Topotecan

1 INDICATIONS AND USAGE Topotecan Injection is indicated for the treatment of: 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 [see Clinical Studies ( 14 ) ] . Topotecan Injection in combination with cisplatin is indicated for the treatment of: stage IV-B, recurrent, or persistent carcinoma of the cervix which is not amenable to curative treatment with surgery and/or radiation therapy. Topotecan is a topoisomerase inhibitor indicated for: small cell lung cancer sensitive disease after failure of first-line chemotherapy. ( 1 ) combination therapy with cisplatin for stage IV-B, recurrent, or persistent carcinoma of the cervix which is not amenable to curative treatment with surgery and/or radiation therapy. ( 1 )

6 ADVERSE REACTIONS Small cell lung cancer: The most common hematologic adverse reactions were: neutropenia (97%), leukopenia (97%), anemia (89%), and thrombocytopenia (69%). ( 6.1 ) The most common (>25%) non-hematologic adverse reactions (all grades) were: nausea, alopecia, vomiting, sepsis or pyrexia/infection with neutropenia, diarrhea, constipation, fatigue, and pyrexia. ( 6.1 ) Cervical cancer (Topotecan Injection plus cisplatin): The most common hematologic adverse reactions (all grades) were: anemia (94%), leukopenia (91%), neutropenia (89%), and thrombocytopenia (74%). ( 6.1 ) The most common (>25%) non-hematologic adverse reactions (all grades) were: pain, nausea, vomiting, and infection/febrile neutropenia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Small Cell Lung Cancer Data in the following section are based on the combined experiences of the 879 patients studied, including 426 patients with small cell lung cancer treated with topotecan. Table 1 lists the principle hematologic adverse reactions and Table 2 lists non-hematologic adverse reactions occurring in at least 15% of patients. Table 1. Hematologic Adverse Reactions Experienced in ≥15% of Patients, Including 426 Patients With Small Cell Lung Cancer, Receiving Topotecan Hematologic Adverse Reaction Patients (n=879) % Incidence Neutropenia <1,500 cells/mm 3 <500 cells/mm 3 97 78 Leukopenia <3,000 cells/mm 3 <1,000 cells/mm 3 97 32 Thrombocytopenia <75,000/mm 3 <25,000/mm 3 69 27 Anemia <10 g/dL <8 g/dL 89 37 Table 2. Non-hematologic Adverse Reactions Experienced by ≥15% of 879 Patients, Including 426 Patients With Small Cell Lung Cancer, Receiving Topotecan Non-hematologic Adverse Reaction Percentage of Patients with Adverse Reaction (879 Patients) All Grades Grade 3 Grade 4 Infections and infestations Sepsis or pyrexia/infection with neutropenia a 43 NR 23 Metabolism and nutrition disorders Anorexia 19 2 <1 Nervous system disorders Headache 18 1 <1 Respiratory, thoracic, and mediastinal disorders Dyspnea 22 5 3 Coughing 15 1 0 Gastrointestinal disorders Nausea 64 7 1 Vomiting 45 4 1 Diarrhea 32 3 1 Constipation 29 2 1 Abdominal pain 22 2 2 Stomatitis 18 1 <1 Skin and subcutaneous tissue disorders Alopecia 49 NA NA Rash b 16 1 0 General disorders and administrative site conditions Fatigue 29 5 0 Pyrexia 28 1 <1 Pain c 23 2 1 Asthenia 25 4 2 NA = Not applicable NR = Not reported separately a Does not include Grade 1 sepsis or pyrexia b Rash also includes pruritus, rash erythematous, urticaria, dermatitis, bullous eruption, and maculopapular rash. c Pain includes body pain, back pain, and skeletal pain. 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 3 shows 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 Adverse Reaction Topotecan (n=107) CAV (n=104) Hematologic Grade 3/4 % % Grade 4 neutropenia (<500 cells/mm 3 ) 70 72 Grade 3/4 anemia (Hgb <8 g dL) 42 20 Grade 4 thrombocytopenia (<25,000 plts/mm 3 ) 29 5 Pyrexia/Grade 4 neutropenia 28 26 Non-hematologic Grade 3/4 % % Infections and infestations Documented sepsis a 5 5 Respiratory, thoracic, and mediastinal disorders Dyspnea 9 14 Pneumonia 8 6 Gastrointestinal disorders Abdominal pain 6 4 Nausea 8 6 General disorders and administrative site conditions Fatigue 6 10 Asthenia 9 7 Pain b 5 7 a Death related to sepsis occurred in 3% of patients receiving topotecan, and in 1% of patients receiving CAV b Pain 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 4 shows the hematologic adverse reactions and Table 5 shows the non-hematologic adverse reactions in patients with cervical cancer. Table 4. Hematologic Adverse Reactions in Patients with Cervical Cancer Treated with Topotecan Injection Plus Cisplatin or Cisplatin Monotherapy a Hematologic Adverse Reaction Topotecan Injection Plus Cisplatin (n = 140) Cisplatin (n = 144) Anemia All grades (Hgb <12 g/dL) 131 (94%) 130 (90%) Grade 3 (Hgb <8 to 6.5 g/dL) 47 (34%) 28 (19%) Grade 4 (Hgb <6.5 g/dL) 9 (6%) 5 (3%) Leukopenia All grades (<3,800 cells/mm 3 ) 128 (91%) 43 (30%) Grade 3 (<2,000 to 1,000 cells/mm 3 ) 58 (41%) 1 (1%) Grade 4 (<1,000 cells/mm 3 ) 35 (25%) 0 (0%) Neutropenia All grades (<2,000 cells/mm 3 ) 125 (89%) 28 (19%) Grade 3 (<1,000 to 500 cells/mm 3 ) 36 (26%) 1 (1%) Grade 4 (<500 cells/mm 3 ) 67 (48%) 1 (1%) Thrombocytopenia All grades (<130,000 cells/mm 3 ) 104 (74%) 21 (15%) Grade 3 (<50,000 to 10,000 cells/mm 3 ) 36 (26%) 5 (3%) Grade 4 (<10,000 cells/mm 3 ) 10 (7%) 0 (0%) a Includes patients who were eligible and treated. Table 5. Non-hematologic Adverse Reactions Experienced by ≥ 5% of Patients with Cervical Cancer Treated with Topotecan Injection Plus Cisplatin or Cisplatin Monotherapy a Topotecan Injection Plus Cisplatin Cisplatin (n = 140) (n = 144) Adverse Reaction All Grades b Grade 3 Grade 4 All Grades b Grade 3 Grade 4 General disorders and administrative site conditions Constitutional c 96 (69%) 11 (8%) 0 89 (62%) 17 (12%) 0 Pain d 82 (59%) 28 (20%) 3 (2%) 72 (50%) 18 (13%) 5 (3%) Gastrointestinal disorders Vomiting 56 (40%) 20 (14%) 2 (1%) 53 (37%) 13 (9%) 0 Nausea 77 (55%) 18 (13%) 2 (1%) 79 (55%) 13 (9%) 0 Stomatitis-pharyngitis 8 (6%) 1 (<1%) 0 0 0 0 Other 88 (63%) 16 (11%) 4 (3%) 80 (56%) 12 (8%) 3 (2%) Dermatology 67 (48%) 1 (<1%) 0 29 (20%) 0 0 Metabolic-Laboratory 55 (39%) 13 (9%) 7 (5%) 44 (31%) 14 (10%) 1 (<1%) Genitourinary 51 (36%) 9 (6%) 9 (6%) 49 (34%) 7 (5%) 7 (5%) Nervous system disorders Neuropathy 4 (3%) 1 (<1%) 0 3 (2%) 1 (<1%) 0 Other 49 (35%) 3 (2%) 1 (<1%) 43 (30%) 7 (5%) 2 (1%) Infection-febrile neutropenia 39 (28%) 21 (15%) 5 (4%) 26 (18%) 11 (8%) 0 Cardiovascular 35 (25%) 7 (5%) 6 (4%) 22 (15%) 8 (6%) 3 (2%) Hepatic 34 (24%) 5 (4%) 2 (1%) 23 (16%) 2 (1%) 0 Pulmonary 24 (17%) 4 (3%) 0 23 (16%) 5 (3%) 3 (2%) Vascular disorders Hemorrhage 21 (15%) 8 (6%) 1 (<1%) 20 (14%) 3 (2%) 1 (<1%) Coagulation 8 (6%) 4 (3%) 3 (2%) 10 (7%) 7 (5%) 0 Musculoskeletal 19 (14%) 3 (2%) 0 7 (5%) 1 (<1%) 1 (<1%) Allergy-Immunology 8 (6%) 2 (1%) 1 (<1%) 4 (3%) 0 1 (<1%) Endocrine 8 (6%) 0 0 4 (3%) 2 (1%) 0 Sexual reproduction function 7 (5%) 0 0 10 (7%) 1 (<1%) 0 Ocular-visual 7 (5%) 0 0 7 (5%) 1 (<1%) 0 Data were collected using NCI Common Toxicity Criteria, v. 2.0. a Includes patients who were eligible and treated. b Grades 1 through 4 only. There were 3 patients who experienced grade 5 deaths with investigator-designated attribution. One was a grade 5 hemorrhage in which the drug-related thrombocytopenia aggravated the event. A second patient experienced bowel obstruction, cardiac arrest, pleural effusion and respiratory failure which were not treatment related but probably aggravated by treatment. A third patient experienced a pulmonary embolism and adult respiratory distress syndrome, the latter was indirectly treatment-related. c Constitutional includes fatigue (lethargy, malaise, asthenia), fever (in the absence of neutropenia), rigors, chills, sweating, and weight gain or loss. d Pain includes abdominal pain or cramping, arthralgia, bone pain, chest pain (non-cardiac and non-pleuritic), dysmenorrhea, dyspareunia, earache, headache, hepatic pain, myalgia, neuropathic pain, pain due to radiation, pelvic pain, pleuritic pain, rectal or perirectal pain, and tumor pain. 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials or listed in other sections of the prescribing information, the following reactions have been identified during post-marketing use of Topotecan 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 ) ]

4 CONTRAINDICATIONS 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. History of severe hypersensitivity reactions (e.g., anaphylactoid reactions) to topotecan or any of its ingredients ( 4 ) Severe bone marrow depression ( 4 )

11 DESCRIPTION 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 23 H 23 N 3 O 5 and a molecular weight of 421.45. 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. 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. 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. The solution must be diluted before administration by intravenous infusion. structural formula

2 DOSAGE AND ADMINISTRATION Verify dose using body surface area prior to dispensing. Recommended dosage should not exceed 4 mg [see Overdosage 10 ]. Prior to administration of the first course of Topotecan Injection, patients must have a baseline neutrophil count of >1,500 cells/mm 3 and a platelet count of >100,000 cells/mm 3 . Small cell lung cancer: 1.5 mg/m 2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on day one of a 21-day course. ( 2.1 ) Cervical cancer: 0.75 mg/m 2 by intravenous infusion over 30 minutes on days 1, 2, and 3 followed by cisplatin 50 mg/m 2 by intravenous infusion on day 1 repeated every 21 days. ( 2.2 ) See Dosage Modification Guidelines for patients with neutropenia or reduced platelets.( 2.1 , 2.2 ) See Dosage Adjustment in Renal Impairment. ( 2.3 ) 2.1 Small Cell Lung Cancer Recommended Dosage The recommended dose of topotecan 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 course. In the absence of tumor progression, a minimum of 4 courses is recommended because tumor response may be delayed. The median time to response in 4 small cell lung cancer trials was 5 to 7 weeks. Dosage Modification Guidelines In the event of severe neutropenia (defined as <500 cells/mm 3 ) during any course, reduce the dose by 0.25 mg/m 2 (to 1.25 mg/m 2 ) for subsequent courses. Alternatively, in the event of severe neutropenia, administer G-CSF (granulocyte-colony stimulating factor) following the subsequent course (before resorting to dose reduction) starting from day 6 of the course (24 hours after completion of topotecan administration). In the event the platelet count falls below 25,000 cells/mm 3 , reduce doses by 0.25 mg/m 2 (to 1.25 mg/m 2 ) for subsequent courses. 2.2 Cervical Cancer Recommended Dosage The recommended dose of Topotecan Injection is 0.75 mg/m 2 by intravenous infusion over 30 minutes daily on days 1, 2, and 3; followed by cisplatin 50 mg/m 2 by 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 In the event of severe febrile neutropenia (defined as <1000 cells/mm 3 with temperature of 38°C or 100.4°F), reduce the dose of Topotecan Injection to 0.60 mg/m 2 for subsequent courses. Alternatively, in the event of severe febrile neutropenia, administer G-CSF following the subsequent course (before resorting to dose reduction) starting from day 4 of the course (24 hours after completion of administration of Topotecan Injection). If febrile neutropenia occurs despite the use of G-CSF, reduce the dose of Topotecan Injection to 0.45 mg/m 2 for subsequent courses. In the event the platelet count falls below 25,000 cells/mm 3 , reduce doses to 0.60 mg/m 2 for subsequent courses. 2.3 Dosage Adjustment in Specific Populations Renal Impairment No dosage adjustment of Topotecan Injection appears to be required for patients with mild renal impairment (Cl cr 40 to 60 mL/min.). Dosage adjustment of Topotecan Injection to 0.75 mg/m 2 is 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. 2.4 Instructions for Handling, Preparation and Intravenous Administration 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.

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

7 DRUG INTERACTIONS 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. 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 2 in Phase 1 studies. In one study, 1 of 3 patients had severe neutropenia for 12 days and a second patient died with neutropenic sepsis. 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 2 on day 1 for cervical cancer [see Dosage and Administration ( 2 ) , Adverse Reactions ( 6 ), Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14 ) ] . Do not initiate G-CSF until 24 hours after completion of treatment with Topotecan Injection. Concomitant administration can prolong duration of neutropenia. ( 7 ) Greater myelosuppression is likely to be seen when used in combination with other cytotoxic agents. ( 7 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 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. 12.2 Pharmacodynamics 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. 12.3 Pharmacokinetics The pharmacokinetics of topotecan have been evaluated in cancer patients following doses of 0.5 to 1.5 mg/m 2 administered 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 vitro studies 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 cr of 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 vitro inhibition 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 )].

12.1 Mechanism of Action 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.

12.2 Pharmacodynamics 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.

12.3 Pharmacokinetics The pharmacokinetics of topotecan have been evaluated in cancer patients following doses of 0.5 to 1.5 mg/m 2 administered 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 vitro studies 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 cr of 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 vitro inhibition 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 )].

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3 DOSAGE FORMS AND STRENGTHS Topotecan Injection is available in the following strengths: 1 mg/mL Multiple Dose Vial 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. 1 mg/mL Multiple Dose Vial 4 mg/4 mL (1 mg/mL) Multiple Dose Vial Each mL contains topotecan hydrochloride equivalent to 1 mg of topotecan free base.

Topotecan Topotecan WATER TARTARIC ACID HYDROCHLORIC ACID SODIUM HYDROXIDE TOPOTECAN TOPOTECAN

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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 2 IV (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 2 IV (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.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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 2 IV (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 2 IV (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.

ANDA204406

Topotecan

Topotecan

16729-243

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

Principal Display Panel - 1 mg/mL Container Label Principal Display Panel - 1 mg/mL Carton image 1 image 2

17 PATIENT COUNSELING INFORMATION 17.1 Bone Marrow Suppression 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. 17.2 Pregnancy and Breastfeeding Advise patients to use effective contraceptive measures to prevent pregnancy and to avoid breastfeeding during treatment with Topotecan Injection. 17.3 Asthenia and Fatigue 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

14 CLINICAL STUDIES 14.1 Small Cell Lung Cancer 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 2 cyclophosphamide, 45 mg/m 2 doxorubicin, 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 . Table 6. Efficacy of Topotecan Versus CAV (cyclophosphamide-doxorubicin-vincristine) in Small Cell Lung Cancer Patients Sensitive to First-Line Chemotherapy Parameter Topotecan (n = 107) CAV (n = 104) Complete response rate Partial response rate Overall response rate 0% 24% 24% 1% 17% 18% Difference in overall response rates 95% Confidence interval of the difference 6% (–6 to 18%) Response duration a (weeks) Median 95% Confidence interval Hazard-ratio n = 26 14.4 13.1 to 18 n = 19 15.3 13.1 to 23.1 (Topotecan:CAV) (95% CI) ( P -value) 1.42 (0.73 to 2.76) (0.30) Time to progression (weeks) Median 95% Confidence interval Hazard ratio 13.3 11.4 to 16.4 12.3 11 to 14.1 (Topotecan:CAV) (95% CI) ( P -value) 0.92 (0.69 to 1.22) (0.55) Survival (weeks) Median 95% Confidence interval Hazard ratio 25 20.6 to 29.6 24.7 21.7 to 30.3 (Topotecan:CAV) (95% CI) ( P -value) 1.04 (0.78 to 1.39) (0.8) a The 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. Table 7. Percentage of Patients with Symptom Improvement a : Topotecan Versus CAV in Patients with Small Cell Lung Cancer Symptom Topotecan Injection (n=107) CAV (n=104) n b (%) n b (%) Shortness of breath 68 (28) 61 (7) Interference with daily activity 67 (27) 63 (11) Fatigue 70 (23) 65 (9) Hoarseness 40 (33) 38 (13) Cough 69 (25) 61 (15) Insomnia 57 (33) 53 (19) Anorexia 56 (32) 57 (16) Chest pain 44 (25) 41 (17) Hemoptysis 15 (27) 12 (33) a Defined as improvement sustained over at least 2 courses compared to baseline. b Number 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. 14.2 Cervical Cancer 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 2 on day 1) and 146 eligible women were randomized to cisplatin (50 mg/m 2 IV 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 figure 10

15 REFERENCES 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 3. American Society of Health-System Pharmacists. ASHP Guidelines on Handling Hazardous Drugs. Am J Health-Syst Pharm . 2006;63:1172-1193. 4. Polovich M, White JM, Kelleher LO (eds.) 2005. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. (2 nd ed) Pittsburgh, PA: Oncology Nursing Society.

8.5 Geriatric Use 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 ) ].

8.3 Nursing Mothers Rats excrete high concentrations of topotecan into milk. Lactating female rats given 4.72 mg/m 2 IV (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.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.1 Pregnancy 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 ) ]

8 USE IN SPECIFIC POPULATIONS Nursing Mothers: Discontinue nursing when receiving Topotecan Injection. ( 8.3 ) 8.1 Pregnancy 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 ) ] 8.3 Nursing Mothers Rats excrete high concentrations of topotecan into milk. Lactating female rats given 4.72 mg/m 2 IV (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. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use 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 ) ]. 8.6 Renal Impairment No dosage adjustment of Topotecan Injection appears to be required for patients with mild renal impairment (Cl cr 40 to 60 mL/min.). Dosage reduction is recommended for patients with moderate renal impairment (Cl cr 20 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 ) ].

16 HOW SUPPLIED/STORAGE AND HANDLING Topotecan Injection is supplied in the following: 1 mg/mL Multiple Dose Vial NDC 16729-243-30 (package of 1) 4 mg/4 mL (1 mg/mL) Multiple Dose Vial 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. 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.

WARNING: BONE MARROW SUPPRESSION Do not give Topotecan Injection to patients with baseline neutrophil counts less than 1,500 cells/mm 3 . In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection and death, monitor peripheral blood counts frequently on all patients receiving Topotecan Injection . [see Warnings and Precautions ( 5.1 ) ] WARNING: BONE MARROW SUPPRESSION See full prescribing information for complete boxed warning Do not give Topotecan to patients with baseline neutrophil counts less than 1,500 cells/mm 3 . In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection and death, monitor peripheral blood cell counts frequently on all patients receiving Topotecan Injection. ( 5.1 )