FDA label c820c18b-db58-4c15-bfe4-82f49e9973a8

WARNING: BONE MARROW SUPPRESSION Do not give topotecan hydrochloride to patients with baseline neutrophil counts less than 1,500 cells/mm 3 . In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection and death, monitor peripheral blood counts frequently on all patients receiving topotecan hydrochloride [see Warnings and Precautions ( 5.1 )]. WARNING: BONE MARROW SUPPRESSION See full prescribing information for complete boxed warning. Do not give topotecan hydrochloride to patients with baseline neutrophil counts less than 1,500 cells/mm 3 . In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection and death, monitor peripheral blood cell counts frequently on all patients receiving topotecan hydrochloride. ( 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 if needed. ( 5.1 ) Topotecan-induced neutropenia can lead to neutropenic colitis. ( 5.2 ) Interstitial lung disease: Topotecan Hydrochloride for Injection has been associated with reports of interstitial lung disease. Monitor patients for symptoms and discontinue Topotecan Hydrochloride for Injection if the diagnosis is confirmed. ( 5.3 ) Pregnancy: Can cause fetal harm. Advise women of potential risk to the fetus. ( 5.4 , 8.1 ) 5.1 Bone Marrow Suppression Bone marrow suppression (primarily neutropenia) is the dose-limiting toxicity of topotecan hydrochloride. Neutropenia is not cumulative over time. In the comparative study in small cell lung cancer, however, the treatment-related death rates were 5% for topotecan hydrochloride and 4% for CAV (cyclophosphamide-doxorubicin-vincristine). Neutropenia: Small cell lung cancer experience: Grade 4 neutropenia (<500 cells/mm 3 ) was most common during course 1 of treatment (60% of patients) and occurred in 39% of all courses, with a median duration of 7 days. The nadir neutrophil count occurred at a median of 12 days. Therapy-related sepsis or febrile neutropenia occurred in 23% of patients, and sepsis was fatal in 1%. Pancytopenia has been reported. Cervical cancer experience: Grade 3 and grade 4 neutropenia affected 26% and 48% of patients, respectively. Thrombocytopenia: Small cell lung cancer experience: Grade 4 thrombocytopenia (<25,000/mm 3 ) occurred in 27% of patients and in 9% of courses, with a median duration of 5 days and platelet nadir at a median of 15 days. Platelet transfusions were given to 15% of patients in 4% of courses. Cervical cancer experience: Grade 3 and grade 4 thrombocytopenia affected 26% and 7% of patients, respectively. Anemia: Small cell lung cancer experience: Grade 3/4 anemia (<8 g/dL) occurred in 37% of patients and in 14% of courses. Median nadir was at day 15. Transfusions were needed in 52% of patients in 22% of courses. Cervical cancer experience: Grade 3 and grade 4 anemia affected 34% and 6% of patients, respectively. Monitoring of Bone Marrow Function: Administer topotecan hydrochloride only in patients with adequate bone marrow reserves, including baseline neutrophil count of at least 1,500 cells/mm 3 and platelet count at least 100,000/mm 3 . Monitor peripheral blood counts frequently during treatment with topotecan hydrochloride. Do not treat patients with subsequent courses of topotecan hydrochloride until neutrophils recover to >1,000 cells/mm 3 , platelets recover to >100,000 cells/mm 3 , and hemoglobin levels recover to 9.0 g/dL (with transfusion if necessary). Severe myelotoxicity has been reported when topotecan hydrochloride is used in combination with cisplatin [see Drug Interactions ( 7 )] . 5.2 Neutropenic Colitis Topotecan-induced neutropenia can lead to neutropenic colitis. Fatalities due to neutropenic colitis have been reported in clinical trials with topotecan hydrochloride. In patients presenting with fever, neutropenia, and a compatible pattern of abdominal pain, consider the possibility of neutropenic colitis. 5.3 Interstitial Lung Disease Topotecan hydrochloride has been associated with reports of interstitial lung disease (ILD), some of which have been fatal [see Adverse Reactions ( 6.2 )] . Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer, thoracic exposure to radiation, and use of pneumotoxic drugs and/or colony stimulating factors. Monitor patients for pulmonary symptoms indicative of interstitial lung disease (e.g., cough, fever, dyspnea, and/or hypoxia), and discontinue topotecan hydrochloride if a new diagnosis of ILD is confirmed. 5.4 Pregnancy Pregnancy Category D Topotecan hydrochloride can cause fetal harm when administered to a pregnant woman. Topotecan caused embryolethality, fetotoxicity, and teratogenicity in rats and rabbits when administered during organogenesis. There are no adequate and well controlled studies of topotecan hydrochloride in pregnant women. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving topotecan hydrochloride, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations, Pregnancy ( 8.1 )]. 5.5 Inadvertent Extravasation Inadvertent extravasation with topotecan hydrochloride has been observed, most reactions have been mild but severe cases have been reported.

6 ADVERSE REACTIONS Small cell lung cancer: The most common hematologic adverse reactions were: neutropenia (97%), leukopenia (97%), anemia (89%), and thrombocytopenia (69%). ( 6.1 ) The most common (>25%) non-hematologic adverse reactions (all grades) were: nausea, alopecia, vomiting, sepsis or pyrexia/infection with neutropenia, diarrhea, constipation, fatigue, and pyrexia. ( 6.1 ) Cervical cancer (topotecan hydrochloride plus cisplatin): The most common hematologic adverse reactions (all grades) were: anemia (94%), leukopenia (91%), neutropenia (89%), and thrombocytopenia (74%). ( 6.1 ) The most common (>25%) non-hematologic adverse reactions (all grades) were: pain, nausea, 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Small Cell Lung Cancer: Data in the following section are based on the combined experience of 879 patients, including 426 patients with small cell lung cancer, treated with topotecan hydrochloride. Table 1 lists the principal hematologic adverse reactions and Table 2 lists non-hematologic adverse reactions occurring in at least 15% of patients. Table 1. Hematologic Adverse Reactions Experienced in ≥15% of 879 Patients, Including 426 Patients With Small Cell Lung Cancer, Receiving Topotecan Hydrochloride Hematologic Adverse Reaction Patients (n = 879) % Incidence Neutropenia <1,500 cells/mm 3 <500 cells/mm 3 97 78 Leukopenia <3,000 cells/mm 3 <1,000 cells/mm 3 97 32 Thrombocytopenia <75,000/mm 3 <25,000/mm 3 69 27 Anemia <10 g/dL <8 g/dL 89 37 Table 2. Non-hematologic Adverse Reactions Experienced by ≥15% of 879 Patients, Including 426 Patients With Small Cell Lung Cancer, Receiving Topotecan Hydrochloride NA = Not applicable NR = Not reported separately a Does not include Grade 1 sepsis or pyrexia. b Rash also includes pruritus, rash erythematous, urticaria, dermatitis, bullous eruption, and maculopapular rash. c Pain includes body pain, back pain, and skeletal pain. Non-hematologic Adverse Reaction Percentage of Patients with Adverse Reaction (879 Patients) All Grades Grade 3 Grade 4 Infections and infestations Sepsis or pyrexia/infection with 43 NR 23 neutropenia a Metabolism and nutrition disorders Anorexia 19 2 <1 Nervous system disorders Headache 18 1 <1 Respiratory, thoracic, and mediastinal disorders Dyspnea 22 5 3 Coughing 15 1 0 Gastrointestinal disorders Nausea 64 7 1 Vomiting 45 4 1 Diarrhea 32 3 1 Constipation 29 2 1 Abdominal pain 22 2 2 Stomatitis 18 1 <1 Skin and subcutaneous tissue disorders Alopecia 49 NA NA Rash b 16 1 0 General disorders and administrative site conditions Fatigue 29 5 0 Pyrexia 28 1 <1 Pain c 23 2 1 Asthenia 25 4 2 Nervous System Disorders: Paresthesia occurred in 7% of patients but was generally grade 1. Hepatobiliary Disorders: Grade 1 transient elevations in hepatic enzymes occurred in 8% of patients. Greater elevations, grade 3/4, occurred in 4%. Grade 3/4 elevated bilirubin occurred in <2% of patients. Table 4 shows the grade 3/4 hematologic and major non-hematologic adverse reactions in the topotecan/CAV comparator trial in small cell lung cancer. Table 4. Adverse Reactions Experienced by ≥5% of Small Cell Lung Cancer Patients Randomized to Receive Topotecan Hydrochloride or CAV a Death related to sepsis occurred in 3% of patients receiving topotecan hydrochloride, and 1% of patients receiving CAV. b Pain includes body pain, skeletal pain, and back pain. Adverse Reaction Topotecan Hydrochloride (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 Pyrexia/Grade 4 neutropenia 28 26 Non-hematologic Grade 3/4 % % Infections and infestations 5 5 Documented sepsis a 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 b 5 7 Cervical Cancer: In the comparative trial with topotecan hydrochloride plus cisplatin versus cisplatin in patients with cervical cancer, the most common dose-limiting adverse reaction was myelosuppression. Table 5 shows the hematologic adverse reactions and Table 6 shows the non-hematologic adverse reactions in patients with cervical cancer. Table 5. Hematologic Adverse Reactions in Patients with Cervical Cancer Treated with Topotecan Hydrochloride Plus Cisplatin or Cisplatin Monotherapy a a Includes patients who were eligible and treated. Hematologic Adverse Reaction Topotecan Hydrochloride Plus Cisplatin (n = 140) Cisplatin (n = 144) Anemia All grades (Hgb <12 g/dL) 131 (94%) 130 (90%) Grade 3 (Hgb <8-6.5 g/dL) 47 (34%) 28 (19%) Grade 4 (Hgb <6.5 g/dL) 9 (6%) 5 (3%) Leukopenia All grades (<3,800 cells/mm 3 ) 128 (91%) 43 (30%) Grade 3 (<2,000-1,000 cells/mm 3 ) 58 (41%) 1 (1%) Grade 4 (<1,000 cells/mm 3 ) 35 (25%) 0 (0%) Neutropenia All grades (<2,000 cells/mm 3 ) 125 (89%) 28 (19%) Grade 3 (<1,000-500 cells/mm 3 ) 36 (26%) 1 (1%) Grade 4 (<500 cells/mm 3 ) 67 (48%) 1 (1%) Thrombocytopenia All grades (<130,000 cells/mm 3 ) 104 (74%) 21 (15%) Grade 3 (<50,000-10,000 cells/mm 3 ) 36 (26%) 5 (3%) Grade 4 (<10,000 cells/mm 3 ) 10 (7%) 0 (0%) Table 6. Non-hematologic Adverse Reactions Experienced by ≥5% of Patients with Cervical Cancer Treated with Topotecan Hydrochloride Plus Cisplatin or Cisplatin Monotherapy a Data were collected using NCI Common Toxicity Criteria, v. 2.0. a Includes patients who were eligible and treated. b Grades 1 through 4 only. There were 3 patients who experienced grade 5 deaths with investigator-designated attribution. One was 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. c Constitutional includes fatigue (lethargy, malaise, asthenia), fever (in the absence of neutropenia), rigors, chills, sweating, and weight gain or loss. d 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. Adverse Reactions Topotecan Hydrochloride Plus Cisplatin (n = 140) Cisplatin (n = 144) All Grades b Grade 3 Grade 4 All Grades b Grade 3 Grade 4 General disorders and administrative site conditions Constitutional c 96 (69%) 11 (8%) 0 89 (62%) 17 (12%) 0 Pain d 82 (59%) 28 (20%) 3 (2%) 72 (50%) 18 (13%) 5 (3%) Gastrointestinal disorders Vomiting 56 (40%) 20 (14%) 2 (1%) 53 (37%) 13 (9%) 0 Nausea 77 (55%) 18 (13%) 2 (1%) 79 (55%) 13 (9%) 0 Stomatitis-pharyngitis 8 (6%) 1 (<1%) 0 0 0 0 Other 88 (63%) 16 (11%) 4 (3%) 80 (56%) 12 (8%) 3 (2%) Dermatology 67 (48%) 1 (<1%) 0 29 (20%) 0 0 Metabolic-Laboratory 55 (39%) 13 (9%) 7 (5%) 44 (31%) 14 (10%) 1 (<1%) Genitourinary 51 (36%) 9 (6%) 9 (6%) 49 (34%) 7 (5%) 7 (5%) Nervous system disorders Neuropathy 4 (3%) 1 (<1%) 0 3 (2%) 1 (<1%) 0 Other 49 (35%) 3 (2%) 1 (<1%) 43 (30%) 7 (5%) 2 (1%) Infection-febrile neutropenia 39 (28%) 21 (15%) 5 (4%) 26 (18%) 11 (8%) 0 Cardiovascular 35 (25%) 7 (5%) 6 (4%) 22 (15%) 8 (6%) 3 (2%) Hepatic 34 (24%) 5 (4%) 2 (1%) 23 (16%) 2 (1%) 0 Pulmonary 24 (17%) 4 (3%) 0 23 (16%) 5 (3%) 3 (2%) Vascular disorders Hemorrhage 21 (15%) 8 (6%) 1 (<1%) 20 (14%) 3 (2%) 1 (<1%) Coagulation 8 (6%) 4 (3%) 3 (2%) 10 (7%) 7 (5%) 0 Musculoskeletal 19 (14%) 3 (2%) 0 7 (5%) 1 (<1%) 1 (<1%) Allergy-Immunology 8 (6%) 2 (1%) 1 (<1%) 4 (3%) 0 1 (<1%) Endocrine 8 (6%) 0 0 4 (3%) 2 (1%) 0 Sexual reproduction function 7 (5%) 0 0 10 (7%) 1 (<1%) 0 Ocular-visual 7 (5%) 0 0 7 (5%) 1 (<1%) 0 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials or listed in other sections of the prescribing information, the following reactions have been identified during post-marketing use of topotecan hydrochloride. 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. 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 colitis [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: Inadvertent extravasation [see Warnings and Precautions ( 5.5 )] .

<table ID="t1" width="100%"> <caption>Table 1. Hematologic Adverse Reactions Experienced in &#x2265;15% of 879 Patients, Including 426 Patients With Small Cell Lung Cancer, Receiving Topotecan Hydrochloride </caption> <col width="62.700%" align="left"/> <col width="37.300%" align="left"/> <tbody> <tr> <td align="center" valign="top" styleCode="Toprule Botrule Lrule Rrule">Hematologic Adverse Reaction </td> <td align="center" valign="top" styleCode="Toprule Botrule Rrule">Patients (n = 879) % Incidence </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Neutropenia &lt;1,500 cells/mm³ &lt;500 cells/mm³ </td> <td align="center" valign="top" styleCode="Botrule Rrule"> 97 78 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Leukopenia &lt;3,000 cells/mm³ &lt;1,000 cells/mm³ </td> <td align="center" valign="top" styleCode="Botrule Rrule"> 97 32 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Thrombocytopenia &lt;75,000/mm³ &lt;25,000/mm³ </td> <td align="center" valign="top" styleCode="Botrule Rrule"> 69 27 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Anemia &lt;10 g/dL &lt;8 g/dL </td> <td align="center" valign="top" styleCode="Botrule Rrule"> 89 37 </td> </tr> </tbody> </table>

<table ID="t2" width="100%"> <caption>Table 2. Non-hematologic Adverse Reactions Experienced by &#x2265;15% of 879 Patients, Including 426 Patients With Small Cell Lung Cancer, Receiving Topotecan Hydrochloride </caption> <col width="39.375%" align="left"/> <col width="21.900%" align="left"/> <col width="20.175%" align="left"/> <col width="18.550%" align="left"/> <tfoot> <tr> <td colspan="4" align="left" valign="top"> <paragraph styleCode="footnote">NA = Not applicable NR = Not reported separately ^a Does not include Grade 1 sepsis or pyrexia. ^b Rash also includes pruritus, rash erythematous, urticaria, dermatitis, bullous eruption, and maculopapular rash. ^c Pain includes body pain, back pain, and skeletal pain. </paragraph> </td> </tr> </tfoot> <tbody> <tr> <td rowspan="2" align="center" valign="top" styleCode="Toprule Botrule Lrule Rrule">Non-hematologic Adverse Reaction </td> <td colspan="3" align="center" valign="top" styleCode="Toprule Botrule Rrule">Percentage of Patients with Adverse Reaction (879 Patients) </td> </tr> <tr> <td align="center" valign="top" styleCode="Botrule Rrule">All Grades </td> <td align="center" valign="top" styleCode="Botrule Rrule">Grade 3 </td> <td align="center" valign="top" styleCode="Botrule Rrule">Grade 4 </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> <td align="center" valign="top" styleCode="Rrule"> </td> <td align="center" valign="top" styleCode="Rrule"> </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> Sepsis or pyrexia/infection with </td> <td align="center" valign="top" styleCode="Rrule">43 </td> <td align="center" valign="top" styleCode="Rrule">NR </td> <td align="center" valign="top" styleCode="Rrule">23 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> neutropenia^a </td> <td align="center" valign="top" styleCode="Botrule Rrule"/> <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">Metabolism and nutrition disorders</content> </td> <td align="center" valign="top" styleCode="Rrule"/> <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"> Anorexia </td> <td align="center" valign="top" styleCode="Botrule Rrule">19 </td> <td align="center" valign="top" styleCode="Botrule Rrule">2 </td> <td align="center" valign="top" styleCode="Botrule Rrule">&lt;1 </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Nervous system disorders</content> </td> <td align="center" valign="top" styleCode="Rrule"/> <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"> Headache </td> <td align="center" valign="top" styleCode="Botrule Rrule">18 </td> <td align="center" valign="top" styleCode="Botrule Rrule">1 </td> <td align="center" valign="top" styleCode="Botrule Rrule">&lt;1 </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"/> <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">22 </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"> Coughing </td> <td align="center" valign="top" styleCode="Botrule Rrule">15 </td> <td align="center" valign="top" styleCode="Botrule Rrule">1 </td> <td align="center" valign="top" styleCode="Botrule Rrule">0 </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"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> Nausea </td> <td align="center" valign="top" styleCode="Rrule">64 </td> <td align="center" valign="top" styleCode="Rrule">7 </td> <td align="center" valign="top" styleCode="Rrule">1 </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> Vomiting </td> <td align="center" valign="top" styleCode="Rrule">45 </td> <td align="center" valign="top" styleCode="Rrule">4 </td> <td align="center" valign="top" styleCode="Rrule">1 </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> Diarrhea </td> <td align="center" valign="top" styleCode="Rrule">32 </td> <td align="center" valign="top" styleCode="Rrule">3 </td> <td align="center" valign="top" styleCode="Rrule">1 </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> Constipation </td> <td align="center" valign="top" styleCode="Rrule">29 </td> <td align="center" valign="top" styleCode="Rrule">2 </td> <td align="center" valign="top" styleCode="Rrule">1 </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> Abdominal pain </td> <td align="center" valign="top" styleCode="Rrule">22 </td> <td align="center" valign="top" styleCode="Rrule">2 </td> <td align="center" valign="top" styleCode="Rrule">2 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> Stomatitis </td> <td align="center" valign="top" styleCode="Botrule Rrule">18 </td> <td align="center" valign="top" styleCode="Botrule Rrule">1 </td> <td align="center" valign="top" styleCode="Botrule Rrule">&lt;1 </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Skin and subcutaneous tissue disorders</content> </td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> Alopecia </td> <td align="center" valign="top" styleCode="Rrule">49 </td> <td align="center" valign="top" styleCode="Rrule">NA </td> <td align="center" valign="top" styleCode="Rrule">NA </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> Rash^b </td> <td align="center" valign="top" styleCode="Botrule Rrule">16 </td> <td align="center" valign="top" styleCode="Botrule Rrule">1 </td> <td align="center" valign="top" styleCode="Botrule Rrule">0 </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="bottom" styleCode="Rrule"/> <td align="center" valign="bottom" styleCode="Rrule"/> <td align="center" valign="bottom" styleCode="Rrule"/> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> Fatigue </td> <td align="center" valign="bottom" styleCode="Rrule">29 </td> <td align="center" valign="bottom" styleCode="Rrule">5 </td> <td align="center" valign="bottom" styleCode="Rrule">0 </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> Pyrexia </td> <td align="center" valign="bottom" styleCode="Rrule">28 </td> <td align="center" valign="bottom" styleCode="Rrule">1 </td> <td align="center" valign="bottom" styleCode="Rrule">&lt;1 </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> Pain^c </td> <td align="center" valign="bottom" styleCode="Rrule">23 </td> <td align="center" valign="bottom" styleCode="Rrule">2 </td> <td align="center" valign="bottom" styleCode="Rrule">1 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> Asthenia </td> <td align="center" valign="bottom" styleCode="Botrule Rrule">25 </td> <td align="center" valign="bottom" styleCode="Botrule Rrule">4 </td> <td align="center" valign="bottom" styleCode="Botrule Rrule">2 </td> </tr> </tbody> </table>

<table ID="t4" width="100%"> <caption>Table 4. Adverse Reactions Experienced by &#x2265;5% of Small Cell Lung Cancer Patients Randomized to Receive Topotecan Hydrochloride or CAV </caption> <col width="54.900%" align="left"/> <col width="23.967%" align="left"/> <col width="21.133%" align="left"/> <tfoot> <tr> <td colspan="3" align="left" valign="top"> <paragraph styleCode="footnote"> ^a Death related to sepsis occurred in 3% of patients receiving topotecan hydrochloride, and 1% of patients receiving CAV. ^b 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">Adverse Reaction </td> <td align="center" valign="top" styleCode="Toprule Botrule Rrule">Topotecan Hydrochloride (n = 107) </td> <td align="center" valign="top" styleCode="Toprule Botrule Rrule">CAV (n = 104) </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="bottom" styleCode="Rrule"/> <td align="center" valign="bottom" styleCode="Rrule"/> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule Botrule"> (&lt;500 cells/mm³) </td> <td align="center" valign="bottom" styleCode="Rrule Botrule">70 </td> <td align="center" valign="bottom" styleCode="Rrule Botrule">72 </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule">Grade 3/4 anemia </td> <td align="center" valign="bottom" styleCode="Rrule"/> <td align="center" valign="bottom" styleCode="Rrule"/> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> (Hgb &lt;8 g/dL) </td> <td align="center" valign="bottom" styleCode="Botrule Rrule">42 </td> <td align="center" valign="bottom" styleCode="Botrule Rrule">20 </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule">Grade 4 thrombocytopenia </td> <td align="center" valign="bottom" styleCode="Rrule"/> <td align="center" valign="bottom" styleCode="Rrule"/> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> (&lt;25,000 plts/mm³) </td> <td align="center" valign="bottom" styleCode="Botrule Rrule">29 </td> <td align="center" valign="bottom" styleCode="Botrule Rrule">5 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Pyrexia/Grade 4 neutropenia </td> <td align="center" valign="bottom" styleCode="Botrule Rrule">28 </td> <td align="center" valign="bottom" 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="bottom" styleCode="Botrule Rrule"> <content styleCode="bold">%</content> </td> <td align="center" valign="bottom" 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="bottom" styleCode="Rrule">5 </td> <td align="center" valign="bottom" styleCode="Rrule">5 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> Documented sepsis^a </td> <td align="center" valign="bottom" styleCode="Botrule Rrule"/> <td align="center" valign="bottom" styleCode="Botrule Rrule"/> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Respiratory, thoracic, and mediastinal disorders</content> </td> <td align="center" valign="bottom" styleCode="Rrule"/> <td align="center" valign="bottom" styleCode="Rrule"/> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> Dyspnea </td> <td align="center" valign="bottom" styleCode="Rrule">9 </td> <td align="center" valign="bottom" styleCode="Rrule">14 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> Pneumonia </td> <td align="center" valign="bottom" styleCode="Botrule Rrule">8 </td> <td align="center" valign="bottom" 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="bottom" styleCode="Rrule"/> <td align="center" valign="bottom" styleCode="Rrule"/> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> Abdominal pain </td> <td align="center" valign="bottom" styleCode="Rrule">6 </td> <td align="center" valign="bottom" styleCode="Rrule">4 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> Nausea </td> <td align="center" valign="bottom" styleCode="Botrule Rrule">8 </td> <td align="center" valign="bottom" 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="bottom" styleCode="Rrule"/> <td align="center" valign="bottom" styleCode="Rrule"/> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> Fatigue </td> <td align="center" valign="bottom" styleCode="Rrule">6 </td> <td align="center" valign="bottom" styleCode="Rrule">10 </td> </tr> <tr> <td align="left" valign="top" styleCode="Lrule Rrule"> Asthenia </td> <td align="center" valign="bottom" styleCode="Rrule">9 </td> <td align="center" valign="bottom" styleCode="Rrule">7 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> Pain^b </td> <td align="center" valign="bottom" styleCode="Botrule Rrule">5 </td> <td align="center" valign="bottom" styleCode="Botrule Rrule">7 </td> </tr> </tbody> </table>