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 (ILD) [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 (ILD) [see Warnings and Precautions (5.2)] Extravasation and Tissue Injury [see Warnings and Precautions (5.3)] Ovarian cancer:The most common Grade or hematologic adverse reactions (incidence 5%) were: neutropenia, anemia, thrombocytopenia, and febrile neutropenia. (6.1)The most common (incidence 5%) non-hematologic adverse reactions (all Grades) were: nausea, vomiting, fatigue, diarrhea, and dyspnea. (6.1)SCLC:The most common Grade or hematologic adverse reactions were (incidence 5%): neutropenia, anemia, thrombocytopenia, and febrile neutropenia. (6.1)The most common (incidence 5%) non-hematologic adverse reactions (all Grades) were: asthenia, dyspnea, nausea, pneumonia, abdominal pain, and fatigue. (6.1)Cervical cancer:The most common Grade or hematologic adverse reactions 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 Fresenius Kabi USA, LLC at 1-800-551-7176 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 (incidence 5%) non-hematologic adverse reactions (all Grades) were: nausea, vomiting, fatigue, diarrhea, and dyspnea. (6.1). The most common Grade or hematologic adverse reactions were (incidence 5%): neutropenia, anemia, thrombocytopenia, and febrile neutropenia. (6.1). The most common (incidence 5%) non-hematologic adverse reactions (all Grades) were: asthenia, dyspnea, nausea, pneumonia, abdominal pain, and fatigue. (6.1). The most common Grade or hematologic adverse reactions 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). 6.1 Clinical 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 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/m2 by intravenous infusion daily for consecutive days, starting on Day of 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/m2 by intravenous infusion daily on Days 1, 2, and 3, with cisplatin 50 mg/m2 by intravenous infusion on Day 1, of 21-day cycle.. Ovarian CancerThe safety of topotecan hydrochloride for injection was evaluated in randomized trial conducted in 226 patients with metastatic ovarian cancer (Study 039) [see Clinical Studies (14.1)]. Table shows the incidence of Grade and 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 039a Death related to sepsis occurred in 2% of patients receiving topotecan hydrochloride and 0% of patients receiving paclitaxel.b Pain includes body pain, skeletal pain, and back pain.Adverse ReactionsTopotecanHydrochloride(n=112)Paclitaxel(n=114)Grade 3-4 (%)Grade 3-4 (%)HematologicGrade neutropenia (< 500/mm3)8021Grade or anemia (Hgb 8 g/dL)416Grade thrombocytopenia (< 25,000/mm3)273Febrile neutropenia234Non-HematologicInfectionsSepsisa52Respiratory, thoracic, and mediastinalDyspnea65GastrointestinalVomiting103Nausea102Diarrhea61Abdominal pain54Intestinal obstruction54Constipation50General and administrative site conditionsFatigue76Painb 57Asthenia53. 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 shows the Grade or 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 090a Death related to sepsis occurred in 3% of patients receiving topotecan hydrochloride and 1% of patients receiving CAV.b Pain includes body pain, skeletal pain, and back pain.c CAV cyclophosphamide, doxorubicin and vincristine.Adverse ReactionsTopotecanHydrochloride(n=107)CAVc (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-HematologicInfectionsSepsisa55Respiratory, thoracic, and mediastinalDyspnea914Pneumonia86GastrointestinalNausea86Abdominal pain64General and administrative site conditionsAsthenia97Fatigue610Painb 57. 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 or increases aspartate transaminase (AST) or alanine transaminase (ALT) occurred in 4% and Grade or elevated bilirubin occurred in less than 2%.. Cervical CancerThe safety of topotecan hydrochloride for injection was evaluated in comparative trial of topotecan hydrochloride with cisplatin versus cisplatin as single agent in patients with cervical cancer (Study GOG 0179). Table 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 0179a Includes patients who were eligible and treated.b Severity based on using National Cancer Institute (NCI) Common Toxicity Criteria (CTC), Version 2.0.cGrades through only. There were patients who experienced deaths with investigator-designated attribution. The first patient experienced Grade hemorrhage in which the drug-related thrombocytopenia aggravated the event. second patient experienced bowel obstruction, cardiac arrest, pleural effusion, and respiratory failure which were not treatment-related but probably aggravated by treatment. third patient experienced pulmonary embolism and adult respiratory distress syndrome; the latter was indirectly treatment-related.dConstitutional includes fatigue (lethargy, malaise, asthenia), fever (in the absence of neutropenia), rigors, chills, sweating, and weight gain or loss.ePain 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.fHigh-level terms were included if the between-arm difference was >= 10%.Adverse ReactionsTopotecanHydrochloride WithCisplatin(n =140)%Cisplatin(n =144)%HematologicNeutropeniaGrade (< 1,000 to 500/mm3)261Grade (< 500/mm3)481AnemiaGrade (Hgb 8 to 6.5 g/dL)3419Grade (Hgb 6.5 g/dL)63ThrombocytopeniaGrade (< 50,000 to 10,000/mm3)263Grade (< 10,000/mm3)70Non-Hematologicb,cGeneral and administrative site conditionsConstitutionald6962Paine 5950GastrointestinalVomiting4037Stomatitis-pharyngitis60Other6356Dermatologyf4820InfectionFebrile neutropeniaf2818Cardiovascularf2515. 6.2 Postmarketing Experience. The following reactions have been identified during post approval use of topotecan hydrochloride.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.

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 hydrochloride for injection at doses of 0.5 to 1.5 mg/m2 (0.1 to 0.3 times the recommended single agent dose) administered as 30-minute infusion, area under the curve (AUC) increases proportionally 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 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.. ExcretionThe overall recovery of total topotecan and its N-desmethyl metabolite in urine and feces over days averaged 73.0% +- 2.0% following an intravenous dose. Mean values of 51.0% +- 3.0% as total topotecan and 3.0% +- 1.0% as N-desmethyl topotecan were excreted in the urine. Fecal elimination of total topotecan accounted for 18.0% +- 4.0% 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 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 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. 14.1 Ovarian Cancer. The efficacy of topotecan hydrochloride was evaluated in clinical trials of 223 patients with metastatic ovarian cancer. All patients had disease that had recurred on, or was unresponsive to, platinum-containing regimen. Patients in these trials received an initial dose of 1.5 mg/m2 as an intravenous infusion for consecutive days, starting on Day of 21-day cycle.One trial (Study 039) was randomized trial of 112 patients who received topotecan hydrochloride and of 114 patients who received paclitaxel (175 mg/m2 intravenously over hours on Day of 21-day cycle). All patients had recurrent ovarian cancer after platinum-containing regimen or had not responded to at least prior platinum-containing regimen. Patients who did not respond to the trial therapy, or who progressed, could be given the alternative treatment. 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 4.Table 4. Efficacy Results in Ovarian Cancer in Study 039Abbreviation: CI, confidence interval.a The calculation for response duration was based on the interval between first response and time to progression.ParametersTopotecanHydrochloride(n 112)Paclitaxel(n 114)Overall response rate (95% Cl)21% (13%, 28%)14% (8%, 20%)Complete response rate5%3%Partial response rate16%11%Response durationa (months)Median (95% Cl)6.0 (5.1, 7.6)5.0 (3.7, 7.8)Time to progression (months)Median (95% Cl)4.4 (2.8, 5.4)3.4 (2.7, 4.2)Hazard ratio (95% Cl)0.76 (0.57, 1.02)Overall survival (months)Median (95% Cl)14.5 (10.7, 16.5)12.2 (9.7, 15.8)Hazard ratio (95% Cl)0.97 (0.71, 1.34)The median time to response was 7.6 weeks (3.1 weeks to months) with topotecan hydrochloride compared with 6.0 weeks (2.4 weeks to 4.1 months) with paclitaxel. In the crossover phase, 13% of 61 patients who received topotecan hydrochloride after paclitaxel had partial response and 10% of 49 patients who received paclitaxel after topotecan hydrochloride had response (2 complete responses).Topotecan hydrochloride was active in ovarian cancer patients who had developed resistance to platinum-containing therapy, defined as tumor progression while on, or tumor relapse within months after completion of, platinum-containing regimen. One complete and partial responses were seen in 60 patients, for response rate of 12%. In the same trial, there were no complete responders and partial responders on the paclitaxel arm, for response rate of 7%.Topotecan hydrochloride was also studied in an open-label, non-comparative trial in 111 patients with recurrent ovarian cancer after treatment with platinum-containing regimen, or who had not responded to prior platinum-containing regimen. The response rate was 14% (95% CI: 7%, 20%). The median duration of response was 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 was evaluated in 426 patients with recurrent or progressive small cell lung cancer (SCLC) in randomized, comparative trial and in single-arm trials.. Randomized Comparative TrialIn randomized, comparative trial, 211 patients were randomized 1:1 to receive topotecan hydrochloride (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 hydrochloride 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 090Abbreviations: CI, confidence intervala The calculation for duration of response was based on the interval between first response and time to progression.b CAV cyclophosphamide, doxorubicin and vincristine.ParameterTopotecanHydrochloride(n 107)CAVb (n 104)Overall response rate (95% Cl)24% (16%, 32%)18% (11%, 26%)Complete response rate0%1%Partial response rate24%17%Response durationa(months) Median (95% Cl)3.3 (3, 4.1)3.5 (3, 5.3)Time to progression (months) Median (95% Cl)3.1 (2.6, 4.1)2.8 (2.5, 3.2)Hazard ratio (95% Cl)0.92 (0.69, 1.22)Overall survival (months) Median (95% Cl)5.8 (4.7, 6.8)5.7 (5, 7)Hazard ratio (95% Cl)1.04 (0.78, 1.39)The median time to response was similar in both arms: topotecan hydrochloride, 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 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 4category scale with an improvement defined as change in category from baseline sustained over courses. Limitations in interpretation of the rating scale and responses preclude formal statistical analysis.Table 6. Symptom Improvementa in Patients with Small Cell Lung Cancer in Study 090a Defined as improvement sustained over at least courses compared with baseline.b Number of patients with baseline and at least post-baseline assessment.SymptomTopotecan Hydrochloride(n=107)CAV(n=104)nb (%)nb(%)Shortness of breath6828617Interference with daily activity67276311Fatigue7023659Hoarseness40333813Cough69256115Insomnia57335319Anorexia56325716Chest pain44254117Hemoptysis15271233. Single-Arm TrialsTopotecan hydrochloride 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.. 14.3 Cervical Cancer. The efficacy of topotecan hydrochloride was evaluated in 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 (0.75 mg/m2 once daily intravenously for consecutive days starting on Day of 21-day cycle) with cisplatin (50 mg/m2 intravenously on Day 1) or cisplatin as single agent. Fifty-six percent of patients treated with topotecan hydrochloride 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 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 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.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical 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 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/m2 by intravenous infusion daily for consecutive days, starting on Day of 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/m2 by intravenous infusion daily on Days 1, 2, and 3, with cisplatin 50 mg/m2 by intravenous infusion on Day 1, of 21-day cycle.. Ovarian CancerThe safety of topotecan hydrochloride for injection was evaluated in randomized trial conducted in 226 patients with metastatic ovarian cancer (Study 039) [see Clinical Studies (14.1)]. Table shows the incidence of Grade and 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 039a Death related to sepsis occurred in 2% of patients receiving topotecan hydrochloride and 0% of patients receiving paclitaxel.b Pain includes body pain, skeletal pain, and back pain.Adverse ReactionsTopotecanHydrochloride(n=112)Paclitaxel(n=114)Grade 3-4 (%)Grade 3-4 (%)HematologicGrade neutropenia (< 500/mm3)8021Grade or anemia (Hgb 8 g/dL)416Grade thrombocytopenia (< 25,000/mm3)273Febrile neutropenia234Non-HematologicInfectionsSepsisa52Respiratory, thoracic, and mediastinalDyspnea65GastrointestinalVomiting103Nausea102Diarrhea61Abdominal pain54Intestinal obstruction54Constipation50General and administrative site conditionsFatigue76Painb 57Asthenia53. 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 shows the Grade or 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 090a Death related to sepsis occurred in 3% of patients receiving topotecan hydrochloride and 1% of patients receiving CAV.b Pain includes body pain, skeletal pain, and back pain.c CAV cyclophosphamide, doxorubicin and vincristine.Adverse ReactionsTopotecanHydrochloride(n=107)CAVc (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-HematologicInfectionsSepsisa55Respiratory, thoracic, and mediastinalDyspnea914Pneumonia86GastrointestinalNausea86Abdominal pain64General and administrative site conditionsAsthenia97Fatigue610Painb 57. 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 or increases aspartate transaminase (AST) or alanine transaminase (ALT) occurred in 4% and Grade or elevated bilirubin occurred in less than 2%.. Cervical CancerThe safety of topotecan hydrochloride for injection was evaluated in comparative trial of topotecan hydrochloride with cisplatin versus cisplatin as single agent in patients with cervical cancer (Study GOG 0179). Table 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 0179a Includes patients who were eligible and treated.b Severity based on using National Cancer Institute (NCI) Common Toxicity Criteria (CTC), Version 2.0.cGrades through only. There were patients who experienced deaths with investigator-designated attribution. The first patient experienced Grade hemorrhage in which the drug-related thrombocytopenia aggravated the event. second patient experienced bowel obstruction, cardiac arrest, pleural effusion, and respiratory failure which were not treatment-related but probably aggravated by treatment. third patient experienced pulmonary embolism and adult respiratory distress syndrome; the latter was indirectly treatment-related.dConstitutional includes fatigue (lethargy, malaise, asthenia), fever (in the absence of neutropenia), rigors, chills, sweating, and weight gain or loss.ePain 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.fHigh-level terms were included if the between-arm difference was >= 10%.Adverse ReactionsTopotecanHydrochloride WithCisplatin(n =140)%Cisplatin(n =144)%HematologicNeutropeniaGrade (< 1,000 to 500/mm3)261Grade (< 500/mm3)481AnemiaGrade (Hgb 8 to 6.5 g/dL)3419Grade (Hgb 6.5 g/dL)63ThrombocytopeniaGrade (< 50,000 to 10,000/mm3)263Grade (< 10,000/mm3)70Non-Hematologicb,cGeneral and administrative site conditionsConstitutionald6962Paine 5950GastrointestinalVomiting4037Stomatitis-pharyngitis60Other6356Dermatologyf4820InfectionFebrile neutropeniaf2818Cardiovascularf2515.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Ovarian cancer and small cell lung cancer: 1.5 mg/m2 by intravenous infusion over 30 minutes daily for consecutive days, starting on Day of 21-day cycle. (2.2, 2.3)Cervical cancer: 0.75 mg/m2 by intravenous infusion over 30 minutes on Days 1, 2, and with cisplatin 50 mg/m2 on Day 1, of 21-day cycle. (2.4)Renal impairment: Reduce dose if creatinine clearance (CLcr) 20 to 39 mL/min. (2.6). Ovarian cancer and small cell lung cancer: 1.5 mg/m2 by intravenous infusion over 30 minutes daily for consecutive days, starting on Day of 21-day cycle. (2.2, 2.3). Cervical cancer: 0.75 mg/m2 by intravenous infusion over 30 minutes on Days 1, 2, and with cisplatin 50 mg/m2 on Day 1, of 21-day cycle. (2.4). Renal impairment: Reduce dose if creatinine clearance (CLcr) 20 to 39 mL/min. (2.6). 2.1 Important Safety Information. Verify dosage using body surface area. Do not exceed single dose of mg intravenously.. 2.2 Recommended Dosage for Ovarian Cancer. The recommended dosage of topotecan hydrochloride is 1.5 mg/m2 by intravenous infusion over 30 minutes daily for consecutive days, starting on Day of 21-day cycle until disease progression or unacceptable toxicity.. 2.3 Recommended Dosage for Small Cell Lung Cancer (SCLC). The recommended dosage of topotecan hydrochloride is 1.5 mg/m2 by intravenous infusion over 30 minutes daily for consecutive days, starting on Day of 21-day cycle.. 2.4 Recommended Dosage for Cervical Cancer. The recommended dosage of topotecan hydrochloride is 0.75 mg/m2 by intravenous infusion over 30 minutes daily on Days 1, 2, and in combination with cisplatin 50 mg/m2 on Day 1, of 21-day cycle.. 2.5 Dosage Modifications for Adverse Reactions. HematologicDo not administer subsequent cycles of topotecan hydrochloride for 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).For topotecan hydrochloride as single agent, reduce the dose to 1.25 mg/m2/day for:neutrophil counts of less than 500/mm3, or administer granulocyte-colony stimulating factor (GCSF) starting no sooner than 24 hours following the last dose.platelet counts less than 25,000/mm3 during previous cycle.For topotecan hydrochloride in combination with cisplatin, reduce the dose to 0.60 mg/m2/day (and further to 0.45 mg/m2if necessary) for:febrile neutropenia (defined as neutrophil counts less than 1,000/mm3 with temperature of greater than or equal to 38.0C (100.4F), or administer G-CSF starting no sooner than 24 hours following the last dose. platelet counts less than 25,000/mm3 during previous cycle.. neutrophil counts of less than 500/mm3, or administer granulocyte-colony stimulating factor (GCSF) starting no sooner than 24 hours following the last dose.. platelet counts less than 25,000/mm3 during previous cycle.. febrile neutropenia (defined as neutrophil counts less than 1,000/mm3 with temperature of greater than or equal to 38.0C (100.4F), or administer G-CSF starting no sooner than 24 hours following the last dose. platelet counts less than 25,000/mm3 during previous cycle.. 2.6 Dosage Modification for Renal Impairment. For topotecan hydrochloride as 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.. PreparationReconstitute each mg vial of topotecan hydrochloride with 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.. StabilityBecause the vials contain no preservative, use contents immediately after reconstitution. Discard any unused portion.Store reconstituted product diluted for infusion at approximately 20C to 25C (68F to 77F) protected from light for no more than 24 hours. Discard after 24 hours.Topotecan hydrochloride is cytotoxic drug. Follow applicable handling and disposal procedures.1.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Topotecan hydrochloride for injection is topoisomerase inhibitor indicated for treatment of:Patients with metastatic ovarian cancer after disease progression on or after initial or subsequent chemotherapy, as single agent. (1.1)Patients with small cell lung cancer (SCLC) platinum-sensitive disease who progressed at least 60 days after initiation of first-line chemotherapy, as single agent. (1.2)Patients with Stage IV-B, recurrent, or persistent cervical cancer which is not amenable to curative treatment, in combination with cisplatin. (1.3). Patients with metastatic ovarian cancer after disease progression on or after initial or subsequent chemotherapy, as single agent. (1.1). Patients with small cell lung cancer (SCLC) platinum-sensitive disease who progressed at least 60 days after initiation of first-line chemotherapy, as single agent. (1.2). Patients with Stage IV-B, recurrent, or persistent cervical cancer which is not amenable to curative treatment, in combination with cisplatin. (1.3). 1.1 Ovarian Cancer. Topotecan hydrochloride for injection, as single agent, is indicated for the treatment of patients with metastatic ovarian cancer after disease progression on or after initial or subsequent chemotherapy.. 1.2 Small Cell Lung Cancer. Topotecan hydrochloride for injection, as single agent, is indicated for the treatment of patients with small cell lung cancer (SCLC) with platinum-sensitive disease 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. MyelosuppressionInform patients that topotecan hydrochloride 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 hydrochloride for 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 and for months after the last dose of topotecan hydrochloride for injection [see Use in Specific Populations (8.1, 8.3)].Advise males with female partner of reproductive potential to use effective contraception during treatment and for months after the last dose of topotecan hydrochloride for injection [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].LactationAdvise women to discontinue breastfeeding during treatment and for week after the last dose of topotecan hydrochloride for injection [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 hydrochloride for injection may cause asthenia or fatigue. These symptoms may impair the ability to safely drive or operate machinery.PREMIERProRx(R) is registered trademark of Premier Healthcare Alliance, L.P., used under license.Manufactured by: Fresenius Kabi Lake Zurich, IL 60047www.fresenius-kabi.com/us451322B. Myelosuppression. Interstitial Lung Disease (ILD). Embryo-Fetal Toxicity. Lactation. Infertility. Asthenia and Fatigue. Fresenius Kabi Logo.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Following administration of topotecan hydrochloride for injection at doses of 0.5 to 1.5 mg/m2 (0.1 to 0.3 times the recommended single agent dose) administered as 30-minute infusion, area under the curve (AUC) increases proportionally 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 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.. ExcretionThe overall recovery of total topotecan and its N-desmethyl metabolite in urine and feces over days averaged 73.0% +- 2.0% following an intravenous dose. Mean values of 51.0% +- 3.0% as total topotecan and 3.0% +- 1.0% as N-desmethyl topotecan were excreted in the urine. Fecal elimination of total topotecan accounted for 18.0% +- 4.0% 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 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 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.

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 hydrochloride can cause fetal harm when administered to pregnant woman. There are no available clinical data on the use of topotecan hydrochloride 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 Data: In 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 hydrochloride for 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 48fold 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 hydrochloride for injection [see Use in Specific Populations (8.1)].. ContraceptionTopotecan hydrochloride can cause fetal harm when administered to 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 six months after the last dose.Males: Topotecan hydrochloride 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 hydrochloride for injection and for three months after the last dose [see Nonclinical Toxicology (13.1)].. InfertilityFemales: Topotecan hydrochloride can have both acute and long-term effects on fertility [see Nonclinical Toxicology (13.1)].Males: Effects on spermatogenesis occurred in animals administered topotecan hydrochloride [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 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 CLcr of 20 to 39 mL/min [see Dosage and Administration (2.6), 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 hydrochloride for 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 patients of potential risk to the fetus and to use effective contraception. (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 patients of potential risk to the fetus and to use effective contraception. (5.4, 8.1, 8.3). 5.1 Myelosuppression. Topotecan hydrochloride can cause severe myelosuppression.. Single AgentGrade 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% of patients and was fatal in 1%. Grade thrombocytopenia occurred in 27%, with median duration of days. Grade or anemia occurred in 37% of patients.. Combination with cisplatinGrade neutropenia occurred in 48% and Grade thrombocytopenia occurred in 7% of 147 patients. Grade or 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 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 hydrochloride 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.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. If signs or symptoms of extravasation occur, immediately stop administration of topotecan hydrochloride and institute recommended management procedures [see Adverse Reactions (6.1)]. 5.4 Embryo-Fetal Toxicity. Based on animal data, topotecan hydrochloride 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 hydrochloride for injection. Advise males with female partner of reproductive potential to use effective contraception during treatment with topotecan hydrochloride for injection and for months after the last dose [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].