WARNING: MYELOSUPPRESSION HYCAMTIN can cause severe myelosuppression. Administer first cycle only to patients with baseline neutrophil counts of greater than or equal to 1,500/mm 3 and platelet counts greater than or equal to 100,000/mm 3 . Monitor blood cell counts [see Warnings and Precautions (5.1)] . WARNING: MYELOSUPPRESSION See full prescribing information for complete boxed warning. HYCAMTIN can cause severe myelosuppression. Administer first cycle only to patients with baseline neutrophil counts of greater than or equal to 1,500/mm 3 and platelet counts of greater than or equal to 100,000/mm 3 . Monitor blood cell counts ( 2.2 , 5.1 ).
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warnings and cautions
5 WARNINGS AND PRECAUTIONS • Diarrhea: Severe diarrhea can occur. Withhold and reduce dose as recommended. ( 2.2 , 5.2 ) • Interstitial Lung Disease (ILD): Fatal cases have occurred. Permanently discontinue if confirmed ILD. ( 5.3 ) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of potential risk to the fetus and to use effective contraception. ( 5.4 , 8.1 , 8.3 ) 5.1 Myelosuppression 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/m 2 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/mm 3 and a platelet count greater than or equal to 100,000/mm 3 . 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)] . 5.2 Diarrhea 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)] . 5.3 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 capsules if ILD is confirmed. 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 fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 6 months after the last dose of HYCAMTIN capsules. 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 Use in Specific Populations (8.1, 8.3), Nonclincial Toxicology (13.1)] .
6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: • Myelosuppression [see Warnings and Precautions (5.1)] • Diarrhea [see Warnings and Precautions (5.2)] • Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.3)] • The most common Grade 3 or 4 hematologic adverse reactions (incidence > 20%) were neutropenia, anemia, and thrombocytopenia. • The most common (incidence > 10%) non-hematologic adverse reactions (all Grades) were nausea, diarrhea, vomiting, alopecia, fatigue, and anorexia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 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 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/m 2 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. Table 1. Adverse Reactions Occurring in Greater than or Equal to 5% of Patients With Lung Cancer Adverse Reactions Adverse reactions were graded using National Cancer Institute (NCI) Common Toxicity Criteria (CTC) Version 2.0. HYCAMTIN Capsules With Best Supportive Care (Study 478) HYCAMTIN Capsules Lung Cancer Population (Studies 478, 065, 396 and 387) N = 70 N = 682 All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Hematologic Anemia 94 15 10 98 18 7 Neutropenia 91 28 33 83 24 32 Thrombocytopenia 81 30 7 81 29 6 Non-hematologic Nausea 27 1 0 33 3 0 Vomiting 19 1 0 21 3 0.4 Diarrhea 14 4 1 22 4 0.4 Fatigue 11 0 0 19 4 0.1 Alopecia 10 0 0 20 0.1 0 Pyrexia 7 1 0 5 1 1 Anorexia 7 0 0 14 2 0 Asthenia 3 0 0 7 2 0 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. Gastrointestinal: Gastrointestinal perforation General and Administration Site Conditions: Mucosal inflammation Hypersensitivity: Allergic manifestations, anaphylactoid reactions, angioedema