to 0.75 mg/mis recommended for patients with moderate renal impairment (Clcr 20 to 39 mL/min). Treatment in patients with severe renal impairment (Clcr
Children: Insufficient data are available in pediatric patients to provide a dosage recommendation.

Preparation for Administration: Precautions: Topotecan is a cytotoxic anticancer drug. As with other potentially toxic compounds, it should be prepared under a vertical laminar flow hood while wearing gloves and protective clothing. If the solution contacts the skin, wash the skin immediately and thoroughly with soap and water. If the drug contacts mucous membranes, flush thoroughly with water.

Preparation for I.V. Administration: Each 4 mg vial is reconstituted with 4 mL Sterile Water for Injection, giving a final concentration of 1 mg/mL. Then the appropriate volume of the reconstituted solution is further diluted to an infusion concentration of 20 to 500 µg/mL in 50 to 100 mL of either 0.9% Sodium Chloride i.v. infusion or 5% Dextrose i.v. infusion prior to administration.

Reconstituted Vials: Vials which have been reconstituted with Water for Injection are stable for up to 24 hours when refrigerated at 5°C or stored at 30°C.

The reconstituted solution ranges in color from yellow to yellow-green and is intended for administration by i.v. infusion. However, since the vials contain no preservative, it is recommended that the product should be used immediately after reconstitution. If not used immediately, the reconstituted solution should be stored in a refrigerator and discarded after 24 hours.

Diluted Solutions: Reconstituted vials diluted for infusion are stable for up to 24 hours at approximately 20 to 25°C and ambient lighting conditions. If not used immediately, the diluted solution should be stored in a refrigerator in line with good pharmaceutical practice.

As with all parenteral drug products, i.v. admixtures should be inspected visually for clarity and particulate matter, discoloration and leakage prior to administration, whenever solution and container permit.

Handling and Disposal: Procedures for proper handling and disposal of anticancer drugs should be used. Several guidelines on this subject have been published.

Availability And Storage: Each single dose vial of a sterile lyophilized, buffered, light yellow to greenish powder contains: topotecan HCl equivalent to 4 mg of topotecan as free base. Nonmedicinal ingredients: mannitol and tartaric acid. Hydrochloric acid and sodium hydroxide may be used to adjust to a pH of 3. The solution pH ranges from 2.5 to 3.5. Single dose vials. Packages of 5. Unopened vials are stable until the date indicated on the package when stored between 15 and 30°C and protected from light in the original package.

HYCAMTIN™ SmithKline Beecham Topotecan HCl Antineoplastic

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