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adverse reactions
6 ADVERSE REACTIONS The following clinically significant 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 )] Ovarian Cancer The most common Grade 3 or 4 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 3 or 4 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 3 or 4 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 Teva Pharmaceuticals USA, Inc. at 1-866-832-8537 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 eight trials in which 879 patients with ovarian cancer or small cell lung cancer (SCLC) received topotecan 1.5 mg/m2 by intravenous infusion daily for 5 consecutive days, starting on Day 1 of a 21 day cycle and from one trial (Study GOG 0179) in which 147 patients with cervical cancer received topotecan 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 a 21 day cycle. Ovarian Cancer The safety of topotecan was evaluated in a randomized trial conducted in 226 patients with metastatic ovarian cancer (Study 039) [see Clinical Studies ( 14.1 )] . Table 1 shows the incidence of Grade 3 and 4 hematologic and non-hematologic adverse reactions that occurred in patients receiving topotecan. Table 1. Adverse Reactions Occurring in ≥ 5% of Patients with Ovarian Cancer in Study 039 Adverse Reaction Topotecan (n = 112) Paclitaxel (n = 114) Grade 3 to 4 (%) Grade 3 to 4 (%) Hematologic Grade 4 neutropenia (< 500/mm3) 80 21 Grade 3 or 4 anemia (Hgb < 8 g/dL) Grade 4 thrombocytopenia (< 25,000/mm3) 41 27 6 3 Febrile neutropenia 23 4 Non-Hematologic Infections Sepsis a 5 2 Respiratory, thoracic, and mediastinal Dyspnea 6 5 Gastrointestinal 10 3 Vomiting Nausea 10 2 Diarrhea 6 1 Abdominal pain 5 4 Intestinal obstruction 5 4 Constipation 5 0 General and administrative site conditions 7 6 Fatigue Pain b 5 7 Asthenia 5 3 a Death related to sepsis occurred in 2% of patients receiving topotecan and 0% of patients receiving paclitaxel. b Pain includes body pain, skeletal pain, and back pain. 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 ( 14.2 )]. Table 2 shows the Grade 3 or 4 hematologic and non-hematologic adverse reactions in patients with SCLC. Table 2. Adverse Reactions Occurring in ≥ 5% of Patients with Small Cell Lung Cancer in Study 090 Adverse Reactions Topotecan (n = 107) CAV c (n = 104) Grades 3 to 4 (%) Grades 3 to 4 (%) Hematologic Grade 4 neutropenia (< 500/mm3) 70 72 Grade 3 or 4 anemia (Hgb < 8 g/dL) Grade 4 thrombocytopenia (< 25,000/mm3) 42 29 20 5 Febrile neutropenia 28 26 Non-Hematologic Infections Sepsis a 5 5 Respiratory, thoracic, and mediastinal 9 14 Dyspnea Pneumonia 8 6 Gastrointestinal 8 6 Nausea Abdominal pain 6 4 General and administrative site conditions 9 7 Asthenia Fatigue 6 10 Pain b 5 7 a Death related to sepsis occurred in 3% of patients receiving topotecan and 1% of patients receiving CAV. b Pain includes body pain, skeletal pain, and back pain. c CAV = cyclophosphamide, doxorubicin and vincristine. Hepatobiliary Disorders in Ovarian and Small Cell Lung Cancer Based on the combined experience of 453 patients with metastatic ovarian cancer and 426 patients with SCLC treated with topotecan, Grade 3 or 4 increases aspartate transaminase (AST) or alanine transaminase (ALT) occurred in 4% and Grade 3 or 4 elevated bilirubin occurred in less than 2%. Cervical Cancer The safety of topotecan was evaluated in a comparative trial of topotecan with cisplatin versus cisplatin as a single agent in patients with cervical cancer (Study GOG 0179). Table 3 shows the hematologic and non-hematologic adverse reactions in patients with cervical cancer. Table 3. Adverse Reactions Occurring in ≥ 5% of Patients with Cervical Cancer (Between-Arm Difference ≥ 2%) a in Study GOG 0179 Adverse Reaction Topotecan with Cisplatin (n = 140) % Cisplatin (n = 144) % Hematologic Neutropenia 26 1 Grade 3 (< 1,000 to 500/mm3) Grade 4 (< 500/mm3) 48 1 Anemia 34 19 Grade 3 (Hgb < 8 to 6.5 g/dL) Grade 4 (Hgb < 6.5 g/dL) 6 3 Thrombocytopenia 26 3 Grade 3 (< 50,000 to 10,000/mm3) Grade 4 (< 10,000/mm3) 7 0 Non-Hematologic b ,c General and administrative site conditions 69 62 Constitutional d Pain e 59 50 Gastrointestinal 40 37 Vomiting Stomatitis-pharyngitis 6 0 Other 63 56 Dermatology f 48 20 Infection Febrile neutropenia f 28 18 Cardiovascular f 25 15 a Includes patients who were eligible and treated. b Severity based on using National Cancer Institute (NCI) Common Toxicity Criteria (CTC), Version 2.0. c Grades 1 through 4 only. There were 3 patients who experienced deaths with investigator-designated attribution. The first patient experienced a Grade 5 hemorrhage in which the drug-related thrombocytopenia aggravated the event. A second patient experienced bowel obstruction, cardiac arrest, pleural effusion, and respiratory failure which were not treatment-related but probably aggravated by treatment. A third patient experienced a pulmonary embolism and adult respiratory distress syndrome; the latter was indirectly treatment-related. d Constitutional includes fatigue (lethargy, malaise, asthenia), fever (in the absence of neutropenia), rigors, chills, sweating, and weight gain or loss. e Pain 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. f High-level terms were included if the between-arm difference was ≥ 10%. 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