Topotecan Hydrochloride for Injection - Product Information
|Manufacture:||Fresenius Kabi USA, LLC|
|Condition:||Ovarian Cancer, Small Cell Lung Cancer|
|Form:||Intravenous (IV), Powder|
|Ingredients:||Topotecan hydrochloride, Mannitol, Tartaric acid, Hydrochloric acid, Sodium hydroxide|
Powder for injection, 4 mg topotecan (as topotecan hydrochloride) per vial
Summary Product Information
|Route of Administration||Dosage Form/Strength||Clinically Relevant Nonmedicinal Ingredients|
|Intravenous infusion||Lyophilized powder
Topotecan 4 mg per vial, incorporated as topotecan hydrochloride for reconstitution.
|mannitol and tartaric acid
For a complete, listing see Dosage Forms, Composition and Packaging section.
Indications and Clinical Use
Topotecan for Injection (topotecan hydrochloride) is indicated for the treatment of:
- metastatic carcinoma of the ovary after failure of initial or subsequent therapy;
- sensitive small cell lung cancer after failure of first line chemotherapy (defined as recurrence at least 60 days after first line chemotherapy).
No data is available.
Safety and effectiveness in pediatric patients have not been established, therefore is not recommended for use in this population.
Topotecan hydrochloride is contraindicated:
- in patients who have a history of hypersensitivity reactions to topotecan or to any of its other ingredients;
- in patients who are pregnant or breast-feeding;
- in patients who already have severe bone marrow depression prior to starting first course, as evidenced by baseline absolute neutrophils < 1.5 x 109/L and/or a platelet count of ≤ 100 x 109/L;
- in patients with severe renal impairment (creatinine clearance of < 20 mL/min or < 0.33 mL/sec).
Warnings and Precautions
Serious Warnings and Precautions
Topotecan hydrochloride should be prescribed by a qualified healthcare professional who is experienced in the use of antineoplastic therapy agents.
The following is a clinically significant adverse event:
- Bone marrow suppression, primarily neutropenia (see Warnings and Precautions, Hematologic);
- Potentially fatal neutropenic colitis (see Warnings and Precautions, Gastrointestinal);
- Potentially fatal interstitial lung disease (see Warnings and Precautions, Respiratory).
Topotecan hydrochloride 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 hydrochloride should not be given to patients with baseline absolute neutrophil counts of 1.5 x 109/L or less. In order to monitor the occurrence of bone marrow suppression, frequent peripheral blood cell counts should be performed on all patients receiving topotecan hydrochloride (see Dosage and Administration).
Inadvertent extravasation with topotecan hydrochloride has been associated only with mild local reactions such as erythema (and bruising).
Caution should be observed when driving or operating machinery if fatigue or asthenia persists.
Selection of Patients in Small Cell Lung Cancer
Clinical studies were conducted in patients with sensitive and refractory small cell lung cancer; a reduced chance for benefit in the refractory patients was noted with response rates ranging from 11-31% for patients with sensitive disease and 2.1% to 7.3% for patients with refractory disease. As the risk for toxicity is similar, the overall benefit/risk is reduced.
The benefit to patients versus the risk of toxicity must be carefully weighed.
Carcinogenesis and Mutagenesis
The carcinogenic potential of topotecan hydrochloride has not been studied (see Warnings and Precautions, Special Populations, Pregnant Women).
Topotecan hydrochloride 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 (Salmonella typhimurium and Escherichia coli).
Topotecan-induced neutropenia can cause neutropenic colitis (cecitis or typhlitis). Fatalities due to neutropenic colitis have been reported in clinical trials with topotecan. In patients presenting with fever, neutropenia, and a compatible pattern of abdominal pain, the possibility of neutropenic colitis should be considered.
Bone marrow suppression (primarily neutropenia) is the dose-limiting toxicity of topotecan. Neutropenia is not cumulative over time. Myelosuppression leading to sepsis and fatalities due to sepsis have been reported in patients treated with topotecan [2% fatalities across all SCLC studies (n = 426 subjects), which includes 3% fatalities in one Phase III SCLC study (n = 107 subjects, Table 4)] (see Adverse Reactions).
Topotecan hydrochloride should not be administered to patients with baseline absolute neutrophil counts of less than 1.5 x 109 /L. To monitor the occurrence of myelotoxicity, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving topotecan hydrochloride. Patients should not be retreated with subsequent courses of topotecan hydrochloride until neutrophils recover to a level > 1 x 109/L; platelets recover to a level > 100 x 109/L and hemoglobin recovers to 90 g/L, using transfusion if necessary.
Grade 4 neutropenia (< 0.5 x 109/L) occurred in 78% of patients and in 39% of all courses, with a median duration of 7 days. The nadir neutrophil count occurred at a median of 12 days. Therapy-related sepsis or febrile neutropenia occurred in 23% of patients and sepsis was fatal in 1.3%.
Topotecan-induced neutropenia can cause neutropenic colitis (see Warnings and Precautions, Gastrointestinal).
In the case of severe neutropenia (< 0.5 x 109/L for 7 days or more) during a course of topotecan hydrochloride, a reduction in dose of 0.25 mg/m2 for subsequent courses of therapy is recommended.
Grade 4 thrombocytopenia (< 25 x 109 /L) occurred in 27% of patients and in 9% of courses, with a median duration of 5 days and platelet nadir at a median of 15 days. Platelet transfusions were given to 15% of patients in 4% of courses.
Severe anemia (grade 3/4, < 80 g/L) occurred in 37% of patients and in 14% of courses. Median nadir was at day 15. Transfusions were needed in 52% of patients in 22% of courses.
Monitoring of Bone Marrow Function
Topotecan hydrochloride should only be administered in patients with adequate bone marrow reserves including baseline neutrophil counts of at least 1.5 x 109/L and platelet count at least 100 x 109/L. Frequent monitoring of blood counts should be instituted during treatment with topotecan hydrochloride.
Topotecan has been associated with reports of interstitial lung disease (ILD), some of which have been fatal (see Adverse Reactions). Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer, thoracic exposure to radiation and use of pneumotoxic drugs and/or colony stimulating factors. Patients should be monitored for pulmonary symptoms indicative of ILD (e.g., cough, fever, dyspnea and/or hypoxia), and topotecan should be discontinued if a new diagnosis of ILD is confirmed.
Topotecan hydrochloride may cause fetal harm when administered to a pregnant woman. Topotecan was shown to cause embryonic and fetal lethality when given to rats (0.59 mg/m2) and rabbits (1.25 mg/m2) at doses less than the human clinical intravenous dose (1.5 mg/m2). At maternally toxic doses (0.59 mg/m2), topotecan caused malformations, primarily of the eye, brain, skull, and vertebrae. This drug is contraindicated during pregnancy. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with topotecan hydrochloride.
Topotecan hydrochloride is contraindicated during breast-feeding (see Contraindications).
Safety and effectiveness of topotecan in pediatric patients have not been established, and therefore is not indicated for use in this population.
Clinical Trial Adverse Drug Reactions
Data in the following section are based on the combined experience of 453 patients with metastatic ovarian carcinoma, and 426 patients with small cell lung cancer, treated with topotecan hydrochloride. Table 1 lists the principal hematologic toxicities and Table 2 lists non-hematologic toxicities occurring in at least 15% of patients.
|Hematologic Adverse Events||Patients n=879||Courses n=4124|
|% Incidence||% Incidence|
< 1.5 x 109 /L
< 0.5 x 109 /L
< 3 x 109 /L
< 1 x 109 /L
< 75 x 109 /L
< 25 x 109 /L
< 100 g/L
< 80 g/L
|Sepsis or fever/infection with grade 4 neutropenia||23||7|
|Non-hematologic Adverse Events||All Grades % Incidence||Grade 3 % Incidence||Grade 4 % Incidence|
|n=879 Patients||n=4124 Courses||n=879 Patients||n=4124 Courses||n=879 Patients||n=4124 Courses|
|Body as a Whole|
|CNS/Peripheral Nervous System|
*Pain includes body pain, back pain and skeletal pain.
** Rash also includes pruritus, rash erythematous, urticaria, dermatitis, bullous eruption and rash maculo-papular.
(see Warnings and Precautions)
The prophylactic use of anti-emetics was not routine in patients treated with topotecan hydrochloride. Gastrointestinal effects were usually mild at the recommended dose level. The incidence of nausea was 64% (8% grade 3/4) and vomiting occurred in 45% (6% grade 3/4) of patients (see Table 2).
Thirty-two percent of patients had diarrhea (4% grade 3/4), 29% constipation (2% grade 3/4) and 22% had abdominal pain (4% grade 3/4). Grade 3/4 abdominal pain was 6% in ovarian cancer patients and 2% in small cell lung cancer patients.
Total alopecia (grade 2) occurred in 31% of patients.
Central and Peripheral Nervous System
Headache (18%) was the most frequently reported neurologic toxicity. Paresthesia occurred in 7% of patients, but was generally grade 1.
Grade 1 transient elevations in hepatic enzymes (8%); grade 3/4 elevated bilirubin elevations occurred in < 2% of patients.
The incidence of grade 3/4 dyspnea was 3.8% in ovarian cancer patients and 12.2% in small cell lung cancer patients. Table 3 shows the grade 3/4 hematologic and major non-hematologic adverse events in the topotecan/paclitaxel comparator trial. Table 4 shows the grade 3/4 hematologic and major non-hematologic adverse events in the topotecan/CAV comparator trial in small cell lung cancer.
Note: All grading scales are based on National Cancer Institute criteria.
|Adverse Event||Topotecan Hydrochloride||Paclitaxel|
|Patients n=112 %||Courses n=597 %||Patients n=114 %||Courses n=589 %|
|Hematologic Grade 3/4|
|Grade 4 Neutropenia (< 0.5 x 109/L)||80.2||35.8||21.4||8.6|
|Grade 3/4 Anemia (Hgb < 80 g/L)||41.4||16.1||6.3||1.9|
|Grade 4 Thrombocytopenia (< 25 x 109/L)||27.0||10.0||2.7||0.5|
|Fever/Grade 4 Neutropenia||23.2||6.0||4.0||1.0|
|Death related to Sepsis||1.8||N/A||0||N/A|
|Non-hematologic Grade 3/4|
|Increased Hepatic Enzymes+||0.9||0.2||0.9||0.2|
* Pain includes body pain, skeletal pain, and back pain.
** Rash also includes pruritus, rash erythematous, urticaria, dermatitis, bullous eruption, and rash maculo-papular.
+Increased Hepatic Enzymes includes increased SGOT/AST, increased SGPT/ALT and increased hepatic enzymes.
|Adverse Event||Topotecan Hydrochloride||CAV|
|Patients n=107 %||Courses n=446 %||Patients n=104 %||Courses n=359 %|
|Hematologic Grade 3/4|
|Grade 4 Neutropenia (< 0.5 x 109/L)||70||38||72||51|
|Grade 3/4 Anemia (Hgb < 80 g/L)||42||18||20||7|
|Grade 4 Thrombocytopenia (< 25 x 109/L)||29||10||5||1|
|Fever/Grade 4 Neutropenia||28||9||26||13|
|Death related to Sepsis||3||N/A||1||N/A|
|Non-hematologic Grade 3/4|
|Increased Hepatic Enzymes+||1||<1||0||0|
*Pain includes body pain, skeletal pain, and back pain.
**Rash also includes pruritus, rash erythematous, urticaria, dermatitis, bullous eruption, and rash maculo-papular.
+Increased Hepatic Enzymes includes increased SGOT/AST, increased SGPT/ALT and increased hepatic enzymes.
Premedications were not routinely used in patients randomized to topotecan hydrochloride, while patients receiving CAV received routine pretreatment with corticosteroids, diphenhydramine, and histamine receptor type 2 blockers.
Postmarketing Report of Adverse Events
Reports of adverse events in patients taking topotecan hydrochloride after market introduction include the following:
|Body as a Whole:||allergic manifestations, angioedema, anaphylactoid reactions,
|severe bleeding (in association with thrombocytopenia)|
|Respiratory, Thoracic and Mediastinal Disorders:||interstitial lung disease|
|Skin/Appendages:||severe dermatitis, severe pruritus|
*Reactions associated with extravasation have been mild and have not generally required specific therapy.
** Neutropenic colitis, including fatal neutropenic colitis, has been reported to occur as a complication of topotecan-induced neutropenia (see Warnings and Precautions).
There are no adequate data to define a safe and effective regimen for topotecan hydrochloride in combination with other cytotoxic agents. Preliminary studies combining topotecan hydrochloride with platinum-containing agents (e.g., cisplatin or carboplatin) suggest a sequence-dependent interaction whereby greater myelosuppression is seen when the platinum-containing agent is given on day 1 compared to day 5 of the topotecan hydrochloride dosing. If topotecan is administered in combination with other cytotoxic agents, dose reduction may be necessary.
Dosage and Administration
Prior to administration of the first course of Topotecan for Injection (topotecan hydrochloride), patients must have:
- A baseline absolute neutrophil count of ≥ 1.5 x 109/L
- A platelet count of > 100 x 109/L
- A hemoglobin level of ≥ 90 g/L
Recommended Dose and Dosage Adjustment
The recommended dose of Topotecan for Injection is 1.5 mg/m2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on day one of a 21-day course. Because median time to response in three clinical trials was 9 to 12 weeks and median time to response in four small cell lung cancer trials was 5 to 7 weeks, a minimum of four courses of Topotecan for Injection is recommended.
Topotecan should not be re-administered unless the absolute neutrophil count is more than or equal to 1 x 109/L, the platelet count is more than or equal to 100 x 109/L, and the hemoglobin level is more than or equal to 90 g/L (after transfusion if necessary).
Standard oncology practice for the management of neutropenia is either to administer topotecan with other medications (e.g., G-CSF) or to dose reduce to maintain neutrophil counts.
If dose reduction is chosen for patients who experience severe neutropenia (absolute neutrophil count less than or equal to 0.5 x 109/L) for 7 days or more, or severe neutropenia associated with fever or infection, or who have had treatment delayed due to neutropenia, the dose should be reduced by 0.25 mg/m2/day to 1.25 mg/m2/day (or subsequently down to 1.0 mg/m2/day if necessary).
Doses should be similarly reduced if the platelet count falls below 25 x 109/L.
Routine pre-medication for the prevention of non-hematological adverse events is not required with Topotecan for Injection.
Hepatic impairment: No dosage adjustment is required for treating patients with hepatic impairment [plasma bilirubin > 1.5 to < 10 mg/dL or (SI units) > 25.7 to < 171 µmol/L].
Renally impaired patients: No dosage adjustment is required for patients with mild renal impairment (CrC1 40 to 60 mL/min or 0.67 to 1 mL/sec). Dosage adjustment to 0.75 mg/m2 /day is recommended for patients with moderate renal impairment (CrC1 20 to 39 mL/min or 0.33 to 0.65 mL/sec). Advice on dosing of topotecan for patients with moderate renal impairment (20 to 39 mL/min) is based on studies involving patients with advanced cancer. Treatment with Topotecan for Injection in patients with severe renal impairment (CrC1 < 20 mL/min or < 0.33 mL/sec) is not recommended (see Contraindications).
Use in Children: Insufficient data are available in pediatric patients to provide a dosage recommendation (see Warnings and Precautions).
Use in the Elderly: No dosage adjustment appears to be needed in the elderly, other than adjustments related to renal function.
Dosage in Combination with Cytotoxic Agents: Dose adjustment may be necessary if topotecan is administered in combination with other cytotoxic agents (see Drug Interactions).
Topotecan for Injection is a cytotoxic anticancer drug. As with other potentially toxic compounds, Topotecan for Injection should be prepared under a vertical laminar flow hood while wearing gloves and protective clothing. If Topotecan for Injection solution contacts the skin, wash the skin immediately and thoroughly with soap and water. If Topotecan for Injection contacts mucous membranes, flush thoroughly with water.
Preparation for Intravenous Administration
Each Topotecan for Injection 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 - 500 µg/mL in 50 to 100 mL of either 0.9% Sodium Chloride Intravenous Infusion or 5% Dextrose Intravenous Infusion prior to administration.
Since the vials contain no preservative, it is recommended that the product be used immediately after reconstitution. If not used immediately, the reconstituted product should be stored in a refrigerator, for up to 24 hours.
As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity and particulate matter, discolouration and leakage prior to administration, whenever solution and container permit.
There is no known antidote for overdosage with topotecan hydrochloride. 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/m2 during course 9 of therapy and experienced hematologic toxicity associated with this increased dose.
The LD10 rate in mice receiving single intravenous infusions of topotecan hydrochloride was 74.85 mg/m2 (CI 95%: 47.22 to 97.41).
For management of a suspected drug overdose, contact your regional Poison Control Centre.
Action and Clinical Pharmacology
Mechanism of Action
Topotecan hydrochloride 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.
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.
Following intravenous administration of topotecan at doses of 0.5 to 1.5 mg/m2 as a 30-minute infusion daily for 5 days, topotecan demonstrated a clearance of 1030 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. Area under the curve increased approximately in proportion to the increase in dose.
Topotecan has a volume of distribution of 130 L. Binding of topotecan to plasma proteins is about 35%. Topotecan is evenly distributed between blood cells and plasma.
Topotecan undergoes pH-dependant hydrolysis, with the equilibrium favouring the ring-opened hydroxy-acid form at physiologic pH.
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.
Special Populations and Conditions
The pharmacokinetics of topotecan were studied in 12 pediatric patients treated with topotecan at doses between 2.0 and 7.5 mg/m2 as a 24-hour continuous infusion. Mean plasma clearance was 28.3 L/h/m2 with a range of 18.1 to 44.2 L/h/m2. These values are similar to plasma clearance values seen in adults (approx. 36 L/h/m2) who received 24-hour topotecan infusions.
Topotecan pharmacokinetics has 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.
The overall mean topotecan plasma clearance in male patients was approximately 24% higher than in female patients, largely reflecting difference in body size.
The effect of race on topotecan pharmacokinetics has not been determined.
Based on clinical data and total topotecan pharmacokinetics, no dosage adjustment is required in patients with hepatic impairment (serum bilirubin < 10 mg/dL or < 171 µmol/L). Plasma clearance in patients with hepatic impairment decreased to about 67% when compared with a control group of patients. Topotecan half- life was increased by about 30% but no change in volume of distribution was observed. Total topotecan clearance in patients with hepatic impairment only decreased by about 10% compared with the control group of patients.
Plasma clearance of topotecan in patients with mild renal impairment (creatinine clearance [CrC1] of 40 to 60 mL/min or 0.67 to 1 mL/sec) 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 (CrC1 of 20 to 39 mL/min or 0.33 to 0.65 mL/sec), 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 hours 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 (CrC1 40 to 60 mL/min or 0.67 to 1 mL/sec) . Dosage adjustment to 0.75 mg/m2/day is recommended for patients with moderate renal impairment. Topotecan for Injection is not recommended for patients with a creatinine clearance of < 20 mL/min (0.33 mL/sec).
Storage and Stability
Unopened vials of Topotecan for Injection (topotecan hydrochloride) are stable until the date indicated on the package, when stored between 15 ºC and 30 ºC and protected from light in the original package.
Since the vials contain no preservative, it is recommended that the product be used immediately after reconstitution. If not used immediately, the reconstituted solution should be stored in a refrigerator between 2 ºC and 8 ºC or stored at room temperature between 15 ºC and 30 ºC and discarded after 24 hours.
Reconstituted vials of Topotecan for Injection diluted for infusion are stable for up to 24 hours at room temperature between 15ºC and 30ºC with ambient lighting conditions. If not used immediately, the diluted solution should be stored in a refrigerator between 2ºC and 8ºC, up to 24 hours, and in line with good pharmaceutical practice.
Special Handling Instructions
Handling and Disposal
Procedures for proper handling and disposal of anticancer drugs should be used. Several guidelines on this subject have been published.
Dosage Forms, Composition and Packaging
Topotecan for Injection is supplied as a sterile lyophilized, buffered, light yellow to greenish powder available in single-dose vials. Each vial contains topotecan hydrochloride equivalent to 4 mg of topotecan as free base. The reconstituted solution ranges in colour from yellow to yellow-green and is intended for administration by intravenous infusion.
Inactive ingredients consist of 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.
Topotecan for Injection is supplied in a 4 mg (free base) single-dose vial, in a package of 5 vials.