Capecitabine 150 mg Tablet, Film Coated, 60-count — NDC 82249-207-60 (Billing 82249-0207-60)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Capecitabine is metabolized to fluorouracil in vivo. Both normal and tumor cells metabolize fluorouracil to 5-fluoro-2’-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites cause cell injury by two different mechanisms.

First, FdUMP and the folate cofactor, N 5-10 -methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a covalently bound ternary complex. This binding inhibits the formation of thymidylate from 2’-deoxyuridylate. Thymidylate is the necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, so that a deficiency of this compound can inhibit cell division.

Second, nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis.

12.2Pharmacodynamics Population-based exposure-effect analyses demonstrated a positive association between AUC of fluorouracil and grade 3 to 4 hyperbilirubinemia.

12.3Pharmacokinetics The AUC of capecitabine and its metabolite 5’-DFCR increases proportionally over a dosage range of 500 mg/m 2 /day to 3,500 mg/m 2 /day (0.2 to 1.4 times the approved recommended dosage). The AUC of capecitabine’s metabolites 5’-DFUR and fluorouracil increased greater than proportional to the dose. The interpatient variability in the C max and AUC of fluorouracil was greater than 85%.

Absorption Following oral administration of capecitabine tablets 1,255 mg/m 2 orally twice daily (the recommended dosage when used as single agent), the median T max of capecitabine and its metabolite fluorouracil was approximately 1.5 hours and 2 hours, respectively. Effect of Food Following administration of a meal (breakfast medium-rich in fat and carbohydrates), the mean C max and AUC 0-INF of capecitabine was decreased by 60% and 34%, respectively. The mean C max and AUC 0-INF of fluorouracil were also decreased by 37 % and 12%, respectively.

The T max of both capecitabine and fluorouracil was delayed by 1.5 hours. Distribution Plasma protein binding of capecitabine and its metabolites is less than 60% and is not concentration-dependent. Capecitabine was primarily bound to human albumin (approximately 35%).

Following oral administration of capecitabine tablets 7 days before surgery in patients with colorectal cancer, the median ratio of concentration for the active metabolite fluorouracil in colorectal tumors to adjacent tissues was 2.9 (range: 0.9 to 8.0). Elimination The elimination half-lives of capecitabine and fluorouracil were approximately 0.75 hour. Metabolism Capecitabine undergoes metabolism by carboxylesterase and is hydrolyzed to 5’-DFCR.

5’- DFCR is subsequently converted to 5’-DFUR by cytidine deaminase. 5’-DFUR is then hydrolized by thymidine phosphorylase (dThdPase) enzymes to the active metabolite fluorouracil. Fluorouracil is subsequently metabolized by dihydropyrimidine dehydrogenase to 5-fluoro-5, 6- dihydro-fluorouracil (FUH 2 ).

The pyrimidine ring of FUH 2 is cleaved by dihydropyrimidinase to yield 5-fluoro-ureido-propionic acid (FUPA). Finally, FUPA is cleaved by β-ureido-propionase to α-fluoro-β-alanine (FBAL). Excretion Following administration of radiolabeled capecitabine, 96% of the administered capecitabine dose was recovered in urine (3% unchanged and 57% as metabolite FBAL) and 2.6% in feces.

Specific Populations Following therapeutic doses of capecitabine tablets, no clinically meaningful difference in the pharmacokinetics of 5’-DFUR, fluorouracil or FBAL were observed based on sex (202 females and 303 males) and race (455 White, 22 Black, and 28 Other). No clinically meaningful difference on the pharmacokinetics of 5’-DFUR and fluorouracil were observed based on age (range: 27 to 86 years); however, the AUC of FBAL increased by 15% following a 20% increase in age. Racial or Ethnic Groups Following administration… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Capecitabine is metabolized to fluorouracil in vivo. Both normal and tumor cells metabolize fluorouracil to 5-fluoro-2’-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites cause cell injury by two different mechanisms.

First, FdUMP and the folate cofactor, N 5-10 -methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a covalently bound ternary complex. This binding inhibits the formation of thymidylate from 2’-deoxyuridylate. Thymidylate is the necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, so that a deficiency of this compound can inhibit cell division.

Second, nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis.

12.3Pharmacokinetics The AUC of capecitabine and its metabolite 5’-DFCR increases proportionally over a dosage range of 500 mg/m 2 /day to 3,500 mg/m 2 /day (0.2 to 1.4 times the approved recommended dosage). The AUC of capecitabine’s metabolites 5’-DFUR and fluorouracil increased greater than proportional to the dose. The interpatient variability in the C max and AUC of fluorouracil was greater than 85%.

Absorption Following oral administration of capecitabine tablets 1,255 mg/m 2 orally twice daily (the recommended dosage when used as single agent), the median T max of capecitabine and its metabolite fluorouracil was approximately 1.5 hours and 2 hours, respectively. Effect of Food Following administration of a meal (breakfast medium-rich in fat and carbohydrates), the mean C max and AUC 0-INF of capecitabine was decreased by 60% and 34%, respectively. The mean C max and AUC 0-INF of fluorouracil were also decreased by 37 % and 12%, respectively.

The T max of both capecitabine and fluorouracil was delayed by 1.5 hours. Distribution Plasma protein binding of capecitabine and its metabolites is less than 60% and is not concentration-dependent. Capecitabine was primarily bound to human albumin (approximately 35%).

Following oral administration of capecitabine tablets 7 days before surgery in patients with colorectal cancer, the median ratio of concentration for the active metabolite fluorouracil in colorectal tumors to adjacent tissues was 2.9 (range: 0.9 to 8.0). Elimination The elimination half-lives of capecitabine and fluorouracil were approximately 0.75 hour. Metabolism Capecitabine undergoes metabolism by carboxylesterase and is hydrolyzed to 5’-DFCR.

5’- DFCR is subsequently converted to 5’-DFUR by cytidine deaminase. 5’-DFUR is then hydrolized by thymidine phosphorylase (dThdPase) enzymes to the active metabolite fluorouracil. Fluorouracil is subsequently metabolized by dihydropyrimidine dehydrogenase to 5-fluoro-5, 6- dihydro-fluorouracil (FUH 2 ).

The pyrimidine ring of FUH 2 is cleaved by dihydropyrimidinase to yield 5-fluoro-ureido-propionic acid (FUPA). Finally, FUPA is cleaved by β-ureido-propionase to α-fluoro-β-alanine (FBAL). Excretion Following administration of radiolabeled capecitabine, 96% of the administered capecitabine dose was recovered in urine (3% unchanged and 57% as metabolite FBAL) and 2.6% in feces.

Specific Populations Following therapeutic doses of capecitabine tablets, no clinically meaningful difference in the pharmacokinetics of 5’-DFUR, fluorouracil or FBAL were observed based on sex (202 females and 303 males) and race (455 White, 22 Black, and 28 Other). No clinically meaningful difference on the pharmacokinetics of 5’-DFUR and fluorouracil were observed based on age (range: 27 to 86 years); however, the AUC of FBAL increased by 15% following a 20% increase in age. Racial or Ethnic Groups Following administration of capecitabine tablets 825 mg/m 2 orally twice daily for 14 days (0.66 times the recommended dosage), the C max and AUC of capecitabine decreased by 36% and 24%, respectively in Japanese patients (n=18) compared to White patients (n=22).

The C max and AUC of FBAL decreased by approximately 25% and 34%, respectively in Japanese patients compared to White patients; however, the clinical significance of these differences is unknown. No clinically significant differences in the pharmacokinetics of 5’-DFCR, 5’-DFUR or fluorouracil were observed. Patients with Renal Impairment Table 8 Effect of Renal Impairment on the Pharmacokinetics of Capecitabine, 5’-DFUR, and FBAL Renal Impairment a Changes in AUC b Capecitabine 5’-DFUR c FBAL c 5-FU CLcr 30 to 50 mL/min Increased by 25% Increased by 42% Increased by 85% No relevant change CLcr <30 mL/min Increased by 25% Increased by 71% Increased by 258% Increased by 24% a Compared to patients with CLcr >80 mL/min b Following administration of capecitabine tablets 1,250 mg/m 2 orally twice daily; day 1 observations c Capecitabine metabolite CLc… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Population-based exposure-effect analyses demonstrated a positive association between AUC of fluorouracil and grade 3 to 4 hyperbilirubinemia.

14 CLINICAL STUDIES

14.1Colorectal Cancer Adjuvant Treatment of Colon Cancer Single Agent The efficacy of capecitabine tablets was evaluated in X-ACT (NCT00009737), a multicenter, randomized, controlled clinical trial. Eligible patients were between 18 and 75 years of age with histologically-confirmed Dukes’ Stage C colon cancer with at least one positive lymph node and to have undergone (within 8 weeks prior to randomization) complete resection of the primary tumor without macroscopic or microscopic evidence of remaining tumor. Patients were also required to have no prior cytotoxic chemotherapy or immunotherapy (except steroids) and have an ECOG performance status of 0 or 1 (KPS > 70%), ANC > 1.5x10 9 /L, platelets > 100x10 9 /L, serum creatinine <

1.5 ULN, total bilirubin <

1.5 ULN, AST/ALT <

2.5ULN and CEA within normal limits at time of randomization. Patients (n=1,987) were randomized to capecitabine tablets 1,250 mg/m 2 orally twice daily for the first 14 days of a 21-day cycle for a total of 8 cycles or fluorouracil 425 mg/m 2 and leucovorin 20 mg/m 2 intravenously on days 1 to 5 of each 28-day cycle for a total of 6 cycles. The capecitabine tablets dose was reduced in patients with baseline CLcr of 30 to 50 mL/min.

The major efficacy outcome measure was disease-free survival (DFS). The baseline demographics are shown in Table 9. The baseline characteristics were well- balanced between arms.

Table 9 Baseline Demographics in X-ACT Capecitabine Tablets (N=1,004) Fluorouracil + Leucovorin (N=983) Age (median, years) 62 63 Range (25 to 80) (22 to 82) Sex Male, % 54 54 Female, % 46 46 ECOG Performance Status 0, % 85 85 1, % 15 15 Staging – Primary Tumor PT1, % 1

0.6PT2, % 9 9 PT3, % 76 76 PT4, % 14 0 Other, % 0.1 14 Staging – Lymph Node pN1, % 69 71 pN2, % 30 29 Other, % 0.4

0.1Efficacy results are summarized in Table 10 and Figures 1 and 2. The median follow-up at the time of the analysis was 6.9 years. Because the upper 2-sided 95% confidence limit of hazard ratio for DFS was less than 1.20, capecitabine tablets was non-inferior to fluorouracil + leucovorin.

The choice of the non-inferiority margin of 1.20 corresponds to the retention of approximately 75% of the fluorouracil + leucovorin effect on DFS. The hazard ratio for capecitabine tablets compared to fluorouracil + leucovorin with respect to overall survival was 0.86 (95% CI 0.74, 1.01). The 5- year overall survival rates were 71% for capecitabine tablets and 68% for fluorouracil + leucovorin.

Table 10 Efficacy Results in X-ACTa (All Randomized Population) Efficacy Parameters Capecitabine Tablets (N=1,004) Fluorouracil + Leucovorin (N=983) 5-year Disease-free Survival Rate b 59% 55% Hazard Ratio 0.88 (95% CI) (0.77, 1.01) p -value c p = 0.068 a Approximately 93.4% had 5-year DFS information b Based on Kaplan-Meier estimates c Wald chi-square test Figure 1 Kaplan-Meier Estimates of Disease-Free Survival in X-ACT (All Randomized Population) Figure 2 Kaplan-Meier Estimates of Overall Survival in X-ACT (All Randomized Population) In Combination with Oxaliplatin-Containing Regimens The efficacy of capecitabine tablets in combination with oxaliplatin for the adjuvant treatment of patients with Stage III colon cancer as a component of a combination chemotherapy regimen was derived from studies in the published literature, including NO16968 [NCT00069121], a multicenter, open-label, randomized trial, where the major efficacy outcome measure was disease free survival.

Perioperative Treatment of Rectal Cancer The efficacy of capecitabine tablets for the perioperative treatment of adults with locally advanced rectal cancer as a component of chemoradiotherapy was derived from studies in the published literature, including Rektum-III [NCT01500993], a randomized, open-label, multicenter, non- inferiority trial, where the major efficacy outcome measure was overall survival. Metastatic Colorectal Cancer The efficacy of capecitabine tablets as a single agent was evaluated in two op… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Adequate studies investigating the carcinogenic potential of capecitabine have not been conducted. Capecitabine was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster V79/HPRT gene mutation assay). Capecitabine was clastogenic in vitro to human peripheral blood lymphocytes but not clastogenic in vivo to mouse bone marrow (micronucleus test).

Fluorouracil causes mutations in bacteria and yeast. Fluorouracil also causes chromosomal abnormalities in the mouse micronucleus test in vivo. In studies of fertility and general reproductive performance in female mice, oral capecitabine doses of 760 mg/kg/day (about 2,300 mg/m 2 /day) disturbed estrus and consequently caused a decrease in fertility.

In mice that became pregnant, no fetuses survived this dose. The disturbance in estrus was reversible. In males, this dose caused degenerative changes in the testes, including decreases in the number of spermatocytes and spermatids.

In separate pharmacokinetic studies, this dose in mice produced 5’-DFUR AUC values about 0.7 times the corresponding values in patients administered the recommended daily dose.