Topotecan

Dosage Form: injection
FULL PRESCRIBING INFORMATION

WARNING: BONE MARROW SUPPRESSION

Do not give Topotecan Injection to patients with baseline neutrophil counts less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection and death, monitor peripheral blood counts frequently on all patients receiving Topotecan Injection. [see Warnings and Precautions (5.1)]

Indications and Usage for Topotecan

Topotecan Injection 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 at least 60 days (in the Phase 3 study) or at least 90 days (in the Phase 2 studies) after chemotherapy [see Clinical Studies (14)].

Topotecan Injection in combination with cisplatin is indicated for the treatment of:

• stage IV-B, recurrent, or persistent carcinoma of the cervix which is not amenable to curative treatment with surgery and/or radiation therapy.

Topotecan Dosage and Administration

Prior to administration of the first course of Topotecan Injection, patients must have a baseline neutrophil count of >1,500 cells/mm3 and a platelet count of >100,000 cells/mm3.

Small Cell Lung Cancer

Recommended Dosage

• The recommended dose of Topotecan 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 4 small cell lung cancer trials was 5 to 7 weeks.

Dosage Modification Guidelines

• In the event of severe neutropenia (defined as <500 cells/mm3) during any course, reduce the dose by 0.25 mg/m2 (to 1.25 mg/m2) 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/mm3, reduce doses by 0.25 mg/m2 (to 1.25 mg/m2) for subsequent courses.

Cervical Cancer

Recommended Dosage

The recommended dose of Topotecan Injection 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 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/mm3 with temperature of 38°C or 100.4°F), reduce the dose of Topotecan Injection to 0.60 mg/m2 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/m2 for subsequent courses.


• In the event the platelet count falls below 25,000 cells/mm3, reduce doses to 0.60 mg/m2 for subsequent courses.

Dosage Adjustment in Specific Populations

Renal Impairment

No dosage adjustment of Topotecan Injection appears to be required for patients with mild renal impairment (Clcr 40 to 60 mL/min.). Dosage adjustment of Topotecan Injection to 0.75 mg/m2 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. [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]

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.

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 under refrigerated conditions.

Dosage Forms and Strengths

Topotecan Injection is available in the following strengths:

1 mg/mL Multiple Dose Vial

3 mg/3 mL (1 mg/mL) Multiple Dose Vial

4 mg/4 mL (1 mg/mL) Multiple Dose Vial

Each mL contains Topotecan hydrochloride equivalent to 1 mg of Topotecan free base for intravenous infusion only following dilution.

Contraindications

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.

Warnings and Precautions

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/mm3) 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/mm3) 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/mm3 and platelet count at least 100,000/mm3.

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/mm3, platelets recover to >100,000 cells/mm3, 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)].

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.

Interstitial Lung Disease

Topotecan Injection has been associated with reports of interstitial lung disease (ILD), some of which have been fatal [see Adverse Reactions (6.2)]. 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.

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. [see Use in Specific Populations, Pregnancy (8.1)]

Inadvertent Extravasation

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

Adverse Reactions

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/mm3 <500 cells/mm3	97 78
Leukopenia <3,000 cells/mm3 <1,000 cells/mm3	97 32
Thrombocytopenia <75,000/mm3 <25,000/mm3	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 neutropeniaa	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
Rashb	16	1	0
General disorders and administrative site conditions
Fatigue	29	5	0
Pyrexia	28	1	<1
Painc	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/mm3)	70	72
Grade 3/4 anemia (Hgb <8 g dL)	42	20
Grade 4 thrombocytopenia (<25,000 plts/mm3)	29	5
Pyrexia/Grade 4 neutropenia	28	26
Non-hematologic Grade 3/4	%	%
Infections and infestations Documented sepsisa	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
Painb	5	7

a Death related to sepsis occurred in 3% of patients receiving Topotecan, and 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 Monotherapya

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/mm3)	128 (91%)	43 (30%)
Grade 3 (<2,000 to 1,000 cells/mm3)	58 (41%)	1 (1%)
Grade 4 (<1,000 cells/mm3)	35 (25%)	0 (0%)
Neutropenia
All grades (<2,000 cells/mm3)	125 (89%)	28 (19%)
Grade 3 (<1,000 to 500 cells/mm3)	36 (26%)	1 (1%)
Grade 4 (<500 cells/mm3)	67 (48%)	1 (1%)
Thrombocytopenia
All grades (<130,000 cells/mm3)	104 (74%)	21 (15%)
Grade 3 (<50,000 to 10,000 cells/mm3)	36 (26%)	5 (3%)
Grade 4 (<10,000 cells/mm3)	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 Monotherapya

	Topotecan Injection Plus Cisplatin			Cisplatin
	(n = 140)			(n = 144)
Adverse Reaction	All Gradesb	Grade 3	Grade 4	All Gradesb	Grade 3	Grade 4
General disorders and administrative site conditions
Constitutionalc	96 (69%)	11 (8%)	0	89 (62%)	17 (12%)	0
Paind	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.

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). [see Warnings and Precautions (5.1)]

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)]

Drug 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/m2/day for 5 days, was given in combination with cisplatin at a dose of 50 mg/m2 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/m2/day on days 1, 2, and 3 in combination with cisplatin 50 mg/m2 on day 1 for cervical cancer, see Dosage and Administration (2), Adverse Reactions (6), Clinical Pharmacology (12.3), and Clinical Studies (14). 

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category D [see Warnings and Precautions (5.4)].

Topotecan Injection can cause fetal harm w