HIGHLIGHTS OF PRESCRIBING INFORMATION Single-use vial containing 4 mg of topotecan free base as a 4 mg/4 mL (1 These highlights do not include all the information needed to use mg/mL) solution. (3) TOPOTECAN INJECTION safely and effectively. See full prescribing information for TOPOTECAN INJECTION. -------------------------------CONTRAINDICATIONS------------------------------ History of severe hypersensitivity reactions (e.g., anaphylactoid reactions) to TOPOTECAN INJECTION, for intravenous use topotecan. (4) Initial U.S. Approval: 1996 -----------------------WARNINGS AND PRECAUTIONS------------------------ Bone marrow suppression: Administer topotecan only to patients with WARNING: BONE MARROW SUPPRESSION adequate bone marrow reserves. Monitor peripheral blood counts and See full prescribing information for complete boxed warning. adjust the dose if needed. (5.1) Do not initiate topotecan treatment in patients with bone marrow Neutropenia colitis, in some cases fatal, can occur. (5.2) 3 suppression (e.g., neutrophil counts less than 1,500 cells/mm ). Monitor Interstitial lung disease: Topotecan can cause interstitial lung disease. peripheral blood counts frequently during treatment. Reduce or withhold Monitor patients for symptoms and discontinue topotecan if the topotecan dosing as recommended [see Dosage and Administration (2.1, diagnosis is confirmed. (5.3) 2.2), Warnings and Precautions (5.1)]. Embryofetal Toxicity: Topotecan can cause fetal harm. Advise women of potential risk to a fetus. (5.4, 8.1) ----------------------------RECENT MAJOR CHANGES-------------------------- ------------------------------ADVERSE REACTIONS------------------------------- Dosage and Administration (2) 2/2014 In patients with small cell lung cancer or other malignancies, the most ----------------------------INDICATIONS AND USAGE--------------------------- common (≥ 25%) adverse reactions are neutropenia (97%), anemia (89%), thrombocytopenia (69%), nausea (64%), alopecia (49%), vomiting (45%), Topotecan Injection is a topoisomerase inhibitor indicated: sepsis or pyrexia/infection with neutropenia (43%), diarrhea (32%), constipation (29%), fatigue (29%), and pyrexia (28%). (6.1) for the treatment of small cell lung cancers in patients with In patients with cervical cancer, the most common adverse reactions (≥ 25%) chemotherapy-sensitive disease after failure of first-line chemotherapy. are: anemia (94%), neutropenia (89%), thrombocytopenia (74%), pain (59%), (1.1) nausea (55%), dermatologic (48%), vomiting (40%), neurologic/non­ in combination therapy with cisplatin, for the treatment of stage IVB, neuropathy (35%), and infection/febrile neutropenia (28%). (6.1) recurrent, or persistent carcinoma of the cervix which is not amenable to To report SUSPECTED ADVERSE REACTIONS, contact TEVA USA, curative treatment with surgery or radiation therapy. (1.2) PHARMACOVIGILANCE at 1-866-832-8537 or [email protected]; or FDA at 1-800-FDA-1088 or ----------------------DOSAGE AND ADMINISTRATION----------------------- www.fda.gov/medwatch. Small cell lung cancer: Topotecan Injection 1.5 mg/m2 by intravenous infusion over 30 minutes daily on days 1 to 5 of each 21-day cycle. (2.1) -----------------------USE IN SPECIFIC POPULATIONS------------------------ 2 Cervical cancer: Topotecan Injection 0.75 mg/m by intravenous infusion over Nursing Mothers: Discontinue nursing when receiving topotecan. (8.3) 30 minutes daily on days 1, 2, and 3 of each 21-day cycle. (2.2) See Dosage Modification Guidelines for patients with neutropenia, thrombocytopenia, or renal impairment. (2.1, 2.2) See 17 for PATIENT COUNSELING INFORMATION ---------------------DOSAGE FORMS AND STRENGTHS---------------------- Revised: 2/2014 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: BONE MARROW SUPPRESSION 8 USE IN SPECIFIC POPULATIONS 1 INDICATIONS AND USAGE 8.1 Pregnancy 1.1 Small Cell Lung Cancer 8.3 Nursing Mothers 1.2 Cervical Cancer 8.4 Pediatric Use 2 DOSAGE AND ADMINISTRATION 8.5 Geriatric Use 2.1 Small Cell Lung Cancer 8.6 Renal Impairment 2.2 Cervical Cancer 10 OVERDOSAGE 2.3 Instructions for Handling, and Preparation for Intravenous 11 DESCRIPTION Administration 12 CLINICAL PHARMACOLOGY 3 DOSAGE FORMS AND STRENGTHS 12.1 Mechanism of Action 4 CONTRAINDICATIONS 12.2 Pharmacodynamics 5 WARNINGS AND PRECAUTIONS 12.3 Pharmacokinetics 5.1 Bone Marrow Suppression 13 NONCLINICAL TOXICOLOGY 5.2 Neutropenic Colitis 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.3 Interstitial Lung Disease 14 CLINICAL STUDIES 5.4 Embryofetal Toxicity 14.1 Small Cell Lung Cancer 5.5 Extravasation 14.2 Cervical Cancer 6 ADVERSE REACTIONS 15 REFERENCES 6.1 Clinical Trials Experience 16 HOW SUPPLIED/STORAGE AND HANDLING 6.2 Postmarketing Experience 17 PATIENT COUNSELING INFORMATION 7 DRUG INTERACTIONS *Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION Reference ID: 3463172 WARNING: BONE MARROW SUPPRESSION Do not initiate Topotecan Injection treatment in patients with bone marrow suppression (e.g., neutrophil counts less than 1,500 cells/mm3). Monitor peripheral blood counts frequently during treatment. Reduce or withhold Topotecan Injection dosing as recommended [see Dosage and Administration (2.1, 2.2) and Warnings and Precautions (5.1)]. 1 INDICATIONS AND USAGE 1.1 Small Cell Lung Cancer Topotecan Injection is indicated for the treatment of chemotherapy-sensitive small cell lung cancer (SCLC) after failure of first-line chemotherapy. Chemotherapy-sensitive SCLC is defined as responding to first-line chemotherapy but subsequently progressing at least 60 days after chemotherapy. 1.2 Cervical Cancer Topotecan Injection, in combination with cisplatin, is indicated for the treatment of stage IVB, recurrent or persistent carcinoma of the cervix which is not amenable to curative treatment with surgery and/or radiation therapy. 2 DOSAGE AND ADMINISTRATION Verify dose using body surface area prior to dispensing. Recommended dosage should generally not exceed 4 mg intravenously [see Overdosage (10)]. 2.1 Small Cell Lung Cancer Recommended Dosage: The recommended dose of Topotecan Injection is 1.5 mg/m2 by intravenous infusion over 30 minutes daily on days 1 to 5 of each 21-day cycle until disease progression. Dosage Modification Guidelines: Recommended dose modifications in patients with bone marrow suppression or renal impairment are provided in the table below [see Warnings and Precautions (5.1), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. Table 1. Recommended Dose Modifications in Patients with Small Cell Lung Cancer Adverse Reaction or Laboratory Values Recommended Dose Modification On Day 1 of first cycle Delay initiation of Topotecan Injection until hematologic or renal recovery --neutrophil count of ≤ 1,500 cells/mm3 or --platelet count ≤ 100,000 cells/mm3 or --serum creatinine > 1.5 mg/dL On Day 1 of subsequent cycles (cycle 2 and Delay next cycle of Topotecan Injection until beyond) hematologic or renal recovery --neutrophil count of ≤ 1,000 cells/mm3 or --platelet count ≤ 100,000 cells/mm3 or --hemoglobin < 9.0 gm/dL or --serum creatinine > 1.5 mg/dL For neutropenia < 500 cells/mm3 in Permanently reduce Topotecan Injection dose to preceding cycle 1.25 mg/m2 or administer prophylactic granulocyte colony-stimulating factor during subsequent cycles. For platelets < 25,000 cells/mm3 in Permanently reduce Topotecan Injection dose to preceding cycle 1.25 mg/m2 For creatinine clearance 20-39 mL/min Reduce the Topotecan Injection dose to 0.75 mg/m2 Reference ID: 3463172 2.2 Cervical Cancer Recommended Dosage: The recommended dose of Topotecan Injection is 0.75 mg/m2 by intravenous infusion over 30 minutes daily on days 1, 2, and 3 of each 21-day cycle. Administer cisplatin 50 mg/m2 by intravenous infusion on day 1 of each 21-day cycles. Dosage Modification Guidelines: Recommended dose modifications in patients with bone marrow suppression or renal impairment are provided in the table below [see Warnings and Precautions (5.1), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. See manufacturer’s prescribing information for cisplatin administration and hydration guidelines and for cisplatin dosage adjustment in the event of hematologic toxicity. Table 2. Recommended Dose Modifications in Patients with Cervical Cancer Adverse Reaction or Laboratory Values Recommended Dose Modification On Day 1 of first cycle Delay initiation of Topotecan Injection until hematologic or renal recovery --neutrophil count of ≤ 1,500 cells/mm3 or --platelet count ≤ 100,000 cells/mm3 or --serum creatinine > 1.5 mg/dL On Day 1 of subsequent cycles (cycle 2 and Delay next cycle of Topotecan Injection until beyond) hematologic or renal recovery --neutrophil count of ≤ 1,000 cells/mm3 or --platelet count ≤ 100,000 cells/mm3 or --hemoglobin < 9.0 gm/dL or --serum creatinine > 1.5 mg/dL For the first occurrence of febrile neutropenia [ Permanently reduce the daily Topotecan < 1,000 neutrophils/mm3 with fever ≥ 38.0°C (≥ Injection dose to 0.60 mg/m2 or administer 100.4°F) in preceding cycle prophylactic granulocyte colony-stimulating factor (G-CSF) during subsequent cycles. For re-occurrence of febrile neutropenia [< Permanently reduce the daily Topotecan 1,000 neutrophils/mm3 with fever ≥ 38.0°C (≥ Injection dose to 0.45 mg/m2 100.4°F) in preceding cycle despite use of G­ CSF For platelet nadir < 25,000 cells/mm3 in Permanently reduce the daily Topotecan preceding cycle Injection dose to 0.60 mg/m2 For serum creatinine