Hycamtin Drug Information

® 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. HYCAMTIN capsules is a topoisomerase inhibitor indicated for treatment of patients with relapsed small cell lung cancer (SCLC).

• The recommended dosage is 2.3 mg/m 2 /day orally once daily for 5 consecutive days starting on Day 1 of a 21-day cycle. ( 2.1 )
• Renal Impairment: Reduce dose if creatinine clearance (CLcr) less than 50 mL/min. ( 2.3 ) 2.1 Recommended Dosage The recommended dosage of HYCAMTIN capsules is 2.3 mg/m 2 /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. If a dose of HYCAMTIN capsules is missed or vomiting occurs after taking a dose, do not administer an additional dose and take the next dose at the scheduled time. 2.2 Dosage Modifications for Adverse Reactions 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/m 2 /day for subsequent courses [see Warnings and Precautions (5.2)] . Hematologic Do not administer subsequent cycles of HYCAMTIN capsules 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) [see Warnings and Precautions (5.1)] . Reduce dose by 0.4 mg/m 2 /day for:
• neutrophil counts of less than 500/mm 3 associated with fever or infection or lasting for 7 days or more;
• neutrophil counts of 500 to 1,000/mm 3 lasting beyond day 21 of the treatment course; or
• platelet counts less than 25,000/mm 3 . 2.3 Dosage Modifications for Renal Impairment Reduce the dose of HYCAMTIN capsules in patients with the following creatinine clearance (CLcr), calculated with the Cockcroft-Gault method using ideal body weight.
• CLcr 30 to 49 mL/min: Administer 1.5 mg/m 2 /day.
• CLcr less than 30 mL/min: Administer 0.6 mg/m 2 /day.

• 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

• Avoid concomitant use of P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) inhibitors with HYCAMTIN capsules. ( 7.1 , 12.3 ) 7.1 Effect of Other Drugs on HYCAMTIN 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.

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 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 intravenous 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 intravenous dose based on BSA) 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.

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

• 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 )

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.