Topotecan

Recommended dosage: 1.5 mg/m 2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on Day 1 of a 21-day cycle. (2.2) Renal impairment: Reduce dose for creatinine clearance (CLcr) of 20 to 39 mL/min. (2.4)

2.1Important Safety Information

Verify dosage using body surface area. Do not exceed a single dose of 4 mg intravenously. 2.2 Recommended Dosage for Small Cell Lung Cancer The recommended dosage of Topotecan Injection 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 cycle. 2.3 Dosage Modifications for Adverse Reactions Hematologic Do not administer subsequent cycles of Topotecan Injection until neutrophils recover to greater than 1,000/mm 3, platelets recover to greater than 100,000/mm 3, and hemoglobin levels recover to greater than or equal to 9 g/dL (with transfusion if necessary). Reduce the dose of Topotecan Injection to 1.25 mg/m 2 /day for: neutrophil counts of less than 500/mm 3 or administer granulocyte-colony stimulating factor (G-CSF) starting no sooner than 24 hours following the last dose platelet counts less than 25,000/mm 3 during previous cycle

2.4Dosage Modification for Renal Impairment

Reduce the dose of Topotecan Injection to 0.75 mg/m 2 /day for patients with creatinine clearance (CLcr) of 20 to 39 mL/min (calculated with the Cockcroft-Gault method using ideal body weight) [see Clinical Pharmacology (12.3)]. 2.5 Preparation and Administration Topotecan Injection is a cytotoxic drug. Follow applicable special handling and disposable procedures. 1 Withdraw the appropriate volume from the vial and discard any unused portion. Dilute Topotecan Injection in a minimum of 50 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP prior to administration. Infuse diluted Topotecan Injection over 30 minutes. Store diluted Topotecan Injection at 20°C and 25°C (68°F and 77°F) in ambient lighting conditions for no more than 24 hours. Discard unused portion after 24 hours. Visually inspect for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard if particulate matter or discoloration is observed.

Interstitial lung disease (ILD): Fatal cases have occurred. Permanently discontinue if ILD confirmed. (5.2) Extravasation and tissue injury: Severe cases have occurred. If extravasation occurs, immediately stop administration and institute recommended management procedures. (5.3) Embryo-fetal toxicity: Can cause fetal harm. Advise women of potential risk to the fetus. (5.4, 8.1, 8.3)

5.1Myelosuppression

Topotecan can cause severe myelosuppression. Grade 4 neutropenia occurred in 78% of 879 patients, with a median duration of 7 days and was most common during Cycle 1 (58% of patients). Grade 4 neutropenia associated with infection occurred in 13% and febrile neutropenia occurred in 5%. Sepsis occurred in 4% and was fatal in 1%. Grade 4 thrombocytopenia occurred in 27%, with a median duration of 5 days. Grade 3 or 4 anemia occurred in 37% of patients. Topotecan can cause fatal typhlitis (neutropenic enterocolitis). Consider the possibility of typhlitis in patients presenting with fever, neutropenia, and abdominal pain. Administer the first cycle of Topotecan Injection only to patients with a baseline neutrophil count of greater than or equal to 1,500/mm 3 and a platelet count greater than or equal to 100,000/mm 3. Monitor blood counts frequently during treatment. Withhold and reduce dose of Topotecan Injection based on neutrophil counts, platelet counts and hemoglobin levels [see Dosage and Administration (2.3)]. 5.2 Interstitial Lung Disease Interstitial lung disease (ILD), including fatalities, has occurred with topotecan [see Adverse Reactions (6.2)]. Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer, thoracic radiation, and use of pneumotoxic drugs and/or colony stimulating factors. Monitor patients for pulmonary symptoms indicative of ILD (e.g., cough, fever, dyspnea, and/or hypoxia), and discontinue Topotecan Injection if a new diagnosis of ILD is confirmed. 5.3 Extravasation and Tissue Injury Extravasation with topotecan has been observed; severe cases have been reported. If signs or symptoms of extravasation occur, immediately stop administration of Topotecan Injection and institute recommended management procedures [see Adverse Reactions (6.2)]. 5.4 Embryo-Fetal Toxicity 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. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months after the last dose of Topotecan Injection. Advise males with a female partner of reproductive potential to use effective contraception during treatment with Topotecan Injection and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

The following serious adverse reactions are described elsewhere in the labeling: Myelosuppression [see Warnings and Precautions (5.1)] Interstitial Lung Disease [see Warnings and Precautions (5.2)] Extravasation and Tissue Injury [see Warnings and Precautions (5.3)] The most common Grade 3 or 4 hematologic adverse reactions (incidence >5%) were: neutropenia, anemia, thrombocytopenia, and febrile neutropenia. (6.1) The most common non-hematologic adverse reactions (incidence >5%) (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. The data in Warnings and Precautions reflect exposure to topotecan from 8 trials in which 879 patients with small cell lung cancer (SCLC) and other solid tumors received topotecan 1.5 mg/m 2 by intravenous infusion daily for 5 consecutive days, starting on Day 1 of a 21-day cycle. Small Cell Lung Cancer (SCLC) The safety of topotecan was evaluated in randomized, comparative trial in patients with recurrent or progressive SCLC (Study 090) [see Clinical Studies (14.1)]. Table 1 shows the Grade 3 or 4 hematologic and non-hematologic adverse reactions in patients with SCLC. Table 1. Adverse Reactions Occurring in ≥5% of Patients with Small Cell Lung Cancer in Study 090 Adverse Reactions Topotecan (n = 107) CAV CAV = cyclophosphamide, doxorubicin and vincristine. (n = 104) Grade 3-4 (%) Grade 3-4 (%) Hematologic Grade 4 neutropenia (< 500/mm 3) 70 72 Grade 3 or 4 anemia (Hgb < 8 g/dL) 42 20 Grade 4 thrombocytopenia (< 25,000/mm 3) 29 5 Febrile neutropenia 28 26 Non-Hematologic Respiratory, thoracic, and mediastinal Dyspnea 9 14 Pneumonia 8 6 General and administrative site conditions Asthenia 9 7 Fatigue 6 10 Pain Pain includes body pain, skeletal pain, and back pain. 5 7 Gastrointestinal Nausea 8 6 Abdominal pain 6 4 Infections Sepsis Death related to sepsis occurred in 3% of patients receiving topotecan and 1% of patients receiving CAV. 5 5 Hepatobiliary Disorders Based on 879 patients with small cell lung cancer or another solid tumor who were treated with topotecan, Grade 3 or 4 elevated aspartate (AST) or alanine transaminase (ALT) occurred in 4% and Grade 3 or 4 elevated bilirubin occurred in less than 2% of patients. 6.2 Postmarketing Experience The following reactions have been identified during postapproval use of topotecan. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Severe bleeding (in association with thrombocytopenia) Hypersensitivity Allergic manifestations, anaphylactoid reactions, angioedema Gastrointestinal Abdominal pain potentially associated with neutropenic enterocolitis, gastrointestinal perforation Pulmonary Interstitial lung disease Skin and Subcutaneous Tissue Severe dermatitis, severe pruritus General and Administration Site Conditions Extravasation, mucosal inflammation

Lactation: Advise not to breastfeed. (8.2)

8.1Pregnancy Risk Summary

Based on animal data and its mechanism of action, Topotecan Injection can cause fetal harm when administered to a pregnant woman. There are no available clinical data on the use of topotecan in pregnancy. Topotecan caused embryolethality, fetotoxicity, and teratogenicity in rats and rabbits when administered during organogenesis at doses similar to the clinical dose (see Data). Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data Animal Data In rabbits, an intravenous dose of 0.10 mg/kg/day [(about equal to the 1.5 mg/m 2 clinical dose based on body surface area (BSA)] given on Days 6 through 20 of gestation caused maternal toxicity, embryolethality, and reduced fetal body weight. In the rat, an intravenous dose of 0.23 mg/kg/day (about equal to the 1.5 mg/m 2 clinical dose based on BSA) 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 1.5 mg/m 2 clinical dose based on BSA) 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 There are no data on the presence of topotecan or its metabolites in human milk or their effects on the breastfed infant or on milk production. Lactating rats excrete high concentrations of topotecan in milk (see Data). Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with Topotecan Injection and for 1 week after the last dose. Data Following intravenous administration of topotecan to lactating rats at a dose of 4.72 mg/m 2 (about twice the 1.5 mg/m 2 clinical dose based on BSA), topotecan was excreted into milk at concentrations up to 48-fold higher than those in plasma. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to initiating Topotecan Injection [see Use in Specific Populations (8.1)]. Contraception Topotecan can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Females Advise female patients of reproductive potential to use effective contraception during treatment with Topotecan Injection and for 6 months after the last dose. Males Topotecan may damage spermatozoa, resulting in possible genetic and fetal abnormalities. Advise males with a female partner of reproductive potential to use effective contraception during treatment with Topotecan Injection and for 3 months after the last dose [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 occurred in animals administered topotecan [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 with SCLC or another solid tumor who received topotecan in clinical trials, 32% were aged 65 years and older, while 3.8% were aged 75 years and older. No overall differences in effectiveness or safety were observed between these patients and younger patients and other reported clinical experience has not identified differences in responses between the elderly and younger patients. 8.6 Renal Impairment Reduce the dose of Topotecan Injection for patients with a CLcr of 20 to 39 mL/min [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]. No dosage adjustment is recommended for patients with CLcr greater than or equal to 40 mL/min. Insufficient data are available in patients with CLcr less than 20 mL/min to provide a dosage recommendation for Topotecan Injection.

Risk Summary Based on animal data and its mechanism of action, Topotecan Injection can cause fetal harm when administered to a pregnant woman. There are no available clinical data on the use of topotecan in pregnancy. Topotecan caused embryolethality, fetotoxicity, and teratogenicity in rats and rabbits when administered during organogenesis at doses similar to the clinical dose (see Data). Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data Animal Data In rabbits, an intravenous dose of 0.10 mg/kg/day [(about equal to the 1.5 mg/m 2 clinical dose based on body surface area (BSA)] given on Days 6 through 20 of gestation caused maternal toxicity, embryolethality, and reduced fetal body weight. In the rat, an intravenous dose of 0.23 mg/kg/day (about equal to the 1.5 mg/m 2 clinical dose based on BSA) 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 1.5 mg/m 2 clinical dose based on BSA) 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.