HYCAMTIN

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 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 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 a Adverse reactions were graded using National Cancer Institute (NCI) Common Toxicity Criteria (CTC) Version 2.0. Adverse Reactions a 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

4 CONTRAINDICATIONS 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 )

11 DESCRIPTION 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 monohydrochloride. The molecular formula is C 23 H 23 N 3 O 5 •HCl and the molecular weight is 457.9 g/mol. It is soluble in water and melts with decomposition at 213°C to 218°C. Topotecan hydrochloride has the following structural formula: HYCAMTIN capsules, contain topotecan hydrochloride, the content of which is expressed as topotecan free base. Each 0.25 mg and 1 mg capsule contain topotecan hydrochloride equivalent to 0.25 mg and 1 mg topotecan free-base, respectively. The excipients are gelatin, glyceryl monostearate, hydrogenated vegetable oil, and titanium dioxide. The capsules are imprinted with edible black ink. The 1 mg capsules also contain red iron oxide. topotecan hydrochloride chemical structure

2 DOSAGE AND ADMINISTRATION 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.

1 INDICATIONS AND USAGE HYCAMTIN ® 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). ( 1 )

10 OVERDOSAGE 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.

7 DRUG INTERACTIONS 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.

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 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. 12.3 Pharmacokinetics Following administration of HYCAMTIN capsules at doses of 1.2 to 3.1 mg/m 2 (0.52 to 1.35 times the recommended dose) administered daily for 5 days, the area under the curve (AUC) increased proportionally with dose. Absorption The time to the peak plasma concentrations is between 1 to 2 hours following oral administration. The oral bioavailability of topotecan is approximately 40%. Food Effect Following a high-fat meal, the AUC was similar in the fed and fasted states, while T max was delayed from 1.5 to 3 hours for topotecan lactone and from 3 to 4 hours for total topotecan. Distribution Protein binding of topotecan is approximately 35%. Elimination The mean terminal half-life (t½) of topotecan is 3 to 6 hours following oral administration. Metabolism Topotecan undergoes a reversible pH-dependent hydrolysis of a pharmacologically active lactone moiety. At pH less than or equal to 4, the lactone is exclusively present, whereas the ring-opened hydroxy-acid form predominates at physiologic pH. The mean metabolite: parent AUC ratio was less than 10% for total topotecan and topotecan lactone. Excretion The overall recovery of drug-related material following 5 daily doses of topotecan was 57% of the administered oral dose. In the urine, 20% of the orally administered dose was excreted as total topotecan and 2% was excreted as N-desmethyl topotecan. Fecal elimination of total topotecan accounted for 33%, while fecal elimination of the active metabolite N-desmethyl topotecan accounted for 1.5%. Overall, the N-desmethyl metabolite contributed a mean of less than 6% (range: 4% to 8%) of the total drug-related material accounted for in the urine and feces. Specific Populations No clinically significant differences in the pharmacokinetics of topotecan were observed based on age, sex, or hepatic impairment following oral administration. Racial and Ethnic Groups In patients with creatinine clearance (CLcr) greater than 80 mL/min, the dose-normalized AUC inf to topotecan lactone and total topotecan each were approximately 30% higher in Asians compared to Whites Patients with Renal Impairment The mean dose-normalized for total topotecan and topotecan lactone AUC inf increased in advanced cancer patients with renal impairment compared to patients with CLcr greater than 80 mL/min as presented in Table 2 [see Dosage and Administration (2.3)] . Prior platinum-based chemotherapy had no effect on the systemic exposure to both total topotecan and topotecan lactone in patients with CLcr greater than 80 mL/min. Table 2. AUC inf Increases Compared to Normal Renal Function Renal Impairment Geometric Mean Dose-Normalized AUC inf Total Topotecan Topotecan Lactone Whites CLcr 50-79 mL/min CLcr 30-49 mL/min < 30 mL/min 70% 108% 227% 34% 80% 114% Asians CLcr 50-79 mL/min CLcr 30-49 mL/min < 30 mL/min 26% 153% 331% 34% 121% 247% Drug Interaction Studies Clinical Studies Effect of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) Inhibitors Following coadministration of escalating doses of a dual inhibitor of BCRP and P-gp, the AUCinf of topotecan lactone and total topotecan increased approximately 2.5-fold compared to topotecan alone [see Drug Interactions (7.1)] . Coadministration of single oral dose of cyclosporine A (15 mg/kg), an inhibitor of P-gp, multidrug-resistance-associated protein (MRP-1) and CYP3A4, within 4 hours of oral topotecan increased the dose-normalized AUC 0-24h of topotecan lactone and total topotecan 2- to 3-fold compared to topotecan alone [see Drug Interactions (7.1)]. Effect of Gastric Acid Reducing Agents No clinically significant changes in the pharmacokinetics of oral topotecan were observed when coadministered with ranitidine, a histamine-2 receptor antagonist. In Vitro Studies Topotecan does not inhibit CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A, CYP4A, or dihydropyrimidine dehydrogenase.

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 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.

12.3 Pharmacokinetics Following administration of HYCAMTIN capsules at doses of 1.2 to 3.1 mg/m 2 (0.52 to 1.35 times the recommended dose) administered daily for 5 days, the area under the curve (AUC) increased proportionally with dose. Absorption The time to the peak plasma concentrations is between 1 to 2 hours following oral administration. The oral bioavailability of topotecan is approximately 40%. Food Effect Following a high-fat meal, the AUC was similar in the fed and fasted states, while T max was delayed from 1.5 to 3 hours for topotecan lactone and from 3 to 4 hours for total topotecan. Distribution Protein binding of topotecan is approximately 35%. Elimination The mean terminal half-life (t½) of topotecan is 3 to 6 hours following oral administration. Metabolism Topotecan undergoes a reversible pH-dependent hydrolysis of a pharmacologically active lactone moiety. At pH less than or equal to 4, the lactone is exclusively present, whereas the ring-opened hydroxy-acid form predominates at physiologic pH. The mean metabolite: parent AUC ratio was less than 10% for total topotecan and topotecan lactone. Excretion The overall recovery of drug-related material following 5 daily doses of topotecan was 57% of the administered oral dose. In the urine, 20% of the orally administered dose was excreted as total topotecan and 2% was excreted as N-desmethyl topotecan. Fecal elimination of total topotecan accounted for 33%, while fecal elimination of the active metabolite N-desmethyl topotecan accounted for 1.5%. Overall, the N-desmethyl metabolite contributed a mean of less than 6% (range: 4% to 8%) of the total drug-related material accounted for in the urine and feces. Specific Populations No clinically significant differences in the pharmacokinetics of topotecan were observed based on age, sex, or hepatic impairment following oral administration. Racial and Ethnic Groups In patients with creatinine clearance (CLcr) greater than 80 mL/min, the dose-normalized AUC inf to topotecan lactone and total topotecan each were approximately 30% higher in Asians compared to Whites Patients with Renal Impairment The mean dose-normalized for total topotecan and topotecan lactone AUC inf increased in advanced cancer patients with renal impairment compared to patients with CLcr greater than 80 mL/min as presented in Table 2 [see Dosage and Administration (2.3)] . Prior platinum-based chemotherapy had no effect on the systemic exposure to both total topotecan and topotecan lactone in patients with CLcr greater than 80 mL/min. Table 2. AUC inf Increases Compared to Normal Renal Function Renal Impairment Geometric Mean Dose-Normalized AUC inf Total Topotecan Topotecan Lactone Whites CLcr 50-79 mL/min CLcr 30-49 mL/min < 30 mL/min 70% 108% 227% 34% 80% 114% Asians CLcr 50-79 mL/min CLcr 30-49 mL/min < 30 mL/min 26% 153% 331% 34% 121% 247% Drug Interaction Studies Clinical Studies Effect of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) Inhibitors Following coadministration of escalating doses of a dual inhibitor of BCRP and P-gp, the AUCinf of topotecan lactone and total topotecan increased approximately 2.5-fold compared to topotecan alone [see Drug Interactions (7.1)] . Coadministration of single oral dose of cyclosporine A (15 mg/kg), an inhibitor of P-gp, multidrug-resistance-associated protein (MRP-1) and CYP3A4, within 4 hours of oral topotecan increased the dose-normalized AUC 0-24h of topotecan lactone and total topotecan 2- to 3-fold compared to topotecan alone [see Drug Interactions (7.1)]. Effect of Gastric Acid Reducing Agents No clinically significant changes in the pharmacokinetics of oral topotecan were observed when coadministered with ranitidine, a histamine-2 receptor antagonist. In Vitro Studies Topotecan does not inhibit CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A, CYP4A, or dihydropyrimidine dehydrogenase.

20220707

8

3 DOSAGE FORMS AND STRENGTHS Capsules 0.25 mg: opaque white to yellowish-white and imprinted with HYCAMTIN and 0.25 mg. 1 mg: opaque pink and imprinted with HYCAMTIN and 1 mg. Capsules: 0.25 mg or 1 mg ( 3 )

HYCAMTIN topotecan TOPOTECAN HYDROCHLORIDE TOPOTECAN GLYCERYL MONOSTEARATE GELATIN TITANIUM DIOXIDE FERRIC OXIDE RED opaque white to yellowish-white HYCAMTIN;0;25;mg HYCAMTIN topotecan TOPOTECAN HYDROCHLORIDE TOPOTECAN GLYCERYL MONOSTEARATE GELATIN TITANIUM DIOXIDE FERRIC OXIDE RED opaque pink HYCAMTIN;1mg

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity testing of topotecan has not been done. Nevertheless, 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 an intravenous dose of 1.4 mg/m 2 [(about 0.6 times the 2.3 mg/m 2 oral clinical dose based on body surface area (BSA)] 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 an intravenous dose of 0.4 mg/m 2 (about 0.2 times the 2.3 mg/m 2 oral clinical dose based on BSA) of topotecan daily for a month suggest that treatment may cause an increase in the incidence of multinucleated spermatogonial giant cells in the testes.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity testing of topotecan has not been done. Nevertheless, 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 an intravenous dose of 1.4 mg/m 2 [(about 0.6 times the 2.3 mg/m 2 oral clinical dose based on body surface area (BSA)] 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 an intravenous dose of 0.4 mg/m 2 (about 0.2 times the 2.3 mg/m 2 oral clinical dose based on BSA) of topotecan daily for a month suggest that treatment may cause an increase in the incidence of multinucleated spermatogonial giant cells in the testes.

NDA020981

HYCAMTIN

topotecan

0078-0672

HUMAN PRESCRIPTION DRUG

ORAL

Principal Display Panel NDC 0078-0672-01 HYCAMTIN ® (topotecan) Capsules 0.25 mg R x only 10 Capsules Novartis Hycamtin .25 mg capsule 10 count label

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Myelosuppression Inform patients that HYCAMTIN decreases blood cell counts, such as white blood cells, platelets, and red blood cells. Instruct patients to notify their healthcare provider promptly for fever or other signs of infection [see Warnings and Precautions (5.1)] . Diarrhea Inform patients that HYCAMTIN capsules can cause diarrhea which may be severe and life-threatening. Instruct patients how to manage and/or prevent diarrhea and to inform their physician if severe diarrhea occurs during treatment with HYCAMTIN capsules [see Warnings and Precautions (5.2)] . Interstitial Lung Disease (ILD) Inform patients of the risks of severe ILD. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms [see Warnings and Precautions (5.3)] . Embryo-Fetal Toxicity Advise females of reproductive potential and males with female partners of reproductive potential of the potential risk to a fetus. Advise women to contact their healthcare provider if they become pregnant, or if pregnancy is suspected during treatment with HYCAMTIN capsules [see Warnings and Precautions (5.4), Use in Specific Populations (8.1, 8.3)] . Advise females of reproductive potential to use effective contraception during treatment and for 6 months after the last dose of HYCAMTIN capsules [see Use in Specific Populations (8.1, 8.3)] . Advise males with a female partner of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of HYCAMTIN capsules [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)] . Lactation Advise women to discontinue breastfeeding during treatment and for 1 week after the last dose of HYCAMTIN capsules [see Use in Specific Populations (8.2)] . Infertility Advise male and female patients of the potential risk for impaired fertility [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)] . Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis T2018-112

14 CLINICAL STUDIES 14.1 Small Cell Lung Cancer (SCLC) The efficacy of HYCAMTIN capsules was studied in 141 patients with relapsed SCLC in a randomized, controlled, open-label trial (Study 478). The patients were prior responders (complete or partial) to first-line chemotherapy, were not considered candidates for standard intravenous chemotherapy and had relapsed at least 45 days from the end of first-line chemotherapy. Patients were randomized 1:1 to HYCAMTIN capsules (2.3 mg/m 2 orally once daily for 5 consecutive days, starting on Day 1 of a 21-day cycle) with best supportive care (BSC) or BSC alone. The major efficacy outcome measure was overall survival (OS). Patients randomized to HYCAMTIN capsules with BSC received a median of 4 courses (range: 1 to 10) and maintained a median dose intensity of 3.77 mg/m 2 /week. The median patient age in patients receiving HYCAMTIN capsules with BSC and BSC alone was 60 years and 58 years, while the percentage of patients aged greater than or equal to 65 years was 34% and 29%, respectively. The majority of patients were White (99%) and male (73%). In the HYCAMTIN capsules with BSC arm, 68% of patients had extensive disease and 28% had liver metastasis. In the BSC alone arm, 61% had extensive disease and 20% had liver metastases. Eighty percent of patients receiving HYCAMTIN capsules with BSC previously received carboplatin or cisplatin and 77% of patients in the BSC alone arm received prior carboplatin or cisplatin. In the arm receiving HYCAMTIN capsules with BSC, 18% of patients had prior carboplatin and 62% had prior cisplatin. In the BSC-alone arm, 26% of patients had prior carboplatin and 51% had prior cisplatin. The arm receiving HYCAMTIN capsules with BSC showed a statistically significant improvement in OS compared with the BSC-alone arm (Log-rank P = 0.0104). Efficacy results are shown in Table 3 and Figure 1. Table 3. Efficacy Results in Small Cell Lung Cancer in Study 478 Abbreviations: BSC, Best Supportive Care; N, Total number of patients randomized; CI, Confidence Interval. Parameters Treatment Group HYCAMTIN Capsules with BSC BSC (N = 71) (N = 70) Median Overall Survival (months) (95% CI) 6.0 (4.2, 7.3) 3.2 (2.6, 4.3) Hazard ratio (95% CI) 0.64 (0.45, 0.90) Log-rank P -value 0.0104 Figure 1. Kaplan-Meier Curves for Overall Survival in Small Cell Lung Cancer in Study 478 Figure 1. Kaplan-Meier Curves for Overall Survival in Small Cell Lung Cancer in Study 478

15 REFERENCES “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

8.5 Geriatric Use Of the 682 patients with lung cancer who received HYCAMTIN capsules in the four clinical trials, 33% were aged 65 years and older, while 4.8% were aged 75 years and older. Treatment-related diarrhea was more frequent in patients aged greater than or equal to 65 years (28%) compared with those younger than 65 years (19%) [see Warnings and Precautions (5.2), Adverse Reactions (6.1)] . No overall differences in effectiveness were observed between patients 65 years and older and younger patients.

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

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 intravenous 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 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.

8 USE IN SPECIFIC POPULATIONS 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 intravenous 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 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. 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 milk production. Lactating rats excrete high concentrations of topotecan into milk ( see Data ). Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with HYCAMTIN 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 intravenous dose based on BSA), 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 capsules [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 female patients of reproductive potential to use effective contraception during treatment with HYCAMTIN capsules and for 6 months after the last dose. Males HYCAMTIN capsules 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 capsules 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 have 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 682 patients with lung cancer who received HYCAMTIN capsules in the four clinical trials, 33% were aged 65 years and older, while 4.8% were aged 75 years and older. Treatment-related diarrhea was more frequent in patients aged greater than or equal to 65 years (28%) compared with those younger than 65 years (19%) [see Warnings and Precautions (5.2), Adverse Reactions (6.1)] . No overall differences in effectiveness were observed between patients 65 years and older and younger patients. 8.6 Renal Impairment No dosage adjustment is recommended for patients with creatinine clearance (CLcr) greater than or equal to 50 mL/min. Reduce the dose of HYCAMTIN capsules in patients with CLcr less than 49 mL/min [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].

16 HOW SUPPLIED/STORAGE AND HANDLING The 0.25 mg HYCAMTIN capsules are opaque white to yellowish-white imprinted with HYCAMTIN and 0.25 mg and are available in bottles of 10: NDC 0078-0672-01. The 1 mg HYCAMTIN capsules are opaque pink imprinted with HYCAMTIN and 1 mg and are available in bottles of 10: NDC 0078-0673-01. Store refrigerated 2ºC to 8ºC (36ºF to 46ºF) protected from light in the original carton. HYCAMTIN is a cytotoxic drug. Follow applicable special handling and disposable procedures. 1

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 ).