FDA label 9a438a29-0a0f-44e6-978c-32d098c41047

WARNING: BONE MARROW SUPPRESSION Topotecan can cause severe myelosuppression. Administer only to patients with baseline neutrophil counts of greater than or equal to 1,500 cells/mm 3 and platelet counts greater than or equal to 100,000 cells/mm 3 . Monitor blood cell counts [ see Warnings and Precautions ( 5.1 ) ] . WARNING: BONE MARROW SUPPRESSION See full prescribing information for complete boxed warning. Topotecan can cause severe myelosuppression. Administer only to patients with baseline neutrophil counts greater than or equal to 1,500 cells/mm 3 and platelet count greater than or equal to 100,000/mm 3 . Monitor blood cell counts. ( 5.1 )

5 WARNINGS AND PRECAUTIONS Bone marrow suppression: Administer topotecan only to patients with adequate bone marrow reserves. Monitor peripheral blood counts and adjust the dose as needed. ( 2.4 , 5.1 ) Neutropenic enterocolitis: Fatal typhlitis can occur. ( 5.2 ) Interstitial lung disease (ILD): Fatal cases have occurred. Permanently discontinue for confirmed ILD. ( 5.3 ) Embryofetal toxicity: Can cause fetal harm. Advise women of potential risk to the fetus. ( 5.4 , 8.1 , 8.3 ) Extravasation and tissue injury: Severe cases have been reported. If extravasation occurs, immediately stop administration and institute recommended management procedures. ( 5.5 ) 5.1 Bone Marrow Suppression Bone marrow suppression (primarily neutropenia) is the dose-limiting toxicity of topotecan. Neutropenia is not cumulative over time. Severe myelotoxicity has been reported when topotecan is used in combination with cisplatin [see Drug Interactions ( 7 )]. The following data on myelosuppression are based on an integrated safety database from 8 trials (N = 879) using topotecan injection at 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 patients with ovarian cancer and small cell lung cancer and from one trial in patients with cervical cancer (N = 147) using topotecan 0.75 mg/m 2 by intravenous infusion over 30 minutes daily on Days 1, 2, and 3 repeated every 21 days in combination with cisplatin 50 mg/m 2 on Day 1. Neutropenia Monotherapy: Grade 4 neutropenia (less than 500 cells/mm 3 ) occurred in 78% of patients, with a median duration of 7 days and was most common during Course 1 of treatment (58% of patients). Grade 4 neutropenia associated with infection occurred in 13% of patients and febrile neutropenia occurred in 5% of patients. Sepsis occurred in 4% of patients and was fatal in 1% of patients. Pancytopenia has been reported. Combination with cisplatin: Grade 4 neutropenia occurred in 48% of patients. Thrombocytopenia Monotherapy: Grade 4 thrombocytopenia (less than 25,000/mm 3 ) occurred in 27% of patients, with a median duration of 5 days. Combination with cisplatin: Grade 4 thrombocytopenia occurred in 7% of patients. Anemia Monotherapy: Grade 3 or 4 anemia (less than 8 g/dL) occurred in 37% of patients. Combination with cisplatin: Grade 3 or Grade 4 anemia occurred in 40% of patients. Administer topotecan only to patients with a baseline neutrophil count of greater than or equal to 1,500 cells/mm 3 and a platelet count greater than or equal to 100,000/mm 3 . Monitor peripheral blood counts frequently during treatment with topotecan. Refer to Section 2.4 for dose modification guidelines for hematological toxicities in subsequent courses. Do not treat patients with subsequent courses of topotecan until neutrophils recover to greater than 1,000 cells/mm 3 , platelets recover to greater than 100,000 cells/mm 3 , and hemoglobin levels recover to 9 g/dL (with transfusion if necessary). 5.2 Neutropenic Enterocolitis Topotecan can cause fatal typhlitis (neutropenic enterocolitis). Consider the possibility of typhlitis in patients presenting with fever, neutropenia, and abdominal pain. 5.3 Interstitial Lung Disease Interstitial lung disease (ILD), including fatalities, has occurred with topotecan. 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 if a new diagnosis of ILD is confirmed. 5.4 Embryofetal 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 females of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose of topotecan. Advise women of the potential risk to a fetus [see Use in Specific Populations ( 8.1 , 8.3 )]. 5.5 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 and institute recommended management procedures [see Adverse Reactions ( 6 )].

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Bone Marrow Suppression [see Warnings and Precautions ( 5.1 )] Neutropenic Enterocolitis [see Warnings and Precautions ( 5.2 )] Interstitial Lung Disease [see Warnings and Precautions ( 5.3 )] Extravasation and Tissue Injury [see Warnings and Precautions ( 5.5 )] Ovarian cancer: The most common hematologic adverse reactions were: neutropenia (Grade 4: 80%), anemia (Grade 3/4: 41%), thrombocytopenia (Grade 4: 27%), and febrile neutropenia (23%). ( 6.1 ) The most common (>5%) non-hematologic adverse reactions (all grades) were: nausea, vomiting, fatigue, diarrhea, and dyspnea. ( 6.1 ) Small cell lung cancer: The most common hematologic adverse reactions were: neutropenia (Grade 4: 70%), anemia (Grade 3/4: 42%), thrombocytopenia (Grade 4: 29%), and febrile neutropenia (28%). ( 6.1 ) The most common (>5%) non-hematologic adverse reactions (all grades) were: asthenia, dyspnea, nausea, pneumonia, abdominal pain, and fatigue. ( 6.1 ) Cervical cancer (topotecan plus cisplatin): The most common hematologic adverse reactions were: neutropenia (Grade 3/4: 74%), anemia (Grade 3/4: 40%), and thrombocytopenia (Grade 3/4: 33%). ( 6.1 ) The most common (>25% and greater than or equal to 2% more than cisplatin alone) non-hematologic adverse reactions (all grades) were: pain, vomiting, and infection/febrile neutropenia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sagent Pharmaceuticals, Inc. at 1-866-625-1618, 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. Ovarian Cancer Table 1 shows the Grade 3/4 hematologic and major non-hematologic adverse reactions in the topotecan/paclitaxel comparator trial in ovarian cancer. Table 1. Adverse Reactions Experienced by ≥5% of Ovarian Cancer Patients Randomized to Receive Topotecan or Paclitaxel 1 Death related to sepsis occurred in 2% of patients receiving topotecan and 0% of patients receiving paclitaxel. 2 Pain includes body pain, skeletal pain, and back pain. Adverse Reaction Topotecan (n = 112) Paclitaxel (n = 114) Hematologic Grade 3/4 % % Grade 4 neutropenia (<500 cells/mm 3 ) 80 21 Grade 3/4 anemia (Hgb <8 g/dL) 41 6 Grade 4 thrombocytopenia (<25,000 plts/mm 3 ) 27 3 Febrile neutropenia 23 4 Non-hematologic Grade 3/4 % % Infections and infestations Sepsis 1 5 2 Respiratory, thoracic, and mediastinal disorders Dyspnea 6 5 Gastrointestinal disorders Abdominal pain 5 4 Constipation 5 0 Diarrhea 6 1 Intestinal obstruction 5 4 Nausea 10 2 Vomiting 10 3 General disorders and administrative site conditions Fatigue 7 6 Asthenia 5 3 Pain 2 5 7 Small Cell Lung Cancer Table 2 shows the Grade 3/4 hematologic and major non-hematologic adverse reactions in the topotecan/CAV (cyclophosphamide-doxorubicin-vincristine) comparator trial in small cell lung cancer. Table 2. Adverse Reactions Experienced by ≥5% of Small Cell Lung Cancer Patients Randomized to Receive Topotecan or CAV 1 Death related to sepsis occurred in 3% of patients receiving topotecan and 1% of patients receiving CAV. 2 Pain includes body pain, skeletal pain, and back pain. 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 Febrile neutropenia 28 26 Non-hematologic Grade 3/4 % % Infections and infestations Sepsis 1 5 5 Respiratory, thoracic, and mediastinal disorders Dyspnea 9 14 Pneumonia 8 6 Gastrointestinal disorders Abdominal pain 6 4 Nausea 8 6 General disorders and administrative site conditions Fatigue 6 10 Asthenia 9 7 Pain 2 5 7 Hepatobiliary Disorders in Ovarian and Small Cell Lung Cancer Patients Receiving Topotecan: Based on the combined experience of 453 patients with metastatic ovarian carcinoma, and 426 patients with small cell lung cancer treated with topotecan, Grade 1 transient elevations in hepatic enzymes occurred in 8% of patients. Grade 3/4 elevations occurred in 4%. Grade 3/4 elevated bilirubin occurred in less than 2% of patients. Cervical Cancer In the comparative trial with topotecan plus cisplatin versus cisplatin in patients with cervical cancer, the most common dose-limiting adverse reaction was myelosuppression. Table 3 shows the hematologic and non-hematologic adverse reactions in patients with cervical cancer. Table 3. Adverse Reactions Experienced by ≥5% of Patients with Cervical Cancer Randomized to Receive Topotecan plus Cisplatin or Cisplatin Monotherapy (Between-Arm Difference ≥2%) 1 1 Includes patients who were eligible and treated. 2 Data were collected using NCI Common Toxicity Criteria, v. 2.0 3 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. 4 Constitutional includes fatigue (lethargy, malaise, asthenia), fever (in the absence of neutropenia), rigors, chills, sweating, and weight gain or loss. 5 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. 6 High-level terms were included if the between-arm difference was ≥10%. Adverse Reaction Topotecan plus Cisplatin (n = 140) % Cisplatin (n = 144) % Hematologic Neutropenia Grade 3 (<1,000 to 500 cells/mm 3 ) 26 1 Grade 4 (<500 cells/mm 3 ) 48 1 Anemia Grade 3 (Hgb <8 to 6.5 g/dL) 34 19 Grade 4 (Hgb <6.5 g/dL) 6 3 Thrombocytopenia Grade 3 (<50,000 to 10,000 cells/mm 3 ) 26 3 Grade 4 (<10,000 cells/mm 3 ) 7 0 Non-hematologic 2,3 General disorders and administrative site conditions Constitutional 4 69 62 Pain 5 59 50 Gastrointestinal disorders Vomiting 40 37 Stomatitis-pharyngitis 6 0 Other 63 56 Dermatology 6 48 20 Infection-febrile neutropenia 6 28 18 Cardiovascular 6 25 15 6.2 Postmarketing Experience The following reactions have been identified during postmarketing use of topotecan. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to topotecan. Blood and Lymphatic System Disorders Severe bleeding (in association with thrombocytopenia) [see Warnings and Precautions ( 5.1 )] . Immune System Disorders Allergic manifestations, anaphylactoid reactions. Gastrointestinal Disorders Abdominal pain potentially associated with neutropenic enterocolitis [see Warnings and Precautions ( 5.2 )] . Pulmonary Disorders Interstitial lung disease [see Warnings and Precautions ( 5.3 )]. Skin and Subcutaneous Tissue Disorders Angioedema, severe dermatitis, severe pruritus. General Disorders and Administration Site Conditions Extravasation [see Warnings and Precautions ( 5.5 )] .

<table ID="t1" width="100%"> <caption>Table 1. Adverse Reactions Experienced by &#x2265;5% of Ovarian Cancer Patients Randomized to Receive Topotecan or Paclitaxel </caption> <col width="48.850%" align="left"/> <col width="25.575%" align="left"/> <col width="25.575%" align="left"/> <tfoot> <tr> <td colspan="3" align="left" valign="top"> <paragraph styleCode="footnote"> ¹ Death related to sepsis occurred in 2% of patients receiving topotecan and 0% of patients receiving paclitaxel. </paragraph> </td> </tr> <tr> <td colspan="3" align="left" valign="top"> <paragraph styleCode="footnote"> ² Pain includes body pain, skeletal pain, and back pain. </paragraph> </td> </tr> </tfoot> <tbody> <tr> <td align="center" valign="top" styleCode="Toprule Botrule Lrule Rrule"> <content styleCode="bold">Adverse Reaction</content> </td> <td align="center" valign="top" styleCode="Toprule Botrule Rrule"> <content styleCode="bold">Topotecan (n = 112)</content> </td> <td align="center" valign="top" styleCode="Toprule Botrule Rrule"> <content styleCode="bold">Paclitaxel (n = 114)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Hematologic Grade 3/4</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">%</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">%</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Grade 4 neutropenia (&lt;500 cells/mm³) </td> <td align="center" valign="top" styleCode="Botrule Rrule">80 </td> <td align="center" valign="top" styleCode="Botrule Rrule">21 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Grade 3/4 anemia (Hgb &lt;8 g/dL) </td> <td align="center" valign="top" styleCode="Botrule Rrule">41 </td> <td align="center" valign="top" styleCode="Botrule Rrule">6 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Grade 4 thrombocytopenia (&lt;25,000 plts/mm³) </td> <td align="center" valign="top" styleCode="Botrule Rrule">27 </td> <td align="center" valign="top" styleCode="Botrule Rrule">3 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Febrile neutropenia </td> <td align="center" valign="top" styleCode="Botrule Rrule">23 </td> <td align="center" valign="top" styleCode="Botrule Rrule">4 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Non-hematologic Grade 3/4</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">%</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">%</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Infections and infestations</content> </td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> Sepsis<content styleCode="italics"> ¹ </content> </td> <td align="center" valign="top" styleCode="Botrule Rrule">5 </td> <td align="center" valign="top" styleCode="Botrule Rrule">2 </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Respiratory, thoracic, and mediastinal disorders</content> </td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> Dyspnea </td> <td align="center" valign="top" styleCode="Botrule Rrule">6 </td> <td align="center" valign="top" styleCode="Botrule Rrule">5 </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Gastrointestinal disorders</content> </td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> Abdominal pain </td> <td align="center" valign="top" styleCode="Rrule">5 </td> <td align="center" valign="top" styleCode="Rrule">4 </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> Constipation </td> <td align="center" valign="top" styleCode="Rrule">5 </td> <td align="center" valign="top" styleCode="Rrule">0 </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> Diarrhea </td> <td align="center" valign="top" styleCode="Rrule">6 </td> <td align="center" valign="top" styleCode="Rrule">1 </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> Intestinal obstruction </td> <td align="center" valign="top" styleCode="Rrule">5 </td> <td align="center" valign="top" styleCode="Rrule">4 </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> Nausea </td> <td align="center" valign="top" styleCode="Rrule">10 </td> <td align="center" valign="top" styleCode="Rrule">2 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> Vomiting </td> <td align="center" valign="top" styleCode="Botrule Rrule">10 </td> <td align="center" valign="top" styleCode="Botrule Rrule">3 </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">General disorders and administrative site conditions</content> </td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> Fatigue </td> <td align="center" valign="top" styleCode="Rrule">7 </td> <td align="center" valign="top" styleCode="Rrule">6 </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> Asthenia </td> <td align="center" valign="top" styleCode="Rrule">5 </td> <td align="center" valign="top" styleCode="Rrule">3 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> Pain<content styleCode="italics"> ² </content> </td> <td align="center" valign="top" styleCode="Botrule Rrule">5 </td> <td align="center" valign="top" styleCode="Botrule Rrule">7 </td> </tr> </tbody> </table>

<table ID="t2" width="100%"> <caption>Table 2. Adverse Reactions Experienced by &#x2265;5% of Small Cell Lung Cancer Patients Randomized to Receive Topotecan or CAV </caption> <col width="47.482%" align="left"/> <col width="26.676%" align="left"/> <col width="25.842%" align="left"/> <tfoot> <tr> <td colspan="3" align="left" valign="top"> <paragraph styleCode="footnote"> ¹ Death related to sepsis occurred in 3% of patients receiving topotecan and 1% of patients receiving CAV. </paragraph> </td> </tr> <tr> <td colspan="3" align="left" valign="top"> <paragraph styleCode="footnote"> ² Pain includes body pain, skeletal pain, and back pain. </paragraph> </td> </tr> </tfoot> <tbody> <tr> <td align="center" valign="top" styleCode="Toprule Botrule Lrule Rrule"> <content styleCode="bold">Adverse Reaction</content> </td> <td align="center" valign="top" styleCode="Toprule Botrule Rrule"> <content styleCode="bold">Topotecan</content> <content styleCode="bold">(n = 107)</content> </td> <td align="center" valign="top" styleCode="Toprule Botrule Rrule"> <content styleCode="bold">CAV</content> <content styleCode="bold">(n = 104)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Hematologic Grade 3/4</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">%</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">%</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule">Grade 4 neutropenia </td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> (&lt;500 cells/mm³) </td> <td align="center" valign="top" styleCode="Botrule Rrule">70 </td> <td align="center" valign="top" styleCode="Botrule Rrule">72 </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule">Grade 3/4 anemia </td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> (Hgb &lt;8 g/dL) </td> <td align="center" valign="top" styleCode="Botrule Rrule">42 </td> <td align="center" valign="top" styleCode="Botrule Rrule">20 </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule">Grade 4 thrombocytopenia </td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> (&lt;25,000 plts/mm³) </td> <td align="center" valign="top" styleCode="Botrule Rrule">29 </td> <td align="center" valign="top" styleCode="Botrule Rrule">5 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Febrile neutropenia </td> <td align="center" valign="top" styleCode="Botrule Rrule">28 </td> <td align="center" valign="top" styleCode="Botrule Rrule">26 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Non-hematologic Grade 3/4</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">%</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">%</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Infections and infestations</content> </td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Sepsis<content styleCode="italics"> ¹ </content> </td> <td align="center" valign="top" styleCode="Botrule Rrule">5 </td> <td align="center" valign="top" styleCode="Botrule Rrule">5 </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Respiratory, thoracic, and mediastinal disorders</content> </td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> Dyspnea </td> <td align="center" valign="top" styleCode="Rrule">9 </td> <td align="center" valign="top" styleCode="Rrule">14 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> Pneumonia </td> <td align="center" valign="top" styleCode="Botrule Rrule">8 </td> <td align="center" valign="top" styleCode="Botrule Rrule">6 </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Gastrointestinal disorders</content> </td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> Abdominal pain </td> <td align="center" valign="top" styleCode="Rrule">6 </td> <td align="center" valign="top" styleCode="Rrule">4 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> Nausea </td> <td align="center" valign="top" styleCode="Botrule Rrule">8 </td> <td align="center" valign="top" styleCode="Botrule Rrule">6 </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">General disorders and administrative site conditions</content> </td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> Fatigue </td> <td align="center" valign="top" styleCode="Rrule">6 </td> <td align="center" valign="top" styleCode="Rrule">10 </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> Asthenia </td> <td align="center" valign="top" styleCode="Rrule">9 </td> <td align="center" valign="top" styleCode="Rrule">7 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> Pain<content styleCode="italics"> ² </content> </td> <td align="center" valign="top" styleCode="Botrule Rrule">5 </td> <td align="center" valign="top" styleCode="Botrule Rrule">7 </td> </tr> </tbody> </table>

<table ID="t3" width="100%"> <caption>Table 3. Adverse Reactions Experienced by &#x2265;5% of Patients with Cervical Cancer Randomized to Receive Topotecan plus Cisplatin or Cisplatin Monotherapy (Between-Arm Difference &#x2265;2%)¹ </caption> <col width="53.067%" align="left"/> <col width="23.167%" align="left"/> <col width="23.767%" align="left"/> <tfoot> <tr> <td colspan="3" align="left" valign="top"> <paragraph styleCode="footnote"> ¹ Includes patients who were eligible and treated. </paragraph> </td> </tr> <tr> <td colspan="3" align="left" valign="top"> <paragraph styleCode="footnote"> ² Data were collected using NCI Common Toxicity Criteria, v. 2.0 </paragraph> </td> </tr> <tr> <td colspan="3" align="left" valign="top"> <paragraph styleCode="footnote"> ³ 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. </paragraph> </td> </tr> <tr> <td colspan="3" align="left" valign="top"> <paragraph styleCode="footnote"> ⁴ Constitutional includes fatigue (lethargy, malaise, asthenia), fever (in the absence of neutropenia), rigors, chills, sweating, and weight gain or loss. </paragraph> </td> </tr> <tr> <td colspan="3" align="left" valign="top"> <paragraph styleCode="footnote"> ⁵ 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. </paragraph> </td> </tr> <tr> <td colspan="3" align="left" valign="top"> <paragraph styleCode="footnote"> ⁶ High-level terms were included if the between-arm difference was &#x2265;10%. </paragraph> </td> </tr> </tfoot> <tbody> <tr> <td align="center" valign="top" styleCode="Toprule Botrule Lrule Rrule"> <content styleCode="bold">Adverse Reaction</content> </td> <td align="center" valign="top" styleCode="Toprule Botrule Rrule"> <content styleCode="bold">Topotecan</content> <content styleCode="bold">plus Cisplatin</content> <content styleCode="bold">(n = 140)</content> <content styleCode="bold">%</content> </td> <td align="center" valign="top" styleCode="Toprule Botrule Rrule"> <content styleCode="bold">Cisplatin</content> <content styleCode="bold">(n = 144)</content> <content styleCode="bold">%</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Hematologic</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"/> <td align="center" valign="top" styleCode="Botrule Rrule"/> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule">Neutropenia </td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> Grade 3 (&lt;1,000 to 500 cells/mm³) </td> <td align="center" valign="top" styleCode="Rrule">26 </td> <td align="center" valign="top" styleCode="Rrule">1 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> Grade 4 (&lt;500 cells/mm³) </td> <td align="center" valign="top" styleCode="Botrule Rrule">48 </td> <td align="center" valign="top" styleCode="Botrule Rrule">1 </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule">Anemia </td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> Grade 3 (Hgb &lt;8 to 6.5 g/dL) </td> <td align="center" valign="top" styleCode="Rrule">34 </td> <td align="center" valign="top" styleCode="Rrule">19 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> Grade 4 (Hgb &lt;6.5 g/dL) </td> <td align="center" valign="top" styleCode="Botrule Rrule">6 </td> <td align="center" valign="top" styleCode="Botrule Rrule">3 </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule">Thrombocytopenia </td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> Grade 3 (&lt;50,000 to 10,000 cells/mm³) </td> <td align="center" valign="top" styleCode="Rrule">26 </td> <td align="center" valign="top" styleCode="Rrule">3 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> Grade 4 (&lt;10,000 cells/mm³) </td> <td align="center" valign="top" styleCode="Botrule Rrule">7 </td> <td align="center" valign="top" styleCode="Botrule Rrule">0 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Non-hematologic</content> <content styleCode="italics"> ^2,3 </content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"/> <td align="center" valign="top" styleCode="Botrule Rrule"/> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">General disorders and administrative site conditions</content> </td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> Constitutional<content styleCode="italics"> ⁴ </content> </td> <td align="center" valign="top" styleCode="Rrule">69 </td> <td align="center" valign="top" styleCode="Rrule">62 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> Pain<content styleCode="italics"> ⁵ </content> </td> <td align="center" valign="top" styleCode="Botrule Rrule">59 </td> <td align="center" valign="top" styleCode="Botrule Rrule">50 </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Gastrointestinal disorders</content> </td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> Vomiting </td> <td align="center" valign="top" styleCode="Rrule">40 </td> <td align="center" valign="top" styleCode="Rrule">37 </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> Stomatitis-pharyngitis </td> <td align="center" valign="top" styleCode="Rrule">6 </td> <td align="center" valign="top" styleCode="Rrule">0 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> Other </td> <td align="center" valign="top" styleCode="Botrule Rrule">63 </td> <td align="center" valign="top" styleCode="Botrule Rrule">56 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Dermatology</content> ⁶ </td> <td align="center" valign="top" styleCode="Botrule Rrule">48 </td> <td align="center" valign="top" styleCode="Botrule Rrule">20 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Infection-febrile neutropenia</content> <content styleCode="italics"> ⁶ </content> </td> <td align="center" valign="top" styleCode="Botrule Rrule">28 </td> <td align="center" valign="top" styleCode="Botrule Rrule">18 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Cardiovascular</content> ⁶ </td> <td align="center" valign="top" styleCode="Botrule Rrule">25 </td> <td align="center" valign="top" styleCode="Botrule Rrule">15 </td> </tr> </tbody> </table>