Topotecan

1 INDICATIONS AND USAGE Topotecan Injection is indicated for the treatment of: small cell lung cancer sensitive disease after failure of first-line chemotherapy. In clinical studies submitted to support approval, sensitive disease was defined as disease responding to chemotherapy but subsequently progressing at least 60 days (in the Phase 3 study) or at least 90 days (in the Phase 2 studies) after chemotherapy [see Clinical Studies ( 14 ) ] . Topotecan Injection in combination with cisplatin is indicated for the treatment of: stage IV-B, recurrent, or persistent carcinoma of the cervix which is not amenable to curative treatment with surgery and/or radiation therapy. Topotecan is a topoisomerase inhibitor indicated for: small cell lung cancer sensitive disease after failure of first-line chemotherapy. ( 1 ) combination therapy with cisplatin for stage IV-B, recurrent, or persistent carcinoma of the cervix which is not amenable to curative treatment with surgery and/or radiation therapy. ( 1 )

2 DOSAGE AND ADMINISTRATION Verify dose using body surface area prior to dispensing. Recommended dosage should not exceed 4 mg [see Overdosage 10 ]. Prior to administration of the first course of Topotecan Injection, patients must have a baseline neutrophil count of >1,500 cells/mm 3 and a platelet count of >100,000 cells/mm 3 . Small cell lung cancer: 1.5 mg/m 2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on day one of a 21-day course. ( 2.1 ) Cervical cancer: 0.75 mg/m 2 by intravenous infusion over 30 minutes on days 1, 2, and 3 followed by cisplatin 50 mg/m 2 by intravenous infusion on day 1 repeated every 21 days. ( 2.2 ) See Dosage Modification Guidelines for patients with neutropenia or reduced platelets.( 2.1 , 2.2 ) See Dosage Adjustment in Renal Impairment. ( 2.3 ) 2.1 Small Cell Lung Cancer Recommended Dosage The recommended dose of topotecan is 1.5 mg/m 2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on day 1 of a 21-day course. In the absence of tumor progression, a minimum of 4 courses is recommended because tumor response may be delayed. The median time to response in 4 small cell lung cancer trials was 5 to 7 weeks. Dosage Modification Guidelines In the event of severe neutropenia (defined as <500 cells/mm 3 ) during any course, reduce the dose by 0.25 mg/m 2 (to 1.25 mg/m 2 ) for subsequent courses. Alternatively, in the event of severe neutropenia, administer G-CSF (granulocyte-colony stimulating factor) following the subsequent course (before resorting to dose reduction) starting from day 6 of the course (24 hours after completion of topotecan administration). In the event the platelet count falls below 25,000 cells/mm 3 , reduce doses by 0.25 mg/m 2 (to 1.25 mg/m 2 ) for subsequent courses. 2.2 Cervical Cancer Recommended Dosage The recommended dose of Topotecan Injection is 0.75 mg/m 2 by intravenous infusion over 30 minutes daily on days 1, 2, and 3; followed by cisplatin 50 mg/m 2 by intravenous infusion on day 1 repeated every 21 days (a 21-day course). Dosage Modification Guidelines Dosage adjustments for subsequent courses of Topotecan Injection in combination with cisplatin are specific for each drug. See manufacturer’s prescribing information for cisplatin administration and hydration guidelines and for cisplatin dosage adjustment in the event of hematologic toxicity In the event of severe febrile neutropenia (defined as <1000 cells/mm 3 with temperature of 38°C or 100.4°F), reduce the dose of Topotecan Injection to 0.60 mg/m 2 for subsequent courses. Alternatively, in the event of severe febrile neutropenia, administer G-CSF following the subsequent course (before resorting to dose reduction) starting from day 4 of the course (24 hours after completion of administration of Topotecan Injection). If febrile neutropenia occurs despite the use of G-CSF, reduce the dose of Topotecan Injection to 0.45 mg/m 2 for subsequent courses. In the event the platelet count falls below 25,000 cells/mm 3 , reduce doses to 0.60 mg/m 2 for subsequent courses. 2.3 Dosage Adjustment in Specific Populations Renal Impairment No dosage adjustment of Topotecan Injection appears to be required for patients with mild renal impairment (Cl cr 40 to 60 mL/min.). Dosage adjustment of Topotecan Injection to 0.75 mg/m 2 is recommended for patients with moderate renal impairment (20 to 39 mL/min.). Insufficient data are available in patients with severe renal impairment to provide a dosage recommendation for Topotecan Injection. [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 ) ] Topotecan Injection in combination with cisplatin for the treatment of cervical cancer should only be initiated in patients with serum creatinine ≤1.5 mg/dL. In the clinical trial, cisplatin was discontinued for a serum creatinine >1.5 mg/dL. Insufficient data are available regarding continuing monotherapy with Topotecan Injection after cisplatin discontinuation in…

5 WARNINGS AND PRECAUTIONS Bone marrow suppression: Administer Topotecan Injection only to patients with adequate bone marrow reserves. Monitor peripheral blood counts and adjust the dose if needed. ( 5.1 ) Topotecan-induced neutropenia can lead to neutropenic colitis. ( 5.2 ) Interstitial lung disease: topotecan has been associated with reports of interstitial lung disease. Monitor patients for symptoms and discontinue Topotecan Injection if the diagnosis is confirmed. ( 5.3 ) Pregnancy: Can cause fetal harm. Advise women of potential risk to the fetus. ( 5.4 , 8.1 ) 5.1 Bone Marrow Suppression Bone marrow suppression (primarily neutropenia) is the dose-limiting toxicity of Topotecan Injection. Neutropenia is not cumulative over time. In the comparative study, in small cell lung cancer, the treatment-related death rates were 5% for topotecan and 4% for CAV (cyclophosphamide-doxorubicin-vincristine). Neutropenia From a combined experience of patients receiving topotecan which included patients treated for small cell lung cancer: Grade 4 neutropenia (<500 cells/mm 3 ) was most common during course 1 of treatment (60% of patients) and occurred in 39% of all courses, with a median duration of 7 days. The nadir neutrophil count occurred at a median of 12 days. Therapy-related sepsis or febrile neutropenia occurred in 23% of patients, and sepsis was fatal in 1%. Pancytopenia has been reported. Cervical cancer experience: Grade 3 and grade 4 neutropenia affected 26 % and 48 % of patients, respectively. Thrombocytopenia From a combined experience of patients receiving topotecan which included patients treated for small cell lung cancer: Grade 4 thrombocytopenia (<25,000/mm 3 ) occurred in 27% of patients and in 9% of courses, with a median duration of 5 days and platelet nadir at a median of 15 days. Platelet transfusions were given to 15% of patients in 4% of courses. Cervical cancer experience: Grade 3 and grade 4 thrombocytopenia affected 26 % and 7 % of patients, respectively. Anemia From a combined experience of patients receiving topotecan which included patients treated for small cell lung cancer: Grade 3/4 anemia (<8 g/dL) occurred in 37% of patients and in 14% of courses. Median nadir was at day 15. Transfusions were needed in 52% of patients in 22% of courses. Cervical cancer experience: Grade 3 and grade 4 anemia affected 34 % and 6 % of patients, respectively. Monitoring of Bone Marrow Function Administer Topotecan Injection only in patients with adequate bone marrow reserves, including baseline neutrophil count of at least 1,500 cells/mm 3 and platelet count at least 100,000/mm 3 . Monitor peripheral blood counts frequently during treatment with Topotecan Injection. Do not treat patients with subsequent courses of Topotecan Injection until neutrophils recover to >1,000 cells/mm 3 , platelets recover to >100,000 cells/mm 3 , and hemoglobin levels recover to 9 g/dL (with transfusion if necessary).Severe myelotoxicity has been reported when Topotecan Injection is used in combination with cisplatin [see Drug Interactions ( 7 ) ] 5.2 Neutropenic Colitis Topotecan-induced neutropenia can lead to neutropenic colitis. Fatalities due to neutropenic colitis have been reported in clinical trials with Topotecan Injection. In patients presenting with fever, neutropenia, and a compatible pattern of abdominal pain, consider the possibility of neutropenic colitis. 5.3 Interstitial Lung Disease Topotecan Injection has been associated with reports of interstitial lung disease (ILD), some of which have been fatal [see Adverse Reactions ( 6.2 ) ]. Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer, thoracic exposure to radiation, and use of pneumotoxic drugs and/or colony stimulating factors. Monitor patients for pulmonary symptoms indicative of interstitial lung disease (e.g., cough, fever, dyspnea, and/or hypoxia), and discontinue Topotecan Injection if a new diagnosis of ILD is confirmed. 5.4 Pregnancy Pregna…

4 CONTRAINDICATIONS Topotecan Injection is contraindicated in patients who have a history of severe hypersensitivity reactions (e.g., anaphylactoid reactions) to topotecan or to any of its ingredients. Topotecan Injection should not be used in patients with severe bone marrow depression. History of severe hypersensitivity reactions (e.g., anaphylactoid reactions) to topotecan or any of its ingredients ( 4 ) Severe bone marrow depression ( 4 )

7 DRUG INTERACTIONS G-CSF: Concomitant administration of G-CSF can prolong the duration of neutropenia, so if G-CSF is to be used, do not initiate it until day 6 of the course of therapy, 24 hours after completion of treatment with Topotecan Injection. Platinum and Other Cytotoxic Agents: Myelosuppression was more severe when topotecan, at a dose of 1.25 mg/m 2 /day for 5 days, was given in combination with cisplatin at a dose of 50 mg/m 2 in Phase 1 studies. In one study, 1 of 3 patients had severe neutropenia for 12 days and a second patient died with neutropenic sepsis. Greater myelosuppression is also likely to be seen when Topotecan Injection is used in combination with other cytotoxic agents, thereby necessitating a dose reduction. However, when combining topotecan with platinum agents (e.g., cisplatin or carboplatin), a distinct sequence-dependent interaction on myelosuppression has been reported. Coadministration of a platinum agent on day 1 of dosing with topotecan required lower doses of each agent compared to co-administration on day 5 of the dosing schedule for topotecan. For information on the pharmacokinetics, efficacy, safety, and dosing of Topotecan Injection at a dose of 0.75 mg/m 2 /day on days 1, 2, and 3 in combination with cisplatin 50 mg/m 2 on day 1 for cervical cancer [see Dosage and Administration ( 2 ) , Adverse Reactions ( 6 ), Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14 ) ] . Do not initiate G-CSF until 24 hours after completion of treatment with Topotecan Injection. Concomitant administration can prolong duration of neutropenia. ( 7 ) Greater myelosuppression is likely to be seen when used in combination with other cytotoxic agents. ( 7 )

8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions ( 5.4 ) ]. Topotecan Injection can cause fetal harm when administered to a pregnant woman. In rabbits, a dose of 0.1 mg/kg/day (about equal to the clinical dose of 1.5 mg/m 2 ) given on days 6 through 20 of gestation caused maternal toxicity, embryolethality, and reduced fetal body weight. In the rat, a dose of 0.23 mg/kg/day (about equal to the clinical dose of 1.5 mg/m 2 ) given for 14 days before mating through gestation day 6 caused fetal resorption, microphthalmia, pre-implant loss, and mild maternal toxicity. A dose of 0.1 mg/kg/day (about half the clinical dose of 1.5 mg/m 2 ) 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. There are no adequate and well controlled studies of Topotecan Injection in pregnant women. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving Topotecan Injection, the patient should be apprised of the potential hazard to the fetus. [see Warnings and Precautions ( 5.4 ) ]

8.3 Nursing Mothers Rats excrete high concentrations of topotecan into milk. Lactating female rats given 4.72 mg/m 2 IV (about three times the clinical dose of 1.5 mg/m 2 ) excreted topotecan into milk at concentrations up to 48-fold higher than those in plasma. It is not known whether the drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Topotecan Injection, discontinue breastfeeding when women are receiving Topotecan Injection.

6 ADVERSE REACTIONS Small cell lung cancer: The most common hematologic adverse reactions were: neutropenia (97%), leukopenia (97%), anemia (89%), and thrombocytopenia (69%). ( 6.1 ) The most common (>25%) non-hematologic adverse reactions (all grades) were: nausea, alopecia, vomiting, sepsis or pyrexia/infection with neutropenia, diarrhea, constipation, fatigue, and pyrexia. ( 6.1 ) Cervical cancer (Topotecan Injection plus cisplatin): The most common hematologic adverse reactions (all grades) were: anemia (94%), leukopenia (91%), neutropenia (89%), and thrombocytopenia (74%). ( 6.1 ) The most common (>25%) non-hematologic adverse reactions (all grades) were: pain, nausea, 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Small Cell Lung Cancer Data in the following section are based on the combined experiences of the 879 patients studied, including 426 patients with small cell lung cancer treated with topotecan. Table 1 lists the principle hematologic adverse reactions and Table 2 lists non-hematologic adverse reactions occurring in at least 15% of patients. Table 1. Hematologic Adverse Reactions Experienced in ≥15% of Patients, Including 426 Patients With Small Cell Lung Cancer, Receiving Topotecan Hematologic Adverse Reaction Patients (n=879) % Incidence Neutropenia <1,500 cells/mm 3 <500 cells/mm 3 97 78 Leukopenia <3,000 cells/mm 3 <1,000 cells/mm 3 97 32 Thrombocytopenia <75,000/mm 3 <25,000/mm 3 69 27 Anemia <10 g/dL <8 g/dL 89 37 Table 2. Non-hematologic Adverse Reactions Experienced by ≥15% of 879 Patients, Including 426 Patients With Small Cell Lung Cancer, Receiving Topotecan Non-hematologic Adverse Reaction Percentage of Patients with Adverse Reaction (879 Patients) All Grades Grade 3 Grade 4 Infections and infestations Sepsis or pyrexia/infection with neutropenia a 43 NR 23 Metabolism and nutrition disorders Anorexia 19 2 <1 Nervous system disorders Headache 18 1 <1 Respiratory, thoracic, and mediastinal disorders Dyspnea 22 5 3 Coughing 15 1 0 Gastrointestinal disorders Nausea 64 7 1 Vomiting 45 4 1 Diarrhea 32 3 1 Constipation 29 2 1 Abdominal pain 22 2 2 Stomatitis 18 1 <1 Skin and subcutaneous tissue disorders Alopecia 49 NA NA Rash b 16 1 0 General disorders and administrative site conditions Fatigue 29 5 0 Pyrexia 28 1 <1 Pain c 23 2 1 Asthenia 25 4 2 NA = Not applicable NR = Not reported separately a Does not include Grade 1 sepsis or pyrexia b Rash also includes pruritus, rash erythematous, urticaria, dermatitis, bullous eruption, and maculopapular rash. c Pain includes body pain, back pain, and skeletal pain. Nervous System Disorders Paresthesia occurred in 7% of patients but was generally grade 1. Hepatobiliary Disorders Grade 1 transient elevations in hepatic enzymes occurred in 8% of patients. Greater elevations, grade 3/4, occurred in 4%. Grade 3/4 elevated bilirubin occurred in <2% of patients. Table 3 shows the grade 3/4 hematologic and major non-hematologic adverse reactions in the topotecan/CAV comparator trial in small cell lung cancer. Table 3. Adverse Reactions Experienced by ≥5% of Small Cell Lung Cancer Patients Randomized to Receive Topotecan or CAV Adverse Reaction Topotecan (n=107) CAV (n=104) Hematologic Grade 3/4 % % Grade 4 neutropenia (<500 cells/mm 3 ) 70 72 Grade 3/4 anemia (Hgb <8 g dL) 42 20 Grade 4 thrombocytopenia (<25,000 plts/mm 3 ) 29 5 Pyrexia/Grade 4 neutropenia 28 26 Non-hematologic Grade 3/4 % % Infections and infestations Documented sepsis a 5 5 Respiratory, thoracic, and mediastinal disorders Dyspnea 9 14 Pneumonia 8 6 Gastrointestinal disorde…