TOPOTECAN: 3,537 Adverse Event Reports & Safety Profile

Topotecan is a semi-synthetic derivative of camptothecin and is an anti-tumor drug with topoisomerase I-inhibitory activity. The chemical name for topotecan free base is ( S )-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1 H -pyrano[3’,4’:6,7]indolizino[1,2- b ]quinoline-3,14-(4 H ,12 H )-dione. It has the molecular formula C 23 H 23 N 3 O 5 and a molecular weight of 421.45. Topotecan has three pKa values: pKa 1 = 10.50 corresponding to the benzyldimethylamino group, pKa 2 = 6.99 corresponding to the phenol group and pKa 3 = 0.60 corresponding to the quinoline group. As formulated in Topotecan Injection, topotecan has the following structural formula: where n is >1, corresponding to HCl added to adjust the pH to approximately 1.5 to 2.5.

Topotecan

Injection is supplied as a sterile, non-pyrogenic, clear, yellow solution at a topotecan free base concentration of 4 mg/4 mL (1 mg/mL) and 1 mg/mL available in multiple dose vials. Each mL of Topotecan Injection contains topotecan hydrochloride equivalent to 1 mg of topotecan as free base, 5 mg tartaric acid, NF, and water for injection, USP. Hydrochloric acid and/or sodium hydroxide may be used to adjust the pH.. The hydrochloride salt of topotecan is soluble in water and melts with decomposition at 213 ° C to 218°C. The solution must be diluted before administration by intravenous infusion. structural formula

AND USAGE Topotecan hydrochloride for injection is a topoisomerase inhibitor indicated for treatment of:

• Patients with metastatic ovarian cancer after disease progression on or after initial or subsequent chemotherapy, as a single agent. ( 1.1 )
• Patients with small cell lung cancer (SCLC) platinum-sensitive disease who progressed at least 60 days after initiation of first-line chemotherapy, as a single agent. ( 1.2 )
• Patients with Stage IV-B, recurrent, or persistent cervical cancer which is not amenable to curative treatment, in combination with cisplatin. ( 1.3 )

1.1 Ovarian Cancer Topotecan hydrochloride for injection, as a single agent, is indicated for the treatment of patients with metastatic ovarian cancer after disease progression on or after initial or subsequent chemotherapy.

1.2 Small Cell Lung Cancer Topotecan hydrochloride for injection, as a single agent, is indicated for the treatment of patients with small cell lung cancer (SCLC) with platinum-sensitive disease who progressed at least 60 days after initiation of first-line chemotherapy.

1.3 Cervical Cancer Topotecan hydrochloride for injection in combination with cisplatin is indicated for the treatment of patients with Stage IV-B, recurrent, or persistent cervical cancer not amenable to curative treatment.

AND ADMINISTRATION Verify dose using body surface area prior to dispensing. Recommended dosage should not exceed 4 mg [see Overdosage 10 ]. Prior to administration of the first course of Topotecan Injection, patients must have a baseline neutrophil count of >1,500 cells/mm 3 and a platelet count of >100,000 cells/mm 3 . Small cell lung cancer: 1.5 mg/m 2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on day one of a 21-day course. ( 2.1 ) Cervical cancer: 0.75 mg/m 2 by intravenous infusion over 30 minutes on days 1, 2, and 3 followed by cisplatin 50 mg/m 2 by intravenous infusion on day 1 repeated every 21 days. ( 2.2 )

See Dosage Modification

Guidelines for patients with neutropenia or reduced platelets.( 2.1 , 2.2 )

See Dosage

Adjustment in Renal Impairment. ( 2.3 )

2.1 Small Cell Lung Cancer Recommended Dosage The recommended dose of topotecan is 1.5 mg/m 2 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 4 small cell lung cancer trials was 5 to 7 weeks.

Dosage Modification

Guidelines In the event of severe neutropenia (defined as <500 cells/mm 3 ) during any course, reduce the dose by 0.25 mg/m 2 (to 1.25 mg/m 2 ) for subsequent courses. Alternatively, in the event of severe neutropenia, administer G-CSF (granulocyte-colony stimulating factor) following the subsequent course (before resorting to dose reduction) starting from day 6 of the course (24 hours after completion of topotecan administration). In the event the platelet count falls below 25,000 cells/mm 3 , reduce doses by 0.25 mg/m 2 (to 1.25 mg/m 2 ) for subsequent courses.

2.2 Cervical Cancer Recommended Dosage The recommended dose of Topotecan Injection is 0.75 mg/m 2 by intravenous infusion over 30 minutes daily on days 1, 2, and 3; followed by cisplatin 50 mg/m 2 by intravenous infusion on day 1 repeated every 21 days (a 21-day course).

Dosage Modification Guidelines

Dosage adjustments for subsequent courses of Topotecan Injection in combination with cisplatin are specific for each drug. See manufacturer’s prescribing information for cisplatin administration and hydration guidelines and for cisplatin dosage adjustment in the event of hematologic toxicity In the event of severe febrile neutropenia (defined as <1000 cells/mm 3 with temperature of 38°C or 100.4°F), reduce the dose of Topotecan Injection to 0.60 mg/m 2 for subsequent courses. Alternatively, in the event of severe febrile neutropenia, administer G-CSF following the subsequent course (before resorting to dose reduction) starting from day 4 of the course (24 hours after completion of administration of Topotecan Injection). If febrile neutropenia occurs despite the use of G-CSF, reduce the dose of Topotecan Injection to 0.45 mg/m 2 for subsequent courses. In the event the platelet count falls below 25,000 cells/mm 3 , reduce doses to 0.60 mg/m 2 for subsequent courses.

2.3 Dosage Adjustment in Specific Populations Renal Impairment No dosage adjustment of Topotecan Injection appears to be required for patients with mild renal impairment (Cl cr 40 to 60 mL/min.). Dosage adjustment of Topotecan Injection to 0.75 mg/m 2 is recommended for patients with moderate renal impairment (20 to 39 mL/min.). Insufficient data are available in patients with severe renal impairment to provide a dosage recommendation for Topotecan Injection. <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 ) ]</span>

Topotecan

Injection in combination with cisplatin for the treatment of cervical cancer should only be initiated in patients with serum creatinine ≤1.5 mg/dL. In the clinical trial, cisplatin was discontinued for a serum creatinine >1.5 mg/dL. Insufficient data are available regarding continuing monotherapy with Topotecan Injection after cisplatin discontinuation in patients with cervical cancer.

2.4 Instructions for Handling, Preparation and Intravenous Administration Handling Topotecan is a cytotoxic anticancer drug.

Prepare Topotecan

Injection under a vertical laminar flow hood while wearing gloves and protective clothing.

If Topotecan

Injection solution contacts the skin, wash the skin immediately and thoroughly with soap and water.

If Topotecan

Injection contacts mucous membranes, flush thoroughly with water. Use procedures for proper handling and disposal of anticancer drugs. Several guidelines on this subject have been published. 1-4 Preparation and Administration The appropriate volume of the Topotecan Injection is diluted in a minimum of 50 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP prior to administration. Infuse over 30 minutes.

Topotecan

Injection diluted for infusion is stable for 4 hours at room temperature or 24 hours at refrigerated temperature in ambient lighting conditions.

Topotecan

Injection is supplied as a multiple dose vial. Studies have shown the product is stable for 28 days after initial puncture when stored at room temperature.

Topotecan Injection is contraindicated in patients who have a history of severe hypersensitivity reactions (e.g., anaphylactoid reactions) to topotecan or to any of its ingredients.

Topotecan

Injection should not be used in patients with severe bone marrow depression. History of severe hypersensitivity reactions (e.g., anaphylactoid reactions) to topotecan or any of its ingredients ( 4 ) Severe bone marrow depression ( 4 )

REACTIONS Small cell lung cancer: The most common hematologic adverse reactions were: neutropenia (97%), leukopenia (97%), anemia (89%), and thrombocytopenia (69%). ( 6.1 ) The most common (>25%) non-hematologic adverse reactions (all grades) were: nausea, alopecia, vomiting, sepsis or pyrexia/infection with neutropenia, diarrhea, constipation, fatigue, and pyrexia. ( 6.1 ) Cervical cancer (Topotecan Injection plus cisplatin): The most common hematologic adverse reactions (all grades) were: anemia (94%), leukopenia (91%), neutropenia (89%), and thrombocytopenia (74%). ( 6.1 ) The most common (>25%) non-hematologic adverse reactions (all grades) were: pain, nausea, vomiting, and infection/febrile neutropenia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Small Cell Lung Cancer

Data in the following section are based on the combined experiences of the 879 patients studied, including 426 patients with small cell lung cancer treated with topotecan.

Table

1 lists the principle hematologic adverse reactions and Table 2 lists non-hematologic adverse reactions occurring in at least 15% of patients.

Table

1.

Hematologic Adverse Reactions

Experienced in ≥15% of Patients, Including 426 Patients With Small Cell Lung Cancer, Receiving Topotecan Hematologic Adverse Reaction Patients (n=879) % Incidence Neutropenia <1,500 cells/mm 3 <500 cells/mm 3 97 78 Leukopenia <3,000 cells/mm 3 <1,000 cells/mm 3 97 32 Thrombocytopenia <75,000/mm 3 <25,000/mm 3 69 27 Anemia <10 g/dL <8 g/dL 89 37 Table 2. Non-hematologic Adverse Reactions Experienced by ≥15% of 879 Patients, Including 426 Patients With Small Cell Lung Cancer, Receiving Topotecan Non-hematologic Adverse Reaction Percentage of Patients with Adverse Reaction (879 Patients)

All Grades Grade

3 Grade 4 Infections and infestations Sepsis or pyrexia/infection with neutropenia a 43 NR 23 Metabolism and nutrition disorders Anorexia 19 2 <1 Nervous system disorders Headache 18 1 <1 Respiratory, thoracic, and mediastinal disorders Dyspnea 22 5 3 Coughing 15 1 0 Gastrointestinal disorders Nausea 64 7 1 Vomiting 45 4 1 Diarrhea 32 3 1 Constipation 29 2 1 Abdominal pain 22 2 2 Stomatitis 18 1 <1 Skin and subcutaneous tissue disorders Alopecia 49 NA NA Rash b 16 1 0 General disorders and administrative site conditions Fatigue 29 5 0 Pyrexia 28 1 <1 Pain c 23 2 1 Asthenia 25 4 2 NA = Not applicable NR = Not reported separately a Does not include Grade 1 sepsis or pyrexia b Rash also includes pruritus, rash erythematous, urticaria, dermatitis, bullous eruption, and maculopapular rash. c Pain includes body pain, back pain, and skeletal pain.

Nervous System Disorders

Paresthesia occurred in 7% of patients but was generally grade 1.

Hepatobiliary Disorders Grade

1 transient elevations in hepatic enzymes occurred in 8% of patients. Greater elevations, grade 3/4, occurred in 4%.

Grade

3/4 elevated bilirubin occurred in <2% of patients.

Table

3 shows the grade 3/4 hematologic and major non-hematologic adverse reactions in the topotecan/CAV comparator trial in small cell lung cancer.

Table

3.

Adverse Reactions

Experienced by ≥5% of Small Cell Lung Cancer Patients Randomized to Receive Topotecan or CAV Adverse Reaction Topotecan (n=107) CAV (n=104)

Hematologic Grade

3/4 % % Grade 4 neutropenia (<500 cells/mm 3 ) 70 72 Grade 3/4 anemia (Hgb <8 g dL) 42 20 Grade 4 thrombocytopenia (<25,000 plts/mm 3 ) 29 5 Pyrexia/Grade 4 neutropenia 28 26 Non-hematologic Grade 3/4 % % Infections and infestations Documented sepsis a 5 5 Respiratory, thoracic, and mediastinal disorders Dyspnea 9 14 Pneumonia 8 6 Gastrointestinal disorders Abdominal pain 6 4 Nausea 8 6 General disorders and administrative site conditions Fatigue 6 10 Asthenia 9 7 Pain b 5 7 a Death related to sepsis occurred in 3% of patients receiving topotecan, and in 1% of patients receiving CAV b Pain includes body pain, skeletal pain, and back pain.

Cervical

Cancer In the comparative trial with Topotecan Injection plus cisplatin versus cisplatin in patients with cervical cancer, the most common dose-limiting adverse reaction was myelosuppression.

Table

4 shows the hematologic adverse reactions and Table 5 shows the non-hematologic adverse reactions in patients with cervical cancer.

Table

4.

Hematologic Adverse

Reactions in Patients with Cervical Cancer Treated with Topotecan Injection Plus Cisplatin or Cisplatin Monotherapy a Hematologic Adverse Reaction Topotecan Injection Plus Cisplatin (n = 140) Cisplatin (n = 144)

Anemia

All grades (Hgb <12 g/dL) 131 (94%) 130 (90%)

Grade

3 (Hgb <8 to 6.5 g/dL) 47 (34%) 28 (19%)

Grade

4 (Hgb <6.5 g/dL) 9 (6%) 5 (3%)

Leukopenia

All grades (<3,800 cells/mm 3 ) 128 (91%) 43 (30%)

Grade

3 (<2,000 to 1,000 cells/mm 3 ) 58 (41%) 1 (1%)

Grade

4 (<1,000 cells/mm 3 ) 35 (25%) 0 (0%)

Neutropenia

All grades (<2,000 cells/mm 3 ) 125 (89%) 28 (19%)

Grade

3 (<1,000 to 500 cells/mm 3 ) 36 (26%) 1 (1%)

Grade

4 (<500 cells/mm 3 ) 67 (48%) 1 (1%)

Thrombocytopenia

All grades (<130,000 cells/mm 3 ) 104 (74%) 21 (15%)

Grade

3 (<50,000 to 10,000 cells/mm 3 ) 36 (26%) 5 (3%)

Grade

4 (<10,000 cells/mm 3 ) 10 (7%) 0 (0%) a Includes patients who were eligible and treated.

Table

5. Non-hematologic Adverse Reactions Experienced by ≥ 5% of Patients with Cervical Cancer Treated with Topotecan Injection Plus Cisplatin or Cisplatin Monotherapy a Topotecan Injection Plus Cisplatin Cisplatin (n = 140) (n = 144)

Adverse Reaction All

Grades b Grade 3 Grade 4 All Grades b Grade 3 Grade 4 General disorders and administrative site conditions Constitutional c 96 (69%) 11 (8%) 0 89 (62%) 17 (12%) 0 Pain d 82 (59%) 28 (20%) 3 (2%) 72 (50%) 18 (13%) 5 (3%) Gastrointestinal disorders Vomiting 56 (40%) 20 (14%) 2 (1%) 53 (37%) 13 (9%) 0 Nausea 77 (55%) 18 (13%) 2 (1%) 79 (55%) 13 (9%) 0 Stomatitis-pharyngitis 8 (6%) 1 (<1%) 0 0 0 0 Other 88 (63%) 16 (11%) 4 (3%) 80 (56%) 12 (8%) 3 (2%)

Dermatology

67 (48%) 1 (<1%) 0 29 (20%) 0 0 Metabolic-Laboratory 55 (39%) 13 (9%) 7 (5%) 44 (31%) 14 (10%) 1 (<1%)

Genitourinary

51 (36%) 9 (6%) 9 (6%) 49 (34%) 7 (5%) 7 (5%) Nervous system disorders Neuropathy 4 (3%) 1 (<1%) 0 3 (2%) 1 (<1%) 0 Other 49 (35%) 3 (2%) 1 (<1%) 43 (30%) 7 (5%) 2 (1%) Infection-febrile neutropenia 39 (28%) 21 (15%) 5 (4%) 26 (18%) 11 (8%) 0 Cardiovascular 35 (25%) 7 (5%) 6 (4%) 22 (15%) 8 (6%) 3 (2%)

Hepatic

34 (24%) 5 (4%) 2 (1%) 23 (16%) 2 (1%) 0 Pulmonary 24 (17%) 4 (3%) 0 23 (16%) 5 (3%) 3 (2%) Vascular disorders Hemorrhage 21 (15%) 8 (6%) 1 (<1%) 20 (14%) 3 (2%) 1 (<1%)

Coagulation

8 (6%) 4 (3%) 3 (2%) 10 (7%) 7 (5%) 0 Musculoskeletal 19 (14%) 3 (2%) 0 7 (5%) 1 (<1%) 1 (<1%) Allergy-Immunology 8 (6%) 2 (1%) 1 (<1%) 4 (3%) 0 1 (<1%)

Endocrine

8 (6%) 0 0 4 (3%) 2 (1%) 0 Sexual reproduction function 7 (5%) 0 0 10 (7%) 1 (<1%) 0 Ocular-visual 7 (5%) 0 0 7 (5%) 1 (<1%) 0 Data were collected using NCI Common Toxicity Criteria, v. 2.0. a Includes patients who were eligible and treated. b Grades 1 through 4 only. There were 3 patients who experienced grade 5 deaths with investigator-designated attribution. One was a grade 5 hemorrhage in which the drug-related thrombocytopenia aggravated the event. A second patient experienced bowel obstruction, cardiac arrest, pleural effusion and respiratory failure which were not treatment related but probably aggravated by treatment. A third patient experienced a pulmonary embolism and adult respiratory distress syndrome, the latter was indirectly treatment-related. c Constitutional includes fatigue (lethargy, malaise, asthenia), fever (in the absence of neutropenia), rigors, chills, sweating, and weight gain or loss. d Pain includes abdominal pain or cramping, arthralgia, bone pain, chest pain (non-cardiac and non-pleuritic), dysmenorrhea, dyspareunia, earache, headache, hepatic pain, myalgia, neuropathic pain, pain due to radiation, pelvic pain, pleuritic pain, rectal or perirectal pain, and tumor pain.

6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials or listed in other sections of the prescribing information, the following reactions have been identified during post-marketing use of Topotecan Injection. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to Topotecan Injection. Blood and Lymphatic System Disorders: Severe bleeding (in association with thrombocytopenia). <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 ) ]</span>

Immune System

Disorders: Allergic manifestations; Anaphylactoid reactions.

Gastrointestinal

Disorders: Abdominal pain potentially associated with neutropenic colitis. [see Warnings and Precautions ( 5.2 ) ]

Pulmonary

Disorders: Interstitial lung disease [see Warnings and Precautions ( 5.3 ) ] Skin and Subcutaneous Tissue Disorders: Angioedema, severe dermatitis, severe pruritus General Disorders and Administration Site Conditions: Inadvertent extravasation [see Warnings and Precautions ( 5.5 ) ]

AND PRECAUTIONS Bone marrow suppression: Administer Topotecan Injection only to patients with adequate bone marrow reserves. Monitor peripheral blood counts and adjust the dose if needed. ( 5.1 ) Topotecan-induced neutropenia can lead to neutropenic colitis. ( 5.2 ) Interstitial lung disease: topotecan has been associated with reports of interstitial lung disease. Monitor patients for symptoms and discontinue Topotecan Injection if the diagnosis is confirmed. ( 5.3 ) Pregnancy: Can cause fetal harm. Advise women of potential risk to the fetus. ( 5.4 , 8.1 )

5.1 Bone Marrow Suppression Bone marrow suppression (primarily neutropenia) is the dose-limiting toxicity of Topotecan Injection. Neutropenia is not cumulative over time. In the comparative study, in small cell lung cancer, the treatment-related death rates were 5% for topotecan and 4% for CAV (cyclophosphamide-doxorubicin-vincristine).

Neutropenia

From a combined experience of patients receiving topotecan which included patients treated for small cell lung cancer: Grade 4 neutropenia (<500 cells/mm 3 ) was most common during course 1 of treatment (60% of patients) and occurred 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%. Pancytopenia has been reported. Cervical cancer experience: Grade 3 and grade 4 neutropenia affected 26 % and 48 % of patients, respectively.

Thrombocytopenia

From a combined experience of patients receiving topotecan which included patients treated for small cell lung cancer: Grade 4 thrombocytopenia (<25,000/mm 3 ) 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. Cervical cancer experience: Grade 3 and grade 4 thrombocytopenia affected 26 % and 7 % of patients, respectively.

Anemia

From a combined experience of patients receiving topotecan which included patients treated for small cell lung cancer: Grade 3/4 anemia (<8 g/dL) 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. Cervical cancer experience: Grade 3 and grade 4 anemia affected 34 % and 6 % of patients, respectively. Monitoring of Bone Marrow Function Administer Topotecan Injection only in patients with adequate bone marrow reserves, including baseline neutrophil count of at least 1,500 cells/mm 3 and platelet count at least 100,000/mm 3 . Monitor peripheral blood counts frequently during treatment with Topotecan Injection. Do not treat patients with subsequent courses of Topotecan Injection until neutrophils recover to >1,000 cells/mm 3 , platelets recover to >100,000 cells/mm 3 , and hemoglobin levels recover to 9 g/dL (with transfusion if necessary).Severe myelotoxicity has been reported when Topotecan Injection is used in combination with cisplatin [see Drug Interactions ( 7 ) ]

5.2 Neutropenic Colitis Topotecan-induced neutropenia can lead to neutropenic colitis. Fatalities due to neutropenic colitis have been reported in clinical trials with Topotecan Injection. In patients presenting with fever, neutropenia, and a compatible pattern of abdominal pain, consider the possibility of neutropenic colitis.

5.3 Interstitial Lung Disease Topotecan Injection has been associated with reports of interstitial lung disease (ILD), some of which have been fatal <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 ) ]</span>. 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. Monitor patients for pulmonary symptoms indicative of interstitial lung disease (e.g., cough, fever, dyspnea, and/or hypoxia), and discontinue Topotecan Injection if a new diagnosis of ILD is confirmed.

5.4 Pregnancy Pregnancy Category D Topotecan Injection can cause fetal harm when administered to a pregnant woman. Topotecan caused embryolethality, fetotoxicity, and teratogenicity in rats and rabbits when administered during organogenesis. There are no adequate and well controlled studies of Topotecan Injection in pregnant women. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving Topotecan Injection, the patient should be apprised of the potential hazard to the fetus. <span class="opacity-50 text-xs">[see Use in Specific Populations, Pregnancy ( 8.1 ) ]</span>

5.5 Inadvertent Extravasation Inadvertent extravasation with topotecan has been observed, most reactions have been mild but severe cases have been reported.

INTERACTIONS G-CSF: Concomitant administration of G-CSF can prolong the duration of neutropenia, so if G-CSF is to be used, do not initiate it until day 6 of the course of therapy, 24 hours after completion of treatment with Topotecan Injection. Platinum and Other Cytotoxic Agents: Myelosuppression was more severe when topotecan, at a dose of 1.25 mg/m 2 /day for 5 days, was given in combination with cisplatin at a dose of 50 mg/m 2 in Phase 1 studies. In one study, 1 of 3 patients had severe neutropenia for 12 days and a second patient died with neutropenic sepsis. Greater myelosuppression is also likely to be seen when Topotecan Injection is used in combination with other cytotoxic agents, thereby necessitating a dose reduction. However, when combining topotecan with platinum agents (e.g., cisplatin or carboplatin), a distinct sequence-dependent interaction on myelosuppression has been reported. Coadministration of a platinum agent on day 1 of dosing with topotecan required lower doses of each agent compared to co-administration on day 5 of the dosing schedule for topotecan. For information on the pharmacokinetics, efficacy, safety, and dosing of Topotecan Injection at a dose of 0.75 mg/m 2 /day on days 1, 2, and 3 in combination with cisplatin 50 mg/m 2 on day 1 for cervical cancer [see Dosage and Administration ( 2 ) , Adverse Reactions ( 6 ), Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14 ) ] . Do not initiate G-CSF until 24 hours after completion of treatment with Topotecan Injection. Concomitant administration can prolong duration of neutropenia. ( 7 ) Greater myelosuppression is likely to be seen when used in combination with other cytotoxic agents. ( 7 )