Topotecan

1 INDICATIONS AND USAGE Topotecan Injection 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. Topotecan Injection is a topoisomerase inhibitor indicated for treatment of small cell lung cancer (SCLC) platinum-sensitive disease in patients who progressed at least 60 days after initiation of first-line chemotherapy. ( 1 )

2 DOSAGE AND ADMINISTRATION Recommended dosage : 1.5 mg/m 2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on Day 1 of a 21-day cycle. ( 2.2 ) Renal impairment : Reduce dose for creatinine clearance (CLcr) of 20 to 39 mL/min. ( 2.4 ) 2.1 Important Safety Information Verify dosage using body surface area. Do not exceed a single dose of 4 mg intravenously. 2.2 Recommended Dosage for Small Cell Lung Cancer The recommended dosage of Topotecan Injection 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 cycle. 2.3 Dosage Modifications for Adverse Reactions Hematologic Do not administer subsequent cycles of Topotecan 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). Reduce the dose of Topotecan Injection 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 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.

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Myelosuppression [see Warnings and Precautions (5.1) ] Interstitial Lung Disease [see Warnings and Precautions (5.2) ] Extravasation and Tissue Injury [see Warnings and Precautions (5.3) ] The most common Grade 3 or 4 hematologic adverse reactions (incidence >5%) were: neutropenia , anemia , thrombocytopenia, and febrile neutropenia. ( 6.1 ) The most common non-hematologic adverse reactions (incidence >5%) (all grades) were asthenia, dyspnea, nausea, pneumonia, abdominal pain, and fatigue. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 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

12.3 Pharmacokinetics Following administration of topotecan at doses of 0.5 to 1.5 mg/m 2 (0.3 to 1 times the recommended dose) administered as a 30-minute infusion, area under the curve (AUC) increases approximately proportional with dose. Distribution Protein binding of topotecan is approximately 35%. Elimination The terminal half-life of topotecan is 2 to 3 hours following intravenous administration. Metabolism Topotecan undergoes a reversible pH-dependent hydrolysis of its pharmacologically active lactone moiety. At pH ≤ 4, the lactone is exclusively present, whereas the ring-opened hydroxy-acid form predominates at physiologic pH. Topotecan is metabolized to an N-demethylated metabolite in vitro. The mean metabolite: parent AUC ratio was about 3% for total topotecan and topotecan lactone following intravenous administration. 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.