se who progressed at least 60 days after initiation of first-line chemotherapy. 1.3 cervical cancer topotecan hydrochloride for injection, in combination with cisplatin, is indicated for the treatment of patients with stage iv-b, recurrent, or persistent cervical cancer not amenable to curative treatment.

n with cisplatin grade 4 neutropenia occurred in 48% and grade 4 thrombocytopenia occurred in 7% of 147 patients. grade 3 or 4 anemia occurred in 40% 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 hydrochloride for 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 hydrochloride for injection based on neutrophil counts, platelet counts and hemoglobin levels [see dosage and administration ( 2.5 )] . 5.2 interstitial lung disease interstitial lung disease (ild), including fatalities, can occur with topotecan hydrochloride for injection. underlying risk factors include history of ild, pulmonary fibrosis, lung cancer, thoracic radiation, and use of pneumotoxic drugs or colony stimulating factors. monitor for pulmonary symptoms indicative of ild. permanently discontinue topotecan hydrochloride for injection if ild is confirmed. 5.3 extravasation and tissue injury extravasation, including severe cases, can occur with topotecan hydrochloride for injection. if signs or symptoms of extravasation occur, immediately stop administration of topotecan hydrochloride for injection and institute recommended management procedures [see adverse reactions ( 6.1 )] . 5.4 embryo-fetal toxicity based on animal data, topotecan hydrochloride for injection 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 hydrochloride for injection. advise males with a female partner of reproductive potential to use effective contraception during treatment with topotecan hydrochloride for injection and for 3 months after the last dose [see use in specific populations ( 8.1 , 8.3 ), nonclinical toxicology ( 13.1 )] .

er 30 minutes daily for 5 consecutive days, starting on day 1 of a 21-day cycle. 2.4 recommended dosage for cervical cancer the recommended dosage of topotecan hydrochloride for injection is 0.75 mg/m 2 by intravenous infusion over 30 minutes daily on days 1, 2, and 3, in combination with cisplatin 50 mg/m 2 on day 1, of a 21-day cycle. 2.5 dosage modifications for adverse reactions hematologic do not administer subsequent cycles of topotecan hydrochloride for 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). for topotecan hydrochloride for injection as a single agent, reduce the dose 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 for topotecan hydrochloride for injection in combination with cisplatin, reduce the dose to 0.6 mg/m 2 /day (and further to 0.45 mg/m 2 if necessary) for: febrile neutropenia (defined as neutrophil counts less than 1,000/mm 3 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 platelet counts less than 25,000/mm 3 during previous cycle 2.6 dosage modification for renal impairment for topotecan hydrochloride for injection as a single agent, reduce the dose 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 )] . 2.7 preparation and intravenous administration visually inspect for particulate matter and discoloration prior to administration, whenever solution and container permit. preparation reconstitute each 4 mg vial of topotecan hydrochloride for injection with 4 ml sterile water for injection, usp. dilute the appropriate volume of the reconstituted solution in either 0.9% sodium chloride intravenous infusion, usp or 5% dextrose in water injection, usp. stability because the vials contain no preservative, use contents immediately after reconstitution. discard any unused portion. store reconstituted product diluted for infusion at approximately 20°c to 25°c (68°f to 77°f) protected from light for no more than 24 hours. discard after 24 hours. topotecan hydrochloride for injection is a cytotoxic drug. follow applicable handling and disposal procedures. 1

ns were (incidence > 5%) neutropenia, anemia, and thrombocytopenia. ( 6.1 ) the most common (incidence > 25% and ≥ 2% higher than cisplatin alone) non-hematologic adverse reactions were pain, vomiting, and infection/febrile neutropenia. ( 6.1 ) to report suspected adverse reactions, contact accord healthcare inc. at 1-866-941-7875 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 hydrochloride for injection from eight trials in which 879 patients with ovarian cancer or small cell lung cancer (sclc) received topotecan hydrochloride for injection 1.5 mg/m 2 by intravenous infusion daily for 5 consecutive days, starting on day 1 of a 21 day cycle and from one trial (study gog 0179) in which 147 patients with cervical cancer received topotecan hydrochloride for injection 0.75 mg/m 2 by intravenous infusion daily on days 1, 2, and 3, with cisplatin 50 mg/m2 by intravenous infusion on day 1, of a 21-day cycle. ovarian cancer the safety of topotecan hydrochloride for injection was evaluated in a randomized trial conducted in 226 patients with metastatic ovarian cancer (study 039) [see clinical studies ( 14.1 )] . table 1 shows the incidence of grade 3 and 4 hematologic and non-hematologic adverse reactions that occurred in patients receiving topotecan hydrochloride for injection. table 1. adverse reactions occurring in greater than or equal to 5% of patients with ovarian cancer in study 039 a death related to sepsis occurred in 2% of patients receiving topotecan hydrochloride for injection and 0% of patients receiving paclitaxel. b pain includes body pain, skeletal pain, and back pain. adverse reactions topotecan hydrochloride for injection (n = 112) paclitaxel (n = 114) grade 3-4 (%) grade 3-4 (%) hematologic grade 4 neutropenia (< 500/mm 3 ) grade 3 or 4 anemia (hgb < 8 g/dl) grade 4 thrombocytopenia (< 25,000/mm 3 ) febrile neutropenia 80 41 27 23 21 6 3 4 non-hematologic infections sepsis a 5 2 respiratory, thoracic, and mediastinal dyspnea 6 5 gastrointestinal vomiting 10 3 nausea 10 2 diarrhea 6 1 abdominal pain 5 4 intestinal obstruction 5 4 constipation 5 0 general and administrative site conditions fatigue 7 6 pain b 5 7 asthenia 5 3 small cell lung cancer (sclc) the safety of topotecan hydrochloride for injection was evaluated in randomized, comparative trial in patients with recurrent or progressive sclc (study 090) [see clinical studies ( 14.2 )] . table 2 shows the grade 3 or 4 hematologic and non-hematologic adverse reactions in patients with sclc. table 2. adverse reactions occurring in greater than or equal to 5% of patients with small cell lung cancer in study 090 a death related to sepsis occurred in 3% of patients receiving topotecan hydrochloride for injection and 1% of patients receiving cav. b pain includes body pain, skeletal pain, and back pain. c cav = cyclophosphamide, doxorubicin and vincristine. adverse reactions topotecan hydrochloride for injection (n = 107) cav c (n = 104) grade 3-4 (%) grade 3-4 (%) hematologic grade 4 neutropenia (< 500/mm 3 ) grade 3 or 4 anemia (hgb < 8 g/dl) grade 4 thrombocytopenia (< 25,000/mm 3 ) febrile neutropenia 70 42 29 28 72 20 5 26 non-hematologic infections sepsis a 5 5 respiratory, thoracic, and mediastinal dyspnea 9 14 pneumonia 8 6 gastrointestinal nausea 8 6 abdominal pain 6 4 general and administrative site conditions asthenia 9 7 fatigue 6 10 pain b 5 7 hepatobiliary disorders in ovarian and small cell lung cancer (sclc) based on the combined experience of 453 patients with metastatic ovarian cancer and 426 patients with sclc treated with topotecan hydrochloride for injection, grade 3 or 4 increases aspartate transaminase (ast) or alanine transaminase (alt) occurred in 4% and grade 3 or 4 elevated bilirubin occurred in less than 2%. cervical cancer the safety of topotecan hydrochloride for injection was evaluated in a comparative trial of topotecan hydrochloride for injection with cisplatin versus cisplatin as a single agent in patients with cervical cancer (study gog 0179). table 3 shows the hematologic and non-hematologic adverse reactions in patients with cervical cancer. table 3. adverse reactions occurring in greater than or equal to 5% of patients with cervical cancer (between-arm difference ≥ 2%) a in study gog 0179 a includes patients who were eligible and treated. b severity based on using national cancer institute (nci) common toxicity criteria (ctc), version 2.0. c grades 1 through 4 only. there were 3 patients who experienced deaths with investigator-designated attribution. the first patient experienced 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. d constitutional includes fatigue (lethargy, malaise, asthenia), fever (in the absence of neutropenia), rigors, chills, sweating, and weight gain or loss. e 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. f high-level terms were included if the between-arm difference was ≥ 10%. adverse reactions topotecan hydrochloride for injection with cisplatin (n = 140) % cisplatin (n = 144) % hematologic neutropenia grade 3 (< 1,000-500/mm 3 ) 26 1 grade 4 (< 500/mm 3 ) 48 1 anemia grade 3 (hgb < 8-6.5 g/dl) 34 19 grade 4 (hgb < 6.5 g/dl) 6 3 thrombocytopenia grade 3 (< 50,000-10,000/mm 3 ) 26 3 grade 4 (< 10,000/mm 3 ) 7 0 non-hematologic b,c general and administrative site conditions constitutional d 69 62 pain e 59 50 gastrointestinal vomiting 40 37 stomatitis-pharyngitis 6 0 other 63 56 dermatology f 48 20 infection febrile neutropenia f 28 18 cardiovascular f 25 15 6.2 postmarketing experience the following reactions have been identified during post approval use of topotecan hydrochloride for injection. 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

ht. 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 hydrochloride for 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) to lactating rats, 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 hydrochloride for injection [see use in specific populations ( 8.1 )] . contraception topotecan hydrochloride for injection can cause fetal harm when administered to a pregnant woman [see use in specific populations ( 8.1 )] . females advise females of reproductive potential to use effective contraception during treatment with topotecan hydrochloride for injection and for 6 months after the last dose. males topotecan hydrochloride for injection 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 hydrochloride for injection and for 3 months after the last dose [see nonclinical toxicology ( 13.1 )] . infertility females topotecan hydrochloride for injection can 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 metastatic ovarian cancer or small cell lung cancer in clinical trials of topotecan hydrochloride for injection, 32% were aged 65 years and older, while 3.8% were aged 75 years and older. of the 140 patients with stage iv-b, relapsed, or refractory cervical cancer in clinical trials of topotecan hydrochloride for injection who received topotecan hydrochloride for injection with cisplatin in the randomized clinical trial, 6% were aged 65 years and older, while 3% 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 hydrochloride for injection in 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 hydrochloride for injection.

.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.

rgoes a reversible ph-dependent hydrolysis of its pharmacologically active lactone moiety. at ph less than or equal to 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 (calculated by the cockcroft-gault method using ideal body weight) greater than 60 ml/min, plasma clearance of topotecan lactone decreased by 33% in patients with clcr 40-60 ml/min and decreased 65% in patients with clcr 20-39 ml/min. the effect on topotecan pharmacokinetics in patients with clcr less than 20 ml/min is unknown [see dosage and administration ( 2.6 )] . 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.

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 (calculated by the cockcroft-gault method using ideal body weight) greater than 60 ml/min, plasma clearance of topotecan lactone decreased by 33% in patients with clcr 40-60 ml/min and decreased 65% in patients with clcr 20-39 ml/min. the effect on topotecan pharmacokinetics in patients with clcr less than 20 ml/min is unknown [see dosage and administration ( 2.6 )] . 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.

d spermatogonial giant cells in the testes.

ls in the testes.

o 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 4. table 4. efficacy results in ovarian cancer in study 039 abbreviation: ci, confidence interval. a the calculation for response duration was based on the interval between first response and time to progression. parameters topotecan hydrochloride for injection (n = 112) paclitaxel (n = 114) overall response rate (95% ci) 21% (13%, 28%) 14% (8%, 20%) complete response rate 5% 3% partial response rate 16% 11% response duration a (months) median (95% ci) 6 (5.1, 7.6) 5 (3.7, 7.8) time to progression (months) median (95% ci) 4.4 (2.8, 5.4) 3.4 (2.7, 4.2) hazard ratio (95% ci) 0.76 (0.57, 1.02) overall survival (months) median (95% ci) 14.5 (10.7, 16.5) 12.2 (9.7, 15.8) hazard ratio (95% ci) 0.97 (0.71, 1.34) the median time to response was 7.6 weeks (3.1 weeks to 5 months) with topotecan hydrochloride for injection compared with 6 weeks (2.4 weeks to 4.1 months) with paclitaxel. in the cross-over phase, 13% of 61 patients who received topotecan hydrochloride for injection after paclitaxel had a partial response and 10% of 49 patients who received paclitaxel after topotecan hydrochloride for injection had a response (2 complete responses). topotecan hydrochloride for injection was active in ovarian cancer patients who had developed resistance to platinum-containing therapy, defined as tumor progression while on, or tumor relapse within 6 months after completion of, a platinum-containing regimen. one complete and 6 partial responses were seen in 60 patients, for a response rate of 12%. in the same trial, there were no complete responders and 4 partial responders on the paclitaxel arm, for a response rate of 7%. topotecan hydrochloride for injection was also studied in an open-label, non-comparative trial in 111 patients with recurrent ovarian cancer after treatment with a platinum-containing regimen, or who had not responded to 1 prior platinum-containing regimen. the response rate was 14% (95% ci: 7%, 20%). the median duration of response was 5 months (4.6 weeks to 9.6 months). the time to progression was 2.6 months (5 days to 1.4 years). the median survival was 1.3 years (1.4 weeks, to 2.2 years). 14.2 small cell lung cancer (sclc) the efficacy of topotecan hydrochloride for injection was evaluated in 426 patients with recurrent or progressive small cell lung cancer (sclc) in a randomized, comparative trial and in 3 single-arm trials. randomized comparative trial in a randomized, comparative trial, 211 patients were randomized 1:1 to receive topotecan hydrochloride for injection (1.5 mg/m 2 once daily intravenously for 5 days starting on day 1 of a 21-day cycle) or cav (cyclophosphamide 1,000 mg/m 2 , doxorubicin 45 mg/m 2 , vincristine 2 mg administered sequentially on day 1 of a 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). a total of 77% of patients treated with topotecan hydrochloride for injection 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 or os. the results of the trial did not show statistically significant improvements in response rate, response duration, time to progression, or os as shown in table 5. table 5. efficacy results in patients with small cell lung cancer sensitive to first-line chemotherapy in study 090 abbreviations: ci, confidence interval. a the calculation for duration of response was based on the interval between first response and time to progression. b cav = cyclophosphamide, doxorubicin and vincristine. parameter topotecan hydrochloride for injection (n = 107) cav b (n = 104) overall response rate (95% ci) 24% (16%, 32%) 18% (11%, 26%) complete response rate 0% 1% partial response rate 24% 17% response duration a (months) median (95% ci) 3.3 (3, 4.1) 3.5 (3, 5.3) time to progression (months) median (95% ci) 3.1 (2.6, 4.1) 2.8 (2.5, 3.2) hazard ratio (95% ci) 0.92 (0.69, 1.22) overall survival (months) median (95% ci) 5.8 (4.7, 6.8) 5.7 (5, 7) hazard ratio (95% ci) 1.04 (0.78, 1.39) the median time to response was similar in both arms: topotecan hydrochloride for injection, 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 6. 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 courses. limitations in interpretation of the rating scale and responses preclude formal statistical analysis. table 6. symptom improvement a in patients with small cell lung cancer in study 090 a defined as improvement sustained over at least 2 courses compared with baseline. b number of patients with baseline and at least 1 post-baseline assessment. symptoms topotecan hydrochloride for injection (n = 107) cav (n = 104) n b (%) n b (%) 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 hydrochloride for injection was also studied in three 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 three 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 three trials and the comparative trial. 14.3 cervical cancer the efficacy of topotecan hydrochloride for injection was evaluated in a multi-center, randomized (1:1), open-label study (study gog 0179) conducted in 147 patients with histologically confirmed stage iv-b, recurrent, or persistent cervical cancer considered not amenable to curative treatment with surgery and/or radiation. patients were randomized to topotecan hydrochloride for injection (0.75 mg/m 2 once daily intravenously for 3 consecutive days starting on day 1 of a 21-day cycle) with cisplatin (50 mg/m 2 intravenously on day 1) or cisplatin as a single agent. fifty-six percent of patients treated with topotecan hydrochloride for injection with cisplatin and 56% of patients treated with cisplatin had received prior cisplatin with or without other agents as first-line chemotherapy. the efficacy outcome measure was os. median os of eligible patients receiving topotecan hydrochloride for injection with cisplatin was 9.4 months (95% ci: 7.9, 11.9) compared with 6.5 months (95% ci: 5.8, 8.8) among patients randomized to cisplatin alone with a log rank p -value of 0.033 (significance level was 0.044 after adjusting for the interim analysis). the unadjusted hazard ratio for os was 0.76 (95% ci: 0.59, 0.98). figure 1. kaplan-meier curves for overall survival in cervical cancer in study gog 0179 figure 1. kaplan-meier curves for overall survival in cervical cancer in study gog 0179

productive potential to use effective contraception during treatment and for 6 months after the last dose of topotecan hydrochloride for injection [see use in specific populations ( 8.1 , 8.3 )] . advise males with a female partner of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of topotecan hydrochloride for injection [see use in specific populations ( 8.1 , 8.3 ), nonclinical toxicology ( 13.1 )] . lactation advise women to discontinue breastfeeding during treatment and for 1 week after the last dose of topotecan hydrochloride for injection [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 hydrochloride for injection may cause asthenia or fatigue. these symptoms may impair the ability to safely drive or operate machinery. manufactured for: accord healthcare, inc., 1009, slater road, suite 210-b, durham, nc 27703, usa. manufactured by: intas pharmaceuticals limited, plot no. : 457, 458, village – matoda, bavla road, ta. - sanand, dist. - ahmedabad – 382 210, india. 10 4086 0 604281 issued december, 2019