Topotecan Hydrochloride

HYCAMTIN 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 HYCAMTIN ® 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 HYCAMTIN 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 HYCAMTIN 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.

For injection: 4 mg (free base) of topotecan as a light yellow to greenish lyophilized powder in single-dose vial for reconstitution. For injection: 4 mg (free base) lyophilized powder in single-dose vial ( 3 )

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)] . History of severe hypersensitivity reactions to topotecan ( 4 )

Interstitial Lung Disease (ILD): Fatal cases have occurred. Permanently discontinue if ILD confirmed. ( 5.2 ) Extravasation and Tissue Injury: Severe cases have occurred. If extravasation occurs, immediately stop administration and institute recommended management procedures. ( 5.3 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of potential risk to the fetus and to use effectives contraception. ( 5.4 , 8.1 , 8.3 )

5.1 Myelosuppression HYCAMTIN can cause severe myelosuppression. Single Agent Grade 4 neutropenia occurred in 78% of 879 patients, with a median duration of 7 days and was most common during Cycle 1 (58% of patients). Grade 4 neutropenia associated with infection occurred in 13% and febrile neutropenia occurred in 5%. Sepsis occurred in 4% of patients and was fatal in 1%. Grade 4 thrombocytopenia occurred in 27%, with a median duration of 5 days. Grade 3 or 4 anemia occurred in 37% of patients. Combination with Cisplatin Grade 4 neutropenia occurred in 48% and Grade 4 thrombocytopenia occurred in 7% of 147 patients. Grade 3 or 4 anemia occurred in 40% of patients. Topotecan can cause fatal typhlitis (neutropenic enterocolitis). Consider the possibility of typhlitis in patients presenting with fever, neutropenia, and abdominal pain. Administer the first cycle of HYCAMTIN for injection only to patients with a baseline neutrophil count of greater than or equal to 1,500/mm 3 and a platelet count greater than or equal to 100,000/mm 3 . Monitor blood counts frequently during treatment. Withhold and reduce dose of HYCAMTIN for injection based on neutrophil counts, platelet counts and hemoglobin levels [see Dosage and Administration (2.5)].

5.2 Interstitial Lung Disease Interstitial lung disease (ILD), including fatalities, can occur with HYCAMTIN. Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer, thoracic radiation, and use of pneumotoxic drugs or colony stimulating factors. Monitor for pulmonary symptoms indicative of ILD. Permanently discontinue HYCAMTIN for injection if ILD is confirmed.

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

5.4 Embryo-Fetal Toxicity Based on animal data, HYCAMTIN can cause fetal harm when administered to a pregnant woman. Topotecan caused embryolethality, fetotoxicity, and teratogenicity in rats and rabbits when administered during organogenesis. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months after the last dose of HYCAMTIN for injection. Advise males with a female partner of reproductive potential to use effective contraception during treatment with HYCAMTIN for injection and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)] .

The following serious adverse reactions are described elsewhere in the labeling: Myelosuppression [see Warnings and Precautions (5.1)] Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.2)] Extravasation and Tissue Injury [see Warnings and Precautions (5.3)] Ovarian Cancer The most common Grade 3 or 4 hematologic adverse reactions (incidence > 5%) were neutropenia, anemia, thrombocytopenia, and febrile neutropenia. ( 6.1 ) The most common (incidence > 5%) non-hematologic adverse reactions (all Grades) were nausea, vomiting, fatigue, diarrhea, and dyspnea. ( 6.1 ) SCLC The most common Grade 3 or 4 hematologic adverse reactions were (incidence > 5%) neutropenia, anemia, thrombocytopenia, and febrile neutropenia. ( 6.1 ) The most common (incidence > 5%) non-hematologic adverse reactions (all Grades) were asthenia, dyspnea, nausea, pneumonia, abdominal pain, and fatigue. ( 6.1 ) Cervical Cancer The most common Grade 3 or 4 hematologic adverse reactions were (incidence > 5%) neutropenia, anemia, and thrombocytopenia. ( 6.1 ) The most common (incidence > 25% and ≥ 2% higher than cisplatin alone) non-hematologic adverse reactions were pain, vomiting, and infection/febrile neutropenia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in Warnings and Precautions reflect exposure to HYCAMTIN for injection from eight trials in which 879 patients with ovarian cancer or small cell lung cancer (SCLC) received HYCAMTIN for injection 1.5 mg/m 2 by intravenous infusion daily for 5 consecutive days, starting on Day 1 of a 21 day cycle and from one trial (Study GOG 0179) in which 147 patients with cervical cancer received HYCAMTIN for injection 0.75 mg/m 2 by intravenous infusion daily on Days 1, 2, and 3, with cisplatin 50 mg/m 2 by intravenous infusion on Day 1, of a 21-day cycle. Ovarian Cancer The safety of HYCAMTIN for injection was evaluated in a randomized trial conducted in 226 patients with metastatic ovarian cancer (Study 039) [see Clinical Studies (14.1)] . Table 1 shows the incidence of Grade 3 and 4 hematologic and non-hematologic adverse reactions that occurred in patients receiving HYCAMTIN for injection. Table 1. Adverse Reactions Occurring in Greater than or Equal to 5% of Patients With Ovarian Cancer in Study 039 a Death related to sepsis occurred in 2% of patients receiving HYCAMTIN and 0% of patients receiving paclitaxel. b Pain includes body pain, skeletal pain, and back pain. Adverse Reactions HYCAMTIN for Injection (n = 112) Paclitaxel (n = 114) Grade 3-4 (%) Grade 3-4 (%) Hematologic Grade 4 neutropenia (< 500/mm 3 ) Grade 3 or 4 anemia (Hgb < 8 g/dL) Grade 4 thrombocytopenia (< 25,000/mm 3 ) Febrile neutropenia 80 41 27 23 21 6 3 4 Non-Hematologic Infections Sepsis a 5 2 Respiratory, thoracic, and mediastinal Dyspnea 6 5 Gastrointestinal Vomiting 10 3 Nausea 10 2 Diarrhea 6 1 Abdominal pain 5 4 Intestinal obstruction 5 4 Constipation 5 0 General and administrative site conditions Fatigue 7 6 Pain b 5 7 Asthenia 5 3 Small Cell Lung Cancer (SCLC) The safety of HYCAMTIN for injection was evaluated in randomized, comparative trial in patients with recurrent or progressive SCLC (Study 090) [see Clinical Studies (14.2)] . Table 2 shows the Grade 3 or 4 hematologic and non-hematologic adverse reactions in patients with SCLC. Table 2. Adverse Reactions Occurring in Greater than or Equal to 5% of Patients With Small Cell Lung Cancer in Study 090 a Death related to sepsis occurred in 3% of patients receiving HYCAMTIN and 1% of patients receiving CAV. b Pain includes body pain, skeletal pain, and back pain. c CAV = cyclophosphamide, doxorubicin and vincristine. Adverse Reactions HYCAMTIN for Injection (n = 107) CAV c (n = 104) Grade 3-4 (%) Grade 3-4 (%) Hematologic Grade 4 neutropenia (< 500/mm 3 ) Grade 3 or 4 anemia (Hgb < 8 g/dL) Grade 4 thrombocytopenia (< 25,000/mm 3 ) Febrile neutropenia 70 42 29 28 72 20 5 26 Non-Hematologic Infections Sepsis a 5 5 Respiratory, thoracic, and mediastinal Dyspnea 9 14 Pneumonia 8 6 Gastrointestinal Nausea 8 6 Abdominal pain 6 4 General and administrative site conditions Asthenia 9 7 Fatigue 6 10 Pain b 5 7 Hepatobiliary Disorders in Ovarian and Small Cell Lung Cancer (SCLC) Based on the combined experience of 453 patients with metastatic ovarian cancer and 426 patients with SCLC treated with HYCAMTIN for injection, Grade 3 or 4 increases aspartate transaminase (AST) or alanine transaminase (ALT) occurred in 4% and Grade 3 or 4 elevated bilirubin occurred in less than 2%. Cervical Cancer The safety of HYCAMTIN for injection was evaluated in a comparative trial of HYCAMTIN with cisplatin versus cisplatin as a single agent in patients with cervical cancer (Study GOG 0179). Table 3 shows the hematologic and non-hematologic adverse reactions in patients with cervical cancer. Table 3. Adverse Reactions Occurring in Greater than or Equal to 5% of Patients With Cervical Cancer (Between-Arm Difference ≥ 2%) a in Study GOG 0179 a Includes patients who were eligible and treated. b Severity based on using National Cancer Institute (NCI) Common Toxicity Criteria (CTC), Version 2.0. c Grades 1 through 4 only. There were 3 patients who experienced deaths with investigator-designated attribution. The first patient experienced a Grade 5 hemorrhage in which the drug-related thrombocytopenia aggravated the event. A second patient experienced bowel obstruction, cardiac arrest, pleural effusion, and respiratory failure which were not treatment-related but probably aggravated by treatment. A third patient experienced a pulmonary embolism and adult respiratory distress syndrome; the latter was indirectly treatment-related. d Constitutional includes fatigue (lethargy, malaise, asthenia), fever (in the absence of neutropenia), rigors, chills, sweating, and weight gain or loss. e Pain includes abdominal pain or cramping, arthralgia, bone pain, chest pain (non-cardiac and non-pleuritic), dysmenorrhea, dyspareunia, earache, headache, hepatic pain, myalgia, neuropathic pain, pain due to radiation, pelvic pain, pleuritic pain, rectal or perirectal pain, and tumor pain. f High-level terms were included if the between-arm difference was ≥ 10%. Adverse Reactions HYCAMTIN for Injection With Cisplatin (n = 140) % Cisplatin (n = 144) % Hematologic Neutropenia Grade 3 (< 1,000-500/mm 3 ) 26 1 Grade 4 (< 500/mm 3 ) 48 1 Anemia Grade 3 (Hgb < 8-6.5 g/dL) 34 19 Grade 4 (Hgb < 6.5 g/dL) 6 3 Thrombocytopenia Grade 3 (< 50,000-10,000/mm 3 ) 26 3 Grade 4 (< 10,000/mm 3 ) 7 0 Non-Hematologic b,c General and administrative site conditions Constitutional d 69 62 Pain e 59 50 Gastrointestinal Vomiting 40 37 Stomatitis-pharyngitis 6 0 Other 63 56 Dermatology f 48 20 Infection Febrile neutropenia f 28 18 Cardiovascular f 25 15

6.2 Postmarketing Experience The following reactions have been identified during post approval use of HYCAMTIN. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System: severe bleeding (in association with thrombocytopenia) Hypersensitivity: allergic manifestations, anaphylactoid reactions, angioedema Gastrointestinal: abdominal pain potentially associated with neutropenic enterocolitis, gastrointestinal perforation Pulmonary: interstitial lung disease Skin and Subcutaneous Tissue: severe dermatitis, severe pruritus General and Administration Site Conditions: extravasation, mucosal inflammation

Lactation: Advise not to breastfeed. ( 8.2 )

8.1 Pregnancy 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 In rabbits, an intravenous dose of 0.10 mg/kg/day [about equal to the 1.5 mg/m 2 clinical 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 2 clinical 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 2 clinical 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.

8.2 Lactation 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 HYCAMTIN 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 2 clinical dose based on BSA) to lactating rats, topotecan was excreted into milk at concentrations up to 48-fold higher than those in plasma.

8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to initiating HYCAMTIN for injection [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 females of reproductive potential to use effective contraception during treatment with HYCAMTIN for injection and for 6 months after the last dose. Males HYCAMTIN 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 for injection 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 occurred in animals administered topotecan [see Nonclinical Toxicology (13.1)] .

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

8.5 Geriatric Use Of the 879 patients with metastatic ovarian cancer or small cell lung cancer in clinical trials of HYCAMTIN 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 HYCAMTIN for injection who received HYCAMTIN 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.

8.6 Renal Impairment Reduce the dose of HYCAMTIN for injection in patients with a CLcr of 20 to 39 mL/min [see Dosage and Administration (2.6), 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 HYCAMTIN for injection.

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.