Topotecan Injection is indicated for the treatment of:

{ "type": "p", "children": [], "text": "Topotecan Injection is indicated for the treatment of:" }

{ "type": "ul", "children": [ "small cell lung cancer sensitive disease after failure of first-line chemotherapy. In clinical studies submitted to support approval, sensitive disease was defined as disease responding to chemotherapy but subsequently progressing at least 60 days (in the Phase 3 study) or at least 90 days (in the Phase 2 studies) after chemotherapy\n \n [see\n \n Clinical Studies (\n \n 14)\n \n ]\n \n .\n \n " ], "text": "" }

Topotecan Injection in combination with cisplatin is indicated for the treatment of:

{ "type": "p", "children": [], "text": "Topotecan Injection in combination with cisplatin is indicated for the treatment of:" }

{ "type": "ul", "children": [ "stage IV-B, recurrent, or persistent carcinoma of the cervix which is not amenable to curative treatment with surgery and/or radiation therapy." ], "text": "" }

Recommended Dosage

Dosage Modification Guidelines

Recommended Dosage

The recommended dose of Topotecan Injection is 0.75 mg/m 2by intravenous infusion over 30 minutes daily on days 1, 2, and 3; followed by cisplatin 50 mg/m 2by intravenous infusion on day 1 repeated every 21 days (a 21-day course).

Dosage Modification Guidelines

Dosage adjustments for subsequent courses of Topotecan Injection in combination with cisplatin are specific for each drug. See manufacturer’s prescribing information for cisplatin administration and hydration guidelines and for cisplatin dosage adjustment in the event of hematologic toxicity

Renal Impairment

No dosage adjustment of Topotecan Injection appears to be required for patients with mild renal impairment (Cl cr40 to 60 mL/min.). Dosage adjustment of Topotecan Injection to 0.75 mg/m 2is recommended for patients with moderate renal impairment (20 to 39 mL/min.). Insufficient data are available in patients with severe renal impairment to provide a dosage recommendation for Topotecan Injection. [see Use in Specific Populations ( 8.6) and Clinical Pharmacology ( 12.3) ]

Topotecan Injection in combination with cisplatin for the treatment of cervical cancer should only be initiated in patients with serum creatinine ≤1.5 mg/dL. In the clinical trial, cisplatin was discontinued for a serum creatinine >1.5 mg/dL. Insufficient data are available regarding continuing monotherapy with Topotecan Injection after cisplatin discontinuation in patients with cervical cancer.

Handling

Topotecan is a cytotoxic anticancer drug. Prepare Topotecan Injection under a vertical laminar flow hood while wearing gloves and protective clothing. If Topotecan Injection solution contacts the skin, wash the skin immediately and thoroughly with soap and water. If Topotecan Injection contacts mucous membranes, flush thoroughly with water.

Use procedures for proper handling and disposal of anticancer drugs. Several guidelines on this subject have been published. 1-4

Preparation and Administration

The appropriate volume of the Topotecan Injection is diluted in a minimum of 50 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP prior to administration. Infuse over 30 minutes. Topotecan Injection diluted for infusion is stable for 4 hours at room temperature or 24 hours at refrigerated temperature in ambient lighting conditions.

Topotecan Injection is supplied as a multiple dose vial. Studies have shown the product is stable for 28 days after initial puncture when stored at room temperature.

Topotecan Injection is available in the following strengths:

{ "type": "p", "children": [], "text": "Topotecan Injection is available in the following strengths:" }

1 mg/mL Multiple Dose Vial

{ "type": "p", "children": [], "text": "1 mg/mL Multiple Dose Vial" }

4 mg/4 mL (1 mg/mL) Multiple Dose Vial

{ "type": "p", "children": [], "text": "4 mg/4 mL (1 mg/mL) Multiple Dose Vial" }

Each mL contains topotecan hydrochloride equivalent to 1 mg of topotecan free base for intravenous infusion only following dilution.

{ "type": "p", "children": [], "text": "Each mL contains topotecan hydrochloride equivalent to 1 mg of topotecan free base for intravenous infusion only following dilution." }

Topotecan Injection is contraindicated in patients who have a history of severe hypersensitivity reactions (e.g., anaphylactoid reactions) to topotecan or to any of its ingredients. Topotecan Injection should not be used in patients with severe bone marrow depression.

{ "type": "p", "children": [], "text": "Topotecan Injection is contraindicated in patients who have a history of severe hypersensitivity reactions (e.g., anaphylactoid reactions) to topotecan or to any of its ingredients. Topotecan Injection should not be used in patients with severe bone marrow depression." }

Bone marrow suppression (primarily neutropenia) is the dose-limiting toxicity of Topotecan Injection. Neutropenia is not cumulative over time. In the comparative study, in small cell lung cancer, the treatment-related death rates were 5% for topotecan and 4% for CAV (cyclophosphamide-doxorubicin-vincristine).

Neutropenia

Thrombocytopenia

Anemia

Monitoring of Bone Marrow Function

Administer Topotecan Injection only in patients with adequate bone marrow reserves, including baseline neutrophil count of at least 1,500 cells/mm 3and platelet count at least 100,000/mm 3.

Monitor peripheral blood counts frequently during treatment with Topotecan Injection. Do not treat patients with subsequent courses of Topotecan Injection until neutrophils recover to >1,000 cells/mm 3, platelets recover to >100,000 cells/mm 3, and hemoglobin levels recover to 9 g/dL (with transfusion if necessary).Severe myelotoxicity has been reported when Topotecan Injection is used in combination with cisplatin [see Drug Interactions ( 7) ]

Topotecan-induced neutropenia can lead to neutropenic colitis. Fatalities due to neutropenic colitis have been reported in clinical trials with Topotecan Injection. In patients presenting with fever, neutropenia, and a compatible pattern of abdominal pain, consider the possibility of neutropenic colitis.

Topotecan Injection 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 Injection if a new diagnosis of ILD is confirmed.

Pregnancy Category D

Topotecan 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. There are no adequate and well controlled studies of Topotecan Injection in pregnant women. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving Topotecan Injection, the patient should be apprised of the potential hazard to the fetus. [see Use in Specific Populations, Pregnancy ( 8.1) ]

Inadvertent extravasation with topotecan has been observed, most reactions have been mild but severe cases have been reported.

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 experiences of the 879 patients studied, including 426 patients with small cell lung cancer treated with topotecan. Table 1lists the principle hematologic adverse reactions and Table 2lists non-hematologic adverse reactions occurring in at least 15% of patients.

<div class="scrollingtable"><table border="single" width="800"> <caption> <span>Table 1. Hematologic Adverse Reactions Experienced in ≥15% of Patients, Including 426 Patients With Small Cell Lung Cancer, Receiving Topotecan</span> </caption> <col width="50.0%"/> <col width="50.0%"/> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top">Hematologic Adverse Reaction</td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">Patients</p> <p>(n=879)</p>% Incidence </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="middle"> <p class="First">Neutropenia</p> <p>&lt;1,500 cells/mm <span class="Sup">3</span> </p>&lt;500 cells/mm <span class="Sup">3</span></td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">97</p>78 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="middle"> <p class="First">Leukopenia</p> <p>&lt;3,000 cells/mm <span class="Sup">3</span> </p>&lt;1,000 cells/mm <span class="Sup">3</span></td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">97</p>32 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="middle"> <p class="First">Thrombocytopenia</p> <p>&lt;75,000/mm <span class="Sup">3</span> </p>&lt;25,000/mm <span class="Sup">3</span></td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">69</p>27 </td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="middle"> <p class="First">Anemia</p> <p>&lt;10 g/dL</p>&lt;8 g/dL </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">89</p>37 </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table border="single" width="800"> <caption> <span>Table 2. Non-hematologic Adverse Reactions Experienced by ≥15% of 879 Patients, Including 426 Patients With Small Cell Lung Cancer, Receiving Topotecan</span> </caption> <col width="45.6%"/> <col width="20.9%"/> <col width="16.7%"/> <col width="16.7%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" rowspan="3" valign="bottom"> <p class="First"> <span class="Bold">Non-hematologic</span> </p> <span class="Bold">Adverse Reaction</span></td><td align="center" class="Botrule Rrule" colspan="3" valign="top"><span class="Bold">Percentage of Patients with Adverse Reaction (879 Patients)</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">All Grades</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Grade 3</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Grade 4</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Infections and infestations</span></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Sepsis or pyrexia/infection with neutropenia <span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">43</td><td align="center" class="Botrule Rrule" valign="top">NR</td><td align="center" class="Botrule Rrule" valign="top">23</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Metabolism and nutrition disorders</span></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  Anorexia</td><td align="center" class="Botrule Rrule" valign="top">19</td><td align="center" class="Botrule Rrule" valign="top">2</td><td align="center" class="Botrule Rrule" valign="top">&lt;1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Nervous system disorders</span></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  Headache</td><td align="center" class="Botrule Rrule" valign="top">18</td><td align="center" class="Botrule Rrule" valign="top">1</td><td align="center" class="Botrule Rrule" valign="top">&lt;1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Respiratory, thoracic, and mediastinal disorders</span></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  Dyspnea</td><td align="center" class="Botrule Rrule" valign="top">22</td><td align="center" class="Botrule Rrule" valign="top">5</td><td align="center" class="Botrule Rrule" valign="top">3</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  Coughing</td><td align="center" class="Botrule Rrule" valign="top">15</td><td align="center" class="Botrule Rrule" valign="top">1</td><td align="center" class="Botrule Rrule" valign="top">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Gastrointestinal disorders</span></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  Nausea</td><td align="center" class="Botrule Rrule" valign="top">64</td><td align="center" class="Botrule Rrule" valign="top">7</td><td align="center" class="Botrule Rrule" valign="top">1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  Vomiting</td><td align="center" class="Botrule Rrule" valign="top">45</td><td align="center" class="Botrule Rrule" valign="top">4</td><td align="center" class="Botrule Rrule" valign="top">1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  Diarrhea</td><td align="center" class="Botrule Rrule" valign="top">32</td><td align="center" class="Botrule Rrule" valign="top">3</td><td align="center" class="Botrule Rrule" valign="top">1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  Constipation</td><td align="center" class="Botrule Rrule" valign="top">29</td><td align="center" class="Botrule Rrule" valign="top">2</td><td align="center" class="Botrule Rrule" valign="top">1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  Abdominal pain</td><td align="center" class="Botrule Rrule" valign="top">22</td><td align="center" class="Botrule Rrule" valign="top">2</td><td align="center" class="Botrule Rrule" valign="top">2</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  Stomatitis</td><td align="center" class="Botrule Rrule" valign="top">18</td><td align="center" class="Botrule Rrule" valign="top">1</td><td align="center" class="Botrule Rrule" valign="top">&lt;1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Skin and subcutaneous tissue disorders</span></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  Alopecia</td><td align="center" class="Botrule Rrule" valign="top">49</td><td align="center" class="Botrule Rrule" valign="top">NA</td><td align="center" class="Botrule Rrule" valign="top">NA</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  Rash <span class="Sup">b</span></td><td align="center" class="Botrule Rrule" valign="top">16</td><td align="center" class="Botrule Rrule" valign="top">1</td><td align="center" class="Botrule Rrule" valign="top">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">General disorders and administrative site conditions</span></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  Fatigue</td><td align="center" class="Botrule Rrule" valign="top">29</td><td align="center" class="Botrule Rrule" valign="top">5</td><td align="center" class="Botrule Rrule" valign="top">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  Pyrexia</td><td align="center" class="Botrule Rrule" valign="top">28</td><td align="center" class="Botrule Rrule" valign="top">1</td><td align="center" class="Botrule Rrule" valign="top">&lt;1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  Pain <span class="Sup">c</span></td><td align="center" class="Botrule Rrule" valign="top">23</td><td align="center" class="Botrule Rrule" valign="top">2</td><td align="center" class="Botrule Rrule" valign="top">1</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">  Asthenia</td><td align="center" class="Rrule" valign="top">25</td><td align="center" class="Rrule" valign="top">4</td><td align="center" class="Botrule Rrule" valign="top">2</td> </tr> </tbody> </table></div>

NA = Not applicable

NR = Not reported separately

aDoes not include Grade 1 sepsis or pyrexia

bRash also includes pruritus, rash erythematous, urticaria, dermatitis, bullous eruption, and maculopapular rash.

cPain includes body pain, back pain, and skeletal pain.

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 3shows the grade 3/4 hematologic and major non-hematologic adverse reactions in the topotecan/CAV comparator trial in small cell lung cancer.

Table 3. Adverse Reactions Experienced by ≥5% of Small Cell Lung Cancer Patients Randomized to Receive Topotecan or CAV

<div class="scrollingtable"><table border="single" width="800"> <col width="50.1%"/> <col width="23.5%"/> <col width="26.4%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Adverse Reaction</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Topotecan</p>(n=107) </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">CAV</p>(n=104) </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Hematologic Grade 3/4</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">%</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">%</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 4 neutropenia</p>(&lt;500 cells/mm <span class="Sup">3</span>) </td><td align="center" class="Botrule Rrule" valign="top">70</td><td align="center" class="Botrule Rrule" valign="top">72</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 3/4 anemia</p>(Hgb &lt;8 g dL) </td><td align="center" class="Botrule Rrule" valign="top">42</td><td align="center" class="Botrule Rrule" valign="top">20</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 4 thrombocytopenia</p>(&lt;25,000 plts/mm <span class="Sup">3</span>) </td><td align="center" class="Botrule Rrule" valign="top">29</td><td align="center" class="Botrule Rrule" valign="top">5</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Pyrexia/Grade 4 neutropenia</td><td align="center" class="Botrule Rrule" valign="top">28</td><td align="center" class="Botrule Rrule" valign="top">26</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Non-hematologic Grade 3/4</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">%</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">%</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Infections and infestations</span> </p>Documented sepsis <span class="Sup">a</span></td><td align="center" class="Botrule Rrule" valign="top">5</td><td align="center" class="Botrule Rrule" valign="top">5</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Respiratory, thoracic, and mediastinal disorders</span> </p> <p>Dyspnea</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">14</p> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Pneumonia</td><td align="center" class="Botrule Rrule" valign="top">8</td><td align="center" class="Botrule Rrule" valign="top">6</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Gastrointestinal disorders</span> </p> <p>Abdominal pain</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Nausea</td><td align="center" class="Botrule Rrule" valign="top">8</td><td align="center" class="Botrule Rrule" valign="top">6</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">General disorders and administrative site conditions</span> </p> <p>Fatigue</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10</p> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Asthenia</td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7</p> </td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">Pain <span class="Sup">b</span></td><td align="center" class="Rrule" valign="top">5</td><td align="center" class="Botrule Rrule" valign="top">7</td> </tr> </tbody> </table></div>

aDeath related to sepsis occurred in 3% of patients receiving topotecan, and in 1% of patients receiving CAV

bPain includes body pain, skeletal pain, and back pain.

Cervical Cancer

In the comparative trial with Topotecan Injection plus cisplatin versus cisplatin in patients with cervical cancer, the most common dose-limiting adverse reaction was myelosuppression. Table 4shows the hematologic adverse reactions and Table 5shows the non-hematologic adverse reactions in patients with cervical cancer.

<div class="scrollingtable"><table border="single" width="500"> <caption> <span>Table 4. Hematologic Adverse Reactions in Patients with Cervical Cancer Treated with Topotecan Injection Plus Cisplatin or Cisplatin Monotherapy <span class="Sup">a</span></span> </caption> <col width="100%"/> <col width="100%"/> <col width="100%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"><span class="Bold">Hematologic Adverse Reaction</span></td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Topotecan Injection <span class="Bold">Plus Cisplatin</span> </p> <span class="Bold">(n = 140)</span></td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Cisplatin</span> </p> <span class="Bold">(n = 144)</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Anemia</td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  All grades (Hgb &lt;12 g/dL)</td><td align="center" class="Botrule Rrule" valign="top">131 (94%)</td><td align="center" class="Botrule Rrule" valign="top">130 (90%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  Grade 3 (Hgb &lt;8 to 6.5 g/dL)</td><td align="center" class="Botrule Rrule" valign="top">47 (34%)</td><td align="center" class="Botrule Rrule" valign="top">28 (19%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  Grade 4 (Hgb &lt;6.5 g/dL)</td><td align="center" class="Botrule Rrule" valign="top">9 (6%)</td><td align="center" class="Botrule Rrule" valign="top">5 (3%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Leukopenia</td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  All grades (&lt;3,800 cells/mm <span class="Sup">3</span>) </td><td align="center" class="Botrule Rrule" valign="top">128 (91%)</td><td align="center" class="Botrule Rrule" valign="top">43 (30%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  Grade 3 (&lt;2,000 to 1,000 cells/mm <span class="Sup">3</span>) </td><td align="center" class="Botrule Rrule" valign="top">58 (41%)</td><td align="center" class="Botrule Rrule" valign="top">1 (1%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  Grade 4 (&lt;1,000 cells/mm <span class="Sup">3</span>) </td><td align="center" class="Botrule Rrule" valign="top">35 (25%)</td><td align="center" class="Botrule Rrule" valign="top">0 (0%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Neutropenia</td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  All grades (&lt;2,000 cells/mm <span class="Sup">3</span>) </td><td align="center" class="Botrule Rrule" valign="top">125 (89%)</td><td align="center" class="Botrule Rrule" valign="top">28 (19%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  Grade 3 (&lt;1,000 to 500 cells/mm <span class="Sup">3</span>) </td><td align="center" class="Botrule Rrule" valign="top">36 (26%)</td><td align="center" class="Botrule Rrule" valign="top">1 (1%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  Grade 4 (&lt;500 cells/mm <span class="Sup">3</span>) </td><td align="center" class="Botrule Rrule" valign="top">67 (48%)</td><td align="center" class="Botrule Rrule" valign="top">1 (1%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Thrombocytopenia</td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  All grades (&lt;130,000 cells/mm <span class="Sup">3</span>) </td><td align="center" class="Botrule Rrule" valign="top">104 (74%)</td><td align="center" class="Botrule Rrule" valign="top">21 (15%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  Grade 3 (&lt;50,000 to 10,000 cells/mm <span class="Sup">3</span>) </td><td align="center" class="Botrule Rrule" valign="top">36 (26%)</td><td align="center" class="Botrule Rrule" valign="top">5 (3%)</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">  Grade 4 (&lt;10,000 cells/mm <span class="Sup">3</span>) </td><td align="center" class="Rrule" valign="top">10 (7%)</td><td align="center" class="Botrule Rrule" valign="top">0 (0%)</td> </tr> </tbody> </table></div>

aIncludes patients who were eligible and treated.

<div class="scrollingtable"><table border="single" width="500"> <caption> <span>Table 5. Non-hematologic Adverse Reactions Experienced by ≥ 5% of Patients with Cervical Cancer Treated with Topotecan Injection Plus Cisplatin or Cisplatin Monotherapy <span class="Sup">a</span></span> </caption> <col width="30.1%"/> <col width="13.0%"/> <col width="13.7%"/> <col width="11.0%"/> <col width="11.5%"/> <col width="10.8%"/> <col width="9.8%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"></td><td align="center" class="Botrule Rrule" colspan="3" valign="top"><span class="Bold">Topotecan Injection Plus Cisplatin</span></td><td align="center" class="Botrule Rrule" colspan="3" valign="top"><span class="Bold">Cisplatin</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" colspan="3" valign="top"><span class="Bold">(n = 140)</span></td><td align="center" class="Botrule Rrule" colspan="3" valign="top"><span class="Bold">(n = 144)</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">Adverse Reaction</td><td align="center" class="Botrule Rrule" valign="top">All Grades <span class="Sup">b</span></td><td align="center" class="Botrule Rrule" valign="top">Grade 3</td><td align="center" class="Botrule Rrule" valign="top">Grade 4</td><td align="center" class="Botrule Rrule" valign="top">All Grades <span class="Sup">b</span></td><td align="center" class="Botrule Rrule" valign="top">Grade 3</td><td align="center" class="Botrule Rrule" valign="top">Grade 4</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">General disorders and administrative site conditions</span></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  Constitutional <span class="Sup">c</span></td><td align="center" class="Botrule Rrule" valign="top">96 (69%)</td><td align="center" class="Botrule Rrule" valign="top">11 (8%)</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">89 (62%)</td><td align="center" class="Botrule Rrule" valign="top">17 (12%)</td><td align="center" class="Botrule Rrule" valign="top">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  Pain <span class="Sup">d</span></td><td align="center" class="Botrule Rrule" valign="top">82 (59%)</td><td align="center" class="Botrule Rrule" valign="top">28 (20%)</td><td align="center" class="Botrule Rrule" valign="top">3 (2%)</td><td align="center" class="Botrule Rrule" valign="top">72 (50%)</td><td align="center" class="Botrule Rrule" valign="top">18 (13%)</td><td align="center" class="Botrule Rrule" valign="top">5 (3%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Gastrointestinal disorders</span></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  Vomiting</td><td align="center" class="Botrule Rrule" valign="top">56 (40%)</td><td align="center" class="Botrule Rrule" valign="top">20 (14%)</td><td align="center" class="Botrule Rrule" valign="top">2 (1%)</td><td align="center" class="Botrule Rrule" valign="top">53 (37%)</td><td align="center" class="Botrule Rrule" valign="top">13 (9%)</td><td align="center" class="Botrule Rrule" valign="top">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  Nausea</td><td align="center" class="Botrule Rrule" valign="top">77 (55%)</td><td align="center" class="Botrule Rrule" valign="top">18 (13%)</td><td align="center" class="Botrule Rrule" valign="top">2 (1%)</td><td align="center" class="Botrule Rrule" valign="top">79 (55%)</td><td align="center" class="Botrule Rrule" valign="top">13 (9%)</td><td align="center" class="Botrule Rrule" valign="top">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  Stomatitis-pharyngitis</td><td align="center" class="Botrule Rrule" valign="top">8 (6%)</td><td align="center" class="Botrule Rrule" valign="top">1 (&lt;1%)</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  Other</td><td align="center" class="Botrule Rrule" valign="top">88 (63%)</td><td align="center" class="Botrule Rrule" valign="top">16 (11%)</td><td align="center" class="Botrule Rrule" valign="top">4 (3%)</td><td align="center" class="Botrule Rrule" valign="top">80 (56%)</td><td align="center" class="Botrule Rrule" valign="top">12 (8%)</td><td align="center" class="Botrule Rrule" valign="top">3 (2%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Dermatology</span></td><td align="center" class="Botrule Rrule" valign="top">67 (48%)</td><td align="center" class="Botrule Rrule" valign="top">1 (&lt;1%)</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">29 (20%)</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Metabolic-Laboratory</span></td><td align="center" class="Botrule Rrule" valign="top">55 (39%)</td><td align="center" class="Botrule Rrule" valign="top">13 (9%)</td><td align="center" class="Botrule Rrule" valign="top">7 (5%)</td><td align="center" class="Botrule Rrule" valign="top">44 (31%)</td><td align="center" class="Botrule Rrule" valign="top">14 (10%)</td><td align="center" class="Botrule Rrule" valign="top">1 (&lt;1%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Genitourinary</span></td><td align="center" class="Botrule Rrule" valign="top">51 (36%)</td><td align="center" class="Botrule Rrule" valign="top">9 (6%)</td><td align="center" class="Botrule Rrule" valign="top">9 (6%)</td><td align="center" class="Botrule Rrule" valign="top">49 (34%)</td><td align="center" class="Botrule Rrule" valign="top">7 (5%)</td><td align="center" class="Botrule Rrule" valign="top">7 (5%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Nervous system disorders</span></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  Neuropathy</td><td align="center" class="Botrule Rrule" valign="top">4 (3%)</td><td align="center" class="Botrule Rrule" valign="top">1 (&lt;1%)</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">3 (2%)</td><td align="center" class="Botrule Rrule" valign="top">1 (&lt;1%)</td><td align="center" class="Botrule Rrule" valign="top">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  Other</td><td align="center" class="Botrule Rrule" valign="top">49 (35%)</td><td align="center" class="Botrule Rrule" valign="top">3 (2%)</td><td align="center" class="Botrule Rrule" valign="top">1 (&lt;1%)</td><td align="center" class="Botrule Rrule" valign="top">43 (30%)</td><td align="center" class="Botrule Rrule" valign="top">7 (5%)</td><td align="center" class="Botrule Rrule" valign="top">2 (1%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Infection-febrile neutropenia</span></td><td align="center" class="Botrule Rrule" valign="top">39 (28%)</td><td align="center" class="Botrule Rrule" valign="top">21 (15%)</td><td align="center" class="Botrule Rrule" valign="top">5 (4%)</td><td align="center" class="Botrule Rrule" valign="top">26 (18%)</td><td align="center" class="Botrule Rrule" valign="top">11 (8%)</td><td align="center" class="Botrule Rrule" valign="top">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Cardiovascular</span></td><td align="center" class="Botrule Rrule" valign="top">35 (25%)</td><td align="center" class="Botrule Rrule" valign="top">7 (5%)</td><td align="center" class="Botrule Rrule" valign="top">6 (4%)</td><td align="center" class="Botrule Rrule" valign="top">22 (15%)</td><td align="center" class="Botrule Rrule" valign="top">8 (6%)</td><td align="center" class="Botrule Rrule" valign="top">3 (2%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Hepatic</span></td><td align="center" class="Botrule Rrule" valign="top">34 (24%)</td><td align="center" class="Botrule Rrule" valign="top">5 (4%)</td><td align="center" class="Botrule Rrule" valign="top">2 (1%)</td><td align="center" class="Botrule Rrule" valign="top">23 (16%)</td><td align="center" class="Botrule Rrule" valign="top">2 (1%)</td><td align="center" class="Botrule Rrule" valign="top">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Pulmonary</span></td><td align="center" class="Botrule Rrule" valign="top">24 (17%)</td><td align="center" class="Botrule Rrule" valign="top">4 (3%)</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">23 (16%)</td><td align="center" class="Botrule Rrule" valign="top">5 (3%)</td><td align="center" class="Botrule Rrule" valign="top">3 (2%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Vascular disorders</span></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  Hemorrhage</td><td align="center" class="Botrule Rrule" valign="top">21 (15%)</td><td align="center" class="Botrule Rrule" valign="top">8 (6%)</td><td align="center" class="Botrule Rrule" valign="top">1 (&lt;1%)</td><td align="center" class="Botrule Rrule" valign="top">20 (14%)</td><td align="center" class="Botrule Rrule" valign="top">3 (2%)</td><td align="center" class="Botrule Rrule" valign="top">1 (&lt;1%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  Coagulation</td><td align="center" class="Botrule Rrule" valign="top">8 (6%)</td><td align="center" class="Botrule Rrule" valign="top">4 (3%)</td><td align="center" class="Botrule Rrule" valign="top">3 (2%)</td><td align="center" class="Botrule Rrule" valign="top">10 (7%)</td><td align="center" class="Botrule Rrule" valign="top">7 (5%)</td><td align="center" class="Botrule Rrule" valign="top">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Musculoskeletal</span></td><td align="center" class="Botrule Rrule" valign="top">19 (14%)</td><td align="center" class="Botrule Rrule" valign="top">3 (2%)</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">7 (5%)</td><td align="center" class="Botrule Rrule" valign="top">1 (&lt;1%)</td><td align="center" class="Botrule Rrule" valign="top">1 (&lt;1%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Allergy-Immunology</span></td><td align="center" class="Botrule Rrule" valign="top">8 (6%)</td><td align="center" class="Botrule Rrule" valign="top">2 (1%)</td><td align="center" class="Botrule Rrule" valign="top">1 (&lt;1%)</td><td align="center" class="Botrule Rrule" valign="top">4 (3%)</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">1 (&lt;1%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Endocrine</span></td><td align="center" class="Botrule Rrule" valign="top">8 (6%)</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">4 (3%)</td><td align="center" class="Botrule Rrule" valign="top">2 (1%)</td><td align="center" class="Botrule Rrule" valign="top">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Sexual reproduction function</span></td><td align="center" class="Botrule Rrule" valign="top">7 (5%)</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">10 (7%)</td><td align="center" class="Botrule Rrule" valign="top">1 (&lt;1%)</td><td align="center" class="Botrule Rrule" valign="top">0</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Ocular-visual</span></td><td align="center" class="Rrule" valign="top">7 (5%)</td><td align="center" class="Rrule" valign="top">0</td><td align="center" class="Rrule" valign="top">0</td><td align="center" class="Rrule" valign="top">7 (5%)</td><td align="center" class="Rrule" valign="top">1 (&lt;1%)</td><td align="center" class="Botrule Rrule" valign="top">0</td> </tr> </tbody> </table></div>

Data were collected using NCI Common Toxicity Criteria, v. 2.0.

aIncludes patients who were eligible and treated.

bGrades 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.

cConstitutional includes fatigue (lethargy, malaise, asthenia), fever (in the absence of neutropenia), rigors, chills, sweating, and weight gain or loss.

dPain 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.

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 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 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 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) ]

G-CSF:Concomitant administration of G-CSF can prolong the duration of neutropenia, so if G-CSF is to be used, do not initiate it until day 6 of the course of therapy, 24 hours after completion of treatment with Topotecan Injection.

{ "type": "p", "children": [], "text": "\nG-CSF:Concomitant administration of G-CSF can prolong the duration of neutropenia, so if G-CSF is to be used, do not initiate it until day 6 of the course of therapy, 24 hours after completion of treatment with Topotecan Injection.\n\n " }

Platinum and Other Cytotoxic Agents:Myelosuppression was more severe when topotecan, at a dose of 1.25 mg/m 2/day for 5 days, was given in combination with cisplatin at a dose of 50 mg/m 2in Phase 1 studies. In one study, 1 of 3 patients had severe neutropenia for 12 days and a second patient died with neutropenic sepsis.

{ "type": "p", "children": [], "text": "\nPlatinum and Other Cytotoxic Agents:Myelosuppression was more severe when topotecan, at a dose of 1.25 mg/m\n \n 2/day for 5 days, was given in combination with cisplatin at a dose of 50 mg/m\n \n 2in Phase 1 studies. In one study, 1 of 3 patients had severe neutropenia for 12 days and a second patient died with neutropenic sepsis.\n\n " }

Greater myelosuppression is also likely to be seen when Topotecan Injection is used in combination with other cytotoxic agents, thereby necessitating a dose reduction. However, when combining topotecan with platinum agents (e.g., cisplatin or carboplatin), a distinct sequence-dependent interaction on myelosuppression has been reported. Coadministration of a platinum agent on day 1 of dosing with topotecan required lower doses of each agent compared to co-administration on day 5 of the dosing schedule for topotecan.

{ "type": "p", "children": [], "text": "Greater myelosuppression is also likely to be seen when Topotecan Injection is used in combination with other cytotoxic agents, thereby necessitating a dose reduction. However, when combining topotecan with platinum agents (e.g., cisplatin or carboplatin), a distinct sequence-dependent interaction on myelosuppression has been reported. Coadministration of a platinum agent on day 1 of dosing with topotecan required lower doses of each agent compared to co-administration on day 5 of the dosing schedule for topotecan." }

For information on the pharmacokinetics, efficacy, safety, and dosing of Topotecan Injection at a dose of 0.75 mg/m 2/day on days 1, 2, and 3 in combination with cisplatin 50 mg/m 2on day 1 for cervical cancer [see Dosage and Administration ( 2) , Adverse Reactions ( 6), Clinical Pharmacology ( 12.3) and Clinical Studies ( 14) ] .

{ "type": "p", "children": [], "text": "For information on the pharmacokinetics, efficacy, safety, and dosing of Topotecan Injection at a dose of 0.75 mg/m\n \n 2/day on days 1, 2, and 3 in combination with cisplatin 50 mg/m\n \n 2on day 1 for cervical cancer [see\n \n Dosage and Administration (\n \n 2)\n \n ,\n \n Adverse Reactions (\n \n 6),\n \n Clinical Pharmacology (\n \n 12.3)\n \n and\n \n Clinical Studies (\n \n 14)\n \n ]\n \n .\n\n " }

Pregnancy Category D [see Warnings and Precautions ( 5.4) ].

Topotecan Injection can cause fetal harm when administered to a pregnant woman. In rabbits, a dose of 0.1 mg/kg/day (about equal to the clinical dose of 1.5 mg/m 2) given on days 6 through 20 of gestation caused maternal toxicity, embryolethality, and reduced fetal body weight. In the rat, a dose of 0.23 mg/kg/day (about equal to the clinical dose of 1.5 mg/m 2) given for 14 days before mating through gestation day 6 caused fetal resorption, microphthalmia, pre-implant loss, and mild maternal toxicity. A dose of 0.1 mg/kg/day (about half the clinical dose of 1.5 mg/m 2) given to rats on days 6 through 17 of gestation caused an increase in post-implantation mortality. This dose also caused an increase in total fetal malformations. The most frequent malformations were of the eye (microphthalmia, anophthalmia, rosette formation of the retina, coloboma of the retina, ectopic orbit), brain (dilated lateral and third ventricles), skull, and vertebrae.

There are no adequate and well controlled studies of Topotecan Injection in pregnant women. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving Topotecan Injection, the patient should be apprised of the potential hazard to the fetus. [see Warnings and Precautions ( 5.4) ]

Rats excrete high concentrations of topotecan into milk. Lactating female rats given 4.72 mg/m 2IV (about three times the clinical dose of 1.5 mg/m 2) excreted topotecan into milk at concentrations up to 48-fold higher than those in plasma. It is not known whether the drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Topotecan Injection, discontinue breastfeeding when women are receiving Topotecan Injection.

Safety and effectiveness in pediatric patients have not been established.

Of the 879 patients in a combined experience of topotecan which included patients with small cell lung cancer, 32% (n=281) were 65 years of age and older, while 3.8% (n=33) were 75 years of age and older. Of the 140 patients with stage IV-B, relapsed, or refractory cervical cancer in clinical studies of Topotecan Injection who received Topotecan Injection plus cisplatin in the randomized clinical trial, 6% (n = 9) were 65 years of age and older, while 3% (n = 4) were 75 years of age and older.

No overall differences in effectiveness or safety were observed between these patients and younger adult patients, and other reported clinical experience has not identified differences in responses between the elderly and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.

There were no apparent differences in the pharmacokinetics of topotecan in elderly patients, once the age-related decrease in renal function was considered [see Clinical Pharmacology ( 12.3) ].

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Dosage and Administration ( 2.3) ].

No dosage adjustment of Topotecan Injection appears to be required for patients with mild renal impairment (Cl cr40 to 60 mL/min.). Dosage reduction is recommended for patients with moderate renal impairment (Cl cr20 to 39 mL/min.). Insufficient data are available in patients with severe renal impairment to provide a dosage recommendation for Topotecan Injection. [see Dosage and Administration ( 2.3) and Clinical Pharmacology ( 12.3) ].

Overdoses (up to 10-fold of the prescribed dose) occurred in patients treated with intravenous topotecan. The primary complication of overdosage is bone marrow suppression. The observed signs and symptoms of overdose are consistent with the known adverse reactions associated with Topotecan Injection for intravenous use [see Adverse Reactions ( 6.1, 6.2) ]. In addition, elevated hepatic enzymes and mucositis have been reported following overdose.

{ "type": "p", "children": [], "text": "Overdoses (up to 10-fold of the prescribed dose) occurred in patients treated with intravenous topotecan. The primary complication of overdosage is bone marrow suppression. The observed signs and symptoms of overdose are consistent with the known adverse reactions associated with Topotecan Injection for intravenous use [see\n \n Adverse Reactions (\n \n 6.1,\n \n 6.2)\n \n ]. In addition, elevated hepatic enzymes and mucositis have been reported following overdose.\n\n " }

One patient received a single dose of 40 mg/m 2of intravenous topotecan and developed gastrointestinal toxicity, skin toxicity, and myelosuppression leading to septic shock. Another patient received a single dose of 35 mg/m 2and experienced severe, reversible neutropenia.

{ "type": "p", "children": [], "text": "One patient received a single dose of 40 mg/m\n \n 2of intravenous topotecan and developed gastrointestinal toxicity, skin toxicity, and myelosuppression leading to septic shock. Another patient received a single dose of 35 mg/m\n \n 2and experienced severe, reversible neutropenia.\n\n " }

There is no known antidote for overdosage with Topotecan Injection. If an overdose is suspected, monitor the patient for bone marrow suppression and institute supportive-care measures (such as prophylactic G-CSF and antibiotic therapy) as appropriate.

{ "type": "p", "children": [], "text": "There is no known antidote for overdosage with Topotecan Injection. If an overdose is suspected, monitor the patient for bone marrow suppression and institute supportive-care measures (such as prophylactic G-CSF and antibiotic therapy) as appropriate." }

Topotecan is a semi-synthetic derivative of camptothecin and is an anti-tumor drug with topoisomerase I-inhibitory activity.

{ "type": "p", "children": [], "text": "Topotecan is a semi-synthetic derivative of camptothecin and is an anti-tumor drug with topoisomerase I-inhibitory activity." }

The chemical name for topotecan free base is ( S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1 H-pyrano[3’,4’:6,7]indolizino[1,2- b]quinoline-3,14-(4 H,12 H)-dione. It has the molecular formula C 23H 23N 3O 5and a molecular weight of 421.45.

{ "type": "p", "children": [], "text": "The chemical name for topotecan free base is (\n \n S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1\n \n H-pyrano[3’,4’:6,7]indolizino[1,2-\n \n b]quinoline-3,14-(4\n \n H,12\n \n H)-dione. It has the molecular formula C\n \n 23H\n \n 23N\n \n 3O\n \n 5and a molecular weight of 421.45.\n\n " }

Topotecan has three pKa values: pKa 1= 10.50 corresponding to the benzyldimethylamino group, pKa 2= 6.99 corresponding to the phenol group and pKa 3= 0.60 corresponding to the quinoline group.

{ "type": "p", "children": [], "text": "Topotecan has three pKa values: pKa\n \n 1= 10.50 corresponding to the benzyldimethylamino group, pKa\n \n 2= 6.99 corresponding to the phenol group and pKa\n \n 3= 0.60 corresponding to the quinoline group.\n\n " }

As formulated in Topotecan Injection, topotecan has the following structural formula:

{ "type": "p", "children": [], "text": "As formulated in Topotecan Injection, topotecan has the following structural formula:" }

where n is >1, corresponding to HCl added to adjust the pH to approximately 1.5 to 2.5.

{ "type": "p", "children": [], "text": "where n is >1, corresponding to HCl added to adjust the pH to approximately 1.5 to 2.5." }

Topotecan Injection is supplied as a sterile, non-pyrogenic, clear, yellow solution at a topotecan free base concentration of 4 mg/4 mL (1 mg/mL) and 1 mg/mL available in multiple dose vials. Each mL of Topotecan Injection contains topotecan hydrochloride equivalent to 1 mg of topotecan as free base, 5 mg tartaric acid, NF, and water for injection, USP. Hydrochloric acid and/or sodium hydroxide may be used to adjust the pH.. The hydrochloride salt of topotecan is soluble in water and melts with decomposition at 213 °C to 218°C.

{ "type": "p", "children": [], "text": "Topotecan Injection is supplied as a sterile, non-pyrogenic, clear, yellow solution at a topotecan free base concentration of 4 mg/4 mL (1 mg/mL) and 1 mg/mL available in multiple dose vials. Each mL of Topotecan Injection contains topotecan hydrochloride equivalent to 1 mg of topotecan as free base, 5 mg tartaric acid, NF, and water for injection, USP. Hydrochloric acid and/or sodium hydroxide may be used to adjust the pH.. The hydrochloride salt of topotecan is soluble in water and melts with decomposition at 213\n \n °C to 218°C.\n\n " }

The solution must be diluted before administration by intravenous infusion.

{ "type": "p", "children": [], "text": "The solution must be diluted before administration by intravenous infusion." }

Topoisomerase I relieves torsional strain in DNA by inducing reversible single strand breaks. Topotecan binds to the topoisomerase I-DNA complex and prevents religation of these single strand breaks. The cytotoxicity of topotecan is thought to be due to double strand DNA damage produced during DNA synthesis, when replication enzymes interact with the ternary complex formed by topotecan, topoisomerase I, and DNA. Mammalian cells cannot efficiently repair these double strand breaks.

The dose-limiting toxicity of topotecan is leukopenia. White blood cell count decreases with increasing topotecan dose or topotecan AUC. When topotecan is administered at a dose of 1.5 mg/m 2/day for 5 days, an 80% to 90% decrease in white blood cell count at nadir is typically observed after the first cycle of therapy.

The pharmacokinetics of topotecan have been evaluated in cancer patients following doses of 0.5 to 1.5 mg/m 2administered as a 30-minute infusion. Topotecan exhibits multiexponential pharmacokinetics with a terminal half-life of 2 to 3 hours. Total exposure (AUC) is approximately dose-proportional.

Distribution:Binding of topotecan to plasma proteins is about 35%.

Metabolism:Topotecan undergoes a reversible pH dependent hydrolysis of its lactone moiety; it is the lactone form that is pharmacologically active. At pH ≤ 4, the lactone is exclusively present, whereas the ring-opened hydroxy-acid form predominates at physiologic pH. In vitrostudies in human liver microsomes indicate topotecan is metabolized to an N-demethylated metabolite. The mean metabolite:parent AUC ratio was about 3% for total topotecan and topotecan lactone following IV administration.

Excretion:Renal clearance is an important determinant of topotecan elimination.

In a mass balance/excretion study in 4 patients with solid tumors, the overall recovery of total topotecan and its N-desmethyl metabolite in urine and feces over 9 days averaged 73.4 ± 2.3% of the administered IV dose. Mean values of 50.8 ± 2.9% as total topotecan and 3.1 ± 1.0% as N-desmethyl topotecan were excreted in the urine following IV administration. Fecal elimination of total topotecan accounted for 17.9 ± 3.6% while fecal elimination of N-desmethyl topotecan was 1.7 ± 0.6%. An O-glucuronidation metabolite of topotecan and N-desmethyl topotecan has been identified in the urine. These metabolites, topotecan-O-glucuronide and N-desmethyl topotecan-O-glucuronide, were less than 2% of the administered dose.

Effect of Gender:The overall mean topotecan plasma clearance in male patients was approximately 24% higher than that in female patients, largely reflecting difference in body size.

Effect of Age:Topotecan pharmacokinetics have not been specifically studied in an elderly population, but population pharmacokinetic analysis in female patients did not identify age as a significant factor. Decreased renal clearance, which is common in the elderly, is a more important determinant of topotecan clearance [see Dosage and Administration ( 2.3) and Use in Specific Populations ( 8.5) ].

Effect of Race:The effect of race on topotecan pharmacokinetics has not been studied.

Effect of Renal Impairment:In patients with mild renal impairment (creatinine clearance of 40 to 60 mL/min.), topotecan plasma clearance was decreased to about 67% of the value in patients with normal renal function. In patients with moderate renal impairment (Cl crof 20 to 39 mL/min.), topotecan plasma clearance was reduced to about 34% of the value in control patients, with an increase in half-life. Mean half-life, estimated in 3 renally impaired patients, was about 5.0 hours. Dosage adjustment is recommended for these patients [see Dosage and Administration ( 2.3) ].

Effect of Hepatic Impairment:Plasma clearance in patients with hepatic impairment (serum bilirubin levels between 1.7 and 15.0 mg/dL) was decreased to about 67% of the value in patients without hepatic impairment. Topotecan half-life increased slightly, from 2.0 hours to 2.5 hours, but these hepatically impaired patients tolerated the usual recommended topotecan dosage regimen.

Drug Interactions:Pharmacokinetic studies of the interaction of topotecan with concomitantly administered medications have not been formally investigated.

In vitroinhibition studies using marker substrates known to be metabolized by human P450 CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A, or CYP4A or dihydropyrimidine dehydrogenase indicate that the activities of these enzymes were not altered by topotecan. Enzyme inhibition by topotecan has not been evaluated in vivo.

Cisplatin:No pharmacokinetic data are available following topotecan (0.75 mg/m 2/day for 3 consecutive days) and cisplatin (50 mg/m 2/day on day 1) in patients with cervical cancer. Myelosuppression was more severe when topotecan was given in combination with cisplatin. [see Drug Interactions( 7)].

Carcinogenicity testing of topotecan has not been performed. Topotecan is known to be genotoxic to mammalian cells and is a probable carcinogen. Topotecan was mutagenic to L5178Y mouse lymphoma cells and clastogenic to cultured human lymphocytes with and without metabolic activation. It was also clastogenic to mouse bone marrow. Topotecan did not cause mutations in bacterial cells.

Topotecan given to female rats prior to mating at a dose of 1.4 mg/m 2IV (about equal to the clinical dose of 1.5 mg/m 2) caused superovulation possibly related to inhibition of follicular atresia. This dose given to pregnant female rats also caused increased pre-implantation loss. Studies in dogs given 0.4 mg/m 2IV (about 1/4th the clinical dose of 1.5 mg/m 2) of topotecan daily for a month suggest that treatment may cause an increase in the incidence of multinucleated spermatogonial giant cells in the testes. Topotecan may impair fertility in women and men.

Topotecan was studied in 426 patients with recurrent or progressive small cell lung cancer in 1 randomized, comparative study and in 3 single-arm studies.

Randomized Comparative Study

In a randomized, comparative, Phase 3 trial, 107 patients were treated with topotecan (1.5 mg/m 2/day x 5 days starting on day 1 of a 21-day course) and 104 patients were treated with CAV (1,000 mg/m 2cyclophosphamide, 45 mg/m 2doxorubicin, 2 mg vincristine administered sequentially on day 1 of a 21-day course). All patients were considered sensitive to first-line chemotherapy (responders who then subsequently progressed ≥60 days after completion of first-line therapy). A total of 77% of patients treated with topotecan and 79% of patients treated with CAV received platinum/etoposide with or without other agents as first-line chemotherapy.

Response rates, response duration, time to progression, and survival are shown in Table 6.

<div class="scrollingtable"><table border="single" width="800"> <caption> <span>Table 6. Efficacy of Topotecan Versus CAV (cyclophosphamide-doxorubicin-vincristine) in Small Cell Lung Cancer Patients Sensitive to First-Line Chemotherapy</span> </caption> <col width="62.9%"/> <col width="18.5%"/> <col width="18.5%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Parameter</span></td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Topotecan</span> </p> <span class="Bold">(n = 107)</span></td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">CAV</span> </p> <span class="Bold">(n = 104)</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Complete response rate <br/> Partial response rate <br/> Overall response rate </td><td align="center" class="Botrule Rrule" valign="top">0% <br/> 24% <br/> 24% </td><td align="center" class="Botrule Rrule" valign="top">1% <br/> 17% <br/> 18% </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Difference in overall response rates <br/> 95% Confidence interval of the difference </td><td align="center" class="Botrule Rrule" colspan="2" valign="top">6% <br/> (–6 to 18%) </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Response duration <span class="Sup">a</span>(weeks) <br/> Median <br/> 95% Confidence interval <br/> Hazard-ratio </td><td align="center" class="Botrule Rrule" valign="top">n = 26 <br/> 14.4 <br/> 13.1 to 18 </td><td align="center" class="Botrule Rrule" valign="top">n = 19 <br/> 15.3 <br/> 13.1 to 23.1 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">(Topotecan:CAV) (95% CI) <br/>                                                                          ( <span class="Italics">P</span>-value) </td><td align="center" class="Botrule Rrule" colspan="2" valign="top">1.42 (0.73 to 2.76) <br/> (0.30) </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Time to progression (weeks) <br/> Median <br/> 95% Confidence interval <br/> Hazard ratio </td><td align="center" class="Botrule Rrule" valign="top"> <br/> 13.3 <br/> 11.4 to 16.4 </td><td align="center" class="Botrule Rrule" valign="top"> <br/> 12.3 <br/> 11 to 14.1 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">(Topotecan:CAV) (95% CI) <br/>                                                                          ( <span class="Italics">P</span>-value) </td><td align="center" class="Botrule Rrule" colspan="2" valign="top">0.92 (0.69 to 1.22) <br/> (0.55) </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Survival (weeks) <br/> Median <br/> 95% Confidence interval <br/> Hazard ratio </td><td align="center" class="Botrule Rrule" valign="top"> <br/> 25 <br/> 20.6 to 29.6 </td><td align="center" class="Botrule Rrule" valign="top"> <br/> 24.7 <br/> 21.7 to 30.3 </td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">(Topotecan:CAV) (95% CI) <br/>                                                                          ( <span class="Italics">P</span>-value) </td><td align="center" class="Botrule Rrule" colspan="2" valign="top">1.04 (0.78 to 1.39) <br/> (0.8) </td> </tr> </tbody> </table></div>

aThe calculation for duration of response was based on the interval between first response and time to progression.

The time to response was similar to both arms: topotecan median of 6 weeks (range 2.4 to 15.7) versus CAV median 6 weeks (range 5.1 to 18.1).

Changes on a disease-related symptom scale in patients who received topotecan or who received CAV are presented in Table 7. It should be noted that not all patients had all symptoms, nor did all patients respond to all questions. Each symptom was rated on a 4-category scale with an improvement defined as a change in 1 category from baseline sustained over 2 courses. Limitations in interpretation of the rating scale and responses preclude formal statistical analysis.

<div class="scrollingtable"><table border="single" width="800"> <caption> <span>Table 7. Percentage of Patients with Symptom Improvement <span class="Sup">a</span>: Topotecan Versus CAV in Patients with Small Cell Lung Cancer </span> </caption> <col width="36.9%"/> <col width="20.9%"/> <col width="22.2%"/> <col width="9.8%"/> <col width="10.1%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="bottom">Symptom</td><td align="center" class="Botrule Rrule" colspan="2" valign="top"> <p class="First">Topotecan Injection</p>(n=107) </td><td align="center" class="Botrule Rrule" colspan="2" valign="top"> <p class="First">CAV</p>(n=104) </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">n <span class="Sup">b</span></td><td align="center" class="Botrule Rrule" valign="top">(%)</td><td align="center" class="Botrule Rrule" valign="top">n <span class="Sup">b</span></td><td align="center" class="Botrule Rrule" valign="top">(%)</td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top">Shortness of breath</td><td align="center" class="Rrule" valign="top">68</td><td align="center" class="Rrule" valign="top">(28)</td><td align="center" class="Rrule" valign="top">61</td><td align="center" class="Rrule" valign="top">(7)</td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top">Interference with daily activity</td><td align="center" class="Rrule" valign="top">67</td><td align="center" class="Rrule" valign="top">(27)</td><td align="center" class="Rrule" valign="top">63</td><td align="center" class="Rrule" valign="top">(11)</td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top">Fatigue</td><td align="center" class="Rrule" valign="top">70</td><td align="center" class="Rrule" valign="top">(23)</td><td align="center" class="Rrule" valign="top">65</td><td align="center" class="Rrule" valign="top">(9)</td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top">Hoarseness</td><td align="center" class="Rrule" valign="top">40</td><td align="center" class="Rrule" valign="top">(33)</td><td align="center" class="Rrule" valign="top">38</td><td align="center" class="Rrule" valign="top">(13)</td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top">Cough</td><td align="center" class="Rrule" valign="top">69</td><td align="center" class="Rrule" valign="top">(25)</td><td align="center" class="Rrule" valign="top">61</td><td align="center" class="Rrule" valign="top">(15)</td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top">Insomnia</td><td align="center" class="Rrule" valign="top">57</td><td align="center" class="Rrule" valign="top">(33)</td><td align="center" class="Rrule" valign="top">53</td><td align="center" class="Rrule" valign="top">(19)</td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top">Anorexia</td><td align="center" class="Rrule" valign="top">56</td><td align="center" class="Rrule" valign="top">(32)</td><td align="center" class="Rrule" valign="top">57</td><td align="center" class="Rrule" valign="top">(16)</td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top">Chest pain</td><td align="center" class="Rrule" valign="top">44</td><td align="center" class="Rrule" valign="top">(25)</td><td align="center" class="Rrule" valign="top">41</td><td align="center" class="Rrule" valign="top">(17)</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">Hemoptysis</td><td align="center" class="Rrule" valign="top">15</td><td align="center" class="Rrule" valign="top">(27)</td><td align="center" class="Rrule" valign="top">12</td><td align="center" class="Botrule Rrule" valign="top">(33)</td> </tr> </tbody> </table></div>

aDefined as improvement sustained over at least 2 courses compared to baseline.

bNumber of patients with baseline and at least 1 post-baseline assessment.

Single-Arm Studies

Topotecan was also studied in 3 open-label, non-comparative trials in a total of 319 patients with recurrent or progressive small cell lung cancer after treatment with first-line chemotherapy. In all 3 studies, patients were stratified as either sensitive (responders who then subsequently progressed ≥90 days after completion of first-line therapy) or refractory (no response to first-line chemotherapy or who responded to first-line therapy and then progressed within 90 days of completing first-line therapy). Response rates ranged from 11% to 31% for sensitive patients and 2% to 7% for refractory patients. Median time to progression and median survival were similar in all 3 studies and the comparative study.

In a comparative trial, 147 eligible women were randomized to Topotecan Injection (0.75 mg/m 2/day IV over 30 minutes × 3 consecutive days starting on day 1 of a 21-day course) plus cisplatin (50 mg/m 2on day 1) and 146 eligible women were randomized to cisplatin (50 mg/m 2IV on day 1 of a 21-day course). All patients had histologically confirmed Stage IV-B, recurrent, or persistent carcinoma of the cervix considered not amenable to curative treatment with surgery and/or radiation. Fifty-six percent (56%) of patients treated with Topotecan Injection plus cisplatin and 56% of patients treated with cisplatin had received prior cisplatin with or without other agents as first-line chemotherapy.

Median survival of eligible patients receiving Topotecan Injection plus cisplatin was 9.4 months (95% CI: 7.9 to 11.9) compared to 6.5 months (95% CI: 5.8 to 8.8) among patients randomized to cisplatin alone with a log rank P-value of 0.033 (significance level was 0.044 after adjusting for the interim analysis). The unadjusted hazard ratio for overall survival was 0.76 (95% CI: 0.59 to 0.98).

Figure 1. Overall Survival Curves Comparing Topotecan Injection plus Cisplatin versus Cisplatin Monotherapy in Cervical Cancer Patients

1. Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings. NIOSH Alert 2004-165.

{ "type": "p", "children": [], "text": "1. Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings. NIOSH Alert 2004-165." }

2.OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/ dts/osta/otm/otm_vi/otm_vi_2.html

{ "type": "p", "children": [], "text": "2.OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/ dts/osta/otm/otm_vi/otm_vi_2.html" }

3. American Society of Health-System Pharmacists. ASHP Guidelines on Handling Hazardous Drugs. Am J Health-Syst Pharm. 2006;63:1172-1193.

{ "type": "p", "children": [], "text": "3. American Society of Health-System Pharmacists. ASHP Guidelines on Handling Hazardous Drugs.\n \n Am J Health-Syst Pharm. 2006;63:1172-1193.\n\n " }

4. Polovich M, White JM, Kelleher LO (eds.) 2005. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. (2 nded) Pittsburgh, PA: Oncology Nursing Society.

{ "type": "p", "children": [], "text": "4. Polovich M, White JM, Kelleher LO (eds.) 2005. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. (2\n \n nded) Pittsburgh, PA: Oncology Nursing Society.\n\n " }

Topotecan Injection is supplied in the following:

{ "type": "p", "children": [], "text": "Topotecan Injection is supplied in the following:" }

1 mg/mL Multiple Dose Vial

{ "type": "p", "children": [], "text": "1 mg/mL Multiple Dose Vial" }

NDC 16729-243-30 (package of 1)

{ "type": "p", "children": [], "text": "NDC 16729-243-30 (package of 1)" }

4 mg/4 mL (1 mg/mL) Multiple Dose Vial

{ "type": "p", "children": [], "text": "4 mg/4 mL (1 mg/mL) Multiple Dose Vial" }

NDC 16729-243-31 (package of 1)

{ "type": "p", "children": [], "text": "NDC 16729-243-31 (package of 1)" }

Unopened vials of Topotecan Injection are stable until the date indicated on the package when stored at controlled room temperature between 20ºC and 25°C (68°F and 77°F) with excursions allowed from 15°C to 30°C (59°F to 86°F). Retain in carton to protect from light.

{ "type": "p", "children": [], "text": "Unopened vials of Topotecan Injection are stable until the date indicated on the package when stored at controlled room temperature between 20ºC and 25°C (68°F and 77°F) with excursions allowed from 15°C to 30°C (59°F to 86°F). Retain in carton to protect from light." }

Topotecan Injection is supplied as a multiple dose vial. Studies have shown the product is stable for 28 days after initial puncture when stored at room temperature.

{ "type": "p", "children": [], "text": "Topotecan Injection is supplied as a multiple dose vial. Studies have shown the product is stable for 28 days after initial puncture when stored at room temperature." }

Topotecan Injection diluted for infusion is stable for 4 hours at room temperature or 24 hours at refrigerated temperature in ambient lighting conditions.

{ "type": "p", "children": [], "text": "Topotecan Injection diluted for infusion is stable for 4 hours at room temperature or 24 hours at refrigerated temperature in ambient lighting conditions." }

Inform patients that Topotecan Injection decreases blood cell counts such as white blood cells, platelets, and red blood cells. Patients who develop fever, other signs of infection (e.g., chills, cough, or burning pain on urination), or bleeding while on therapy should notify their physician promptly. Inform patients that frequent blood tests will be performed while taking Topotecan Injection to monitor for the occurrence of bone marrow suppression.

Advise patients to use effective contraceptive measures to prevent pregnancy and to avoid breastfeeding during treatment with Topotecan Injection.

Inform patients that Topotecan Injection may cause asthenia or fatigue. If these symptoms occur, caution should be observed when driving or operating machinery.

Rx only

Manufactured for: Accord Healthcare, Inc., 8041 Arco Corporate Drive, Suite 200, Raleigh, NC 27617, USA.

Manufactured by: Intas Pharmaceuticals Limited, Plot No.: 457, 458, Village – Matoda, Bavla Road, Ta.- Sanand, Dist.- Ahmedabad – 382 210, INDIA.

10 7121 0 6027367

Issued December 2023

Principal Display Panel - 1 mg/mL Carton

{ "type": "p", "children": [], "text": "\nPrincipal Display Panel - 1 mg/mL Carton\n" }

Principal Display Panel - 4 mg/4 mL Carton

{ "type": "p", "children": [], "text": "\nPrincipal Display Panel - 4 mg/4 mL Carton\n" }

Topotecan hydrochloride for injection, as a single agent, is indicated for the treatment of patients with metastatic ovarian cancer after disease progression on or after initial or subsequent chemotherapy.

Topotecan hydrochloride for injection, as a single agent, is indicated for the treatment of patients with small cell lung cancer (SCLC) with platinum-sensitive disease who progressed at least 60 days after initiation of first-line chemotherapy.

Topotecan hydrochloride for injection, in combination with cisplatin, is indicated for the treatment of patients with Stage IV-B, recurrent, or persistent cervical cancer not amenable to curative treatment.

Verify dosage using body surface area. Do not exceed a single dose of 4 mg intravenously.

The recommended dosage of topotecan hydrochloride for injection is 1.5 mg/m 2by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on Day 1 of a 21-day cycle until disease progression or unacceptable toxicity.

The recommended dosage of topotecan hydrochloride for injection is 1.5 mg/m 2by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on Day 1 of a 21-day cycle.

The recommended dosage of topotecan hydrochloride for injection is 0.75 mg/m 2by intravenous infusion over 30 minutes daily on Days 1, 2, and 3, in combination with cisplatin 50 mg/m 2on Day 1, of a 21-day cycle.

Hematologic

Do not administer subsequent cycles of topotecan hydrochloride for injection until neutrophils recover to greater than 1,000/mm 3, platelets recover to greater than 100,000/mm 3, and hemoglobin levels recover to greater than or equal to 9 g/dL (with transfusion if necessary).

For topotecan hydrochloride for injection as a single agent, reduce the dose to 1.25 mg/m 2/day for:

For topotecan hydrochloride for injection in combination with cisplatin, reduce the dose to 0.6 mg/m 2/day (and further to 0.45 mg/m 2if necessary) for:

For topotecan hydrochloride for injection as a single agent, reduce the dose to 0.75 mg/m2/day for patients with creatinine clearance (CLcr) of 20 to 39 mL/min (calculated with the Cockcroft-Gault method using ideal body weight) [see Clinical Pharmacology ( 12.3)] .

Preparation

Stability

Topotecan hydrochloride for injection is a cytotoxic drug. Follow applicable handling and disposal procedures. 1

For injection: 4 mg (free base) of topotecan as a light yellow to greenish lyophilized powder in single-dose vial for reconstitution.

{ "type": "p", "children": [], "text": "For injection: 4 mg (free base) of topotecan as a light yellow to greenish lyophilized powder in single-dose vial for reconstitution." }

Topotecan Hydrochloride for Injection is contraindicated in patients who have a history of severe hypersensitivity reactions to topotecan. Reactions have included anaphylactoid reactions [see Adverse Reactions ( 6.2)] .

{ "type": "p", "children": [], "text": "Topotecan Hydrochloride for Injection is contraindicated in patients who have a history of severe hypersensitivity reactions to topotecan. Reactions have included anaphylactoid reactions\n \n [see Adverse Reactions (\n \n 6.2)]\n \n .\n\n " }

Topotecan hydrochloride for injection 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 topotecan hydrochloride for injection only to patients with a baseline neutrophil count of greater than or equal to 1,500/mm 3and a platelet count greater than or equal to 100,000/mm 3. Monitor blood counts frequently during treatment. Withhold and reduce dose of topotecan hydrochloride for injection based on neutrophil counts, platelet counts and hemoglobin levels [see Dosage and Administration ( 2.5)] .

Interstitial lung disease (ILD), including fatalities, can occur with topotecan hydrochloride for injection. 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 topotecan hydrochloride for injection if ILD is confirmed.

Extravasation, including severe cases, can occur with topotecan hydrochloride for injection. If signs or symptoms of extravasation occur, immediately stop administration of topotecan hydrochloride for injection and institute recommended management procedures [see Adverse Reactions ( 6.1)] .

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 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 topotecan hydrochloride for injection. Advise males with a female partner of reproductive potential to use effective contraception during treatment with topotecan hydrochloride for injection and for 3 months after the last dose [see Use in Specific Populations ( 8.1, 8.3), Nonclinical Toxicology ( 13.1)] .

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data in Warnings and Precautions reflect exposure to topotecan hydrochloride for injection from eight trials in which 879 patients with ovarian cancer or small cell lung cancer (SCLC) received topotecan hydrochloride for injection 1.5 mg/m 2by intravenous infusion daily for 5 consecutive days, starting on Day 1 of a 21 day cycle and from one trial (Study GOG 0179) in which 147 patients with cervical cancer received topotecan hydrochloride for injection 0.75 mg/m 2by intravenous infusion daily on Days 1, 2, and 3, with cisplatin 50 mg/m2 by intravenous infusion on Day 1, of a 21-day cycle.

Ovarian Cancer

The safety of topotecan hydrochloride 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 topotecan hydrochloride for injection.

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

Small Cell Lung Cancer (SCLC)

The safety of topotecan hydrochloride 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.

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

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 topotecan hydrochloride 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 topotecan hydrochloride for injection was evaluated in a comparative trial of topotecan hydrochloride for injection 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.

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

The following reactions have been identified during post approval use of topotecan hydrochloride for injection. 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

Risk Summary

Based on animal data and its mechanism of action, topotecan hydrochloride for injection can cause fetal harm when administered to a pregnant woman. There are no available clinical data on the use of topotecan hydrochloride for injection in pregnancy. Topotecan caused embryolethality, fetotoxicity, and teratogenicity in rats and rabbits when administered during organogenesis at doses similar to the clinical dose (see Data). Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Data

Animal Data: In rabbits, an intravenous dose of 0.10 mg/kg/day [about equal to the 1.5 mg/m 2clinical dose based on body surface area (BSA)] given on Days 6 through 20 of gestation caused maternal toxicity, embryolethality and reduced fetal body weight. In the rat, an intravenous dose of 0.23 mg/kg/day (about equal to the 1.5 mg/m 2clinical dose based on BSA) given for 14 days before mating through gestation Day 6 caused fetal resorption, microphthalmia, pre-implant loss, and mild maternal toxicity. Administration of an intravenous dose of 0.10 mg/kg/day (about half the 1.5 mg/m 2clinical dose based on BSA) given to rats on Days 6 through 17 of gestation caused an increase in post-implantation mortality. This dose also caused an increase in total fetal malformations. The most frequent malformations were of the eye (microphthalmia, anophthalmia, rosette formation of the retina, coloboma of the retina, ectopic orbit), brain (dilated lateral and third ventricles), skull, and vertebrae.

Risk Summary

There are no data on the presence of topotecan or its metabolites in human milk or their effects on the breastfed infant or on milk production. Lactating rats excrete high concentrations of topotecan in milk (see Data) . Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with topotecan hydrochloride for injection and for 1 week after the last dose.

Data

Following intravenous administration of topotecan to lactating rats at a dose of 4.72 mg/m 2(about twice the 1.5 mg/m 2clinical dose based on BSA) to lactating rats, topotecan was excreted into milk at concentrations up to 48-fold higher than those in plasma.

Pregnancy Testing

Verify pregnancy status of females of reproductive potential prior to initiating topotecan hydrochloride for injection [see Use in Specific Populations ( 8.1)] .

Contraception

topotecan hydrochloride for injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1)] .

Females

Advise females of reproductive potential to use effective contraception during treatment with topotecan hydrochloride for injection and for 6 months after the last dose.

Males

Topotecan Hydrochloride for Injection may damage spermatozoa, resulting in possible genetic and fetal abnormalities. Advise males with a female partner of reproductive potential to use effective contraception during treatment with topotecan hydrochloride for injection and for 3 months after the last dose [see Nonclinical Toxicology ( 13.1)] .

Infertility

Females

Topotecan Hydrochloride for Injection can have both acute and long-term effects on fertility [see Nonclinical Toxicology ( 13.1)] .

Males

Effects on spermatogenesis occurred in animals administered topotecan [see Nonclinical Toxicology ( 13.1)] .

Safety and effectiveness in pediatric patients have not been established.

Of the 879 patients with metastatic ovarian cancer or small cell lung cancer in clinical trials of topotecan hydrochloride for injection, 32% were aged 65 years and older, while 3.8% were aged 75 years and older. Of the 140 patients with Stage IV-B, relapsed, or refractory cervical cancer in clinical trials of topotecan hydrochloride for injection who received topotecan hydrochloride for injection with cisplatin in the randomized clinical trial, 6% were aged 65 years and older, while 3% were aged 75 years and older. No overall differences in effectiveness or safety were observed between these patients and younger patients and other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Reduce the dose of topotecan hydrochloride for injection in patients with a CLcr of 20 to 39 mL/min [see Dosage and Administration ( 2.4), Clinical Pharmacology ( 12.3)] No dosage adjustment is recommended for patients with CLcr greater than or equal to 40 mL/min.

Insufficient data are available in patients with CLcr less than 20 mL/min to provide a dosage recommendation for topotecan hydrochloride for injection.

Overdoses (up to 10-fold of the recommended dose) have occurred in patients receiving intravenous topotecan. The primary complication of overdosage is myelosuppression.

{ "type": "p", "children": [], "text": "Overdoses (up to 10-fold of the recommended dose) have occurred in patients receiving intravenous topotecan. The primary complication of overdosage is myelosuppression." }

Elevated hepatic enzymes, mucositis, gastrointestinal toxicity, and skin toxicity have occurred with overdosages. If an overdose is suspected, monitor the patient closely for myelosuppression and institute supportive-care measures as appropriate.

{ "type": "p", "children": [], "text": "Elevated hepatic enzymes, mucositis, gastrointestinal toxicity, and skin toxicity have occurred with overdosages. If an overdose is suspected, monitor the patient closely for myelosuppression and institute supportive-care measures as appropriate." }

Topotecan is a topoisomerase inhibitor. The chemical name for topotecan hydrochloride is ( S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1 H-pyrano[3’,4’:6,7] indolizino [1,2- b]quinoline-3,14-(4 H,12 H)-dione monohydrochloride. The molecular formula is C 23H 23N 3O 5•HCl and the molecular weight is 457.9 g/mol.. It is soluble in water and melts with decomposition at 213ºC to 218ºC.

{ "type": "p", "children": [], "text": "Topotecan is a topoisomerase inhibitor. The chemical name for topotecan hydrochloride is (\n \n S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1\n \n H-pyrano[3’,4’:6,7] indolizino [1,2-\n \n b]quinoline-3,14-(4\n \n H,12\n \n H)-dione monohydrochloride. The molecular formula is C\n \n 23H\n \n 23N\n \n 3O\n \n 5•HCl and the molecular weight is 457.9 g/mol.. It is soluble in water and melts with decomposition at 213ºC to 218ºC.\n\n " }

Topotecan hydrochloride has the following structural formula:

{ "type": "p", "children": [], "text": "Topotecan hydrochloride has the following structural formula:" }

Topotecan hydrochloride for injection, for intravenous use is supplied as a sterile, lyophilized, yellow powder available in single-dose vials. Each 4 mg vial contains 4 mg topotecan hydrochloride as free base. The reconstituted solution gives a light yellow color.

{ "type": "p", "children": [], "text": "Topotecan hydrochloride for injection, for intravenous use is supplied as a sterile, lyophilized, yellow powder available in single-dose vials. Each 4 mg vial contains 4 mg topotecan hydrochloride as free base. The reconstituted solution gives a light yellow color." }

Inactive ingredients are mannitol, 48 mg, and tartaric acid, 20 mg. Hydrochloric acid and sodium hydroxide may be used to adjust the pH. The solution pH ranges from 2.5 to 3.5.

{ "type": "p", "children": [], "text": "Inactive ingredients are mannitol, 48 mg, and tartaric acid, 20 mg. Hydrochloric acid and sodium hydroxide may be used to adjust the pH. The solution pH ranges from 2.5 to 3.5." }

Topoisomerase I relieves torsional strain in DNA by inducing reversible single-strand breaks. Topotecan binds to the topoisomerase I-DNA complex and prevents re-ligation of these single-strand breaks. The cytotoxicity of topotecan is thought to be due to double-strand DNA damage produced during DNA synthesis, when replication enzymes interact with the ternary complex formed by topotecan, topoisomerase I, and DNA. Mammalian cells cannot efficiently repair these double-strand breaks.

Following administration of topotecan hydrochloride for injection at doses of 0.5 to 1.5 mg/m 2(0.1 to 0.3 times the recommended single agent dose) administered as a 30-minute infusion, area under the curve (AUC) increases proportionally with dose.

Distribution

Protein binding of topotecan is approximately 35%.

Elimination

The terminal half-life of topotecan is 2 to 3 hours following intravenous administration.

Metabolism

Topotecan undergoes a reversible pH-dependent hydrolysis of its pharmacologically active lactone moiety. At pH less than or equal to 4, the lactone is exclusively present, whereas the ring-opened hydroxy-acid form predominates at physiologic pH. Topotecan is metabolized to an N-demethylated metabolite in vitro. The mean metabolite: parent AUC ratio was about 3% for total topotecan and topotecan lactone following intravenous administration.

Excretion

The overall recovery of total topotecan and its N-desmethyl metabolite in urine and feces over 9 days averaged 73% ± 2% following an intravenous dose. Mean values of 51% ± 3% as total topotecan and 3% ± 1% as N-desmethyl topotecan were excreted in the urine. Fecal elimination of total topotecan accounted for 18% ± 4% while fecal elimination of N-desmethyl topotecan was 1.7% ± 0.6%. An O-glucuronidation metabolite of topotecan and N desmethyl topotecan has been identified in the urine.

Specific Populations

No clinically significant differences in the pharmacokinetics of topotecan were observed based on age, sex, or hepatic impairment following intravenous administration.

Patients with Renal Impairment

Compared to patients with CLcr (calculated by the Cockcroft-Gault method using ideal body weight) greater than 60 mL/min, plasma clearance of topotecan lactone decreased by 33% in patients with CLcr 40-60 mL/min and decreased 65% in patients with CLcr 20-39 mL/min. The effect on topotecan pharmacokinetics in patients with CLcr less than 20 mL/min is unknown [see Dosage and Administration ( 2.6)] .

Drug Interaction Studies

Clinical Studies

No clinically significant changes in topotecan pharmacokinetics were observed when coadministered cisplatin.

No clinically significant changes in the pharmacokinetics of free platinum were observed in patients coadministered cisplatin with topotecan.

In Vitro Studies

Topotecan does not inhibit CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A, or CYP4A or dihydropyrimidine dehydrogenase.

Carcinogenicity testing of topotecan has not been performed. Topotecan is known to be genotoxic to mammalian cells and is a probable carcinogen. Topotecan was mutagenic to L5178Y mouse lymphoma cells and clastogenic to cultured human lymphocytes with and without metabolic activation. It was also clastogenic to mouse bone marrow. Topotecan did not cause mutations in bacterial cells.

Topotecan given to female rats prior to mating at an intravenous dose of 1.4 mg/m 2[about equal to the clinical dose based on body surface area (BSA)] caused superovulation possibly related to inhibition of follicular atresia. This dose given to pregnant female rats also caused increased pre-implantation loss. Studies in dogs given at an intravenous dose of 0.4 mg/m 2(about 0.25 times the clinical dose based on BSA) of topotecan daily for a month suggest that treatment may cause an increase in the incidence of multinucleated spermatogonial giant cells in the testes.

The efficacy of Topotecan hydrochloride for injection was evaluated in two clinical trials of 223 patients with metastatic ovarian cancer. All patients had disease that had recurred on, or was unresponsive to, a platinum-containing regimen. Patients in these trials received an initial dose of 1.5 mg/m 2as an intravenous infusion for 5 consecutive days, starting on Day 1 of a 21-day cycle.

One trial (Study 039) was a randomized trial of 112 patients who received topotecan hydrochloride for injection and of 114 patients who received paclitaxel (175 mg/m 2intravenously over 3 hours on Day 1 of a 21-day cycle). All patients had recurrent ovarian cancer after a platinum-containing regimen or had not responded to at least 1 prior platinum-containing regimen. Patients who did not respond to the trial therapy, or who progressed, could be given the alternative treatment. The efficacy outcome measures were overall response rate, response duration, time to progression, and overall survival (OS).

The results of the trial did not show statistically significant improvements in response rates, response duration, time to progression, and OS as shown in Table 4.

<div class="scrollingtable"><table> <caption> <span>Table 4. Efficacy Results in Ovarian Cancer in Study 039</span> </caption> <col width="51%"/> <col width="22%"/> <col width="25%"/> <tfoot> <tr class="First Last"> <td class="Toprule" colspan="3">Abbreviation: CI, confidence interval. <br/> <span class="Sup">a</span>The calculation for response duration was based on the interval between first response and time to progression. <br/> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">Parameters</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">Topotecan Hydrochloride for <br/> Injection </span> </p> <p> <span class="Bold">(n = 112)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">Paclitaxel</span> </p> <p> <span class="Bold">(n = 114)</span> </p> </td> </tr> <tr> <td class="Lrule"> <p class="First">Overall response rate (95% CI)</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">21% (13%, 28%)</p> </td><td align="center" class="Rrule" valign="bottom"> <p class="First">14% (8%, 20%)</p> </td> </tr> <tr> <td class="Lrule"> <p class="First"> Complete response rate</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">5%</p> </td><td align="center" class="Rrule" valign="bottom"> <p class="First">3%</p> </td> </tr> <tr> <td class="Botrule Lrule"> <p class="First"> Partial response rate</p> </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> <p class="First">16%</p> </td><td align="center" class="Botrule Rrule" valign="bottom"> <p class="First">11%</p> </td> </tr> <tr> <td class="Lrule Rrule Toprule"> <p class="First">Response duration <span class="Sup">a</span>(months) </p> </td><td class="Lrule Rrule Toprule"></td><td class="Lrule Rrule Toprule"></td> </tr> <tr> <td class="Lrule Rrule"> <p class="First"> Median (95% CI)</p> </td><td align="center" class="Lrule Rrule"> <p class="First">6 (5.1, 7.6)</p> </td><td align="center" class="Lrule Rrule"> <p class="First">5 (3.7, 7.8)</p> </td> </tr> <tr> <td class="Lrule Toprule"> <p class="First">Time to progression (months)</p> </td><td class="Lrule Toprule" valign="bottom"></td><td class="Rrule Toprule" valign="bottom"></td> </tr> <tr> <td class="Lrule"> <p class="First"> Median (95% CI)</p> </td><td align="center" class="Lrule" valign="bottom"> <p class="First">4.4 (2.8, 5.4)</p> </td><td align="center" class="Rrule" valign="bottom"> <p class="First">3.4 (2.7, 4.2)</p> </td> </tr> <tr> <td class="Lrule"> <p class="First"> Hazard ratio (95% CI)</p> </td><td align="center" class="Lrule Rrule" colspan="2" valign="bottom"> <p class="First">0.76 (0.57, 1.02)</p> </td> </tr> <tr> <td class="Lrule Toprule"> <p class="First">Overall survival (months)</p> </td><td class="Lrule Toprule" valign="bottom"></td><td class="Rrule Toprule" valign="bottom"></td> </tr> <tr> <td class="Lrule"> <p class="First"> Median (95% CI)</p> </td><td align="center" class="Lrule" valign="bottom"> <p class="First">14.5 (10.7, 16.5)</p> </td><td align="center" class="Rrule" valign="bottom"> <p class="First">12.2 (9.7, 15.8)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule"> <p class="First"> Hazard ratio (95% CI)</p> </td><td align="center" class="Botrule Lrule Rrule" colspan="2" valign="bottom"> <p class="First">0.97 (0.71, 1.34)</p> </td> </tr> </tbody> </table></div>

The median time to response was 7.6 weeks (3.1 weeks to 5 months) with topotecan hydrochloride for injection compared with 6 weeks (2.4 weeks to 4.1 months) with paclitaxel. In the cross-over phase, 13% of 61 patients who received topotecan hydrochloride for injection after paclitaxel had a partial response and 10% of 49 patients who received paclitaxel after topotecan hydrochloride for injection had a response (2 complete responses).

Topotecan hydrochloride for injection was active in ovarian cancer patients who had developed resistance to platinum-containing therapy, defined as tumor progression while on, or tumor relapse within 6 months after completion of, a platinum-containing regimen. One complete and 6 partial responses were seen in 60 patients, for a response rate of 12%. In the same trial, there were no complete responders and 4 partial responders on the paclitaxel arm, for a response rate of 7%.

Topotecan hydrochloride for injection was also studied in an open-label, non-comparative trial in 111 patients with recurrent ovarian cancer after treatment with a platinum-containing regimen, or who had not responded to 1 prior platinum-containing regimen. The response rate was 14% (95% CI: 7%, 20%). The median duration of response was 5 months (4.6 weeks to 9.6 months). The time to progression was 2.6 months (5 days to 1.4 years). The median survival was 1.3 years (1.4 weeks, to 2.2 years).

The efficacy of Topotecan hydrochloride for injection was evaluated in 426 patients with recurrent or progressive small cell lung cancer (SCLC) in a randomized, comparative trial and in 3 single-arm trials.

Randomized Comparative Trial

In a randomized, comparative trial, 211 patients were randomized 1:1 to receive topotecan hydrochloride for injection (1.5 mg/m 2once daily intravenously for 5 days starting on Day 1 of a 21-day cycle) or CAV (cyclophosphamide 1,000 mg/m 2, doxorubicin 45 mg/m 2, vincristine 2 mg administered sequentially on Day 1 of a 21-day cycle). All patients were considered sensitive to first-line chemotherapy (responders who then subsequently progressed greater than or equal to 60 days after completion of first-line therapy). A total of 77% of patients treated with topotecan hydrochloride for injection and 79% of patients treated with CAV received platinum/etoposide with or without other agents as first-line chemotherapy. The efficacy outcome measures were overall response rate, response duration, time to progression or OS.

The results of the trial did not show statistically significant improvements in response rate, response duration, time to progression, or OS as shown in Table 5.

<div class="scrollingtable"><table> <caption> <span>Table 5. Efficacy Results in Patients With Small Cell Lung Cancer Sensitive to First-Line Chemotherapy in Study 090</span> </caption> <col width="49%"/> <col width="25%"/> <col width="25%"/> <tfoot> <tr class="First Last"> <td class="Toprule" colspan="3">Abbreviations: CI, confidence interval. <br/> <span class="Sup">a</span>The calculation for duration of response was based on the interval between first response and time to progression. <br/> <span class="Sup">b</span>CAV = cyclophosphamide, doxorubicin and vincristine. </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">Parameter</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">Topotecan Hydrochloride for Injection</span> </p> <p> <span class="Bold">(n = 107)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">CAV <span class="Sup">b</span></span> </p> <p> <span class="Bold">(n = 104)</span> </p> </td> </tr> <tr> <td class="Lrule Toprule"> <p class="First"> <span class="Bold">Overall response rate (95% CI)</span> </p> </td><td align="center" class="Lrule Rrule Toprule" valign="bottom"> <p class="First">24% (16%, 32%)</p> </td><td align="center" class="Rrule Toprule" valign="bottom"> <p class="First">18% (11%, 26%)</p> </td> </tr> <tr> <td class="Lrule"> <p class="First"> Complete response rate</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">0%</p> </td><td align="center" class="Rrule" valign="bottom"> <p class="First">1%</p> </td> </tr> <tr> <td class="Botrule Lrule"> <p class="First"> Partial response rate</p> </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> <p class="First">24%</p> </td><td align="center" class="Botrule Rrule" valign="bottom"> <p class="First">17%</p> </td> </tr> <tr> <td class="Lrule"> <p class="First"> <span class="Bold">Response duration <span class="Sup">a</span>(months) </span> </p> </td><td class="Lrule Rrule" valign="bottom"></td><td class="Rrule" valign="bottom"></td> </tr> <tr> <td class="Botrule Lrule"> <p class="First"> Median (95% CI)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> <p class="First">3.3 (3, 4.1)</p> </td><td align="center" class="Botrule Rrule" valign="bottom"> <p class="First">3.5 (3, 5.3)</p> </td> </tr> <tr> <td class="Lrule Toprule"> <p class="First"> <span class="Bold">Time to progression (months)</span> </p> </td><td class="Lrule Toprule" valign="bottom"></td><td class="Rrule Toprule" valign="bottom"></td> </tr> <tr> <td class="Lrule"> <p class="First"> Median (95% CI)</p> </td><td align="center" class="Lrule" valign="bottom"> <p class="First">3.1 (2.6, 4.1)</p> </td><td align="center" class="Rrule" valign="bottom"> <p class="First">2.8 (2.5, 3.2)</p> </td> </tr> <tr> <td class="Lrule"> <p class="First"> Hazard ratio (95% CI)</p> </td><td align="center" class="Lrule Rrule" colspan="2" valign="bottom"> <p class="First">0.92 (0.69, 1.22)</p> </td> </tr> <tr> <td class="Lrule Toprule"> <p class="First"> <span class="Bold">Overall survival (months)</span> </p> </td><td class="Lrule Toprule" valign="bottom"></td><td class="Rrule Toprule" valign="bottom"></td> </tr> <tr> <td class="Lrule"> <p class="First"> Median (95% CI)</p> </td><td align="center" class="Lrule" valign="bottom"> <p class="First">5.8 (4.7, 6.8)</p> </td><td align="center" class="Rrule" valign="bottom"> <p class="First">5.7 (5, 7)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule"> <p class="First"> Hazard ratio (95% CI)</p> </td><td align="center" class="Botrule Lrule Rrule" colspan="2" valign="bottom"> <p class="First">1.04 (0.78, 1.39)</p> </td> </tr> </tbody> </table></div>

The median time to response was similar in both arms: Topotecan hydrochloride for injection, 6 weeks (2.4 weeks to 3.6 months) versus CAV, 6 weeks (5.1 weeks to 4.2 months).

Changes on a disease-related symptom scale are presented in Table 6. It should be noted that not all patients had all symptoms, nor did all patients respond to all questions. Each symptom was rated on a 4-category scale with an improvement defined as a change in 1 category from baseline sustained over 2 courses. Limitations in interpretation of the rating scale and responses preclude formal statistical analysis.

<div class="scrollingtable"><table> <caption> <span>Table 6. Symptom Improvement <span class="Sup">a</span>in Patients With Small Cell Lung Cancer in Study 090 </span> </caption> <col width="35%"/> <col width="15%"/> <col width="15%"/> <col width="15%"/> <col width="15%"/> <tfoot> <tr class="First Last"> <td class="Toprule" colspan="3"><span class="Sup">a</span>Defined as improvement sustained over at least 2 courses compared with baseline. <br/> <span class="Sup">b</span>Number of patients with baseline and at least 1 post-baseline assessment. </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Lrule Rrule Toprule" rowspan="2" valign="bottom"> <p class="First"> <span class="Bold">Symptoms</span> </p> </td><td align="center" class="Botrule Toprule" colspan="2" valign="bottom"> <p class="First"> <span class="Bold">Topotecan Hydrochloride for Injection</span> </p> <p> <span class="Bold">(n = 107)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="bottom"> <p class="First"> <span class="Bold">CAV</span> </p> <p> <span class="Bold">(n = 104)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">n <span class="Sup">b</span></span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">(%)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">n <span class="Sup">b</span></span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">(%)</span> </p> </td> </tr> <tr> <td class="Lrule Rrule Toprule"> <p class="First">Shortness of breath</p> </td><td align="center" class="Rrule Toprule" valign="bottom"> <p class="First">68</p> </td><td align="center" class="Lrule Rrule Toprule" valign="bottom"> <p class="First">28</p> </td><td align="center" class="Lrule Rrule Toprule" valign="bottom"> <p class="First">61</p> </td><td align="center" class="Lrule Rrule Toprule" valign="bottom"> <p class="First">7</p> </td> </tr> <tr> <td class="Lrule Rrule"> <p class="First">Interference with daily activity</p> </td><td align="center" class="Rrule" valign="bottom"> <p class="First">67</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">27</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">63</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">11</p> </td> </tr> <tr> <td class="Lrule Rrule"> <p class="First">Fatigue</p> </td><td align="center" class="Rrule" valign="bottom"> <p class="First">70</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">23</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">65</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">9</p> </td> </tr> <tr> <td class="Lrule Rrule"> <p class="First">Hoarseness</p> </td><td align="center" class="Rrule" valign="bottom"> <p class="First">40</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">33</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">38</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">13</p> </td> </tr> <tr> <td class="Lrule Rrule"> <p class="First">Cough</p> </td><td align="center" class="Rrule" valign="bottom"> <p class="First">69</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">25</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">61</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">15</p> </td> </tr> <tr> <td class="Lrule Rrule"> <p class="First">Insomnia</p> </td><td align="center" class="Rrule" valign="bottom"> <p class="First">57</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">33</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">53</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">19</p> </td> </tr> <tr> <td class="Lrule Rrule"> <p class="First">Anorexia</p> </td><td align="center" class="Rrule" valign="bottom"> <p class="First">56</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">32</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">57</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">16</p> </td> </tr> <tr> <td class="Lrule Rrule"> <p class="First">Chest pain</p> </td><td align="center" class="Rrule" valign="bottom"> <p class="First">44</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">25</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">41</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">17</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule"> <p class="First">Hemoptysis</p> </td><td align="center" class="Botrule Rrule" valign="bottom"> <p class="First">15</p> </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> <p class="First">27</p> </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> <p class="First">12</p> </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> <p class="First">33</p> </td> </tr> </tbody> </table></div>

Single-Arm Trials

Topotecan hydrochloride for injection was also studied in three open-label, non-comparative trials (Studies 014, 092 and 053) in a total of 319 patients with recurrent or progressive SCLC after treatment with first-line chemotherapy. In all three trials, patients were stratified as either sensitive (responders who then subsequently progressed greater than or equal to 90 days after completion of first-line therapy) or refractory (no response to first-line chemotherapy or who responded to first-line therapy and then progressed within 90 days of completing first-line therapy). Response rates ranged from 11% to 31% for sensitive patients and 2% to 7% for refractory patients. Median time to progression and median survival were similar in all three trials and the comparative trial.

The efficacy of topotecan hydrochloride for injection was evaluated in a multi-center, randomized (1:1), open-label study (Study GOG 0179) conducted in 147 patients with histologically confirmed Stage IV-B, recurrent, or persistent cervical cancer considered not amenable to curative treatment with surgery and/or radiation. Patients were randomized to topotecan hydrochloride for injection (0.75 mg/m 2once daily intravenously for 3 consecutive days starting on Day 1 of a 21-day cycle) with cisplatin (50 mg/m 2intravenously on Day 1) or cisplatin as a single agent. Fifty-six percent of patients treated with topotecan hydrochloride for injection with cisplatin and 56% of patients treated with cisplatin had received prior cisplatin with or without other agents as first-line chemotherapy. The efficacy outcome measure was OS.

Median OS of eligible patients receiving topotecan hydrochloride for injection with cisplatin was 9.4 months (95% CI: 7.9, 11.9) compared with 6.5 months (95% CI: 5.8, 8.8) among patients randomized to cisplatin alone with a log rank P-value of 0.033 (significance level was 0.044 after adjusting for the interim analysis). The unadjusted hazard ratio for OS was 0.76 (95% CI: 0.59, 0.98).

Figure 1. Kaplan-Meier Curves for Overall Survival in Cervical Cancer in Study GOG 0179

{ "type": "ul", "children": [ "\"OSHA Hazardous Drugs.\"\n \n OSHA. http:// www.osha.gov/SLTC/hazardousdrugs/index.html.\n \n " ], "text": "" }

Topotecan hydrochloride for injection is supplied as a sterile, lyophilized, yellow powder for reconstitution in 4-mg (free base) single-dose vials.

{ "type": "p", "children": [], "text": "Topotecan hydrochloride for injection is supplied as a sterile, lyophilized, yellow powder for reconstitution in 4-mg (free base) single-dose vials." }

NDC 16729-151-31 (package of 1)

{ "type": "p", "children": [], "text": "NDC 16729-151-31 (package of 1)" }

Store between 20°C and 25°C (68°F and 77°F) [see USP Controlled Room Temperature] in original carton. Protect from light.

{ "type": "p", "children": [], "text": "Store between 20°C and 25°C (68°F and 77°F) [see USP Controlled Room Temperature] in original carton. Protect from light." }

Topotecan Hydrochloride for injection is a cytotoxic drug. Follow applicable handling and disposal procedures. 1

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Myelosuppression

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Inform patients that topotecan hydrochloride for injection decreases blood cell counts such as white blood cells, platelets, and red blood cells. Advise patients to notify their healthcare provider promptly for fever, other signs of infection, or bleeding [see Warnings and Precautions ( 5.1)] .

{ "type": "p", "children": [], "text": "Inform patients that topotecan hydrochloride for injection decreases blood cell counts such as white blood cells, platelets, and red blood cells. Advise patients to notify their healthcare provider promptly for fever, other signs of infection, or bleeding\n \n [see Warnings and Precautions (\n \n 5.1)]\n \n .\n\n " }

Interstitial Lung Disease (ILD)

{ "type": "p", "children": [], "text": "\nInterstitial Lung Disease (ILD)\n" }

Inform patients of the risks of severe ILD. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms [see Warnings and Precautions ( 5.2)] .

{ "type": "p", "children": [], "text": "Inform patients of the risks of severe ILD. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms\n \n [see Warnings and Precautions (\n \n 5.2)]\n \n .\n\n " }

Embryo-Fetal Toxicity

{ "type": "p", "children": [], "text": "\nEmbryo-Fetal Toxicity\n" }

Advise females of reproductive potential and males with female partners of reproductive potential of the potential risk to a fetus. Advise women to contact their healthcare provider if they become pregnant, or if pregnancy is suspected during treatment with topotecan hydrochloride for injection [see Warnings and Precautions ( 5.4), Use in Specific Populations ( 8.1, 8.3)] .

{ "type": "p", "children": [], "text": "Advise females of reproductive potential and males with female partners of reproductive potential of the potential risk to a fetus. Advise women to contact their healthcare provider if they become pregnant, or if pregnancy is suspected during treatment with topotecan hydrochloride for injection\n \n [see Warnings and Precautions (\n \n 5.4), Use in Specific Populations (\n \n 8.1,\n \n 8.3)]\n \n .\n\n " }

Advise females of reproductive potential to use effective contraception during treatment and for 6 months after the last dose of topotecan hydrochloride for injection [see Use in Specific Populations ( 8.1, 8.3)] .

{ "type": "p", "children": [], "text": "Advise females of reproductive potential to use effective contraception during treatment and for 6 months after the last dose of topotecan hydrochloride for injection\n \n [see Use in Specific Populations (\n \n 8.1,\n \n 8.3)]\n \n .\n\n " }

Advise males with a female partner of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of topotecan hydrochloride for injection [see Use in Specific Populations ( 8.1, 8.3), Nonclinical Toxicology ( 13.1)] .

{ "type": "p", "children": [], "text": "Advise males with a female partner of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of topotecan hydrochloride for injection\n \n [see Use in Specific Populations (\n \n 8.1,\n \n 8.3), Nonclinical Toxicology (\n \n 13.1)]\n \n .\n\n " }

Lactation

{ "type": "p", "children": [], "text": "\nLactation\n" }

Advise women to discontinue breastfeeding during treatment and for 1 week after the last dose of topotecan hydrochloride for injection [see Use in Specific Populations ( 8.2)] .

{ "type": "p", "children": [], "text": "Advise women to discontinue breastfeeding during treatment and for 1 week after the last dose of topotecan hydrochloride for injection\n \n [see Use in Specific Populations (\n \n 8.2)]\n \n .\n\n " }

Infertility

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Advise male and female patients of the potential risk for impaired fertility [see Use in Specific Populations ( 8.3), Nonclinical Toxicology ( 13.1)] .

{ "type": "p", "children": [], "text": "Advise male and female patients of the potential risk for impaired fertility\n \n [see Use in Specific Populations (\n \n 8.3), Nonclinical Toxicology (\n \n 13.1)]\n \n .\n\n " }

Asthenia and Fatigue

{ "type": "p", "children": [], "text": "\nAsthenia and Fatigue\n" }

Advise patients that topotecan hydrochloride for injection may cause asthenia or fatigue. These symptoms may impair the ability to safely drive or operate machinery.

{ "type": "p", "children": [], "text": "Advise patients that topotecan hydrochloride for injection may cause asthenia or fatigue. These symptoms may impair the ability to safely drive or operate machinery." }

Manufactured For:

{ "type": "p", "children": [], "text": "\nManufactured For:\n" }

Accord Healthcare, Inc., 8041 Arco Corporate Drive, Suite 200, Raleigh, NC 27617, USA.

{ "type": "p", "children": [], "text": "Accord Healthcare, Inc., \n 8041 Arco Corporate Drive, \n Suite 200, \n Raleigh, NC 27617, \n USA.\n " }

Manufactured By:

{ "type": "p", "children": [], "text": "\nManufactured By:\n" }

Intas Pharmaceuticals Limited, Plot No. : 457, 458, Village – Matoda, Bavla Road, Ta. - Sanand, Dist. - Ahmedabad – 382 210, India.

{ "type": "p", "children": [], "text": "Intas Pharmaceuticals Limited, \n Plot No. : 457, 458, \n Village – Matoda, \n Bavla Road, Ta. - Sanand, \n Dist. - Ahmedabad – 382 210, \n India.\n " }

10 4086 1 6027351

{ "type": "p", "children": [], "text": "10 4086 1 6027351" }

Issued December, 2023

{ "type": "p", "children": [], "text": "Issued December, 2023" }

PRINCIPAL DISPLAY PANEL

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL\n" }

PRINCIPAL DISPLAY PANEL

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL\n" }

HYCAMTIN® capsules are indicated for the treatment of relapsed small cell lung cancer (SCLC) in patients with a prior complete or partial response and who are at least 45 days from the end of first-line chemotherapy.

{ "type": "p", "children": [], "text": "HYCAMTIN® capsules are indicated for the treatment of relapsed small cell lung cancer (SCLC) in patients with a prior complete or partial response and who are at least 45 days from the end of first-line chemotherapy." }

The recommended dosage of HYCAMTIN capsules is 2.3 mg/m2/day orally once daily, with or without food, for 5 consecutive days, starting on Day 1 of a 21-day cycle. Round the dose to the nearest 0.25 mg and prescribe the minimum number of 1 mg and 0.25 mg capsules. Prescribe the same number of capsules for each of the 5 dosing days.

Swallow capsules whole. Do not chew, crush, or divide the capsules.

Diarrhea

Do not administer HYCAMTIN capsules to patients with Grade 3 or 4 diarrhea. After recovery to Grade 1 or less, reduce the dose by 0.4 mg/m2/day for subsequent courses [see Warnings and Precautions (5.2)].

Hematologic

Reduce dose by 0.4 mg/m2/day for:

Capsules

{ "type": "p", "children": [], "text": "\nCapsules\n" }

{ "type": "", "children": [], "text": "" }

HYCAMTIN is contraindicated in patients who have a history of severe hypersensitivity reactions to topotecan. Reactions have included anaphylactoid reactions [see Adverse Reactions (6.2)].

{ "type": "p", "children": [], "text": "HYCAMTIN is contraindicated in patients who have a history of severe hypersensitivity reactions to topotecan. Reactions have included anaphylactoid reactions [see Adverse Reactions (6.2)]." }

HYCAMTIN can cause severe myelosuppression. The following safety data are based on an integrated safety database from four trials in patients with lung cancer (N = 682) who received HYCAMTIN capsules at a dose of 2.3 mg/m2 orally once daily for 5 consecutive days, starting on Day 1 of a 21-day cycle.

The median day for neutrophil and platelet nadirs occurred on Day 15. Grade 4 neutropenia occurred in 32% of the 682 patients, with a median duration of 7 days. Grade 4 neutropenia most commonly occurred during cycle 1 (20% of patients). Clinical sequelae of neutropenia included infection (17%), febrile neutropenia (4%), sepsis (2%), and septic death (1%). Grade 4 thrombocytopenia occurred in 6%, with a median duration of 3 days. Grade 3 or 4 anemia occurred in 25%.

HYCAMTIN 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 capsules only to patients with a baseline neutrophil count greater than or equal to 1,500/mm3 and a platelet count greater than or equal to 100,000/mm3. Monitor blood cell counts frequently during treatment. Withhold and reduce dose of HYCAMTIN capsules based on neutrophil counts, platelet counts and hemoglobin levels [see Dosage and Administration (2.2)].

Diarrhea, including severe and life-threatening diarrhea requiring hospitalization, can occur with HYCAMTIN capsules. Diarrhea can occur at the same time as drug-induced neutropenia and its sequelae. In the 682 patients who received HYCAMTIN capsules in the four lung cancer trials, the incidence of diarrhea caused by HYCAMTIN capsules was 22%, including Grade 3 (4%) and Grade 4 (0.4%). The incidence of Grade 3 or 4 diarrhea proximate (within 5 days) to Grade 3 or 4 neutropenia was 5%. The median time to onset of Grade 2 to 4 diarrhea was 9 days in the group receiving HYCAMTIN capsules.

Monitor patients for diarrhea and treat with antidiarrheals at the first sign of diarrhea. Withhold and dose reduce as recommended based on severity [see Dosage and Administration (2.2)].

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 capsules if ILD is confirmed.

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 the Warnings and Precautions and below reflects exposure to HYCAMTIN capsules in 682 patients with recurrent lung cancer enrolled in four randomized, open label trials, including 275 patients with small lung cell lung cancer (SCLC) (Studies 478, 065 and 396), and 407 patients with non-small cell lung cancer (NSCLC) (Study 387), who received at least one dose of HYCAMTIN capsules. Patients in these trials had advanced lung cancer and received prior chemotherapy in the first-line setting. Patients received HYCAMTIN capsules 2.3 mg/m2 orally once daily for 5 consecutive days, starting on Day 1 of a 21-day cycle. The median number of cycles was 3 (range: 1 to 20).

The safety of HYCAMTIN capsules was evaluated in a randomized trial (Study 478) conducted in 70 patients with recurrent SCLC [see Clinical Studies (14)].

In the 682 patients who received HYCAMTIN capsules in the four lung cancer trials, 39 deaths (6%) occurred within 30 days after the last dose for a reason other than progressive disease: 13 due to hematologic toxicity, 5 due to non-hematologic toxicity (2 from diarrhea), and 21 due to other causes.

Table 1 describes the hematologic and non-hematologic adverse reactions that occurred in greater than 5% of patients treated with HYCAMTIN capsules in these trials.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 1. Adverse Reactions Occurring in Greater than or Equal to 5% of Patients With Lung Cancer </span> </caption> <col width="21%"/> <col width="20%"/> <col width="13%"/> <col width="10%"/> <col width="13%"/> <col width="13%"/> <col width="10%"/> <tfoot> <tr> <td align="left" colspan="7"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Adverse reactions were graded using National Cancer Institute (NCI) Common Toxicity Criteria (CTC) Version 2.0.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" rowspan="3" valign="top"> <p class="First"> <span class="Bold">Adverse Reactions</span><a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a> </p> </td><td class="Lrule Rrule Toprule" colspan="3" valign="top"> <dl> <dt> </dt> <dd> <span class="Bold">HYCAMTIN Capsules With Best</span> <br/> <span class="Bold">Supportive Care </span> <br/> <span class="Bold">(Study 478)</span> </dd> </dl> </td><td class="Lrule Rrule Toprule" colspan="3" valign="top"> <dl> <dt> </dt> <dd> <span class="Bold">HYCAMTIN Capsules</span> <br/> <span class="Bold">Lung Cancer Population </span> <br/> <span class="Bold">(Studies 478, 065, 396 and 387)</span> </dd> </dl> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">N = 70</span> </p> </td><td align="center" class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">N = 682</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">All Grades</span> </p> <p> <span class="Bold">(%)</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Grade 3</span> </p> <p> <span class="Bold">(%)</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Grade 4</span> </p> <p> <span class="Bold">(%)</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">All Grades</span> </p> <p> <span class="Bold">(%)</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Grade 3</span> </p> <p> <span class="Bold">(%)</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Grade 4</span> </p> <p> <span class="Bold">(%)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First"> <span class="Bold">Hematologic</span> </p> </td><td class="Botrule" valign="top"></td><td class="Botrule" valign="top"></td><td class="Botrule" valign="top"></td><td class="Botrule" valign="top"></td><td class="Botrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Anemia</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">94</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">15</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">98</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">18</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Neutropenia</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">91</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">28</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">33</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">83</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">24</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">32</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Thrombocytopenia</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">81</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">30</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">81</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">29</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First"> <span class="Bold">Non-hematologic</span> </p> </td><td class="Botrule" valign="top"></td><td class="Botrule" valign="top"></td><td class="Botrule" valign="top"></td><td class="Botrule" valign="top"></td><td class="Botrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Nausea</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">27</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">33</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Vomiting</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">19</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">21</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0.4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Diarrhea</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">14</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">22</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0.4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Fatigue</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">11</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">19</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0.1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Alopecia</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">20</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0.1</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Pyrexia</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Anorexia</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">14</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Asthenia</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> </tbody> </table></div>

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.

P-glycoprotein or Breast Cancer Resistance Protein Inhibitor

Concomitant use of a P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) inhibitor increases topotecan AUC [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions. Avoid concomitant use HYCAMTIN capsules with P-gp inhibitors or BCRP inhibitors.

Risk Summary

Based on animal data and its mechanism of action, HYCAMTIN can cause fetal harm when administered to a pregnant woman. There are no available clinical data on the use of HYCAMTIN in pregnancy. Topotecan caused embryolethality, fetotoxicity, and teratogenicity in rats and rabbits when administered during organogenesis at doses similar to the clinical dose (see Data). Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Data

Animal Data

Risk Summary

There are no data on the presence of topotecan or its metabolites in human milk, or their effects on the breastfed infant or milk production. Lactating rats excrete high concentrations of topotecan into milk (see Data). Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with HYCAMTIN and for 1 week after the last dose.

Data

Following intravenous administration of topotecan to lactating rats at a dose of 4.72 mg/m2 (about twice the 1.5 mg/m2 clinical intravenous dose based on BSA), topotecan was excreted into milk at concentrations up to 48-fold higher than those in plasma.

Pregnancy Testing

Verify pregnancy status of females of reproductive potential prior to initiating HYCAMTIN capsules [see Use in Specific Populations (8.1)].

Contraception

HYCAMTIN can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Females

Advise female patients of reproductive potential to use effective contraception during treatment with HYCAMTIN capsules and for 6 months after the last dose.

Males

HYCAMTIN capsules may damage spermatozoa, resulting in possible genetic and fetal abnormalities. Advise males with a female partner of reproductive potential to use effective contraception during treatment with HYCAMTIN capsules and for 3 months after the last dose [see Nonclinical Toxicology (13.1)].

Infertility

Females

HYCAMTIN can have both acute and long-term effects on fertility [see Nonclinical Toxicology (13.1)].

Males

Effects on spermatogenesis have occurred in animals administered topotecan [see Nonclinical Toxicology (13.1)].

Safety and effectiveness in pediatric patients have not been established.

Of the 682 patients with lung cancer who received HYCAMTIN capsules in the four clinical trials, 33% were aged 65 years and older, while 4.8% were aged 75 years and older. Treatment-related diarrhea was more frequent in patients aged greater than or equal to 65 years (28%) compared with those younger than 65 years (19%) [see Warnings and Precautions (5.2), Adverse Reactions (6.1)]. No overall differences in effectiveness were observed between patients 65 years and older and younger patients.

No dosage adjustment is recommended for patients with creatinine clearance (CLcr) greater than or equal to 50 mL/min. Reduce the dose of HYCAMTIN capsules in patients with CLcr less than 49 mL/min [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].

Overdoses (up to 5-fold of the prescribed dose) have occurred in patients receiving HYCAMTIN capsules. The primary complication of overdosage is myelosuppression. Mucositis have occurred with overdosages. If an overdose is suspected, monitor the patient closely for myelosuppression and institute supportive-care measures as appropriate.

{ "type": "p", "children": [], "text": "Overdoses (up to 5-fold of the prescribed dose) have occurred in patients receiving HYCAMTIN capsules. The primary complication of overdosage is myelosuppression. Mucositis have occurred with overdosages. If an overdose is suspected, monitor the patient closely for myelosuppression and institute supportive-care measures as appropriate." }

Topotecan is a topoisomerase inhibitor. The chemical name for topotecan hydrochloride is (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7] indolizino [1,2-b]quinoline-3,14-(4H,12H)-dione monohydrochloride. The molecular formula is C23H23N3O5•HCl and the molecular weight is 457.9 g/mol. It is soluble in water and melts with decomposition at 213°C to 218°C.

{ "type": "p", "children": [], "text": "Topotecan is a topoisomerase inhibitor. The chemical name for topotecan hydrochloride is (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7] indolizino [1,2-b]quinoline-3,14-(4H,12H)-dione monohydrochloride. The molecular formula is C23H23N3O5•HCl and the molecular weight is 457.9 g/mol. It is soluble in water and melts with decomposition at 213°C to 218°C." }

Topotecan hydrochloride has the following structural formula:

{ "type": "p", "children": [], "text": "Topotecan hydrochloride has the following structural formula:" }

HYCAMTIN capsules, contain topotecan hydrochloride, the content of which is expressed as topotecan free base. Each 0.25 mg and 1 mg capsule contain topotecan hydrochloride equivalent to 0.25 mg and 1 mg topotecan free-base, respectively. The excipients are gelatin, glyceryl monostearate, hydrogenated vegetable oil, and titanium dioxide. The capsules are imprinted with edible black ink. The 1 mg capsules also contain red iron oxide.

{ "type": "p", "children": [], "text": "HYCAMTIN capsules, contain topotecan hydrochloride, the content of which is expressed as topotecan free base. Each 0.25 mg and 1 mg capsule contain topotecan hydrochloride equivalent to 0.25 mg and 1 mg topotecan free-base, respectively. The excipients are gelatin, glyceryl monostearate, hydrogenated vegetable oil, and titanium dioxide. The capsules are imprinted with edible black ink. The 1 mg capsules also contain red iron oxide." }

Topoisomerase I relieves torsional strain in DNA by inducing reversible single-strand breaks. Topotecan binds to the topoisomerase I-DNA complex and prevents re-ligation of these single-strand breaks. The cytotoxicity of topotecan is thought to be due to double-strand DNA damage produced during DNA synthesis, when replication enzymes interact with the ternary complex formed by topotecan, topoisomerase I, and DNA. Mammalian cells cannot efficiently repair these double-strand breaks.

Following administration of HYCAMTIN capsules at doses of 1.2 to 3.1 mg/m2 (0.52 to 1.35 times the recommended dose) administered daily for 5 days, the area under the curve (AUC) increased proportionally with dose.

Absorption

The time to the peak plasma concentrations is between 1 to 2 hours following oral administration. The oral bioavailability of topotecan is approximately 40%.

Food Effect

Following a high-fat meal, the AUC was similar in the fed and fasted states, while Tmax was delayed from 1.5 to 3 hours for topotecan lactone and from 3 to 4 hours for total topotecan.

Distribution

Protein binding of topotecan is approximately 35%.

Elimination

The mean terminal half-life (t½) of topotecan is 3 to 6 hours following oral administration.

Metabolism

Topotecan undergoes a reversible pH-dependent hydrolysis of a pharmacologically active lactone moiety. At pH less than or equal to 4, the lactone is exclusively present, whereas the ring-opened hydroxy-acid form predominates at physiologic pH. The mean metabolite: parent AUC ratio was less than 10% for total topotecan and topotecan lactone.

Excretion

The overall recovery of drug-related material following 5 daily doses of topotecan was 57% of the administered oral dose. In the urine, 20% of the orally administered dose was excreted as total topotecan and 2% was excreted as N-desmethyl topotecan. Fecal elimination of total topotecan accounted for 33%, while fecal elimination of the active metabolite N-desmethyl topotecan accounted for 1.5%. Overall, the N-desmethyl metabolite contributed a mean of less than 6% (range: 4% to 8%) of the total drug-related material accounted for in the urine and feces.

Specific Populations

No clinically significant differences in the pharmacokinetics of topotecan were observed based on age, sex, or hepatic impairment following oral administration.

Racial and Ethnic Groups

In patients with creatinine clearance (CLcr) greater than 80 mL/min, the dose-normalized AUCinf to topotecan lactone and total topotecan each were approximately 30% higher in Asians compared to Whites

Patients with Renal Impairment

The mean dose-normalized for total topotecan and topotecan lactone AUCinf increased in advanced cancer patients with renal impairment compared to patients with CLcr greater than 80 mL/min as presented in Table 2 [see Dosage and Administration (2.3)]. Prior platinum-based chemotherapy had no effect on the systemic exposure to both total topotecan and topotecan lactone in patients with CLcr greater than 80 mL/min.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 2. AUC<span class="Sub">inf</span> Increases Compared to Normal Renal Function </span> </caption> <col width="43%"/> <col width="21%"/> <col width="21%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Renal Impairment</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="bottom"> <p class="First"> <span class="Bold">Geometric Mean Dose-Normalized AUC<span class="Sub">inf</span></span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Total Topotecan</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Topotecan Lactone</span> </p> </td> </tr> <tr> <td class="Botrule Lrule" valign="bottom"> <p class="First"> <span class="Bold">Whites</span> </p> </td><td class="Botrule" valign="bottom"></td><td class="Botrule Rrule" valign="bottom"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>CLcr 50-79 mL/min<br/>CLcr 30-49 mL/min <br/> &lt; 30 mL/min</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">70%<br/>108%<br/>227%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">34%<br/>80%<br/>114%</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="bottom"> <p class="First"> <span class="Bold">Asians</span> </p> </td><td class="Botrule" valign="bottom"></td><td class="Botrule Rrule" valign="bottom"></td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>CLcr 50-79 mL/min<br/>CLcr 30-49 mL/min <br/> &lt; 30 mL/min</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">26%<br/>153%<br/>331%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">34%<br/>121%<br/>247%</p> </td> </tr> </tbody> </table></div>

Drug Interaction Studies

Clinical Studies

Effect of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) Inhibitors

Following coadministration of escalating doses of a dual inhibitor of BCRP and P-gp, the AUCinf of topotecan lactone and total topotecan increased approximately 2.5-fold compared to topotecan alone [see Drug Interactions (7.1)].

Coadministration of single oral dose of cyclosporine A (15 mg/kg), an inhibitor of P-gp, multidrug-resistance-associated protein (MRP-1) and CYP3A4, within 4 hours of oral topotecan increased the dose-normalized AUC0-24h of topotecan lactone and total topotecan 2- to 3-fold compared to topotecan alone [see Drug Interactions (7.1)].

Effect of Gastric Acid Reducing Agents

No clinically significant changes in the pharmacokinetics of oral topotecan were observed when coadministered with ranitidine, a histamine-2 receptor antagonist.

In Vitro Studies

Topotecan does not inhibit CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A, CYP4A, or dihydropyrimidine dehydrogenase.

Carcinogenicity testing of topotecan has not been done. Nevertheless, topotecan is known to be genotoxic to mammalian cells and is a probable carcinogen. Topotecan was mutagenic to L5178Y mouse lymphoma cells and clastogenic to cultured human lymphocytes with and without metabolic activation. It was also clastogenic to mouse bone marrow. Topotecan did not cause mutations in bacterial cells.

Topotecan given to female rats prior to mating at an intravenous dose of 1.4 mg/m2 [(about 0.6 times the 2.3 mg/m2 oral clinical dose based on body surface area (BSA)] caused superovulation possibly related to inhibition of follicular atresia. This dose given to pregnant female rats also caused increased pre-implantation loss. Studies in dogs given an intravenous dose of 0.4 mg/m2 (about 0.2 times the 2.3 mg/m2 oral clinical dose based on BSA) of topotecan daily for a month suggest that treatment may cause an increase in the incidence of multinucleated spermatogonial giant cells in the testes.

The efficacy of HYCAMTIN capsules was studied in 141 patients with relapsed SCLC in a randomized, controlled, open-label trial (Study 478). The patients were prior responders (complete or partial) to first-line chemotherapy, were not considered candidates for standard intravenous chemotherapy and had relapsed at least 45 days from the end of first-line chemotherapy. Patients were randomized 1:1 to HYCAMTIN capsules (2.3 mg/m2 orally once daily for 5 consecutive days, starting on Day 1 of a 21-day cycle) with best supportive care (BSC) or BSC alone. The major efficacy outcome measure was overall survival (OS).

Patients randomized to HYCAMTIN capsules with BSC received a median of 4 courses (range: 1 to 10) and maintained a median dose intensity of 3.77 mg/m2/week. The median patient age in patients receiving HYCAMTIN capsules with BSC and BSC alone was 60 years and 58 years, while the percentage of patients aged greater than or equal to 65 years was 34% and 29%, respectively. The majority of patients were White (99%) and male (73%). In the HYCAMTIN capsules with BSC arm, 68% of patients had extensive disease and 28% had liver metastasis. In the BSC alone arm, 61% had extensive disease and 20% had liver metastases. Eighty percent of patients receiving HYCAMTIN capsules with BSC previously received carboplatin or cisplatin and 77% of patients in the BSC alone arm received prior carboplatin or cisplatin. In the arm receiving HYCAMTIN capsules with BSC, 18% of patients had prior carboplatin and 62% had prior cisplatin. In the BSC-alone arm, 26% of patients had prior carboplatin and 51% had prior cisplatin.

The arm receiving HYCAMTIN capsules with BSC showed a statistically significant improvement in OS compared with the BSC-alone arm (Log-rank P = 0.0104). Efficacy results are shown in Table 3 and Figure 1.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 3. Efficacy Results in Small Cell Lung Cancer in Study 478</span> </caption> <col width="32%"/> <col width="34%"/> <col width="34%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" rowspan="3" valign="middle"> <p class="First"> <span class="Bold">Parameters</span> </p> </td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Treatment Group</span> </p> </td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">HYCAMTIN Capsules with BSC</span> </p> </td><td align="center" class="Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">BSC</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">(N = 71)</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">(N = 70)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Median Overall Survival (months) (95% CI)</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6.0 (4.2, 7.3)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3.2 (2.6, 4.3)</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Hazard ratio (95% CI)</span> </p> </td><td align="center" class="Lrule Rrule" colspan="2" valign="top"> <p class="First">0.64 (0.45, 0.90)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Log-rank <span class="Italics">P</span>-value</p> </td><td align="center" class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First">0.0104</p> </td> </tr> </tbody> </table></div>

Figure 1. Kaplan-Meier Curves for Overall Survival in Small Cell Lung Cancer in Study 478

{ "type": "", "children": [], "text": "" }

The 0.25 mg HYCAMTIN capsules are opaque white to yellowish-white imprinted with HYCAMTIN and 0.25 mg and are available in bottles of 10: NDC 66758-101-11.

{ "type": "p", "children": [], "text": "The 0.25 mg HYCAMTIN capsules are opaque white to yellowish-white imprinted with HYCAMTIN and 0.25 mg and are available in bottles of 10: NDC 66758-101-11." }

The 1 mg HYCAMTIN capsules are opaque pink imprinted with HYCAMTIN and 1 mg and are available in bottles of 10: NDC 66758-102-11.

{ "type": "p", "children": [], "text": "The 1 mg HYCAMTIN capsules are opaque pink imprinted with HYCAMTIN and 1 mg and are available in bottles of 10: NDC 66758-102-11." }

Store refrigerated 2ºC to 8ºC (36ºF to 46ºF) protected from light in the original carton.

{ "type": "p", "children": [], "text": "Store refrigerated 2ºC to 8ºC (36ºF to 46ºF) protected from light in the original carton." }

HYCAMTIN is a cytotoxic drug. Follow applicable special handling and disposable procedures.1

{ "type": "p", "children": [], "text": "HYCAMTIN is a cytotoxic drug. Follow applicable special handling and disposable procedures.1\n" }

{ "type": "", "children": [], "text": "" }

Myelosuppression

{ "type": "p", "children": [], "text": "\nMyelosuppression\n" }

Inform patients that HYCAMTIN decreases blood cell counts, such as white blood cells, platelets, and red blood cells. Instruct patients to notify their healthcare provider promptly for fever or other signs of infection [see Warnings and Precautions (5.1)].

{ "type": "p", "children": [], "text": "Inform patients that HYCAMTIN decreases blood cell counts, such as white blood cells, platelets, and red blood cells. Instruct patients to notify their healthcare provider promptly for fever or other signs of infection [see Warnings and Precautions (5.1)]." }

Diarrhea

{ "type": "p", "children": [], "text": "\nDiarrhea\n" }

{ "type": "", "children": [], "text": "" }

Interstitial Lung Disease (ILD)

{ "type": "p", "children": [], "text": "\nInterstitial Lung Disease (ILD)\n" }

Inform patients of the risks of severe ILD. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms [see Warnings and Precautions (5.3)].

{ "type": "p", "children": [], "text": "Inform patients of the risks of severe ILD. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms [see Warnings and Precautions (5.3)]." }

Embryo-Fetal Toxicity

{ "type": "p", "children": [], "text": "\nEmbryo-Fetal Toxicity\n" }

Advise females of reproductive potential and males with female partners of reproductive potential of the potential risk to a fetus. Advise women to contact their healthcare provider if they become pregnant, or if pregnancy is suspected during treatment with HYCAMTIN capsules [see Warnings and Precautions (5.4), Use in Specific Populations (8.1, 8.3)].

{ "type": "p", "children": [], "text": "Advise females of reproductive potential and males with female partners of reproductive potential of the potential risk to a fetus. Advise women to contact their healthcare provider if they become pregnant, or if pregnancy is suspected during treatment with HYCAMTIN capsules [see Warnings and Precautions (5.4), Use in Specific Populations (8.1, 8.3)]. " }

Advise females of reproductive potential to use effective contraception during treatment and for 6 months after the last dose of HYCAMTIN capsules [see Use in Specific Populations (8.1, 8.3)].

{ "type": "p", "children": [], "text": "Advise females of reproductive potential to use effective contraception during treatment and for 6 months after the last dose of HYCAMTIN capsules [see Use in Specific Populations (8.1, 8.3)]." }

Advise males with a female partner of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of HYCAMTIN capsules [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

{ "type": "p", "children": [], "text": "Advise males with a female partner of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of HYCAMTIN capsules [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)]." }

Lactation

{ "type": "p", "children": [], "text": "\nLactation\n" }

Advise women to discontinue breastfeeding during treatment and for 1 week after the last dose of HYCAMTIN capsules [see Use in Specific Populations (8.2)].

{ "type": "p", "children": [], "text": "Advise women to discontinue breastfeeding during treatment and for 1 week after the last dose of HYCAMTIN capsules [see Use in Specific Populations (8.2)]." }

Infertility

{ "type": "p", "children": [], "text": "\nInfertility\n" }

Advise male and female patients of the potential risk for impaired fertility [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].

{ "type": "p", "children": [], "text": "Advise male and female patients of the potential risk for impaired fertility [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)]." }

Manufactured by:

{ "type": "p", "children": [], "text": "Manufactured by:" }

GlaxoSmithKline Manufacturing S.p.A.

{ "type": "p", "children": [], "text": "GlaxoSmithKline Manufacturing S.p.A." }

San Polo di Torrile, Parma, Italy for

{ "type": "p", "children": [], "text": "San Polo di Torrile, Parma, Italy for " }

Sandoz Inc., Princeton, NJ 08540

{ "type": "p", "children": [], "text": "Sandoz Inc., Princeton, NJ 08540" }

<div class="scrollingtable"><table width="100%"> <col width="34%"/> <col width="33%"/> <col width="33%"/> <tfoot> <tr class="First"> <td align="left" class="Botrule" colspan="3" valign="top">This Patient Information has been approved by the U.S. Food and Drug Administration.</td> </tr> <tr class="Last"> <td align="left" class="Botrule" colspan="3" valign="top">Revised: 9/2023</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">PATIENT INFORMATION</span> <br/> <span class="Bold">HYCAMTIN<span class="Sup">®</span> (hi-CAM-tin)</span> <br/> <span class="Bold">(topotecan) capsules</span> </p> </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">What is the most important information I should know about HYCAMTIN?</span> <br/> <span class="Bold">HYCAMTIN may cause serious side effects, including:</span> </p> </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> <dl> <dt>•</dt> <dd> <span class="Bold">Bone marrow problems.</span> HYCAMTIN can affect your bone marrow and can cause a severe decrease in your white blood cell, red blood cell, and platelet counts. Decreased blood cell counts can make you more likely to develop bleeding, bruising, anemia, or infections which may be life-threatening. Your healthcare provider will do blood tests regularly to check your blood cell counts during treatment with HYCAMTIN. Tell your healthcare provider right away if you have any signs of infection, including: <dl> <dt>o</dt> <dd>fever (temperature of 100.5°F or greater)</dd> <dt>o</dt> <dd>chills</dd> <dt>o</dt> <dd>cough</dd> <dt>o</dt> <dd>burning or pain on urination</dd> </dl> </dd> <dt>•</dt> <dd> <span class="Bold">Diarrhea.</span> HYCAMTIN can cause severe and life-threatening diarrhea that may need to be treated in a hospital. Tell your healthcare provider right away if you develop: <dl> <dt>o</dt> <dd>diarrhea with fever</dd> <dt>o</dt> <dd>diarrhea 3 or more times a day</dd> <dt>o</dt> <dd>diarrhea with stomach-area pain or cramps</dd> </dl> </dd> </dl> <p class="First"> <span class="Bold">See “What are the possible side effects of HYCAMTIN?”</span> for more information about side effects.</p> </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> <dl> <dt> </dt> <dd> <span class="Bold">What is HYCAMTIN?</span> <br/>HYCAMTIN is a prescription medicine used to treat small cell lung cancer (SCLC) that has come back (relapsed) and: </dd> <dt>•</dt> <dd>the cancer responded to your first chemotherapy, and</dd> <dt>•</dt> <dd>it has been at least 45 days from the last dose of chemotherapy </dd> </dl> <p class="First">It is not known if HYCAMTIN is safe and effective in children.</p> </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> <dl> <dt> </dt> <dd> <span class="Bold">Do not take HYCAMTIN</span> if you are allergic to topotecan or any of the ingreidents in HYCAMTIN. See the end of this leaflet for a complete list of ingredients in HYCAMTIN. </dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Before taking HYCAMTIN, tell your healthcare provider about all of your medical conditions, including if you:</span> <br/> </p> <dl> <dt>•</dt> <dd>have diarrhea or watery stools</dd> <dt>•</dt> <dd>have or have had lung problems</dd> <dt>•</dt> <dd>have kidney problems</dd> <dt>•</dt> <dd>are pregnant or plan to become pregnant. HYCAMTIN can harm your unborn baby. <dl> <dt>o</dt> <dd> <span class="Bold">Females</span> who are able to become pregnant should use effective birth control (contraception) during treatment with HYCAMTIN and for 6 months after the last dose of HYCAMTIN.</dd> <dt>o</dt> <dd> <span class="Bold">Males</span> who have female partners who are able to become pregnant, should use effective birth control during treatment with HYCAMTIN and for 3 months after the last dose of HYCAMTIN.</dd> <dt>o</dt> <dd>Talk to your healthcare provider about birth control methods that may be right for you during treatment with HYCAMTIN.</dd> <dt>o</dt> <dd>Your healthcare provider will do a pregnancy test before you start taking HYCAMTIN. Tell your healthcare provider right away if you become pregnant, think you might be pregnant, or your female partner becomes pregnant during treatment with HYCAMTIN.</dd> </dl> </dd> <dt>•</dt> <dd>are breastfeeding or plan to breastfeed. It is not known if HYCAMTIN passes into your breast milk. Do not breastfeed during treatment with HYCAMTIN and for 1 week after the last dose. Talk to your healthcare provider about the best way to feed your baby during this time. </dd> </dl> <p> <span class="Bold">Tell your healthcare provider about all the medicines you take,</span> including prescription and over-the-counter medicines, vitamins, and herbal supplements.</p> <p>Taking HYCAMTIN with certain other medicines can affect how HYCAMTIN works causing side effects.</p> <p>Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.</p> </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">How should I take HYCAMTIN?</span> <br/> </p> <dl> <dt>•</dt> <dd>Take HYCAMTIN exactly as your healthcare provider tells you to take it.</dd> <dt>•</dt> <dd>Your healthcare provider will tell you how many HYCAMTIN capsules to take and when to take them. Your healthcare provider may change your dose if needed.</dd> <dt>•</dt> <dd>Your healthcare provider may want you to take both 1 mg and 0.25 mg HYCAMTIN capsules for your prescribed dose. It is important for you to be able to tell the difference between the capsules. The 1-mg capsule is a pink color and the 0.25 mg capsule is a white to yellowish-white color.</dd> <dt>•</dt> <dd>Take HYCAMTIN one time a day for 5 days in a row. This treatment will normally be repeated every 3 weeks (a treatment cycle). Your healthcare provider will decide how long you will take HYCAMTIN.</dd> <dt>•</dt> <dd>Take HYCAMTIN with or without food.</dd> <dt>•</dt> <dd>Swallow HYCAMTIN whole. Do not open, chew, crush, or divide HYCAMTIN.</dd> <dt>•</dt> <dd>If any of the HYCAMTIN capsules are broken or leaking, do not touch them with your bare hands. Carefully throw away (dispose of) the capsules, and then wash your hands well with soap and water.</dd> <dt>•</dt> <dd>If you get any of the contents of HYCAMTIN capsules on your skin or in your eyes, do the following: <dl> <dt>°</dt> <dd>Wash the area of skin well with soap and water right away.</dd> <dt>°</dt> <dd>Wash your eyes right away with gently flowing water for at least 15 minutes.</dd> <dt>°</dt> <dd>Call your healthcare provider if you get a skin reaction or get HYCAMTIN in your eyes.</dd> </dl> </dd> <dt>•</dt> <dd>If you take too much HYCAMTIN, call your healthcare provider right away.</dd> <dt>•</dt> <dd>If you miss a dose of HYCAMTIN, or if you vomit after taking your HYCAMTIN, take your next dose at the next scheduled time. Do not take another dose on the same day.</dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">What are the possible side effects of HYCAMTIN?</span> <br/> <span class="Bold">HYCAMTIN may cause serious side effects, including:</span> </p> <dl> <dt>•</dt> <dd>See <span class="Bold">“What is the most important information I should know about HYCAMTIN?”</span> </dd> <dt>•</dt> <dd> <span class="Bold">Lung problems that can cause death.</span> Tell your healthcare provider right away if you have new or worse symptoms of coughing, fever, shortness of breath, or problems breathing. Your healthcare provider may tell you to stop taking HYCAMTIN capsules.</dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">The most common side effects of HYCAMTIN include:</span> </p> </td> </tr> <tr> <td class="Lrule" valign="top"> <dl> <dt> </dt> <dd>• decreased blood cell counts<br/> • diarrhea<br/> • hair loss</dd> </dl> </td><td valign="top"> <dl> <dt> </dt> <dd>• nausea<br/> • vomiting<br/> • fatigue<br/> </dd> </dl> </td><td class="Rrule" valign="top"></td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> <p class="First"> <br/>Your healthcare provider may tell you to decrease your dose, temporarily stop, or completely stop taking HYCAMTIN if you develop certain serious side effects during treatment with HYCAMTIN.</p> <p>HYCAMTIN may cause short-term and long-term fertility problems in females. This could affect your ability to become pregnant.</p> <p>HYCAMTIN may cause lower sperm count problems in men. This could affect your ability to father a child and cause birth defects. Talk to your healthcare provider about family planning options that might be right for you.</p> <p>These are not all the possible side effects of HYCAMTIN.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">How should I store HYCAMTIN?</span> </p> <dl> <dt>•</dt> <dd>Store HYCAMTIN in a refrigerator between 36°F to 46°F (2°C to 8°C).</dd> <dt>•</dt> <dd>Keep the bottle of HYCAMTIN in the carton that it comes in to protect it from light.</dd> <dt>•</dt> <dd>Ask your healthcare provider or pharmacist how to safely throw away any unused or expired HYCAMTIN.</dd> </dl> <p> <span class="Bold">Keep HYCAMTIN and all medicines out of the reach of children.</span> </p> </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">General information about the safe and effective use of HYCAMTIN</span> <br/>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use HYCAMTIN for a condition for which it was not prescribed. Do not give HYCAMTIN to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about HYCAMTIN that is written for health professionals.</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <dl> <dt> </dt> <dd> <span class="Bold">What are the ingredients in HYCAMTIN?</span> <br/> <span class="Bold">Active ingredient:</span> topotecan hydrochloride <br/> <span class="Bold"> Inactive ingredients:</span> gelatin, glyceryl monostearate, hydrogenated vegetable oil, and titanium dioxide. The 1-mg capsules also contain red iron oxide. The capsules are imprinted with edible black ink. <br/> Manufactured by:</dd> </dl> <p class="First">GlaxoSmithKline Manufacturing S.p.A.</p> <p>San Polo di Torrile, Parma, Italy for </p> <p>Sandoz Inc., Princeton, NJ 08540</p> <dl> <dt> </dt> <dd>731516<br/> <br/> For more information go to www.sandoz.com or call 1-800-525-8747.</dd> </dl> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"34%\"/>\n<col width=\"33%\"/>\n<col width=\"33%\"/>\n<tfoot>\n<tr class=\"First\">\n<td align=\"left\" class=\"Botrule\" colspan=\"3\" valign=\"top\">This Patient Information has been approved by the U.S. Food and Drug Administration.</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Botrule\" colspan=\"3\" valign=\"top\">Revised: 9/2023</td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Lrule Rrule Toprule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">PATIENT INFORMATION</span>\n<br/>\n<span class=\"Bold\">HYCAMTIN<span class=\"Sup\">®</span> (hi-CAM-tin)</span>\n<br/>\n<span class=\"Bold\">(topotecan) capsules</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What is the most important information I should know about HYCAMTIN?</span>\n<br/>\n<span class=\"Bold\">HYCAMTIN may cause serious side effects, including:</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Bone marrow problems.</span> HYCAMTIN can affect your bone marrow and can cause a severe decrease in your white blood cell, red blood cell, and platelet counts. Decreased blood cell counts can make you more likely to develop bleeding, bruising, anemia, or infections which may be life-threatening. Your healthcare provider will do blood tests regularly to check your blood cell counts during treatment with HYCAMTIN. Tell your healthcare provider right away if you have any signs of infection, including: <dl>\n<dt>o</dt>\n<dd>fever (temperature of 100.5°F or greater)</dd>\n<dt>o</dt>\n<dd>chills</dd>\n<dt>o</dt>\n<dd>cough</dd>\n<dt>o</dt>\n<dd>burning or pain on urination</dd>\n</dl>\n</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Diarrhea.</span> HYCAMTIN can cause severe and life-threatening diarrhea that may need to be treated in a hospital. Tell your healthcare provider right away if you develop: <dl>\n<dt>o</dt>\n<dd>diarrhea with fever</dd>\n<dt>o</dt>\n<dd>diarrhea 3 or more times a day</dd>\n<dt>o</dt>\n<dd>diarrhea with stomach-area pain or cramps</dd>\n</dl>\n</dd>\n</dl>\n<p class=\"First\">\n<span class=\"Bold\">See “What are the possible side effects of HYCAMTIN?”</span> for more information about side effects.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>\n<span class=\"Bold\">What is HYCAMTIN?</span>\n<br/>HYCAMTIN is a prescription medicine used to treat small cell lung cancer (SCLC) that has come back (relapsed) and: </dd>\n<dt>•</dt>\n<dd>the cancer responded to your first chemotherapy, and</dd>\n<dt>•</dt>\n<dd>it has been at least 45 days from the last dose of chemotherapy </dd>\n</dl>\n<p class=\"First\">It is not known if HYCAMTIN is safe and effective in children.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>\n<span class=\"Bold\">Do not take HYCAMTIN</span> if you are allergic to topotecan or any of the ingreidents in HYCAMTIN. See the end of this leaflet for a complete list of ingredients in HYCAMTIN. </dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Before taking HYCAMTIN, tell your healthcare provider about all of your medical conditions, including if you:</span>\n<br/>\n</p>\n<dl>\n<dt>•</dt>\n<dd>have diarrhea or watery stools</dd>\n<dt>•</dt>\n<dd>have or have had lung problems</dd>\n<dt>•</dt>\n<dd>have kidney problems</dd>\n<dt>•</dt>\n<dd>are pregnant or plan to become pregnant. HYCAMTIN can harm your unborn baby. <dl>\n<dt>o</dt>\n<dd>\n<span class=\"Bold\">Females</span> who are able to become pregnant should use effective birth control (contraception) during treatment with HYCAMTIN and for 6 months after the last dose of HYCAMTIN.</dd>\n<dt>o</dt>\n<dd>\n<span class=\"Bold\">Males</span> who have female partners who are able to become pregnant, should use effective birth control during treatment with HYCAMTIN and for 3 months after the last dose of HYCAMTIN.</dd>\n<dt>o</dt>\n<dd>Talk to your healthcare provider about birth control methods that may be right for you during treatment with HYCAMTIN.</dd>\n<dt>o</dt>\n<dd>Your healthcare provider will do a pregnancy test before you start taking HYCAMTIN. Tell your healthcare provider right away if you become pregnant, think you might be pregnant, or your female partner becomes pregnant during treatment with HYCAMTIN.</dd>\n</dl>\n</dd>\n<dt>•</dt>\n<dd>are breastfeeding or plan to breastfeed. It is not known if HYCAMTIN passes into your breast milk. Do not breastfeed during treatment with HYCAMTIN and for 1 week after the last dose. Talk to your healthcare provider about the best way to feed your baby during this time. </dd>\n</dl>\n<p>\n<span class=\"Bold\">Tell your healthcare provider about all the medicines you take,</span> including prescription and over-the-counter medicines, vitamins, and herbal supplements.</p>\n<p>Taking HYCAMTIN with certain other medicines can affect how HYCAMTIN works causing side effects.</p>\n<p>Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">How should I take HYCAMTIN?</span>\n<br/>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Take HYCAMTIN exactly as your healthcare provider tells you to take it.</dd>\n<dt>•</dt>\n<dd>Your healthcare provider will tell you how many HYCAMTIN capsules to take and when to take them. Your healthcare provider may change your dose if needed.</dd>\n<dt>•</dt>\n<dd>Your healthcare provider may want you to take both 1 mg and 0.25 mg HYCAMTIN capsules for your prescribed dose. It is important for you to be able to tell the difference between the capsules. The 1-mg capsule is a pink color and the 0.25 mg capsule is a white to yellowish-white color.</dd>\n<dt>•</dt>\n<dd>Take HYCAMTIN one time a day for 5 days in a row. This treatment will normally be repeated every 3 weeks (a treatment cycle). Your healthcare provider will decide how long you will take HYCAMTIN.</dd>\n<dt>•</dt>\n<dd>Take HYCAMTIN with or without food.</dd>\n<dt>•</dt>\n<dd>Swallow HYCAMTIN whole. Do not open, chew, crush, or divide HYCAMTIN.</dd>\n<dt>•</dt>\n<dd>If any of the HYCAMTIN capsules are broken or leaking, do not touch them with your bare hands. Carefully throw away (dispose of) the capsules, and then wash your hands well with soap and water.</dd>\n<dt>•</dt>\n<dd>If you get any of the contents of HYCAMTIN capsules on your skin or in your eyes, do the following: <dl>\n<dt>°</dt>\n<dd>Wash the area of skin well with soap and water right away.</dd>\n<dt>°</dt>\n<dd>Wash your eyes right away with gently flowing water for at least 15 minutes.</dd>\n<dt>°</dt>\n<dd>Call your healthcare provider if you get a skin reaction or get HYCAMTIN in your eyes.</dd>\n</dl>\n</dd>\n<dt>•</dt>\n<dd>If you take too much HYCAMTIN, call your healthcare provider right away.</dd>\n<dt>•</dt>\n<dd>If you miss a dose of HYCAMTIN, or if you vomit after taking your HYCAMTIN, take your next dose at the next scheduled time. Do not take another dose on the same day.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are the possible side effects of HYCAMTIN?</span>\n<br/>\n<span class=\"Bold\">HYCAMTIN may cause serious side effects, including:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>See <span class=\"Bold\">“What is the most important information I should know about HYCAMTIN?”</span>\n</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Lung problems that can cause death.</span> Tell your healthcare provider right away if you have new or worse symptoms of coughing, fever, shortness of breath, or problems breathing. Your healthcare provider may tell you to stop taking HYCAMTIN capsules.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">The most common side effects of HYCAMTIN include:</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>•\tdecreased blood cell counts<br/>\t•\tdiarrhea<br/>\t•\thair loss</dd>\n</dl>\n</td><td valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>•\tnausea<br/>\t•\tvomiting<br/>\t•\tfatigue<br/>\n</dd>\n</dl>\n</td><td class=\"Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<br/>Your healthcare provider may tell you to decrease your dose, temporarily stop, or completely stop taking HYCAMTIN if you develop certain serious side effects during treatment with HYCAMTIN.</p>\n<p>HYCAMTIN may cause short-term and long-term fertility problems in females. This could affect your ability to become pregnant.</p>\n<p>HYCAMTIN may cause lower sperm count problems in men. This could affect your ability to father a child and cause birth defects. Talk to your healthcare provider about family planning options that might be right for you.</p>\n<p>These are not all the possible side effects of HYCAMTIN.</p>\n<p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">How should I store HYCAMTIN?</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Store HYCAMTIN in a refrigerator between 36°F to 46°F (2°C to 8°C).</dd>\n<dt>•</dt>\n<dd>Keep the bottle of HYCAMTIN in the carton that it comes in to protect it from light.</dd>\n<dt>•</dt>\n<dd>Ask your healthcare provider or pharmacist how to safely throw away any unused or expired HYCAMTIN.</dd>\n</dl>\n<p>\n<span class=\"Bold\">Keep HYCAMTIN and all medicines out of the reach of children.</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">General information about the safe and effective use of HYCAMTIN</span>\n<br/>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use HYCAMTIN for a condition for which it was not prescribed. Do not give HYCAMTIN to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about HYCAMTIN that is written for health professionals.</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>\n<span class=\"Bold\">What are the ingredients in HYCAMTIN?</span>\n<br/>\n<span class=\"Bold\">Active ingredient:</span> topotecan hydrochloride <br/>\n<span class=\"Bold\">\tInactive ingredients:</span>\t gelatin, glyceryl monostearate, hydrogenated vegetable oil, and titanium dioxide. The 1-mg capsules also contain red iron oxide. The capsules are imprinted with edible black ink. <br/>\tManufactured by:</dd>\n</dl>\n<p class=\"First\">GlaxoSmithKline Manufacturing S.p.A.</p>\n<p>San Polo di Torrile, Parma, Italy for </p>\n<p>Sandoz Inc., Princeton, NJ 08540</p>\n<dl>\n<dt> </dt>\n<dd>731516<br/>\n<br/>\tFor more information go to www.sandoz.com or call 1-800-525-8747.</dd>\n</dl>\n</td>\n</tr>\n</tbody>\n</table></div>" }

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(topotecan) Capsules

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0.25 mg

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Rx only

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10 Capsules

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Sandoz

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1 mg

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10 Capsules

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Sandoz

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