WARNING: MYELOSUPPRESSION Topotecan can cause severe myelosuppression. Administer first cycle only to patients with baseline neutrophil counts of greater than or equal to 1,500/mm 3 and platelet counts greater than or equal to 100,000/mm 3 . Monitor blood cell counts [see Warnings and Precautions (5.1) ] . WARNING: MYELOSUPPRESSION See full prescribing information for complete boxed warning. Topotecan can cause severe myelosuppression. Administer first cycle only to patients with baseline neutrophil counts greater than or equal to 1,500/mm 3 and platelet count greater than or equal to 100,000/mm 3 . Monitor blood cell counts. ( 2.2 , 5.1 )
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warnings and cautions
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 women of potential risk to the fetus. ( 5.4 , 8.1 , 8.3 ) 5.1 Myelosuppression Topotecan can cause severe myelosuppression. Grade 4 neutropenia occurred in 78% of 879 patients, with a median duration of 7 days and was most common during Cycle 1 (58% of patients). Grade 4 neutropenia associated with infection occurred in 13% and febrile neutropenia occurred in 5%. Sepsis occurred in 4% and was fatal in 1%. Grade 4 thrombocytopenia occurred in 27%, with a median duration of 5 days. Grade 3 or 4 anemia occurred in 37% 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 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 Injection based on neutrophil counts, platelet counts and hemoglobin levels [see Dosage and Administration (2.3) ] . 5.2 Interstitial Lung Disease Interstitial lung disease (ILD), including fatalities, has occurred with topotecan [see Adverse Reactions (6.2) ] . Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer, thoracic radiation, and use of pneumotoxic drugs and/or colony stimulating factors. Monitor patients for pulmonary symptoms indicative of ILD (e.g., cough, fever, dyspnea, and/or hypoxia), and discontinue Topotecan Injection if a new diagnosis of ILD is confirmed. 5.3 Extravasation and Tissue Injury Extravasation with topotecan has been observed; severe cases have been reported. If signs or symptoms of extravasation occur, immediately stop administration of Topotecan Injection and institute recommended management procedures [see Adverse Reactions (6.2) ] . 5.4 Embryo-Fetal Toxicity Based on animal data, topotecan 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 Injection. Advise males with a female partner of reproductive potential to use effective contraception during treatment with Topotecan Injection and for 3 months after the last dose [see Use in Specific Populations (8.1 , 8.3) , Nonclinical Toxicology (13.1) ] .
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
adverse reactions table
<table width="100%"><caption>Table 1. Adverse Reactions Occurring in ≥5% of Patients with Small Cell Lung Cancer in Study 090</caption><col width="40%" align="left" valign="middle"/><col width="30%" align="center" valign="middle"/><col width="30%" align="center" valign="middle"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" rowspan="2" valign="bottom">Adverse Reactions</th><th styleCode="Rrule">Topotecan (n = 107)</th><th styleCode="Rrule">CAV<footnote>CAV = cyclophosphamide, doxorubicin and vincristine.</footnote> (n = 104)</th></tr><tr><th styleCode="Rrule" align="center">Grade 3–4 (%)</th><th styleCode="Rrule">Grade 3–4 (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Hematologic</content></td></tr><tr><td styleCode="Lrule Rrule">Grade 4 neutropenia (< 500/mm<sup>3</sup>)</td><td styleCode="Rrule">70</td><td styleCode="Rrule">72</td></tr><tr><td styleCode="Lrule Rrule">Grade 3 or 4 anemia (Hgb < 8 g/dL)</td><td styleCode="Rrule">42</td><td styleCode="Rrule">20</td></tr><tr><td styleCode="Lrule Rrule">Grade 4 thrombocytopenia (< 25,000/mm<sup>3</sup>)</td><td styleCode="Rrule">29</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Febrile neutropenia</td><td styleCode="Rrule">28</td><td styleCode="Rrule">26</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Non-Hematologic</content></td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Respiratory, thoracic, and mediastinal</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule"> Dyspnea</td><td styleCode="Rrule">9</td><td styleCode="Rrule">14</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pneumonia</td><td styleCode="Rrule">8</td><td styleCode="Rrule">6</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">General and administrative site conditions</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule"> Asthenia</td><td styleCode="Rrule">9</td><td styleCode="Rrule">7</td></tr><tr><td styleCode="Lrule Rrule"> Fatigue</td><td styleCode="Rrule">6</td><td styleCode="Rrule">10</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pain<footnote>Pain includes body pain, skeletal pain, and back pain.</footnote></td><td styleCode="Rrule">5</td><td styleCode="Rrule">7</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Gastrointestinal</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">8</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Abdominal pain</td><td styleCode="Rrule">6</td><td styleCode="Rrule">4</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Infections</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule"> Sepsis<footnote>Death related to sepsis occurred in 3% of patients receiving topotecan and 1% of patients receiving CAV.</footnote></td><td styleCode="Rrule">5</td><td styleCode="Rrule">5</td></tr></tbody></table>