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These highlights do not include all the information needed to use Topotecan Hydrochloride for Injection safely and effectively. See full prescribing information for Topotecan Hydrochloride for Injection. Topotecan Hydrochloride for Injection Initia | Topotecan Hydrochloride

13:37 EDT 24th July 2014 | BioPortfolio

Note: While we endeavour to keep our records up-to-date one should not rely on these details being accurate without first consulting a professional. Click here to read our full medical disclaimer.

Do not give topotecan hydrochloride to patients with baseline neutrophil counts less than 1,500 cells/mm. 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 hydrochloride [see Warnings and Precautions (5.1)].

Topotecan hydrochloride is indicated for the treatment of:

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

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

Recommended Dosage:

Dosage Modification Guidelines:

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

Dosage Modification Guidelines: Dosage adjustments for subsequent courses of topotecan hydrochloride 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.

Renal Impairment: No dosage adjustment of topotecan hydrochloride appears to be required for patients with mild renal impairment (Cl 40 to 60 mL/min.). Dosage adjustment of topotecan hydrochloride to 0.75 mg/m 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 hydrochloride [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Topotecan hydrochloride 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 hydrochloride after cisplatin discontinuation in patients with cervical cancer.

Handling: Topotecan Hydrochloride for Injection is a cytotoxic anticancer drug. Prepare Topotecan Hydrochloride for Injection under a vertical laminar flow hood while wearing gloves and protective clothing. If Topotecan Hydrochloride for Injection solution contacts the skin, wash the skin immediately and thoroughly with soap and water. If Topotecan Hydrochloride for 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.

Preparation and Administration: Each 4-mg vial of Topotecan Hydrochloride for Injection is reconstituted with 4 mL Sterile Water for Injection. Then the appropriate volume of the reconstituted solution is diluted in either 0.9% Sodium Chloride Intravenous Infusion or 5% Dextrose Intravenous Infusion prior to administration.

Stability: Unopened vials of Topotecan Hydrochloride for Injection are stable until the date indicated on the package when stored between 20° and 25°C (68° and 77°F) [see USP] and protected from light in the original package. Because the vials contain no preservative, contents should be used immediately after reconstitution.

Reconstituted vials of Topotecan Hydrochloride for Injection diluted for infusion are stable at approximately 20° to 25°C (68° to 77°F) and ambient lighting conditions for 24 hours.

4-mg (free base) single-dose vial, light yellow lyophilisate.

Topotecan hydrochloride 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 hydrochloride should not be used in patients with severe bone marrow depression.

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

Neutropenia:

Thrombocytopenia:

Anemia:

Monitoring of Bone Marrow Function: Administer topotecan hydrochloride only in patients with adequate bone marrow reserves, including baseline neutrophil count of at least 1,500 cells/mm and platelet count at least 100,000/mm. Monitor peripheral blood counts frequently during treatment with topotecan hydrochloride. Do not treat patients with subsequent courses of topotecan hydrochloride until neutrophils recover to >1,000 cells/mm, platelets recover to >100,000 cells/mm, and hemoglobin levels recover to 9.0 g/dL (with transfusion if necessary). Severe myelotoxicity has been reported when topotecan hydrochloride is used in combination with cisplatin [see Drug Interactions (7)].

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

Topotecan hydrochloride 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 hydrochloride if a new diagnosis of ILD is confirmed.

Pregnancy Category D

Topotecan hydrochloride 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 hydrochloride in pregnant women. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving topotecan hydrochloride, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations, Pregnancy (8.1)].

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

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 experience of 879 patients, including 426 patients with small cell lung cancer, treated with topotecan hydrochloride. Table 1 lists the principal 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 879 Patients, Including 426 Patients With Small Cell Lung Cancer, Receiving Topotecan Hydrochloride
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 Hydrochloride
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.
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
43 NR 23
    neutropeniaa
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

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

Table 4. Adverse Reactions Experienced by ≥5% of Small Cell Lung Cancer Patients Randomized to Receive Topotecan Hydrochloride or CAV
a Death related to sepsis occurred in 3% of patients receiving topotecan hydrochloride, and 1% of patients receiving CAV.
b Pain includes body pain, skeletal pain, and back pain.
Adverse Reaction Topotecan Hydrochloride
(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 5 5
    Documented sepsisa
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

Cervical Cancer: In the comparative trial with topotecan hydrochloride plus cisplatin versus cisplatin in patients with cervical cancer, the most common dose-limiting adverse reaction was myelosuppression. Table 5 shows the hematologic adverse reactions and Table 6 shows the non-hematologic adverse reactions in patients with cervical cancer.

Table 5. Hematologic Adverse Reactions in Patients with Cervical Cancer Treated with Topotecan Hydrochloride Plus Cisplatin or Cisplatin Monotherapya
a Includes patients who were eligible and treated.
Hematologic Adverse Reaction Topotecan Hydrochloride
Plus Cisplatin
(n = 140)
Cisplatin
(n = 144)
Anemia
    All grades (Hgb <12 g/dL) 131 (94%) 130 (90%)
    Grade 3 (Hgb <8-6.5 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 (<2,000-1,000 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 (<1,000-500 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 (<50,000-10,000 cells/mm3) 36 (26%) 5 (3%)
    Grade 4 (<10,000 cells/mm3) 10 (7%) 0 (0%)

Manufacturer

Sagent Pharmaceuticals, Inc.

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Table 6. Non-hematologic Adverse Reactions Experienced by ≥5% of Patients with Cervical Cancer Treated with Topotecan Hydrochloride Plus Cisplatin or Cisplatin Monotherapya
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.
Adverse Reactions Topotecan Hydrochloride Plus Cisplatin
(n = 140)
Cisplatin
(n = 144)
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