ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. 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)] 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 or 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.. The most common Grade or 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). 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 trials in which 879 patients with small cell lung cancer (SCLC) and other solid tumors received topotecan 1.5 mg/m2 by intravenous infusion daily for consecutive days, starting on Day of 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 shows the Grade or 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 090Adverse ReactionsTopotecan(n 107)CAVCAV cyclophosphamide, doxorubicin and vincristine. (n 104)Grade 3-4 (%)Grade 3-4 (%)HematologicGrade neutropenia (< 500/mm3)7072Grade or anemia (Hgb 8 g/dL)4220Grade thrombocytopenia (< 25,000/mm3)295Febrile neutropenia2826Non-HematologicRespiratory, thoracic, and mediastinal Dyspnea914 Pneumonia86General and administrative site conditions Asthenia97 Fatigue610 PainPain includes body pain, skeletal pain, and back pain. 57Gastrointestinal Nausea86 Abdominal pain64Infections SepsisDeath related to sepsis occurred in 3% of patients receiving topotecan and 1% of patients receiving CAV. 55. Hepatobiliary DisordersBased on 879 patients with small cell lung cancer or another solid tumor who were treated with topotecan, Grade or elevated aspartate (AST) or alanine transaminase (ALT) occurred in 4% and Grade or elevated bilirubin occurred in less than 2% of patients.. 6.2Postmarketing Experience. The following reactions have been identified during postapproval use of topotecan. Because these reactions are reported voluntarily from population of unknown size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.. Blood and Lymphatic SystemSevere bleeding (in association with thrombocytopenia). HypersensitivityAllergic manifestations, anaphylactoid reactions, angioedema. GastrointestinalAbdominal pain potentially associated with neutropenic enterocolitis, gastrointestinal perforation. PulmonaryInterstitial lung disease. Skin and Subcutaneous TissueSevere dermatitis, severe pruritus. General and Administration Site ConditionsExtravasation, mucosal inflammation.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity testing of topotecan has not been performed. Topotecan is known to be genotoxic to mammalian cells and is probable carcinogen. Topotecan was mutagenic to L5178Y mouse lymphoma cells and clastogenic to cultured human lymphocytes with and without metabolic activation. It was also clastogenic to mouse bone marrow. Topotecan did not cause mutations in bacterial cells.Topotecan given to female rats prior to mating at an intravenous dose of 1.4 mg/m2 (about equal to the 1.5 mg/m2 clinical dose based on BSA) caused superovulation possibly related to inhibition of follicular atresia. This dose given to pregnant female rats also caused increased pre-implantation loss. one month study in dogs given daily intravenous topotecan dose of 0.4 mg/m2 (about 0.25 times the 1.5 mg/m2 clinical dose based on BSA) suggests that treatment may cause an increase in the incidence of multinucleated spermatogonial giant cells in the testes.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Topoisomerase relieves torsional strain in DNA by inducing reversible single-strand breaks. Topotecan binds to the topoisomerase I-DNA complex and prevents re-ligation of these single-strand breaks. The cytotoxicity of topotecan is thought to be due to double-strand DNA damage produced during DNA synthesis, when replication enzymes interact with the ternary complex formed by topotecan, topoisomerase I, and DNA. Mammalian cells cannot efficiently repair these double-strand breaks.. 12.3 Pharmacokinetics. Following administration of topotecan at doses of 0.5 to 1.5 mg/m2 (0.3 to times the recommended dose) administered as 30-minute infusion, area under the curve (AUC) increases approximately proportional with dose.. DistributionProtein binding of topotecan is approximately 35%.. EliminationThe terminal half-life of topotecan is to hours following intravenous administration.. MetabolismTopotecan undergoes reversible pH-dependent hydrolysis of its pharmacologically active lactone moiety. At pH <= 4, the lactone is exclusively present, whereas the ring-opened hydroxy-acid form predominates at physiologic pH. Topotecan is metabolized to an N-demethylated metabolite in vitro. The mean metabolite: parent AUC ratio was about 3% for total topotecan and topotecan lactone following intravenous administration.. ExcretionThe overall recovery of total topotecan and its N-desmethyl metabolite in urine and feces over days averaged 73% +- 2% following an intravenous dose. Mean values of 51% +- 3% as total topotecan and 3% +- 1% as N-desmethyl topotecan were excreted in the urine. Fecal elimination of total topotecan accounted for 18% +- 4% while fecal elimination of N-desmethyl topotecan was 1.7% +- 0.6%. An O-glucuronidation metabolite of topotecan and N-desmethyl topotecan has been identified in the urine.. Specific PopulationsNo clinically significant differences in the pharmacokinetics of topotecan were observed based on age, sex, or hepatic impairment following intravenous administration.. Patients with Renal ImpairmentCompared to patients with CLcr 60 mL/min (calculated by the Cockcroft-Gault method using ideal body weight), plasma clearance of topotecan lactone decreased by 33% in patients with CLcr 40 to 60 mL/min and decreased by 65% in patients with CLcr 20 to 39 mL/min. The effect on topotecan pharmacokinetics in patients with CLcr 20 mL/min is unknown [see Dosage and Administration (2.4)].. Drug Interaction Studies. Clinical StudiesNo clinically significant changes in topotecan pharmacokinetics were observed when coadministered cisplatin.No clinically significant changes in the pharmacokinetics of free platinum were observed in patients coadministered cisplatin with topotecan.. In Vitro StudiesTopotecan does not inhibit CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A, or CYP4A or dihydropyrimidine dehydrogenase.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Small Cell Lung Cancer. The efficacy of topotecan was studied in 426 patients with recurrent or progressive SCLC in randomized, comparative trial and in single-arm trials.. Randomized Comparative TrialIn randomized, comparative trial, 211 patients were randomized 1:1 to received topotecan (1.5 mg/m2 once daily intravenously for days starting on Day of 21-day cycle) or CAV (cyclophosphamide 1,000 mg/m2, doxorubicin 45 mg/m2, vincristine mg administered sequentially on Day of 21-day cycle). All patients were considered sensitive to first-line chemotherapy (responders who then subsequently progressed greater than or equal to 60 days after completion of first-line therapy). total of 77% of patients treated with topotecan and 79% of patients treated with CAV received platinum/etoposide with or without other agents as first-line chemotherapy. The efficacy outcome measures were overall response rate, response duration, time to progression and overall survival (OS).The results of the trial did not show statistically significant improvements in response rates, response duration, time to progression, and OS as shown in Table 2.Table 2. Efficacy Results in Patients with Small Cell Lung Cancer Sensitive to First-Line Chemotherapy in Study 090ParameterTopotecan(n 107)CAVCAV cyclophosphamide, doxorubicin and vincristine. (n 104)Abbreviations: CI confidence interval.Overall response rate (95% CI)24% (16% to 32%)18% (11% to 26%) Complete response rate0%1% Partial response rate24%17%Response durationThe calculation for duration of response was based on the interval between first response and time to progression. (months) Median (95% CI)3.3 (3.0 to 4.1)3.5 (3.0 to 5.3)Time to progression (months) Median (95% CI)3.1 (2.6 to 4.1)2.8 (2.5 to 3.2) Hazard ratio (95% CI)0.92 (0.69 to 1.22)Overall survival (months) Median (95% CI)5.8 (4.7 to 6.8)5.7 (5.0 to 7.0) Hazard ratio (95% CI)1.04 (0.78 to 1.39)The median time to response was similar in both arms: topotecan weeks (2.4 weeks to 3.6 months) versus CAV weeks (5.1 weeks to 4.2 months).Changes on disease-related symptom scale are presented in Table 3. It should be noted that not all patients had all symptoms, nor did all patients respond to all questions. Each symptom was rated on 4-category scale with an improvement defined as change in category from baseline sustained over cycles. Limitations in interpretation of the rating scale and responses preclude formal statistical analysis.Table 3. Symptom ImprovementDefined as improvement sustained over at least cycles compared with baseline. in Patients with Small Cell Lung Cancer in Study 090SymptomTopotecan(n 107)CAVCAV cyclophosphamide, doxorubicin and vincristine. (n 104)nNumber of patients with baseline and at least post-baseline assessment. %n %Shortness of breath6828617Interference with daily activity67276311Fatigue7023659Hoarseness40333813Cough69256115Insomnia57335319Anorexia56325716Chest pain44254117Hemoptysis15271233. Single-Arm TrialsTopotecan was also studied in open-label, non-comparative trials (Studies 014, 092 and 053) in total of 319 patients with recurrent or progressive SCLC after treatment with first-line chemotherapy. In all trials, patients were stratified as either sensitive (responders who then subsequently progressed greater than or equal to 90 days after completion of first-line therapy) or refractory (no response to first-line chemotherapy or who responded to first-line therapy and then progressed within 90 days of completing first-line therapy). Response rates ranged from 11% to 31% for sensitive patients and 2% to 7% for refractory patients. Median time to progression and median survival were similar in all trials and the comparative trial.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 trials in which 879 patients with small cell lung cancer (SCLC) and other solid tumors received topotecan 1.5 mg/m2 by intravenous infusion daily for consecutive days, starting on Day of 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 shows the Grade or 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 090Adverse ReactionsTopotecan(n 107)CAVCAV cyclophosphamide, doxorubicin and vincristine. (n 104)Grade 3-4 (%)Grade 3-4 (%)HematologicGrade neutropenia (< 500/mm3)7072Grade or anemia (Hgb 8 g/dL)4220Grade thrombocytopenia (< 25,000/mm3)295Febrile neutropenia2826Non-HematologicRespiratory, thoracic, and mediastinal Dyspnea914 Pneumonia86General and administrative site conditions Asthenia97 Fatigue610 PainPain includes body pain, skeletal pain, and back pain. 57Gastrointestinal Nausea86 Abdominal pain64Infections SepsisDeath related to sepsis occurred in 3% of patients receiving topotecan and 1% of patients receiving CAV. 55. Hepatobiliary DisordersBased on 879 patients with small cell lung cancer or another solid tumor who were treated with topotecan, Grade or elevated aspartate (AST) or alanine transaminase (ALT) occurred in 4% and Grade or elevated bilirubin occurred in less than 2% of patients.

DESCRIPTION SECTION.

11 DESCRIPTION. Topotecan is semi-synthetic derivative of camptothecin and topoisomerase inhibitor. The chemical name for topotecan hydrochloride is (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3,4:6,7]indolizino[1,2-b]quinoline-3,14-(4H,12H)-dione 1.25 hydrochloride. It has the molecular formula C23H23N3O5xHCl (x=1.25) and molecular weight of 467.02. It is soluble in water and melts with decomposition at 213C to 218C.Topotecan hydrochloride has the following structural formula:Topotecan Injection for intravenous use is supplied as sterile, non-pyrogenic, clear, yellow to yellow-green solution in single-dose vial at topotecan free base concentration of mg/4 mL (1 mg/mL).Each mL contains mg topotecan free base (equivalent to 1.11 mg of topotecan hydrochloride), mg tartaric acid, NF and water for injection, USP. It may also contain hydrochloric acid and/or sodium hydroxide to adjust the pH. The solution pH ranges from 2.6 to 3.2.. Chemical Structure.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity testing of topotecan has not been performed. Topotecan is known to be genotoxic to mammalian cells and is probable carcinogen. Topotecan was mutagenic to L5178Y mouse lymphoma cells and clastogenic to cultured human lymphocytes with and without metabolic activation. It was also clastogenic to mouse bone marrow. Topotecan did not cause mutations in bacterial cells.Topotecan given to female rats prior to mating at an intravenous dose of 1.4 mg/m2 (about equal to the 1.5 mg/m2 clinical dose based on BSA) caused superovulation possibly related to inhibition of follicular atresia. This dose given to pregnant female rats also caused increased pre-implantation loss. one month study in dogs given daily intravenous topotecan dose of 0.4 mg/m2 (about 0.25 times the 1.5 mg/m2 clinical dose based on BSA) suggests that treatment may cause an increase in the incidence of multinucleated spermatogonial giant cells in the testes.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Recommended dosage: 1.5 mg/m2 by intravenous infusion over 30 minutes daily for consecutive days, starting on Day of 21-day cycle. (2.2)Renal impairment: Reduce dose for creatinine clearance (CLcr) of 20 to 39 mL/min. (2.4). Recommended dosage: 1.5 mg/m2 by intravenous infusion over 30 minutes daily for consecutive days, starting on Day of 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 single dose of mg intravenously.. 2.2Recommended Dosage for Small Cell Lung Cancer. The recommended dosage of Topotecan Injection is 1.5 mg/m2 by intravenous infusion over 30 minutes daily for consecutive days, starting on Day of 21-day cycle.. 2.3Dosage Modifications for Adverse Reactions. HematologicDo not administer subsequent cycles of Topotecan Injection until neutrophils recover to greater than 1,000/mm3, platelets recover to greater than 100,000/mm3, and hemoglobin levels recover to greater than or equal to g/dL (with transfusion if necessary).Reduce the dose of Topotecan Injection to 1.25 mg/m2/day for:neutrophil counts of less than 500/mm3 or administer granulocyte-colony stimulating factor (G-CSF) starting no sooner than 24 hours following the last doseplatelet counts less than 25,000/mm3 during previous cycle. neutrophil counts of less than 500/mm3 or administer granulocyte-colony stimulating factor (G-CSF) starting no sooner than 24 hours following the last dose. platelet counts less than 25,000/mm3 during previous cycle. 2.4Dosage Modification for Renal Impairment. Reduce the dose of Topotecan Injection to 0.75 mg/m2/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)].. 2.5Preparation and Administration. Topotecan Injection is 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 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 20C and 25C (68F and 77F) 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.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Pregnancy TestingVerify pregnancy status of females of reproductive potential prior to initiating Topotecan Injection [see Use in Specific Populations (8.1)].. ContraceptionTopotecan can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].. FemalesAdvise female patients of reproductive potential to use effective contraception during treatment with Topotecan Injection and for months after the last dose.. MalesTopotecan may damage spermatozoa, resulting in possible genetic and fetal abnormalities. Advise males with female partner of reproductive potential to use effective contraception during treatment with Topotecan Injection and for months after the last dose [see Nonclinical Toxicology (13.1)].. Infertility. FemalesTopotecan may have both acute and long-term effects on fertility [see Nonclinical Toxicology (13.1)].. MalesEffects on spermatogenesis occurred in animals administered topotecan [see Nonclinical Toxicology (13.1)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. MyelosuppressionInform patients that topotecan decreases blood cell counts such as white blood cells, platelets, and red blood cells. Advise patients to notify their healthcare provider promptly for fever, other signs of infection, or bleeding [see Warnings and Precautions (5.1)].. Interstitial Lung Disease (ILD)Inform patients of the risks of severe ILD. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms [see Warnings and Precautions (5.2)].. Embryo-Fetal ToxicityAdvise females of reproductive potential and males with female partners of reproductive potential of the potential risk to fetus. Advise women to contact their healthcare provider if they become pregnant, or if pregnancy is suspected during treatment with Topotecan Injection [see Warnings and Precautions (5.4), Use in Specific Populations (8.1, 8.3)].Advise females of reproductive potential to use effective contraception during treatment with Topotecan Injection and for months after the last dose [see Use in Specific Populations (8.1, 8.3)].Advise males with female sexual partner of reproductive potential to use effective contraception during treatment with Topotecan Injection and for months after the last dose [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)]. LactationAdvise women to discontinue breastfeeding during treatment with Topotecan Injection and for at least week after the last dose [see Use in Specific Populations (8.2)].. InfertilityAdvise male and female patients of the potential risk for impaired fertility [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].. Asthenia and FatigueAdvise patients that topotecan may cause asthenia or fatigue. These symptoms may impair the ability to safely drive or operate machinery.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Following administration of topotecan at doses of 0.5 to 1.5 mg/m2 (0.3 to times the recommended dose) administered as 30-minute infusion, area under the curve (AUC) increases approximately proportional with dose.. DistributionProtein binding of topotecan is approximately 35%.. EliminationThe terminal half-life of topotecan is to hours following intravenous administration.. MetabolismTopotecan undergoes reversible pH-dependent hydrolysis of its pharmacologically active lactone moiety. At pH <= 4, the lactone is exclusively present, whereas the ring-opened hydroxy-acid form predominates at physiologic pH. Topotecan is metabolized to an N-demethylated metabolite in vitro. The mean metabolite: parent AUC ratio was about 3% for total topotecan and topotecan lactone following intravenous administration.. ExcretionThe overall recovery of total topotecan and its N-desmethyl metabolite in urine and feces over days averaged 73% +- 2% following an intravenous dose. Mean values of 51% +- 3% as total topotecan and 3% +- 1% as N-desmethyl topotecan were excreted in the urine. Fecal elimination of total topotecan accounted for 18% +- 4% while fecal elimination of N-desmethyl topotecan was 1.7% +- 0.6%. An O-glucuronidation metabolite of topotecan and N-desmethyl topotecan has been identified in the urine.. Specific PopulationsNo clinically significant differences in the pharmacokinetics of topotecan were observed based on age, sex, or hepatic impairment following intravenous administration.. Patients with Renal ImpairmentCompared to patients with CLcr 60 mL/min (calculated by the Cockcroft-Gault method using ideal body weight), plasma clearance of topotecan lactone decreased by 33% in patients with CLcr 40 to 60 mL/min and decreased by 65% in patients with CLcr 20 to 39 mL/min. The effect on topotecan pharmacokinetics in patients with CLcr 20 mL/min is unknown [see Dosage and Administration (2.4)].. Drug Interaction Studies. Clinical StudiesNo clinically significant changes in topotecan pharmacokinetics were observed when coadministered cisplatin.No clinically significant changes in the pharmacokinetics of free platinum were observed in patients coadministered cisplatin with topotecan.. In Vitro StudiesTopotecan does not inhibit CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A, or CYP4A or dihydropyrimidine dehydrogenase.

POSTMARKETING EXPERIENCE SECTION.

6.2Postmarketing Experience. The following reactions have been identified during postapproval use of topotecan. Because these reactions are reported voluntarily from population of unknown size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.. Blood and Lymphatic SystemSevere bleeding (in association with thrombocytopenia). HypersensitivityAllergic manifestations, anaphylactoid reactions, angioedema. GastrointestinalAbdominal pain potentially associated with neutropenic enterocolitis, gastrointestinal perforation. PulmonaryInterstitial lung disease. Skin and Subcutaneous TissueSevere dermatitis, severe pruritus. General and Administration Site ConditionsExtravasation, mucosal inflammation.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on animal data and its mechanism of action, Topotecan Injection can cause fetal harm when administered to 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 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 DataIn rabbits, an intravenous dose of 0.10 mg/kg/day [(about equal to the 1.5 mg/m2 clinical dose based on body surface area (BSA)] given on Days 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/m2 clinical dose based on BSA) given for 14 days before mating through gestation Day 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/m2 clinical dose based on BSA) given to rats on Days 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased on animal data and its mechanism of action, Topotecan Injection can cause fetal harm when administered to 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 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 DataIn rabbits, an intravenous dose of 0.10 mg/kg/day [(about equal to the 1.5 mg/m2 clinical dose based on body surface area (BSA)] given on Days 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/m2 clinical dose based on BSA) given for 14 days before mating through gestation Day 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/m2 clinical dose based on BSA) given to rats on Days 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 SummaryThere 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 week after the last dose.. DataFollowing intravenous administration of topotecan to lactating rats at dose of 4.72 mg/m2 (about twice the 1.5 mg/m2 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 TestingVerify pregnancy status of females of reproductive potential prior to initiating Topotecan Injection [see Use in Specific Populations (8.1)].. ContraceptionTopotecan can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].. FemalesAdvise female patients of reproductive potential to use effective contraception during treatment with Topotecan Injection and for months after the last dose.. MalesTopotecan may damage spermatozoa, resulting in possible genetic and fetal abnormalities. Advise males with female partner of reproductive potential to use effective contraception during treatment with Topotecan Injection and for months after the last dose [see Nonclinical Toxicology (13.1)].. Infertility. FemalesTopotecan may have both acute and long-term effects on fertility [see Nonclinical Toxicology (13.1)].. MalesEffects 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.. 8.6Renal Impairment. Reduce the dose of Topotecan Injection for patients with 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 dosage recommendation for Topotecan Injection.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. 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). 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 neutropenia occurred in 78% of 879 patients, with median duration of days and was most common during Cycle (58% of patients). Grade neutropenia associated with infection occurred in 13% and febrile neutropenia occurred in 5%. Sepsis occurred in 4% and was fatal in 1%. Grade thrombocytopenia occurred in 27%, with median duration of days. Grade or 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 baseline neutrophil count of greater than or equal to 1,500/mm3 and platelet count greater than or equal to 100,000/mm3. 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)].. 5.2Interstitial 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 new diagnosis of ILD is confirmed.. 5.3Extravasation 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)].. 5.4Embryo-Fetal Toxicity. Based on animal data, topotecan can cause fetal harm when administered to pregnant woman. Topotecan caused embryolethality, fetotoxicity, and teratogenicity in rats and rabbits when administered during organogenesis. Advise women of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment and for months after the last dose of Topotecan Injection. Advise males with female partner of reproductive potential to use effective contraception during treatment with Topotecan Injection and for months after the last dose [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].