is 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) ] .

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 2.4 dosage 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.

e 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

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.

or 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.

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. excretion the overall recovery of total topotecan and its n-desmethyl metabolite in urine and feces over 9 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 populations no clinically significant differences in the pharmacokinetics of topotecan were observed based on age, sex, or hepatic impairment following intravenous administration. patients with renal impairment compared 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 studies no 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 studies topotecan does not inhibit cyp1a2, cyp2a6, cyp2c8/9, cyp2c19, cyp2d6, cyp2e, cyp3a, or cyp4a or dihydropyrimidine dehydrogenase.

nous 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 populations no clinically significant differences in the pharmacokinetics of topotecan were observed based on age, sex, or hepatic impairment following intravenous administration. patients with renal impairment compared 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 studies no 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 studies topotecan does not inhibit cyp1a2, cyp2a6, cyp2c8/9, cyp2c19, cyp2d6, cyp2e, cyp3a, or cyp4a or dihydropyrimidine dehydrogenase.

matogonial giant cells in the testes.

the testes.

verall 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 090 parameter topotecan (n = 107) cav cav = 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 rate 0% 1% partial response rate 24% 17% response duration the 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 6 weeks (2.4 weeks to 3.6 months) versus cav 6 weeks (5.1 weeks to 4.2 months). changes on a 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 a 4-category scale with an improvement defined as a change in 1 category from baseline sustained over 2 cycles. limitations in interpretation of the rating scale and responses preclude formal statistical analysis. table 3. symptom improvement defined as improvement sustained over at least 2 cycles compared with baseline. in patients with small cell lung cancer in study 090 symptom topotecan (n = 107) cav cav = cyclophosphamide, doxorubicin and vincristine. (n = 104) n number of patients with baseline and at least 1 post-baseline assessment. % n % shortness of breath 68 28 61 7 interference with daily activity 67 27 63 11 fatigue 70 23 65 9 hoarseness 40 33 38 13 cough 69 25 61 15 insomnia 57 33 53 19 anorexia 56 32 57 16 chest pain 44 25 41 17 hemoptysis 15 27 12 33 single-arm trials topotecan was also studied in 3 open-label, non-comparative trials (studies 014, 092 and 053) in a total of 319 patients with recurrent or progressive sclc after treatment with first-line chemotherapy. in all 3 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 3 trials and the comparative trial.

n during treatment with topotecan injection and for 6 months after the last dose [see use in specific populations (8.1 , 8.3) ] . advise males with a female sexual 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) ]. lactation advise women to discontinue breastfeeding during treatment with topotecan injection and for at least 1 week after the last dose [see use in specific populations (8.2) ] . infertility advise male and female patients of the potential risk for impaired fertility [see use in specific populations (8.3) , nonclinical toxicology (13.1) ] . asthenia and fatigue advise patients that topotecan may cause asthenia or fatigue. these symptoms may impair the ability to safely drive or operate machinery.