Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 02 February 2018

Indication(s)

1 INDICATIONS AND USAGE Topotecan injection is indicated for the treatment of patients with small cell lung cancer with platinum-sensitive disease who progressed at least 60 days after initiation of first-line chemotherapy. Topotecan Injection is a topoisomerase inhibitor indicated for: •small cell lung cancer platinum-sensitive disease in patients who progressed after first-line chemotherapy. (1.1)

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Advisory information

contraindications
4 CONTRAINDICATIONS Topotecan injection is contraindicated in patients who have a history of severe hypersensitivity reactions to topotecan. •History of severe hypersensitivity reactions to topotecan. (4)
Adverse reactions
6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: •Bone Marrow Suppression [see Warnings and Precautions (5.1) ] •Neutropenic Enterocolitis [see Warnings and Precautions (5.2) ] •Interstitial Lung Disease [see Warnings and Precautions (5.3) ] •Extravasation and Tissue Injury [see Warnings and Precautions (5.5) ] Small cell lung cancer: •The most common hematologic adverse reactions were: neutropenia (Grade 4: 70%), anemia (Grade 3/4: 42%), thrombocytopenia (Grade 4: 29%), and febrile neutropenia (28%). (6.1) •The most common (>5%) non-hematologic adverse reactions (all grades) were: asthenia, dyspnea, nausea, pneumonia, abdominal pain, and fatigue. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Small Cell Lung Cancer Table 1 shows the Grade 3/4 hematologic and major non-hematologic adverse reactions in the Topotecan/CAV (cyclophosphamide-doxorubicin-vincristine) comparator trial in small cell lung cancer. Table 1. Adverse Reactions Experienced by ≥5% of Small Cell Lung Cancer Patients Randomized to Receive Topotecan or CAV 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. 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 Febrile neutropenia 28 26 Non-hematologic Grade 3/4 % % Infections and infestations Sepsisa 5 5 Respiratory, thoracic, and mediastinal disorders Dyspnea Pneumonia 9 8 14 6 Gastrointestinal disorders Abdominal pain Nausea 6 8 4 6 General disorders and administrative site conditions Fatigue Asthenia Painb 6 9 5 10 7 7 Hepatobiliary Disorders in Small Cell Lung Cancer Patients Receiving Topotecan: Based on 426 patients with small cell lung cancer treated with topotecan, Grade 1 transient elevations in hepatic enzymes occurred in 8% of patients. Grade 3/4 elevations occurred in 4%. Grade 3/4 elevated bilirubin occurred in less than 2% of patients. 6.2 Postmarketing Experience The following reactions have been identified during postmarketing use of topotecan. 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. 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 enterocolitis [ 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 Extravasation [ see Warnings and Precautions (5.5) ].

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Verify dose using body surface area prior to dispensing. Recommended dosage should generally not exceed 4 mg intravenously [see Overdosage (10) ]. •1.5 mg/m2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on Day 1 of a 21-day course. (2.1, 2.2) •Renal impairment: Dose reduce Topotecan injection in patients with moderate renal impairment (20 to 39 mL/min). (2.2) 2.1 Small Cell Lung Cancer Recommended Dose and Schedule The recommended dose of Topotecan injection 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. 2.2 Dose Modifications Hematologic Toxicities Dose reduce Topotecan injection to 1.25 mg/m2 for: •neutrophil counts of less than 500 cells/mm3, or administer granulocyte-colony stimulating factor (G-CSF) starting no sooner than 24 hours following the last dose of Topotecan injection. •platelet counts less than 25,000 cells/mm3 during previous cycle. For combination use with cisplatin, dose reduce Topotecan injection to 0.60 mg/m2 (and further to 0.45 mg/m2 if necessary) for: •febrile neutropenia (defined as neutrophil counts less than 1,000 cells/mm3 with temperature of greater than or equal to 38.0°C (100.4°F), or administer G-CSF starting no sooner than 24 hours following the last dose of Topotecan injection. •platelet counts less than 25,000 cells/mm3 during previous cycle. Renal Impairment For single-agent use, dose reduce Topotecan injection to 0.75 mg/m2 in patients with moderate renal impairment (creatinine clearance [Clcr] = 20 to 39 mL/min). Insufficient data are available in patients with severe renal impairment (Clcr less than 20 mL/min) to provide a dosage recommendation for Topotecan injection [ see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ]. 2.3 Preparation and Intravenous Administration Topotecan injection is a cytotoxic drug. Follow applicable special handling and disposable procedures.1 Preparation and Administration The appropriate volume of 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. Stability Topotecan injection diluted for infusion is stable between 20°C and 25°C (68°F and 77°F) in ambient lighting conditions for 24 hours. Each vial of Topotecan injection is intended for single use only. Any unused drug remaining after injection must be discarded.
Use in special populations
8 USE IN SPECIFIC POPULATIONS •Lactation: Discontinue breastfeeding. (8.2) 8.1 Pregnancy Risk Summary Based on animal data, topotecan can cause fetal harm when administered to a pregnant woman. Topotecan caused embryolethality, fetotoxicity, and teratogenicity in rats and rabbits when administered during organogenesis at doses similar to the clinical dose [see Data]. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated populations are unknown; however, the background risk in the US general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data Animal Data: In rabbits, a dose of 0.10 mg/kg/day (about equal to the clinical dose on a mg/m2 basis) given on Days 6 through 20 of gestation caused maternal toxicity, embryolethality, and reduced fetal body weight. In the rat, a dose of 0.23 mg/kg/day (about equal to the clinical dose on a mg/m2 basis) given for 14 days before mating through gestation Day 6 caused fetal resorption, microphthalmia, pre-implant loss, and mild maternal toxicity. Administration of an intravenous dose of 0.10 mg/kg/day (about half the clinical dose on a mg/m2 basis) given to rats on Days 6 through 17 of gestation caused an increase in post-implantation mortality. This dose also caused an increase in total fetal malformations. The most frequent malformations were of the eye (microphthalmia, anophthalmia, rosette formation of the retina, coloboma of the retina, ectopic orbit), brain (dilated lateral and third ventricles), skull, and vertebrae. 8.2 Lactation Risk Summary It is not known whether this drug is present in human milk; however, topotecan is excreted in rat milk at high concentrations [see Data]. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants with topotecan, advise nursing mothers to discontinue breastfeeding during treatment with topotecan. Data Animal Data: Following intravenous administration of topotecan to lactating rats at a dose of 4.72 mg/m2 (about twice the clinical dose on a mg/m2 basis), topotecan was excreted into milk at concentrations up to 48-fold higher than those in plasma. 8.3 Females and Males of Reproductive Potential Contraception Females: Advise female patients of reproductive potential to use effective contraception during treatment with topotecan and for one month after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking topotecan [see Use in Specific Populations (8.1) ]. Males: Topotecan may damage spermatozoa, resulting in possible genetic and fetal abnormalities. Advise males with a female sexual partner of reproductive potential to use effective contraception during and for three months after treatment with topotecan [see Nonclinical Toxicology (13.1) ]. Infertility Females: Topotecan may have both acute and long-term effects on fertility [see Nonclinical Toxicology (13.1) ]. Males: Effects on spermatogenesis have been observed in animals administered topotecan. Advise males of the potential risk for impaired fertility and to seek counseling on fertility and family planning options prior to starting treatment [see Nonclinical Toxicology (13.1) ]. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Of the 879 patients in a combined experience of topotecan which included patients with small cell lung cancer in clinical trials of topotecan, 32% (n = 281) were aged 65 years and older, while 3.8% (n = 33) were aged 75 years and older. No overall differences in effectiveness or safety were observed between these patients and younger adult patients, and other reported clinical experience has not identified differences in responses between the elderly and younger adult patients. 8.6 Renal Impairment The systemic exposure to both topotecan lactone and total topotecan increased in patients with moderate renal impairment (Clcr = 20 to 39 mL/min) compared with patients with normal renal function (Clcr greater than 60 mL/min). Reduce the dose of Topotecan in patients with moderate renal impairment (Clcr = 20 to 39 mL/min). No dosage adjustment of Topotecan is recommended for patients with mild renal impairment (Clcr = 40 to 60 mL/min) [see Dosage and Administration (2.2) , Clinical Pharmacology (12.3) ]. Insufficient data are available in patients with severe renal impairment (Clcr less than 20 mL/min) to provide a dosage recommendation for Topotecan.

Interactions

7 DRUG INTERACTIONS •Do not initiate G-CSF until 24 hours after completion of treatment with topotecan injection. Concomitant administration can prolong duration of neutropenia. (7) 7.1 G-CSF Concomitant administration with G-CSF can prolong the duration of neutropenia. If G-CSF is used, it should be started no sooner than 24 hours following the last dose of Topotecan injection.

More information

Category Value
Authorisation number NDA200582
Agency product number 956S425ZCY
Orphan designation No
Product NDC 0409-0302
Date Last Revised 24-01-2018
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder Hospira, Inc.
Warnings WARNING: BONE MARROW SUPPRESSION Topotecan injection can cause severe myelosuppression. Administer only to patients with baseline neutrophil counts of greater than or equal to 1,500 cells/mm3 and platelet counts greater than or equal to 100,000 cells/mm3. Monitor blood cell counts [see Warnings and Precautions (5.1) ]. WARNING: BONE MARROW SUPPRESSION See full prescribing information for complete boxed warning. Topotecan injection can cause severe myelosuppression. Administer only to patients with baseline neutrophil counts greater than or equal to 1,500 cells/mm3 and platelet count greater than or equal to 100,000/mm3. Monitor blood cell counts. ( 5.1 )