TOPOTECAN HYDROCHLORIDE

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 1.25 hydrochloride. It is soluble in water and melts with decomposition at 213° to 218°C. Topotecan hydrochloride has the following structural formula: C 23 H 23 N 3 O 5 • 1.25HCl M.W. 467.02 Topotecan hydrochloride for injection is supplied as a sterile, lyophilized, buffered, light yellow to greenish powder available in single-dose vials. Each vial contains topotecan hydrochloride equivalent to 4 mg of topotecan as free base. The reconstituted solution ranges in color from yellow to yellow green and is intended for administration by intravenous infusion. 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. structural formula

Topotecan hydrochloride for injection is a topoisomerase inhibitor indicated for treatment of: • Patients with metastatic ovarian cancer after disease progression on or after initial or subsequent chemotherapy, as a single agent. ( 1.1 ) • Patients with small cell lung cancer (SCLC) platinum-sensitive disease who progressed at least 60 days after initiation of first-line chemotherapy, as a single agent. ( 1.2 ) • Patients with Stage IV-B, recurrent, or persistent cervical cancer which is not amenable to curative treatment, in combination with cisplatin. ( 1.3 ) 1.1 Ovarian Cancer 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. 1.2 Small Cell Lung Cancer 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. 1.3 Cervical Cancer 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.

• Ovarian cancer and small cell lung cancer: 1.5 mg/m 2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on Day 1 of a 21-day cycle. ( 2.2 , 2.3 ) • Cervical cancer: 0.75 mg/m 2 by intravenous infusion over 30 minutes on Days 1, 2, and 3 with cisplatin 50 mg/m 2 on Day 1, of a 21-day cycle. ( 2.4 ) • Renal impairment: Reduce dose if creatinine clearance (CLcr) 20 to 39 mL/min. ( 2.6 ) 2.1 Important Safety Information Verify dosage using body surface area. Do not exceed a single dose of 4 mg intravenously. 2.2 Recommended Dosage for Ovarian Cancer The recommended dosage of topotecan hydrochloride is 1.5 mg/m 2 by 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. 2.3 Recommended Dosage for Small Cell Lung Cancer (SCLC) The recommended dosage of topotecan hydrochloride is 1.5 mg/m 2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on Day 1 of a 21-day cycle. 2.4 Recommended Dosage for Cervical Cancer The recommended dosage of topotecan hydrochloride is 0.75 mg/m 2 by intravenous infusion over 30 minutes daily on Days 1, 2, and 3 in combination with cisplatin 50 mg/m 2 on Day 1, of a 21-day cycle. 2.5 Dosage Modifications for Adverse Reactions 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 as a single agent, reduce the dose to 1.25 mg/m 2 /day for : • neutrophil counts of less than 500/mm 3 , or administer granulocyte-colony stimulating factor (GCSF) starting no sooner than 24 hours following the last dose. • platelet counts less than 25,000/mm 3 during previous cycle. For topotecan hydrochloride in combination with cisplatin, reduce the dose to 0.60 mg/m 2 /day (and further to 0.45 mg/m 2 if necessary) for : • febrile neutropenia (defined as neutrophil counts less than 1,000/mm 3 with temperature of greater than or equal to 38.0°C (100.4°F), or administer G-CSF starting no sooner than 24 hours following the last dose. • platelet counts less than 25,000/mm 3 during previous cycle. 2.6 Dosage Modification for Renal Impairment For topotecan hydrochloride as a single agent, reduce the dose to 0.75 mg/m 2 /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 )] . 2.7 Preparation and Intravenous Administration Visually inspect for particulate matter and discoloration prior to administration, whenever solution and container permit. Preparation Reconstitute each 4 mg vial of topotecan hydrochloride with 4 mL Sterile Water for Injection, USP. Dilute the appropriate volume of the reconstituted solution in either 0.9% Sodium Chloride Intravenous Infusion, USP or 5% Dextrose in Water Injection, USP. Stability Because the vials contain no preservative, use contents immediately after reconstitution. Discard any unused portion. Store reconstituted product diluted for infusion at approximately 20°C to 25°C (68°F to 77°F) protected from light for no more than 24 hours. Discard after 24 hours. Topotecan hydrochloride is a cytotoxic drug. Follow applicable handling and disposal procedures. 1

Topotecan hydrochloride is contraindicated in patients who have a history of severe hypersensitivity reactions to topotecan. Reactions have included anaphylactoid reactions [see Adverse Reactions ( 6.2 )] . History of severe hypersensitivity reactions to topotecan. ( 4 )

The following serious adverse reactions are described elsewhere in the labeling: • Myelosuppression [see Warnings and Precautions ( 5.1 )] • Interstitial Lung Disease (ILD) [see Warnings and Precautions ( 5.2 )] • Extravasation and Tissue Injury [see Warnings and Precautions ( 5.3 )] Ovarian cancer: • The most common Grade 3 or 4 hematologic adverse reactions (incidence > 5%) were: neutropenia, anemia, thrombocytopenia, and febrile neutropenia. ( 6.1 ) • The most common (incidence > 5%) non-hematologic adverse reactions (all Grades) were: nausea, vomiting, fatigue, diarrhea, and dyspnea. ( 6.1 ) SCLC: • The most common Grade 3 or 4 hematologic adverse reactions were (incidence > 5%): neutropenia, anemia, thrombocytopenia, and febrile neutropenia. ( 6.1 ) • The most common (incidence > 5%) non-hematologic adverse reactions (all Grades) were: asthenia, dyspnea, nausea, pneumonia, abdominal pain, and fatigue. ( 6.1 ) Cervical cancer: • The most common Grade 3 or 4 hematologic adverse reactions were (incidence > 5%): neutropenia, anemia, and thrombocytopenia. ( 6.1 ) • The most common (incidence > 25% and ≥ 2% higher than cisplatin alone) non-hematologic adverse reactions were: pain, vomiting, and infection/febrile neutropenia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in Warnings and Precautions reflect exposure to 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 2 by intravenous infusion daily for 5 consecutive days, starting on Day 1 of a 21 day cycle and from one trial (Study GOG 0179) in which 147 patients with cervical cancer received topotecan hydrochloride for injection 0.75 mg/m 2 by intravenous infusion daily on Days 1, 2, and 3, with cisplatin 50 mg/m 2 by intravenous infusion on Day 1, of a 21-day cycle. Ovarian Cancer The safety of 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. Table 1. Adverse Reactions Occurring in Greater than or Equal to 5% of Patients With Ovarian Cancer in Study 039 a Death related to sepsis occurred in 2% of patients receiving topotecan hydrochloride and 0% of patients receiving paclitaxel. b Pain includes body pain, skeletal pain, and back pain. Adverse Reactions Topotecan Hydrochloride (n=112) Paclitaxel (n=114) Grade 3-4 (%) Grade 3-4 (%) Hematologic Grade 4 neutropenia (< 500/mm 3 ) 80 21 Grade 3 or 4 anemia (Hgb < 8 g/dL) 41 6 Grade 4 thrombocytopenia (< 25,000/mm 3 ) 27 3 Febrile neutropenia 23 4 Non-Hematologic Infections Sepsis a 5 2 Respiratory, thoracic, and mediastinal Dyspnea 6 5 Gastrointestinal Vomiting 10 3 Nausea 10 2 Diarrhea 6 1 Abdominal pain 5 4 Intestinal obstruction 5 4 Constipation 5 0 General and administrative site conditions Fatigue 7 6 Pain b 5 7 Asthenia 5 3 Small Cell Lung Cancer (SCLC) The safety of 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. Table 2. Adverse Reactions Occurring in Greater than or Equal to 5% of Patients With Small Cell Lung Cancer in Study 090 a Death related to sepsis occurred in 3% of patients receiving topotecan hydrochloride and 1% of patients receiving CAV. b Pain includes body pain, skeletal pain, and back pain. c CAV = cyclophosphamide, doxorubicin and vincristine. Adverse Reactions Topotecan Hydrochloride (n=107) CAV c (n = 104) Grade 3-4 (%) Grade 3-4 (%) Hematologic Grade 4 neutropenia (< 500/mm 3 ) 70 72 Grade 3 or 4 anemia (Hgb < 8 g/dL) 42 20 Grade 4 thrombocytopenia (< 25,000/mm 3 ) 29 5 Febrile neutropenia 28 26 Non-Hematologic Infections Sepsis a 5 5 Respiratory, thoracic, and mediastinal Dyspnea 9 14 Pneumonia 8 6 Gastrointestinal Nausea 8 6 Abdominal pain 6 4 General and administrative site conditions Asthenia 9 7 Fatigue 6 10 Pain b 5 7 Hepatobiliary Disorders in Ovarian and Small Cell Lung Cancer (SCLC) Based on the combined experience of 453 patients with metastatic ovarian cancer, and 426 patients with SCLC treated with 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 with cisplatin versus cisplatin as a single agent in patients with cervical cancer (Study GOG 0179). Table 3 shows the hematologic and non-hematologic adverse reactions in patients with cervical cancer. Table 3. Adverse Reactions Occurring in Greater than or Equal to 5% of Patients with Cervical Cancer (Between-Arm Difference ≥ 2%) a in Study GOG 0179 a Includes patients who were eligible and treated. b Severity based on using National Cancer Institute (NCI) Common Toxicity Criteria (CTC), Version 2.0. c Grades 1 through 4 only. There were 3 patients who experienced deaths with investigator-designated attribution. The first patient experienced a Grade 5 hemorrhage in which the drug-related thrombocytopenia aggravated the event. A second patient experienced bowel obstruction, cardiac arrest, pleural effusion, and respiratory failure which were not treatment-related but probably aggravated by treatment. A third patient experienced a pulmonary embolism and adult respiratory distress syndrome; the latter was indirectly treatment-related. d Constitutional includes fatigue (lethargy, malaise, asthenia), fever (in the absence of neutropenia), rigors, chills, sweating, and weight gain or loss. e Pain includes abdominal pain or cramping, arthralgia, bone pain, chest pain (non-cardiac and non-pleuritic), dysmenorrhea, dyspareunia, earache, headache, hepatic pain, myalgia, neuropathic pain, pain due to radiation, pelvic pain, pleuritic pain, rectal or perirectal pain, and tumor pain. f High-level terms were included if the between-arm difference was ≥ 10%. Adverse Reactions Topotecan Hydrochloride With Cisplatin (n =140) % Cisplatin (n =144) % Hematologic Neutropenia Grade 3 (< 1,000 to 500/mm 3 ) 26 1 Grade 4 (< 500/mm 3 ) 48 1 Anemia Grade 3 (Hgb < 8 to 6.5 g/dL) 34 19 Grade 4 (Hgb < 6.5 g/dL) 6 3 Thrombocytopenia Grade 3 (< 50,000 to 10,000/mm 3 ) 26 3 Grade 4 (< 10,000/mm 3 ) 7 0 Non-Hematologic b,c General and administrative site conditions Constitutional d 69 62 Pain e 59 50 Gastrointestinal Vomiting 40 37 Stomatitis-pharyngitis 6 0 Other 63 56 Dermatology f 48 20 Infection Febrile neutropenia f 28 18 Cardiovascular f 25 15 6.2 Postmarketing Experience The following reactions have been identified during post approval use of topotecan hydrochloride. 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.

16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from light; product is light-sensitive. Retain in carton. Handle and dispose of topotecan hydrochloride for injection consistent with recommendations for the handling and disposal of hazardous drugs 1 .