2.1 Recommended Dosage

The recommended dosage of HYCAMTIN capsules is 2.3 mg/m2/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/m2/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/mm3, platelets recover to greater than 100,000/mm3, 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/m2/day for:

• neutrophil counts of less than 500/mm3 associated with fever or infection or lasting for 7 days or more;
• neutrophil counts of 500 to 1,000/mm3 lasting beyond day 21 of the treatment course; or
• platelet counts less than 25,000/mm3.

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/m2/day.
• CLcr less than 30 mL/min: Administer 0.6 mg/m2/day.

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/m2 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/mm3 and a platelet count greater than or equal to 100,000/mm3. 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)].

6.1 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/m2 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.

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

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.

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/m2 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/m2 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/m2 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/m2 (about twice the 1.5 mg/m2 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)].

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/m2 (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 Tmax 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 AUCinf 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 AUCinf 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.

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 AUC0-24h 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.

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/m2 [(about 0.6 times the 2.3 mg/m2 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/m2 (about 0.2 times the 2.3 mg/m2 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.

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/m2 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/m2/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.

Figure 1. Kaplan-Meier Curves for Overall Survival in Small Cell Lung Cancer in Study 478