FDA label 4bb29b99-f9cf-4b45-a431-0753149bbd3a

WARNING: BONE MARROW SUPPRESSION Topotecan hydrochloride for injection 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 hydrochloride for injection 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 hydrochloride for injection 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 hydrochloride for injection. Neutropenia is not cumulative over time. Severe myelotoxicity has been reported when topotecan hydrochloride for injection 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 hydrochloride for 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 hydrochloride for injection 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 hydrochloride for injection 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 hydrochloride for injection. Refer to Section 2.4 for dose modification guidelines for hematological toxicities in subsequent courses. Do not treat patients with subsequent courses of topotecan hydrochloride for injection 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 hydrochloride for injection. 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 hydrochloride for injection if a new diagnosis of ILD is confirmed. 5.4 Embryofetal Toxicity Based on animal data, topotecan hydrochloride for injection 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 hydrochloride for injection. 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 hydrochloride for injection has been observed; severe cases have been reported. If signs or symptoms of extravasation occur, immediately stop administration of topotecan hydrochloride for injection 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%). The most common (>5%) non-hematologic adverse reactions (all grades) were: asthenia, dyspnea, nausea, pneumonia, abdominal pain, and fatigue. 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 Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 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 Hydrochloride for Injection or Paclitaxel Adverse Reaction Topotecan Hydrochloride for Injection (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 Death related to sepsis occurred in 2% of patients receiving topotecan hydrochloride for injection and 0% of patients receiving paclitaxel. 5 2 Respiratory, thoracic, and mediastinal disorders Dyspnea 6 5 Gastrointestinal disorders 5 4 Abdominal pain Constipation 5 0 Diarrhea 6 1 Intestinal obstruction 5 4 Nausea 10 2 Vomiting 10 3 General disorders and administrative site 7 6 conditions Fatigue Asthenia 5 3 Pain Pain includes body pain, skeletal pain, and back pain. 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 Hydrochloride for Injection or CAV Adverse Reaction Topotecan Hydrochloride for Injection (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 Death related to sepsis occurred in 3% of patients receiving topotecan hydrochloride for injection and 1% of patients receiving CAV. 5 5 Respiratory, thoracic, and mediastinal disorders Dyspnea Pneumonia 9 8 14 6 Gastrointestinal disorders Abdominal pain Nausea 6 8 4 6 General disorders and administrative site conditions Fatigue Asthenia Pain Pain includes body pain, skeletal pain, and back pain 6 9 5 10 7 7 Hepatobiliary Disorders in Ovarian and Small Cell Lung Cancer Patients Receiving Topotecan Hydrochloride for Injection: Based on the combined experience of 453 patients with metastatic ovarian carcinoma, and 426 patients with small cell lung cancer treated with topotecan hydrochloride for injection, 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 hydrochloride for injection 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 Hydrochloride for Injection plus Cisplatin or Cisplatin Monotherapy (Between-Arm Difference ≥2%) Ad verse Reaction Topotecan Hydrochloride for Injection p lus Cisplatin (n = 140) % C isplatin (n = 144) % Hematologic Neutropenia Grade 3 (<1,000 to 500 cells/mm3) Grade 4 (<500 cells/mm3) 26 48 1 1 Anemia Grade 3 (Hgb <8-6.5 g/dL) Grade 4 (Hgb <6.5 g/dL) 34 6 19 3 Thrombocytopenia Grade 3 (<50,000 to 10,000 cells/mm3) Grade 4 (<10,000 cells/mm3) 26 7 3 0 N on-hematologic Data were collected using NCI Common Toxicity Criteria, v. 2.0. , 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. General disorders and administrative site conditions Constitutional Constitutional includes fatigue (lethargy, malaise, asthenia), fever (in the absence of neutropenia), rigors, chills, sweating, and weight gain or loss. Pain 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. 69 59 62 50 Gastrointestinal disorders Vomiting Stomatitis-pharyngitis Other 40 6 63 37 0 56 D ermatology High-level terms were included if the between-arm difference was ≥10%. 48 20 Infection-febrile neutropenia 28 18 C ardiovascular 25 15 6.2 Postmarketing Experience The following reactions have been identified during postmarketing use of topotecan hydrochloride for injection. 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 hydrochloride for injection. 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 cellspacing="0" cellpadding="0" border="0" width="100%"> <caption>Table 1. Adverse Reactions Experienced by &#x2265;5% of Ovarian Cancer Patients Randomized to Receive Topotecan Hydrochloride for Injection or Paclitaxel </caption> <colgroup> <col width="50%"/> <col width="24%"/> <col width="24%"/> </colgroup> <tbody> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Adverse Reaction</content> </td> <td valign="top" styleCode="Rrule" align="center"> <content styleCode="bold">Topotecan Hydrochloride for Injection</content> <content styleCode="bold">(n = 112)</content> </td> <td valign="top" styleCode="Rrule" align="center"> <content styleCode="bold">Paclitaxel</content> <content styleCode="bold">(n = 114)</content> </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Hematologic Grade 3/4</content> </td> <td valign="top" styleCode="Rrule" align="center"> <content styleCode="bold">%</content> </td> <td valign="top" styleCode="Rrule" align="center"> <content styleCode="bold">%</content> </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule">Grade 4 neutropenia (&lt;500 cells/mm³) </td> <td valign="top" styleCode="Rrule" align="center">80 </td> <td valign="top" styleCode="Rrule" align="center">21 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule">Grade 3/4 anemia (Hgb &lt;8 g/dL) </td> <td valign="top" styleCode="Rrule" align="center">41 </td> <td valign="top" styleCode="Rrule" align="center">6 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule">Grade 4 thrombocytopenia (&lt;25,000 plts/mm³) </td> <td valign="top" styleCode="Rrule" align="center">27 </td> <td valign="top" styleCode="Rrule" align="center">3 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule">Febrile neutropenia </td> <td valign="top" styleCode="Rrule" align="center">23 </td> <td valign="top" styleCode="Rrule" align="center">4 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Non-hematologic Grade 3/4</content> </td> <td valign="top" styleCode="Rrule" align="center"> <content styleCode="bold">%</content> </td> <td valign="top" styleCode="Rrule" align="center"> <content styleCode="bold">%</content> </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Infections and infestations</content> Sepsis<footnote ID="fn8469">Death related to sepsis occurred in 2% of patients receiving topotecan hydrochloride for injection and 0% of patients receiving paclitaxel.</footnote> </td> <td valign="top" styleCode="Rrule" align="center"> 5 </td> <td valign="top" styleCode="Rrule" align="center"> 2 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Respiratory, thoracic, and mediastinal disorders</content> Dyspnea </td> <td valign="top" styleCode="Rrule" align="center"> 6 </td> <td valign="top" styleCode="Rrule" align="center"> 5 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Gastrointestinal disorders</content> </td> <td valign="top" styleCode="Rrule" rowspan="2" align="center"> 5 </td> <td valign="top" styleCode="Rrule" rowspan="2" align="center"> 4 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule">Abdominal pain </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule">Constipation </td> <td valign="top" styleCode="Rrule" align="center">5 </td> <td valign="top" styleCode="Rrule" align="center">0 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule">Diarrhea </td> <td valign="top" styleCode="Rrule" align="center">6 </td> <td valign="top" styleCode="Rrule" align="center">1 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule">Intestinal obstruction </td> <td valign="top" styleCode="Rrule" align="center">5 </td> <td valign="top" styleCode="Rrule" align="center">4 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule">Nausea </td> <td valign="top" styleCode="Rrule" align="center">10 </td> <td valign="top" styleCode="Rrule" align="center">2 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule">Vomiting </td> <td valign="top" styleCode="Rrule" align="center">10 </td> <td valign="top" styleCode="Rrule" align="center">3 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">General disorders and administrative site</content> </td> <td valign="top" styleCode="Rrule" rowspan="3" align="center"> 7 </td> <td valign="top" styleCode="Rrule" rowspan="3" align="center"> 6 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">conditions</content> </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule">Fatigue </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule">Asthenia </td> <td valign="top" styleCode="Rrule" align="center">5 </td> <td valign="top" styleCode="Rrule" align="center">3 </td> </tr> <tr> <td valign="top" styleCode="Lrule Rrule">Pain<footnote ID="fn8470">Pain includes body pain, skeletal pain, and back pain.</footnote> </td> <td valign="top" styleCode="Rrule" align="center">5 </td> <td valign="top" styleCode="Rrule" align="center">7 </td> </tr> </tbody> </table>

<table cellspacing="0" cellpadding="0" border="0" width="465.5"> <caption>Table 2. Adverse Reactions Experienced by &#x2265;5% of Small Cell Lung Cancer Patients Randomized to Receive Topotecan Hydrochloride for Injection or CAV </caption> <colgroup> <col width="69.1428571428571%"/> <col width="30.8571428571429%"/> </colgroup> <tbody> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Adverse Reaction</content> </td> <td valign="top" styleCode="Rrule" align="center"> <content styleCode="bold">Topotecan Hydrochloride for Injection</content> <content styleCode="bold">(n = 107)</content> </td> <td valign="top" styleCode="Rrule" align="center"> <content styleCode="bold">CAV</content> <content styleCode="bold">(n = 104)</content> </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Hematologic Grade 3/4</content> </td> <td valign="top" styleCode="Rrule" align="center"> <content styleCode="bold">%</content> </td> <td valign="top" styleCode="Rrule" align="center"> <content styleCode="bold">%</content> </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule">Grade 4 neutropenia (&lt;500 cells/mm³) </td> <td valign="top" styleCode="Rrule" align="center"> 70 </td> <td valign="top" styleCode="Rrule" align="center"> 72 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule">Grade 3/4 anemia (Hgb &lt;8 g/dL) </td> <td valign="top" styleCode="Rrule" align="center"> 42 </td> <td valign="top" styleCode="Rrule" align="center"> 20 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule">Grade 4 thrombocytopenia (&lt;25,000 plts/mm³) </td> <td valign="top" styleCode="Rrule" align="center"> 29 </td> <td valign="top" styleCode="Rrule" align="center"> 5 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule">Febrile neutropenia </td> <td valign="top" styleCode="Rrule" align="center">28 </td> <td valign="top" styleCode="Rrule" align="center">26 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Non-hematologic Grade 3/4</content> </td> <td valign="top" styleCode="Rrule" align="center"> <content styleCode="bold">%</content> </td> <td valign="top" styleCode="Rrule" align="center"> <content styleCode="bold">%</content> </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Infections and infestations</content> Sepsis<footnote ID="fn8471">Death related to sepsis occurred in 3% of patients receiving topotecan hydrochloride for injection and 1% of patients receiving CAV.</footnote> </td> <td valign="top" styleCode="Rrule" align="center"> 5 </td> <td valign="top" styleCode="Rrule" align="center"> 5 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Respiratory, thoracic, and</content> <content styleCode="bold">mediastinal disorders</content> Dyspnea Pneumonia </td> <td valign="top" styleCode="Rrule" align="center"> 9 8 </td> <td valign="top" styleCode="Rrule" align="center"> 14 6 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Gastrointestinal disorders</content> Abdominal pain Nausea </td> <td valign="top" styleCode="Rrule" align="center"> 6 8 </td> <td valign="top" styleCode="Rrule" align="center"> 4 6 </td> </tr> <tr> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">General disorders and administrative</content> <content styleCode="bold">site conditions</content> Fatigue Asthenia Pain<footnote ID="fn8472">Pain includes body pain, skeletal pain, and back pain</footnote> </td> <td valign="top" styleCode="Rrule" align="center"> 6 9 5 </td> <td valign="top" styleCode="Rrule" align="center"> 10 7 7 </td> </tr> </tbody> </table>

<table cellspacing="0" cellpadding="0" border="0" width="100%"> <caption>Table 3. Adverse Reactions Experienced by &#x2265;5% of Patients with Cervical Cancer Randomized to Receive Topotecan Hydrochloride for Injection plus Cisplatin or Cisplatin Monotherapy (Between-Arm Difference &#x2265;2%) </caption> <colgroup> <col width="50%"/> <col width="24%"/> <col width="24%"/> </colgroup> <tbody> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Ad</content> <content styleCode="bold">verse Reaction</content> </td> <td valign="top" styleCode="Rrule" align="center"> <content styleCode="bold">Topotecan Hydrochloride for Injection</content> <content styleCode="bold">p</content> <content styleCode="bold">lus Cisplatin</content> <content styleCode="bold">(n = 140)</content> <content styleCode="bold">%</content> </td> <td valign="top" styleCode="Rrule" align="center"> <content styleCode="bold">C</content> <content styleCode="bold">isplatin</content> <content styleCode="bold">(n = 144)</content> <content styleCode="bold">%</content> </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Hematologic</content> </td> <td valign="top" styleCode="Rrule" align="center"> </td> <td valign="top" styleCode="Rrule" align="center"> </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule">Neutropenia Grade 3 (&lt;1,000 to 500 cells/mm3) Grade 4 (&lt;500 cells/mm3) </td> <td valign="top" styleCode="Rrule" align="center"> 26 48 </td> <td valign="top" styleCode="Rrule" align="center"> 1 1 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule">Anemia Grade 3 (Hgb &lt;8-6.5 g/dL) Grade 4 (Hgb &lt;6.5 g/dL) </td> <td valign="top" styleCode="Rrule" align="center"> 34 6 </td> <td valign="top" styleCode="Rrule" align="center"> 19 3 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule">Thrombocytopenia Grade 3 (&lt;50,000 to 10,000 cells/mm3) Grade 4 (&lt;10,000 cells/mm3) </td> <td valign="top" styleCode="Rrule" align="center"> 26 7 </td> <td valign="top" styleCode="Rrule" align="center"> 3 0 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">N</content> <content styleCode="bold">on-hematologic<footnote ID="fn8474">Data were collected using NCI Common Toxicity Criteria, v. 2.0.</footnote> </content> <content styleCode="bold">,<footnote ID="fn8475">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.</footnote> </content> </td> <td valign="top" styleCode="Rrule" align="center"> </td> <td valign="top" styleCode="Rrule" align="center"> </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">General disorders and administrative</content> <content styleCode="bold">site conditions</content> Constitutional<footnote ID="fn8476">Constitutional includes fatigue (lethargy, malaise, asthenia), fever (in the absence of neutropenia), rigors, chills, sweating, and weight gain or loss.</footnote> Pain<footnote ID="fn8477">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.</footnote> </td> <td valign="top" styleCode="Rrule" align="center"> 69 59 </td> <td valign="top" styleCode="Rrule" align="center"> 62 50 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Gastrointestinal disorders</content> Vomiting Stomatitis-pharyngitis Other </td> <td valign="top" styleCode="Rrule" align="center"> 40 6 63 </td> <td valign="top" styleCode="Rrule" align="center"> 37 0 56 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">D</content> <content styleCode="bold">ermatology<footnote ID="fn8478">High-level terms were included if the between-arm difference was &#x2265;10%.</footnote> </content> </td> <td valign="top" styleCode="Rrule" align="center">48 </td> <td valign="top" styleCode="Rrule" align="center">20 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Infection-febrile neutropenia<footnoteRef IDREF="fn8478"/> </content> </td> <td valign="top" styleCode="Rrule" align="center">28 </td> <td valign="top" styleCode="Rrule" align="center">18 </td> </tr> <tr> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">C</content> <content styleCode="bold">ardiovascular<footnoteRef IDREF="fn8478"/> </content> </td> <td valign="top" styleCode="Rrule" align="center">25 </td> <td valign="top" styleCode="Rrule" align="center">15 </td> </tr> </tbody> </table>