HYCAMTIN

WARNING: MYELOSUPPRESSION HYCAMTIN can cause severe myelosuppression. Administer first cycle only to patients with baseline neutrophil counts of greater than or equal to 1,500/mm 3 and platelet counts greater than or equal to 100,000/mm 3 . Monitor blood cell counts [see Warnings and Precautions ( 5.1 )] . WARNING: MYELOSUPPRESSION See full prescribing information for complete boxed warning. HYCAMTIN can cause severe myelosuppression. Administer first cycle only to patients with baseline neutrophil counts greater than or equal to 1,500/mm 3 and platelet counts greater than or equal to 100,000/mm 3 . Monitor blood cell counts ( 2.4 , 5.1 ).

5 WARNINGS AND PRECAUTIONS Interstitial Lung Disease (ILD): Fatal cases have occurred. Permanently discontinue if ILD confirmed. ( 5.2 ) Extravasation and Tissue Injury: Severe cases have occurred. If extravasation occurs, immediately stop administration and institute recommended management procedures. ( 5.3 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of potential risk to the fetus and to use effectives contraception. ( 5.4 , 8.1 , 8.3 ) 5.1 Myelosuppression HYCAMTIN can cause severe myelosuppression. Single Agent Grade 4 neutropenia occurred in 78% of 879 patients, with a median duration of 7 days and was most common during Cycle 1 (58% of patients). Grade 4 neutropenia associated with infection occurred in 13% and febrile neutropenia occurred in 5%. Sepsis occurred in 4% of patients and was fatal in 1%. Grade 4 thrombocytopenia occurred in 27%, with a median duration of 5 days. Grade 3 or 4 anemia occurred in 37% of patients. Combination with Cisplatin Grade 4 neutropenia occurred in 48% and Grade 4 thrombocytopenia occurred in 7% of 147 patients. Grade 3 or 4 anemia occurred in 40% of patients. Topotecan can cause fatal typhlitis (neutropenic enterocolitis). Consider the possibility of typhlitis in patients presenting with fever, neutropenia, and abdominal pain. Administer the first cycle of HYCAMTIN for injection only to patients with a baseline neutrophil count of greater than or equal to 1,500/mm 3 and a platelet count greater than or equal to 100,000/mm 3 . Monitor blood counts frequently during treatment. Withhold and reduce dose of HYCAMTIN for injection based on neutrophil counts, platelet counts and hemoglobin levels [see Dosage and Administration (2.5)]. 5.2 Interstitial Lung Disease Interstitial lung disease (ILD), including fatalities, can occur with HYCAMTIN. Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer, thoracic radiation, and use of pneumotoxic drugs or colony stimulating factors. Monitor for pulmonary symptoms indicative of ILD. Permanently discontinue HYCAMTIN for injection if ILD is confirmed. 5.3 Extravasation and Tissue Injury Extravasation, including severe cases, can occur with HYCAMTIN for injection. If signs or symptoms of extravasation occur, immediately stop administration of HYCAMTIN for injection and institute recommended management procedures [see Adverse Reactions (6.1)] . 5.4 Embryo-Fetal Toxicity Based on animal data, HYCAMTIN can cause fetal harm when administered to a pregnant woman. Topotecan caused embryolethality, fetotoxicity, and teratogenicity in rats and rabbits when administered during organogenesis. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months after the last dose of HYCAMTIN for injection. Advise males with a female partner of reproductive potential to use effective contraception during treatment with HYCAMTIN for injection and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)] .

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Myelosuppression [see Warnings and Precautions (5.1)] Interstitial Lung Disease (ILD) [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 Novartis Pharmaceuticals Corporation at 1-888-669-6682 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 HYCAMTIN for injection from eight trials in which 879 patients with ovarian cancer or small cell lung cancer (SCLC) received HYCAMTIN for injection 1.5 mg/m 2 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 HYCAMTIN for injection 0.75 mg/m 2 by intravenous infusion daily on Days 1, 2, and 3, with cisplatin 50 mg/m 2 by intravenous infusion on Day 1, of a 21-day cycle. Ovarian Cancer The safety of HYCAMTIN for injection 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 HYCAMTIN for injection. Table 1. Adverse Reactions Occurring in Greater than or Equal to 5% of Patients With Ovarian Cancer in Study 039 a Death related to sepsis occurred in 2% of patients receiving HYCAMTIN and 0% of patients receiving paclitaxel. b Pain includes body pain, skeletal pain, and back pain. Adverse Reactions HYCAMTIN for Injection (n = 112) Paclitaxel (n = 114) Grade 3-4 (%) Grade 3-4 (%) Hematologic Grade 4 neutropenia (< 500/mm 3 ) Grade 3 or 4 anemia (Hgb < 8 g/dL) Grade 4 thrombocytopenia (< 25,000/mm 3 ) Febrile neutropenia 80 41 27 23 21 6 3 4 Non-Hematologic Infections Sepsis a 5 2 Respiratory, thoracic, and mediastinal Dyspnea 6 5 Gastrointestinal Vomiting 10 3 Nausea 10 2 Diarrhea 6 1 Abdominal pain 5 4 Intestinal obstruction 5 4 Constipation 5 0 General and administrative site conditions Fatigue 7 6 Pain b 5 7 Asthenia 5 3 Small Cell Lung Cancer (SCLC) The safety of HYCAMTIN for injection 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 Greater than or Equal to 5% of Patients With Small Cell Lung Cancer in Study 090 a Death related to sepsis occurred in 3% of patients receiving HYCAMTIN and 1% of patients receiving CAV. b Pain includes body pain, skeletal pain, and back pain. c CAV = cyclophosphamide, doxorubicin and vincristine. Adverse Reactions HYCAMTIN for Injection (n = 107) CAV c (n = 104) Grade 3-4 (%) Grade 3-4 (%) Hematologic Grade 4 neutropenia (< 500/mm 3 ) Grade 3 or 4 anemia (Hgb < 8 g/dL) Grade 4 thrombocytopenia (< 25,000/mm 3 ) Febrile neutropenia 70 42 29 28 72 20 5 26 Non-Hematologic Infections Sepsis a 5 5 Respiratory, thoracic, and mediastinal Dyspnea 9 14 Pneumonia 8 6 Gastrointestinal Nausea 8 6 Abdominal pain 6 4 General and administrative site conditions Asthenia 9 7 Fatigue 6 10 Pain b 5 7 Hepatobiliary Disorders in Ovarian and Small Cell Lung Cancer (SCLC) Based on the combined experience of 453 patients with metastatic ovarian cancer and 426 patients with SCLC treated with HYCAMTIN for injection, 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 HYCAMTIN for injection was evaluated in a comparative trial of HYCAMTIN 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 Greater than or Equal to 5% of Patients With Cervical Cancer (Between-Arm Difference ≥ 2%) a in Study GOG 0179 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%. Adverse Reactions HYCAMTIN for Injection With Cisplatin (n = 140) % Cisplatin (n = 144) % Hematologic Neutropenia Grade 3 (< 1,000-500/mm 3 ) 26 1 Grade 4 (< 500/mm 3 ) 48 1 Anemia Grade 3 (Hgb < 8-6.5 g/dL) 34 19 Grade 4 (Hgb < 6.5 g/dL) 6 3 Thrombocytopenia Grade 3 (< 50,000-10,000/mm 3 ) 26 3 Grade 4 (< 10,000/mm 3 ) 7 0 Non-Hematologic b,c General and administrative site conditions Constitutional d 69 62 Pain e 59 50 Gastrointestinal Vomiting 40 37 Stomatitis-pharyngitis 6 0 Other 63 56 Dermatology f 48 20 Infection Febrile neutropenia f 28 18 Cardiovascular f 25 15 6.2 Postmarketing Experience The following reactions have been identified during post approval use of HYCAMTIN. 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

<table><caption>Table 1. Adverse Reactions Occurring in Greater than or Equal to 5% of Patients With Ovarian Cancer in Study 039</caption><col width="43%"/><col width="21%"/><col width="21%"/><tfoot><tr><td styleCode="Toprule " colspan="3">^aDeath related to sepsis occurred in 2% of patients receiving HYCAMTIN and 0% of patients receiving paclitaxel. ^bPain includes body pain, skeletal pain, and back pain.</td></tr></tfoot><tbody><tr><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Adverse Reactions</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">HYCAMTIN for Injection</content></paragraph><paragraph><content styleCode="bold">(n = 112)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Paclitaxel</content></paragraph><paragraph><content styleCode="bold">(n = 114)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule "><paragraph/></td><td align="center" styleCode="Rrule Lrule Toprule Botrule "><paragraph><content styleCode="bold">Grade 3-4 (%)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule "><paragraph><content styleCode="bold">Grade 3-4 (%)</content></paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">Hematologic</content></paragraph></td><td styleCode="Toprule Botrule " valign="bottom"/><td styleCode="Rrule Toprule Botrule " valign="bottom"/></tr><tr><td styleCode="Rrule Lrule Botrule "><paragraph> Grade 4 neutropenia (&lt; 500/mm³) Grade 3 or 4 anemia (Hgb &lt; 8 g/dL) Grade 4 thrombocytopenia (&lt; 25,000/mm³) Febrile neutropenia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule "><paragraph>80 41 27 23</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule "><paragraph>21 6 3 4</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">Non-Hematologic</content></paragraph></td><td styleCode="Toprule Botrule " valign="bottom"/><td styleCode="Rrule Toprule Botrule " valign="bottom"/></tr><tr><td styleCode="Rrule Lrule "><paragraph><content styleCode="bold">Infections</content></paragraph></td><td/><td styleCode="Rrule Lrule Toprule "/></tr><tr><td styleCode="Rrule Lrule Botrule "><paragraph> Sepsis^a</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule "><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule "><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule "><paragraph><content styleCode="bold">Respiratory, thoracic, and mediastinal</content></paragraph></td><td styleCode="Rrule Lrule Toprule"/><td styleCode="Rrule Lrule Toprule"/></tr><tr><td styleCode="Rrule Lrule Botrule"><paragraph> Dyspnea</paragraph></td><td align="center" styleCode="Botrule"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule"><paragraph>5</paragraph></td></tr><tr><td styleCode="Rrule Lrule "><paragraph><content styleCode="bold">Gastrointestinal</content></paragraph></td><td/><td styleCode="Rrule Lrule "/></tr><tr><td styleCode="Rrule Lrule "><paragraph> Vomiting</paragraph></td><td align="center"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule Lrule "><paragraph>3</paragraph></td></tr><tr><td styleCode="Rrule Lrule"><paragraph> Nausea</paragraph></td><td align="center" styleCode="Rrule Lrule"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule Lrule "><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule "><paragraph> Diarrhea</paragraph></td><td align="center"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule "><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule"><paragraph> Abdominal pain</paragraph></td><td align="center" styleCode="Rrule Lrule"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule "><paragraph>4</paragraph></td></tr><tr><td styleCode="Rrule Lrule "><paragraph> Intestinal obstruction</paragraph></td><td align="center"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule "><paragraph>4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule "><paragraph> Constipation</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule "><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule "><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule "><paragraph><content styleCode="bold">General and administrative site conditions</content></paragraph></td><td styleCode="Rrule Lrule Toprule "/><td styleCode="Rrule Lrule Toprule "/></tr><tr><td styleCode="Rrule Lrule "><paragraph> Fatigue</paragraph></td><td align="center"><paragraph>7</paragraph></td><td align="center" styleCode="Rrule Lrule "><paragraph>6</paragraph></td></tr><tr><td styleCode="Rrule Lrule "><paragraph> Pain^b</paragraph></td><td align="center"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule "><paragraph>7</paragraph></td></tr><tr><td styleCode="Rrule Lrule "><paragraph> Asthenia</paragraph></td><td align="center"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule "><paragraph>3</paragraph></td></tr></tbody></table>

<table><caption>Table 2. Adverse Reactions Occurring in Greater than or Equal to 5% of Patients With Small Cell Lung Cancer in Study 090</caption><col width="43%"/><col width="21%"/><col width="21%"/><tfoot><tr><td styleCode="Toprule " colspan="3">^aDeath related to sepsis occurred in 3% of patients receiving HYCAMTIN and 1% of patients receiving CAV. ^bPain includes body pain, skeletal pain, and back pain. ^cCAV = cyclophosphamide, doxorubicin and vincristine.</td></tr></tfoot><tbody><tr><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Adverse Reactions</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">HYCAMTIN for Injection</content></paragraph><paragraph><content styleCode="bold">(n = 107)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">CAV^c</content></paragraph><paragraph><content styleCode="bold">(n = 104)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule "><paragraph/></td><td align="center" styleCode="Rrule Lrule Toprule Botrule "><paragraph><content styleCode="bold">Grade 3-4 (%)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule "><paragraph><content styleCode="bold">Grade 3-4 (%)</content></paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">Hematologic</content></paragraph></td><td styleCode="Toprule Botrule " valign="bottom"/><td styleCode="Rrule Toprule Botrule " valign="bottom"/></tr><tr><td styleCode="Rrule Lrule Botrule "><paragraph> Grade 4 neutropenia (&lt; 500/mm³) Grade 3 or 4 anemia (Hgb &lt; 8 g/dL) Grade 4 thrombocytopenia (&lt; 25,000/mm³) Febrile neutropenia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule "><paragraph>70 42 29 28</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule "><paragraph>72 20 5 26</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">Non-Hematologic</content></paragraph></td><td styleCode="Toprule Botrule " valign="bottom"/><td styleCode="Rrule Toprule Botrule " valign="bottom"/></tr><tr><td styleCode="Rrule Lrule "><paragraph><content styleCode="bold">Infections</content></paragraph></td><td/><td styleCode="Rrule Lrule Toprule "/></tr><tr><td styleCode="Rrule Lrule Botrule "><paragraph> Sepsis^a</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule "><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule "><paragraph>5</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule "><paragraph><content styleCode="bold">Respiratory, thoracic, and mediastinal</content></paragraph></td><td styleCode="Rrule Lrule Toprule"/><td styleCode="Rrule Lrule Toprule"/></tr><tr><td styleCode="Rrule Lrule"><paragraph> Dyspnea</paragraph></td><td align="center"><paragraph>9</paragraph></td><td align="center" styleCode="Rrule Lrule"><paragraph>14</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule"><paragraph> Pneumonia</paragraph></td><td align="center" styleCode="Botrule"><paragraph>8</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule"><paragraph>6</paragraph></td></tr><tr><td styleCode="Rrule Lrule "><paragraph><content styleCode="bold">Gastrointestinal</content></paragraph></td><td/><td styleCode="Rrule Lrule "/></tr><tr><td styleCode="Rrule Lrule"><paragraph> Nausea</paragraph></td><td align="center" styleCode="Rrule Lrule"><paragraph>8</paragraph></td><td align="center" styleCode="Rrule Lrule "><paragraph>6</paragraph></td></tr><tr><td styleCode="Rrule Lrule"><paragraph> Abdominal pain</paragraph></td><td align="center" styleCode="Rrule Lrule"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule "><paragraph>4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule "><paragraph><content styleCode="bold">General and administrative site conditions</content></paragraph></td><td styleCode="Rrule Lrule Toprule "/><td styleCode="Rrule Lrule Toprule "/></tr><tr><td styleCode="Rrule Lrule "><paragraph> Asthenia</paragraph></td><td align="center"><paragraph>9</paragraph></td><td align="center" styleCode="Rrule Lrule "><paragraph>7</paragraph></td></tr><tr><td styleCode="Rrule Lrule "><paragraph> Fatigue</paragraph></td><td align="center"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule "><paragraph>10</paragraph></td></tr><tr><td styleCode="Rrule Lrule "><paragraph> Pain^b</paragraph></td><td align="center"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule "><paragraph>7</paragraph></td></tr></tbody></table>

<table><caption>Table 3. Adverse Reactions Occurring in Greater than or Equal to 5% of Patients With Cervical Cancer (Between-Arm Difference &#x2265; 2%)^a in Study GOG 0179</caption><col width="43%"/><col width="21%"/><col width="21%"/><tfoot><tr><td styleCode="Toprule " colspan="3">^aIncludes patients who were eligible and treated. ^bSeverity based on using National Cancer Institute (NCI) Common Toxicity Criteria (CTC), Version 2.0. ^cGrades 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. ^dConstitutional includes fatigue (lethargy, malaise, asthenia), fever (in the absence of neutropenia), rigors, chills, sweating, and weight gain or loss. ^ePain 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. ^fHigh-level terms were included if the between-arm difference was &#x2265; 10%. </td></tr></tfoot><tbody><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Adverse Reactions</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">HYCAMTIN for Injection With Cisplatin</content></paragraph><paragraph><content styleCode="bold">(n = 140) %</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Cisplatin</content></paragraph><paragraph><content styleCode="bold">(n = 144) %</content></paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">Hematologic</content></paragraph></td><td styleCode="Toprule Botrule " valign="bottom"/><td styleCode="Rrule Toprule Botrule " valign="bottom"/></tr><tr><td styleCode="Rrule Lrule "><paragraph> Neutropenia </paragraph></td><td/><td styleCode="Rrule Lrule Toprule "/></tr><tr><td styleCode="Rrule Lrule "><paragraph> Grade 3 (&lt; 1,000-500/mm³) </paragraph></td><td align="center" styleCode="Rrule Lrule "><paragraph>26</paragraph></td><td align="center" styleCode="Rrule Lrule "><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule "><paragraph> Grade 4 (&lt; 500/mm³) </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule "><paragraph>48</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule "><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule "><paragraph> Anemia </paragraph></td><td/><td styleCode="Rrule Lrule Toprule "/></tr><tr><td styleCode="Rrule Lrule "><paragraph> Grade 3 (Hgb &lt; 8-6.5 g/dL) </paragraph></td><td align="center" styleCode="Rrule Lrule "><paragraph>34</paragraph></td><td align="center" styleCode="Rrule Lrule "><paragraph>19</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule "><paragraph> Grade 4 (Hgb &lt; 6.5 g/dL) </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule "><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule "><paragraph>3</paragraph></td></tr><tr><td styleCode="Rrule Lrule "><paragraph> Thrombocytopenia </paragraph></td><td/><td styleCode="Rrule Lrule Toprule "/></tr><tr><td styleCode="Rrule Lrule "><paragraph> Grade 3 (&lt; 50,000-10,000/mm³) </paragraph></td><td align="center" styleCode="Rrule Lrule "><paragraph>26</paragraph></td><td align="center" styleCode="Rrule Lrule "><paragraph>3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule "><paragraph> Grade 4 (&lt; 10,000/mm³) </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule "><paragraph>7</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule "><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">Non-Hematologic^b,c</content></paragraph></td><td styleCode="Toprule Botrule " valign="bottom"/><td styleCode="Rrule Toprule Botrule " valign="bottom"/></tr><tr><td styleCode="Rrule Lrule Toprule "><paragraph><content styleCode="bold">General and administrative site conditions</content></paragraph></td><td styleCode="Rrule Lrule Toprule "/><td styleCode="Rrule Lrule Toprule "/></tr><tr><td styleCode="Rrule Lrule "><paragraph> Constitutional^d</paragraph></td><td align="center"><paragraph>69</paragraph></td><td align="center" styleCode="Rrule Lrule "><paragraph>62</paragraph></td></tr><tr><td styleCode="Rrule Lrule "><paragraph> Pain^e</paragraph></td><td align="center"><paragraph>59</paragraph></td><td align="center" styleCode="Rrule Lrule "><paragraph>50</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule"><paragraph><content styleCode="bold">Gastrointestinal</content></paragraph></td><td styleCode="Rrule Lrule Toprule"/><td styleCode="Rrule Lrule Toprule"/></tr><tr><td styleCode="Rrule Lrule"><paragraph> Vomiting</paragraph></td><td align="center" styleCode="Rrule Lrule"><paragraph>40</paragraph></td><td align="center" styleCode="Rrule Lrule "><paragraph>37</paragraph></td></tr><tr><td styleCode="Rrule Lrule"><paragraph> Stomatitis-pharyngitis</paragraph></td><td align="center" styleCode="Rrule Lrule"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule "><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule"><paragraph> Other</paragraph></td><td align="center" styleCode="Rrule Lrule"><paragraph>63</paragraph></td><td align="center" styleCode="Rrule Lrule "><paragraph>56</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule Toprule"><paragraph><content styleCode="bold">Dermatology^f</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule Toprule"><paragraph>48</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule Toprule"><paragraph>20</paragraph></td></tr><tr><td styleCode="Rrule Lrule "><paragraph><content styleCode="bold">Infection</content></paragraph></td><td/><td styleCode="Rrule Lrule Toprule "/></tr><tr><td styleCode="Rrule Lrule Botrule "><paragraph> Febrile neutropenia^f</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule "><paragraph>28</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule "><paragraph>18</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule Toprule"><paragraph><content styleCode="bold">Cardiovascular^f</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule Toprule"><paragraph>25</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule Toprule"><paragraph>15</paragraph></td></tr></tbody></table>