Hycamtin topotecan .25 mg Capsule, 10-count — NDC 66758-101-11 (Billing 66758-0101-11)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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.

12.3Pharmacokinetics 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 topoteca… [Excerpted — this section continues on DailyMed.]

12.1Mechanism 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.

12.3Pharmacokinetics 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.

14 CLINICAL STUDIES

14.1Small 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 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 Abbreviations: BSC, Best Supportive Care; N, Total number of patients randomized; CI, Confidence Interval. 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

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, 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.