CONTROL #: 117867

(r)

Registered Trade-Mark of Hoffmann-La Roche Limited

(r)

Copyright 1998-2008 Hoffmann-La Roche Limited

XELODA(r) (capecitabine) Tablets 150 mg and 500 mg

ACTIONS AND CLINICAL PHARMACOLOGY

CAUTION: XELODA (CAPECITABINE) IS A POTENT DRUG AND SHOULD BE PRESCRIBED ONLY BY PHYSICIANS EXPERIENCED WITH CANCER CHEMOTHERAPEUTIC DRUGS (SEE WARNINGS). IF TOXICITY ON THERAPY OCCURS, XELODA SHOULD BE INTERRUPTED UNTIL THE EVENT RESOLVES, OR THE SEVERITY DECREASES WHEN THE FOLLOWING TOXICITIES OCCUR AT A SEVERITY OF GRADE 2 OR GREATER: DIARRHEA, HAND-FOOT SYNDROME, NAUSEA, HYPERBILIRUBINEMIA, VOMITING OR STOMATITIS (SEE WARNINGS, PRECAUTIONS AND DOSAGE AND ADMINISTRATION). Capecitabine is a tumour- activated antineoplastic agent (antimetabolite) belonging to the novel fluoropyrimidine carbamate class. It was rationally designed as an orally administered precursor of 5'-deoxy-5-fluorouridine (5'-DFUR). Capecitabine is selectively activated to the cytotoxic moiety, 5-fluorouracil (5-FU), by thymidine phosphorylase in tumours.

Bioactivation

: Capecitabine is absorbed unchanged from the gastrointestinal tract, metabolized primarily in the liver by the 60kDa carboxylesterase to 5'-Deoxy-5-fluorocytidine (5'-DFCR) which is then converted to 5'-DFUR by cytidine deaminase, principally located in the liver and tumour tissue. Further metabolism of 5'-DFUR to the pharmacologically-active agent 5-FU occurs mainly at the site of the tumour by thymidine phosphorylase (dThdPase), which has levels considerably higher in tumour tissues compared to normal tissues (see the following figure for the metabolic pathway of capecitabine). Healthy liver tissues also contain a relatively high activity of dThdPase. In human cancer xenograft models, capecitabine demonstrated a synergistic effect in combination with docetaxel which may be related to the upregulation of thymidine phosphorylase by docetaxel.

Metabolic Pathway of Capecitabine to 5-FU

NH-CO-O N F

O

N O

NH2

N

F

O N

O

Carboxylesterase

(liver)

HO OH

5'-DFCR

H3C O

Cyd deaminase (liver, tumors)

O

HN F

dThdPase O

N

(liver, tumors) H

5-FU

Mechanism of Action

: Within normal and tumour cells, 5-FU is further metabolized to 5-fluoro- 2'-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP) which cause cell injury by both DNA and RNA-derived mechanisms (see the PHARMACOLOGY section for more detailed information).

Pharmacokinetics in Colorectal Tumours and Adjacent Healthy Tissue: Following oral administration of capecitabine (1255 mg/m2 b.i.d. 5 to 7 days) in patients with colorectal cancer, concentrations of 5-FU were significantly greater in primary tumour than in adjacent healthy tissue (geometric mean ratio 2.5; CI:1.5 to 4.1) and in plasma (geometric mean ratio 14).

Pharmacokinetics:

The pharmacokinetics of capecitabine and its metabolites have been evaluated in 11 studies in a total of 213 cancer patients at a dosage range of 502 to 3514 mg/m2/day. The parameters of capecitabine, 5'DFCR and 5'DFUR measured on days 1 and 14 were similar. AUC of 5-FU was 30% higher on day 14, but did not increase subsequently (day 22). At therapeutic doses, the pharmacokinetics of capecitabine and its metabolites were dose proportional, except for 5-FU. The elimination half-life of both capecitabine and 5-FU were about 45 minutes. (For more detailed information on the pharmacokinetics of capecitabine, please refer to the PHARMACOLOGY section.) Absorption, Distribution, Metabolism and Excretion: Capecitabine reached peak blood levels in about 1.5 hours (Tmax) with peak 5-FU blood levels occurring slightly later, at 2 hours. Administration with food decreases the rate of capecitabine absorption but only results in a minor decrease in the AUC's of 5'-DFUR and 5-FU (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Plasma protein binding of capecitabine and its metabolites is low (less than 60%) and is not concentration dependent. Capecitabine was primarily bound to human albumin (approximately 35%). Capecitabine is extensively metabolized to 5-FU. The enzyme dihydropyrimidine dehydrogenase hydrogenates 5-FU, the product of capecitabine metabolism, to the much less toxic, 5-fluoro-5,6-dihydro-fluorouracil (FUH2). Dihydropyrimidinase cleaves the pyrimidine ring to yield 5-fluoro-ureido-propionic acid (FUPA). Finally, b-ureido- propionase cleaves FUPA to a-fluoro-b-alanine (FBAL) which is cleared in the urine. Over 70% of the administered capecitabine dose is recovered in urine as drug-related material, about 50% of it as FBAL. Phase I studies evaluating the effect of XELODA on the pharmacokinetics of either docetaxel or paclitaxel and vice versa showed no effect by XELODA on the pharmacokinetics of docetaxel or paclitaxel (Cmax and AUC) and no effect by docetaxel or paclitaxel on the pharmacokinetics of 5'-DFUR (the most important metabolite of capecitabine).

Special Populations:

A population pharmacokinetic analysis was carried out after XELODA treatment of 505 patients with metastatic colorectal cancer dosed at 2500 mg/m2/day. Gender, race, presence or absence of liver metastasis at baseline, Karnofsky Performance Status, total bilirubin, serum albumin, ASAT and ALAT had no statistically-significant effect on the pharmacokinetics of 5'-DFUR, 5- FU and FBAL.

Gender:

Based on population pharmacokinetic analysis including 202 females (40%) and 303 males (60%), gender has no influence on the pharmacokinetics of 5'-DFUR, 5-FU and FBAL.

Geriatrics: Based on the population pharmacokinetic analysis which included patients with a wide range of ages (27 to 86 years) and included 234 (46%) patients greater or equal to 65, age has no influence on the pharmacokinetics of 5'-DFUR and 5-FU. The AUC of FBAL increased with age (20% increase in age results in a 15% increase in the AUC of FBAL). This increase is likely due to a change in renal function (see CLINICAL PHARMACOLOGY: Renal Insufficiency). However, the elderly may be pharmacodynamically more sensitive to the toxic effects of 5-FU (see WARNINGS, Geriatrics and DOSAGE AND ADMINISTRATION).

Ethnicity:

Based on population pharmacokinetic analysis of 455 white patients (90.1%), 22 black patients (4.4%) and 28 patients of other race or ethnicity (5.5%), the pharmacokinetics of black patients were not different compared to white patients. For the other minority groups the numbers were too small to draw a conclusion.

Hepatic Insufficiency: Capecitabine has been evaluated in patients with mild to moderate hepatic dysfunction due to liver metastases. Both Cmax and AUC0- [?] of capecitabine, 5'-DFUR and 5-FU were increased by 49%, 33% and 28% and by 48%, 20% and 15%, respectively. Conversely, Cmax and AUC of 5'-DFCR decreased by 29% and 35%, respectively. Therefore, bioactivation of capecitabine is not affected. There are no pharmacokinetic data on patients with severe hepatic impairment (see WARNINGS and DOSAGE AND ADMINISTRATION).

Renal Insufficiency:

Based on a pharmacokinetic study in cancer patients with mild to severe renal impairment, there is no evidence for an effect of creatinine clearance on the pharmacokinetics of intact drug and 5-FU. Creatinine clearance was found to influence the systemic exposure to 5'-DFUR (35% increase in AUC when creatinine clearance decreases by 50%) and to FBAL (114% increase in AUC when creatinine clearance decreases by 50%). FBAL is a metabolite without antiproliferative activity; 5'-DFUR is the direct precursor of 5-FU.

As seen with 5-FU, the incidence of related grade 3 or 4 adverse events is higher in patients with moderate renal impairment (creatinine clearance 30-50 mL/min) (see CONTRAINDICATIONS, WARNINGS and DOSAGE AND ADMINISTRATION). CLINICAL STUDIES: In a phase I study with XELODA, the maximum-tolerated dose as a single agent in the treatment of patients with solid tumours was 3000 mg/m2 when administered daily for 2 weeks, followed by a 1-week rest period. The dose-limiting toxicities were diarrhea and leucopenia.

Colorectal Carcinoma: Adjuvant Colon Cancer

Data from one open-label, multicenter, randomized, controlled, non-inferiority, phase III clinical trial in patients with stage III (Dukes C) colon cancer supports the use of XELODA for the adjuvant treatment of patients with stage III colon cancer (X-ACT Study). In this trial, 1987 patients were randomized to treatment with monotherapy XELODA (1250 mg/m2 twice daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles for 24 weeks) (N=1004) or 5-FU and leucovorin (Mayo regimen: 20 mg/m2 leucovorin i.v. followed by 425 mg/m2 i.v. bolus 5-FU, on days 1 to 5, every 28 days for 24 weeks) (N=983). Although this trial used bolus 5-FU in the control arm, infusional 5-FU has been shown to be superior to bolus 5-FU. The primary efficacy endpoint was disease-free survival. The original conditional approval was based on primary analysis at a median follow-up time of 3.8 years which showed. XELODA was at least equivalent to i.v. 5-FU/LV in disease-free survival (p=0.0001, non-inferiority margin 1.2) with a trend towards superiority in disease-free survival. The full approval was based on an updated analysis at a median follow-up time of 6.9 years which confirmed XELODA to be at least equivalent to 5-FU/LV in disease-free survival although there was no longer a trend toward superiority in disease-free survival (p=0.06). A summary of the results is provided in Table 1. Compared with 5- FU/LV, XELODA was associated with lower incidence of stomatitis, neutropenia and febrile neutropenia but with a considerably higher incidence of hand-and-foot syndrome and hyperbilirubinemia in the adjuvant treatment of patients with Dukes Stage C colon cancer.

Figure 1: Kaplan-Meier Estimates of Disease-free Survival (All Randomized Population)

Table 1: Efficacy of XELODA vs 5-FU/LV in Adjuvant Treatment of stage III (Dukes Stage C) Colon Cancer

(95% C.I. 0.77-1.01); p =

a

N1- tumor in 1-3 regional lymph nodes; N2- tumor in >= 4 regional lymph nodes

b

Capecitabine versus 5-FU/LV; Non-inferiority margin of 1.20 corresponds to the retention by XELODA of approx. 75% of the 5-FU/LV effect on DFS

c

Wald chi square test for differences of XELODA vs 5-FU/LV

Metastatic Colorectal Cancer

Data from two multicenter, randomized, controlled phase III clinical trials involving 603 patients and one randomized phase II trial of 34 patients support the use of XELODA in the first-line treatment of patients with metastatic colorectal carcinoma (refer to Table 2).

TABLE 2: CLINICAL STUDIES IN METASTATIC COLORECTAL CARCINOMA

*20 mg/m2 leucovorin I.V. followed by 425 mg/m2 I.V. bolus 5-FU on days 1 to 5, every 28 days. XELODA was superior to 5-FU/LV for objective response rate in Study 1 and Study 2. The response rate observed in patients receiving the Mayo regimen was consistent with the published literature. It was also observed that in patients who received prior adjuvant chemotherapy the objective response rate was 15.3% and 14.5% for capecitabine and 5.5% and 4.4% (Study 1 and 2, respectively) for 5-FU/LV. There was no difference in time to disease progression and survival as compared to 5-FU/LV for both studies.

Breast Carcinoma:

XELODA has been evaluated in breast cancer clinical trials in combination with docetaxel and as monotherapy. Table 3 summarizes data from a pivotal combination trial as well as from one pivotal and two supportive monotherapy phase II clinical trials. XELODA in Combination with Docetaxel: The dose of XELODA used in combination with docetaxel in the phase III clinical trial was based on the results of a phase I study, where a range of doses of docetaxel given every 3 weeks in combination with an intermittent regimen of XELODA were evaluated. The combination dose regimen was selected based on the tolerability profile of the 75 mg/m2 every 3 weeks of docetaxel in combination with 1250 mg/m2 twice daily for 14 days of XELODA administered every 3 weeks. The approved dose of 100 mg/m2 of docetaxel administered every 3 weeks was the control arm of the phase III study. As shown in Table 3, XELODA in combination with docetaxel resulted in statistically significant improvement in time to disease progression, overall survival and objective response rate compared to monotherapy with docetaxel. Health Related Quality of Life (HRQoL) was assessed using EORTC QLQ-C30 (version 2) and Breast Cancer Module of the EORTC (BR23). HRQoL was similar in the two treatment groups. Approximately 11% of patients in the combination arm and 10% in the monotherapy arm did not complete a quality of life questionnaire at least once either at baseline or during the treatment phase.

TABLE 3: CLINICAL STUDIES IN BREAST CARCINOMA

CONTRAINDICATIONS

XELODA (capecitabine) is contraindicated in patients who have a known hypersensitivity to capecitabine or to any of its components, or to 5-fluorouracil and in patients with severe renal impairment (calculated creatinine clearance below 30 mL/min, or 0.5 mL/s). As with other fluoropyrimidines, XELODA is contraindicated in patients with known dihydropyrimidine dehydrogenase (DPD) deficiency. Contraindications for docetaxel also apply to the XELODA plus docetaxel combination.

WARNINGS

General:

Patients receiving therapy with XELODA (capecitabine) should be monitored by a physician experienced in the use of cancer chemotherapeutic agents. Most adverse reactions are reversible and do not require discontinuation, although doses may need to be withheld or reduced (see DOSAGE AND ADMINISTRATION).

Diarrhea: XELODA very frequently induces diarrhea, which can sometimes be severe. Patients with severe diarrhea should be carefully monitored and, if they become dehydrated, should be given fluid and electrolyte replacement. If grade 2 (or higher) diarrhea occurs, administration of XELODA should be immediately interrupted until diarrhea resolves or decreases in intensity to grade 1.1 Standard antidiarrheal agents (e.g. loperamide) should be initiated, as medically appropriate, as early as possible. Dose reduction should be applied as necessary (see DOSAGE AND ADMINISTRATION section). Necrotizing enterocolitis (typhlitis) has been reported. Dehydration: Dehydration should be prevented or corrected at the onset. Patients with anorexia, asthenia, nausea, vomiting or diarrhea may rapidly become dehydrated. If Grade 2 (or higher) dehydration occurs, XELODA treatment should be immediately interrupted and the dehydration corrected.2 Treatment should not be restarted until the patient is rehydrated and any precipitating causes have been corrected or controlled. Dose modifications applied should be applied for the precipitating adverse event as necessary (see DOSAGE AND ADMINISTRATION section). Coagulopathy: Altered coagulation parameters and/or bleeding have been reported in patients taking XELODA concomitantly with coumarin-derived anticoagulants such as warfarin. These events occurred within several days and up to several months after initiating XELODA therapy, and, in a few cases, within one month after stopping XELODA. These events occurred in patients with and without liver metastases. In a drug interaction study with single-dose warfarin administration, there was a significant increase in the mean AUC (+57%) of S-warfarin. These results suggest an interaction, probably due to an inhibition of the cytochrome P450 2C9 isoenzyme system by capecitabine. Patients taking coumarin-derivative anticoagulants concomitantly with XELODA should be monitored regularly for alterations in their coagulation parameters (PT or INR) and the anticoagulant dose adjusted accordingly (see PRECAUTIONS: Coumarin Anticoagulants).

1. National Cancer Institute of Canada (NCIC) grade 1 diarrhea is defined as an increase of < 4 stools per day over baseline, mild increase in ostomy output compared to baseline, grade 2 diarrhea is defined as an increase of 4 to 6 stools/day or nocturnal stools, grade 3 diarrhea as an increase of 7 to 9 stools/day or incontinence and malabsorption, grade 4 diarrhea as an increase of 10 stools/day or grossly bloody diarrhea or the need for parenteral support, and grade 5 diarrhea as death.

2. NCIC grade 2 dehydration is defined as IV fluids indicated <24 hours, grade 3 dehydration is defined as IV fluids indicated >=24 hours, grade 4 dehydration is defined as life-threatening consequences (e.g. hemodynamic collapse), and grade 5 dehydration as death.

Geriatrics:

XELODA in Combination with Docetaxel:

An analysis of safety data in patients equal to or greater than 60 years of age showed an increase in the incidence of treatment-related Grade 3 and 4 adverse events, treatment-related serious adverse events and early withdrawals from treatment due to adverse events compared to patients less than 60 years of age. The incidence of grade 3 or 4 stomatitis was greater in the 60 to 70 year old patient group (30%) than the general population (13%) (see DOSAGE AND ADMINISTRATION).

XELODA Monotherapy: Patients >=80 years old may experience a greater incidence of gastrointestinal grade 3/4 events.

Hepatic Insufficiency:

Patients with hepatic impairment should be carefully monitored when XELODA is administered. However, the effect of hepatic impairment not due to liver metastases or of severe hepatic impairment on the disposition of XELODA is not known.

Renal Insufficiency: In patients with moderate renal impairment (calculated creatinine clearance 30-50 mL/min [Cockroft and Gault]) * at baseline, a dose reduction to 75% of the XELODA starting dose when used as monotherapy or in combination with docetaxel is recommended based upon pharmacokinetic and safety data. Careful monitoring and prompt treatment interruption is recommended if the patient develops a grade 2, 3, or 4 adverse event, with subsequent dose adjustment as outlined in Tables 11 in the DOSAGE AND ADMINISTRATION section. Physicians should exercise caution when XELODA is administered to patients with impaired renal function. As seen with 5-FU, the incidence of treatment-related grade 3 or 4 adverse events was higher in patients with moderate renal impairment (calculated creatinine clearance 30- 50 mL/min).

Nursing Women:

In a study of single oral administration of capecitabine in lactating mice, it was found that a significant amount of the capecitabine metabolites is transferred to the milk. Because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving XELODA therapy.

Pediatric Use:

The safety and effectiveness of XELODA in persons <18 years of age has not been established.

*

Cockroft-Gault Formula for males: Creatinine clearance (mL/min)=

(140-age) x weight (kg)

72 x serum creatinine (mg/dl) Cockroft-Gault Formula for females: Creatinine clearance (mL/min)= 0.85 x male value

Creatinine clearance in SI units (mL/s) = 0.01667 x value obtained from above formula in mL/min

Use in Pregnancy:

There are no adequate and well-controlled studies in pregnant women using XELODA. If the drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with XELODA. XELODA was found to be teratogenic and embryolethal in mice and embryolethal in monkeys (see TOXICOLOGY).

Carcinogenesis and Mutagenesis: Although there was no evidence for oncogenic potential of capecitabine in a two-year carcinogenicity study in mice, capecitabine was clastogenic in vitro in human lymphocytes (similar to other nucleoside analogues such as 5-FU). There was also a positive trend in the in vivo mouse micronucleus assay (see TOXICOLOGY-Carcinogenicity, Mutagenicity, and Genotoxicity studies). Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with XELODA (see WARNINGS) and be provided with appropriate counselling if not currently using contraceptives. Males are advised not to father a child during treatment.

PRECAUTIONS

Hand-and-Foot Syndrome:

Hand-and-foot syndrome (palmar-plantar erythrodysesthesia or chemotherapy induced acral erythema) is a cutaneous toxicity which can occur in patients receiving XELODA either as monotherapy or in combination therapy. For patients receiving XELODA monotherapy in the metastatic setting, median time to onset was 79 days (range from

11 to 360 days) with a severity range of grades 1 to 3 *. If grade 2 or 3 hand-and-foot syndrome occurs, administration of XELODA should be interrupted until the event resolves or decreases in intensity to grade 1. Following grade 3 hand-and-foot syndrome, subsequent doses of XELODA should be decreased (see DOSAGE AND ADMINISTRATION). For XELODA in combination with docetaxel, hand-and-foot syndrome was more common in patients in the combination therapy arm than in the monotherapy arm (63% vs. 8%).

Cardiac:

The spectrum of cardiotoxicity observed with XELODA is similar to that of other fluorinated pyrimidines. This includes myocardial infarction, angina, dysrhythmias, cardiac arrest, cardiac failure, and electrocardiograph changes. These adverse events may be more common in patients with a prior history of coronary artery disease. A thorough QT interval prolongation assessment study of XELODA has never been conducted.

*

Grade 1 hand-and-foot syndrome is defined by numbness, dysesthesia/paresthesia, tingling, or erythema of the hands and/or feet and/or discomfort which does not disrupt normal activities. Grade 2 hand-and-foot syndrome is defined as painful erythema and swelling of the hands and/or feet that results in discomfort affecting the patient's activities of daily living and grade 3 hand-and-foot syndrome is defined as moist desquamation, ulceration, blistering or severe pain of the hands and/or feet that results in severe discomfort that causes the patient to be unable to work or perform activities of daily living.

Hematologic:

In 251 patients with metastatic breast cancer who received XELODA in combination with docetaxel, 68% had grade 3 or 4 neutropenia, 2.8% had grade 3 or 4

thrombocytopenia and 9.6% had grade 3 or 4 anemia. In 875 patients with either metastatic breast or colorectal cancer who received XELODA monotherapy, 3.2%, 1.7%, and 2.4% of patients had grade 3/4 neutropenia, thrombocytopenia and decreases in hemoglobin, respectively.

Hyperbilirubinemia:

In 251 patients with metastatic breast cancer who received a combination of XELODA and docetaxel, grade 3 and 4 hyperbilirubinemia occurred in 6.8% (n=17) and 2% (n=5), respectively.

In 875 patients with either metastatic breast or colorectal cancer treated with XELODA monotherapy, grade 3 hyperbilirubinemia occurred in 133 (15.2%) and grade 4 hyperbilirubinemia occurred in 34 (3.9%) patients with either metastatic breast or colorectal cancer. If drug related grade 2, 3 or 4+ elevations in bilirubin occur, administration of XELODA should be immediately interrupted until the hyperbilirubinemia resolves or decreases in intensity to grade 1. Following grade 3 or 4 hyperbilirubinemia, subsequent doses of XELODA should be decreased (see DOSAGE AND ADMINISTRATION).

Information for Patients:

Patients and patients' caregivers should be informed of the expected adverse effects of XELODA, particularly of diarrhea, nausea, vomiting, and hand-and-foot syndrome and stomatitis. The frequent oral administration of XELODA allows patient specific dose adaptations during therapy (see DOSAGE AND ADMINISTRATION). Patients should be taught to recognize and report the common grade 2 toxicities associated with XELODA treatment (please refer to the Information to the Patient Section).

If XELODA is prescribed in combination with docetaxel, patients and patients' caregivers should be informed of the expected adverse effects of the combination of XELODA and docetaxel (see Table 7).

Diarrhea:

Patients experiencing grade 2 diarrhea (an increase of 4 to 6 stools/day or nocturnal stools) or greater should be instructed to stop taking XELODA immediately. Standard antidiarrheal agents (e.g. loperamide) should be prescribed for symptom control (see DOSAGE AND ADMINISTRATION).

Nausea

: Patients experiencing grade 2 nausea (food intake significantly decreased but able to eat intermittently) or greater should be instructed to stop taking XELODA immediately. Standard anti-nausea agents should be prescribed for symptom control (see DOSAGE AND ADMINISTRATION).

+

NCIC grade 2 hyperbilirubinemia is defined as 1.5X normal, grade 3 hyperbilirubinemia as 1.5-3X normal and grade 4 hyperbilirubinemia as >3X normal.

Vomiting

: Patients experiencing grade 2 vomiting (2 to 5 episodes in a 24-hour period) or greater should be instructed to stop taking XELODA immediately. Standard anti- emetic agents should be prescribed for symptom control (see DOSAGE AND ADMINISTRATION).

Hand-and-Foot Syndrome:

Patients experiencing grade 2 hand-and-foot syndrome (painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patients' activities of daily living) or greater should be instructed to stop taking XELODA immediately.

Stomatitis

: Patients experiencing grade 2 stomatitis or greater (painful erythema, edema or ulcers, but are able to eat) should be instructed to stop taking XELODA immediately. Symptomatic treatment should be prescribed (see DOSAGE AND ADMINISTRATION).

Drug-Food Interaction: The effect of food on the pharmacokinetics of capecitabine was investigated in 11 cancer patients. The rate and extent of absorption of capecitabine is decreased when administered with food. The effect on AUC0- [?] of the 3 main metabolites in plasma (5'DFUR, 5-FU, FBAL) is minor. In all clinical trials, patients were instructed to take XELODA within 30 minutes after a meal. Therefore, since current safety and efficacy data are based upon administration with food, it is recommended XELODA be administered with food.

Drug-Drug Interactions:

Phenytoin and Fosphenytoin

: Increased phenytoin plasma concentrations have been reported during concomitant use of XELODA with phenytoin, suggesting a potential interaction. Formal drug-drug interactions studies with phenytoin have not been conducted, but the mechanism of interaction is presumed to be inhibition of the CYP 2C9 isoenzyme system by capecitabine (see subsection below, Cytochrome P450 2C9 Substrates). Patients taking phenytoin or fosphenytoin concomitantly with XELODA should be regularly monitored for increased phenytoin plasma concentrations and associated clinical symptoms.

Coumarin anticoagulants:

Altered coagulation parameters and/or bleeding have been reported in patients taking XELODA concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. These events occurred within several days and up to several months after initiating XELODA therapy and, in a few cases, within one month after stopping XELODA. In a clinical interaction study, after a single 20 mg dose of warfarin, XELODA treatment increased the AUC of S-warfarin by 57% with a 91% increase in INR value. Patients taking coumarin-derivative anticoagulants concomitantly with XELODA should be monitored regularly for alterations in their coagulation parameters (PT or INR) and the anticoagulant dose adjusted accordingly.

Cytochrome P450 2C9 Substrates:

No formal drug-drug interaction studies with capecitabine and other drugs known to be metabolized by the cytochrome P450 2C9 isoenzyme have been conducted. Care should be exercised when XELODA is co-administered with these drugs.

Antacid: The effect of an aluminum hydroxide and magnesium hydroxide-containing antacid (Maalox(r)) on the pharmacokinetics of capecitabine was investigated in 12 cancer patients. There was a small increase in plasma concentrations of capecitabine and one metabolite (5'DFCR); there was no effect on the 3 major metabolites (5'DFUR, 5-FU and FBAL).

Leucovorin:

A phase I study evaluating the effect of leucovorin on the pharmacokinetics of capecitabine was conducted in 22 cancer patients. Leucovorin has no effect on the pharmacokinetics of capecitabine and its metabolites; however, the toxicity of capecitabine may be enhanced by leucovorin.

Use in Pregnancy:

Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with XELODA (see WARNINGS) and be provided with appropriate counselling if not currently using contraceptives.

Geriatric Use: See WARNING and DOSAGE AND ADMINISTRATION.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

The manifestations of acute overdose include: nausea, vomiting, diarrhea, mucositis, GI irritation and bleeding, and bone marrow depression. Management of overdose should include customary therapeutic and supportive medical interventions aimed at correcting the presenting clinical manifestations and preventing their possible complications.

DOSAGE AND ADMINISTRATION

XELODA tablets should be swallowed with water within 30 minutes after a meal. Monotherapy: The recommended dose of XELODA (capecitabine) is 1250 mg/m2 administered twice daily (morning and evening; equivalent to 2500 mg/m2 total daily dose) for 14 days followed by a seven day rest period. XELODA is intended for long-term administration unless clinically inappropriate. Table 11 displays the total daily dose by body surface area and the number of tablets to be taken at each dose. For adjuvant treatment of stage III colon cancer, XELODA is intended to be given for a total of 8 cycles (or 24 weeks). Breast Cancer, Combination Therapy with Docetaxel: The recommended dosage regimen is as given above for XELODA combined with docetaxel 75 mg/m2 administered as a 1-hour intravenous infusion every 3 weeks (see ACTIONS AND CLINICAL PHARMACOLOGY, CLINICAL STUDIES, Breast Carcinoma). Premedication according to the docetaxel labelling, should be started prior to docetaxel administration for patients receiving the XELODA plus docetaxel combination.

Table 11: Standard and reduced dose calculations according to body surface area for a starting dose of XELODA of 1250 mg/m2

Dose Modification Guidelines

: Patients should be carefully monitored for toxicity. Toxicity due to XELODA administration may be managed by symptomatic treatment, dose interruptions and adjustment of XELODA dose. Once the dose has been reduced it should not be increased at a later time.

For those toxicities considered by the treating physician to be unlikely to become serious or life- threatening, treatment can be continued at the same dose without reduction or interruption. Dose modifications for the use of XELODA monotherapy are shown in Table 12.

Table 12: Recommended Dose Modifications for XELODA Monotherapy

* According to the National Cancer Institute of Canada Clinical Trial Group (NCIC CTG) Common Toxicity

Criteria (Version 1 or the Common Terminology Criteria for Adverse Events (CTCAE) of the Cancer Therapy Evaluation Program, US National Cancer Institute, version 3.0. For Hand-and-Foot Syndrome and hyperbilirubinemia (see PRECAUTIONS)

Dosage modifications are not recommended for grade 1 events. Therapy with XELODA should be interrupted upon the occurrence of a grade 2 or 3 adverse experience. Once the adverse event has resolved or decreased in intensity to grade 1, then XELODA therapy may be restarted at full dose or as adjusted according to Table 12 for XELODA monotherapy. If a grade 4 experience occurs, therapy should be discontinued or interrupted until resolved or decreased to grade 1, and therapy should be restarted at 50% of the original dose. Patients taking XELODA should be informed of the need to interrupt treatment immediately if moderate or severe toxicity occurs. Doses of XELODA omitted for toxicity are not replaced. Dosage modifications for the use of XELODA and docetaxel in combination are shown in Table 13.

Table 13: Recommended Dose Modifications for XELODA (X) Combination Therapy with Docetaxel (T)

National Cancer Institute of Canada Common Toxicity Criteria (NCIC CTC), version 1.0 revised December 1994

Specific dose adjustment in combination with docetaxel

XELODA and/or docetaxel dose modifications should be made according to the general dose modification scheme above, if nothing else is stated regarding specific dose adjustments. For those toxicities considered unlikely to become serious or life-threatening, e.g. alopecia, altered taste, nail changes, treatment can be continued at the same dose without reduction or interruption. At the beginning of a treatment cycle, if either a docetaxel or a XELODA treatment delay is indicated, both docetaxel and XELODA administration should be delayed until the requirements for restarting both drugs are met. If docetaxel has to be discontinued, XELODA treatment can be resumed when the requirements for restarting XELODA are met. Haematology: XELODA treatment may continue throughout a grade 3 neutropenic episode. However, the patient should be closely monitored and administration of XELODA should be interrupted if any grade 2 clinical event (e.g. diarrhea, stomatitis, fever) coincides with the grade 3 neutropenic episode. If grade 4 neutropenia occurs treatment with XELODA should be interrupted until recovery to grade 0-1. Treatment should only be re-administered when the neutrophil count is >= 1.5 x 109/L (Grade 0 - 1). Docetaxel dosage should be reduced from 75 mg/m2 to 55 mg/m2 in patients with neutropenia <0.5 x 109/L (Grade 4) for more than 1 week, or febrile (>38oC) neutropenia. Docetaxel should be discontinued if Grade 4 neutropenia or febrile neutropenia occurs at a dose of 55 mg/m2 docetaxel. Patients with baseline neutrophil counts of <1.5 x 109/L and/or thrombocyte counts of <100 x 109/L should not be treated with the XELODA/docetaxel combination.

Hypersensitivity:

Patients who develop severe hypersensitivity reactions (hypotension with a decrease of >= 20 mm Hg, or bronchospasm, or generalised rash/erythema) should stop treatment immediately and be given appropriate therapy. These patients should not be rechallenged with the drug suspected to have caused hypersensitivity.

Peripheral neuropathy: For 1st appearance of Grade 2 toxicity, reduce the docetaxel dose to 55 mg/m2. If Grade 3 toxicity appears, discontinue docetaxel treatment. In both instances follow the above dose modification scheme for XELODA.

Fluid retention:

Severe (Grade 3 or 4) toxicity such as pleural effusion, pericardial effusion or ascites which is possibly related to docetaxel should be closely monitored. In case of appearance of such toxicity docetaxel treatment should be discontinued, XELODA treatment may be continued without dose modification.

Hepatic impairment:

Docetaxel should generally not be given to patients with serum bilirubin above the upper limit of normal. The following modifications should be applied to the docetaxel dose in the event of abnormal values for ASAT, ALAT, and/or alkaline phosphatase levels:

Table 14: Modifications to the docetaxel dose

Once the docetaxel dose is reduced for a given cycle, no further dose reduction is recommended for subsequent cycles unless worsening of the parameters is observed. In case of recovery of liver function tests after previous reduction of the docetaxel dose, the docetaxel dose can be re- escalated to the previous dose level.

Dehydration:

Dehydration should be prevented or corrected at the onset. Patients with anorexia, asthenia, nausea, vomiting or diarrhea may rapidly become dehydrated. If Grade 2 (or higher) dehydration occurs, XELODA treatment should be immediately interrupted and the dehydration corrected. Treatment should not be restarted until the patient is rehydrated and any precipitating causes have been corrected or controlled. Dose modifications applied should be those for the precipitating adverse event in accordance with the above guidelines.

Adjustment of Starting Dose in Special Populations:

Hepatic Impairment:

In patients with mild to moderate hepatic dysfunction due to liver metastases, no dose adjustment is necessary. However, such patients should be carefully monitored. Patients with severe hepatic dysfunction have not been studied (see WARNINGS).

Renal Impairment: In patients with moderate renal impairment (calculated creatinine clearance 30-50 mL/min [Cockroft and Gault]) at baseline, a dose reduction to 75% from a starting dose of 1250 mg/m2 is recommended based upon pharmacokinetic and safety data (see ACTIONS AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Renal Insufficiency, and WARNINGS). In patients with mild renal impairment (calculated creatinine clearance 51-80 mL/min) no adjustment in starting dose is recommended. In patients with severe renal impairment, XELODA should not be administered (see CONTRAINDICATIONS). Careful monitoring and prompt treatment interruption is recommended if the patient develops a grade 2, 3, or 4 adverse event, with subsequent dose adjustment as outlined in the tables above. If the calculated creatinine clearance decreases during treatment to a value below 30 mL/min, XELODA should be discontinued. The dose adjustment recommendation for patients with moderate renal impairment apply both to monotherapy and combination use. For dosage calculations, see Table 11.

Geriatrics

: No adjustment of the starting dose is needed for XELODA. However for XELODA monotherapy in the metastatic setting, severe Grade 3 or 4 treatment-related adverse events were more frequent in patients over 80 years of age compared to younger patients. Careful monitoring of elderly patients is advisable.

For treatment with XELODA in combination with docetaxel, an increased incidence of Grade 3 or 4 treatment-related adverse events and treatment-related serious adverse events was observed in patients 60 years of age or more.

(r)

Taxotere, Registered Trademark of Sanofi-aventis Inc.

(r)

Maalox, Registered Trademark of Novartis Consumer Health Canada, Inc.

PHARMACEUTICAL INFORMATION

DRUG SUBSTANCE

Proper Name: capecitabine Chemical Name: 5'-Deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine Molecular Formula: C15H22FN3O6 Molecular Weight: 359.35 Structural Formula: Physical Form: white to off-white crystalline powder Solubility: Water 2.6 g/100 mL pKa: 8.8 (in water and titrated with 0.1 N KOH with bubbling N2) Partition co-efficient: octanol/buffer: log P =4.4-0.98 (range for pH 5.0-9.5) Melting Point: 120degC with decomposition

DOSAGE FORM

Composition:

Each XELODA 150 mg and 500 mg tablet contains either 150 mg or 500 mg capecitabine, respectively. Non-medicinal ingredients (alphabetic order): croscarmellose sodium, hydroxy propyl methylcellulose, lactose anhydrous, magnesium stearate, microcrystalline cellulose, talc, titanium dioxide, synthetic yellow iron oxide, synthetic red iron oxide.

Stability and Storage Recommendations:

XELODA tablets should be stored between 15-30oC.

AVAILABILITY

XELODA (capecitabine) is available as a film-coated tablet in strengths of either 150 mg or 500 mg. XELODA 150 mg tablets are available in HDPE bottles containing 60 tablets. XELODA 500 mg tablets are available in HDPE bottles containing 120 tablets.

Appearance:

150 mg tablets: light peach coloured, biconvex, film-coated, oblong shaped tablets with XELODA engraved on one side and 150 on the reverse. 500 mg tablets: peach coloured, biconvex, film-coated, oblong shaped tablets with XELODA engraved on one side and 500 on the reverse.

INFORMATION FOR THE PATIENT

Your doctor has prescribed XELODA (pronounced zeh-LO-da) for you. Reading this information can help you learn about XELODA and how to make this medicine work best for you. If you have any questions after reading this information, speak with your doctor, nurse, or pharmacist.

What is XELODA?

XELODA is a prescription medication that is used to treat certain types of cancer. XELODA belongs to a family of medications called the fluoropyrimidines. These medications interfere with the growth of cells that rapidly divide in the body, including cancer cells. XELODA is available as tablets that are taken by mouth. The tablets are coated and oblong shaped. XELODA tablets come in two strengths: 150 mg tablets are light peach coloured, with XELODA engraved on one side and 150 on the other side. 500 mg tablets that are peach coloured with XELODA engraved on one side and 500 on the other side. All XELODA tablets contain the active ingredient capecitabine. XELODA tablets also contain these non-medicinal ingredients: Croscarmellose sodium Hydroxy propyl methylcellulose Lactose Magnesium stearate Microcrystalline cellulose Talc Titanium dioxide Yellow and red iron oxides

How does XELODA work?

XELODA is an inactive substance on its own. When XELODA is taken, it is changed in the body, mostly within the tumour (cancer cells). It changes to become the commonly used cancer medication called 5-fluorouracil (also known as 5-FU). In some patients 5-FU will kill cancer cells and decrease the size of the tumour.

Who should take XELODA?

Advanced or metastatic cancer XELODA is used to treat advanced or metastatic breast cancer. Metastatic means that the cancer has spread outside the breast. When breast cancer has not responded to other chemotherapy medications, XELODA may be one of the choices considered for treatment. Your doctor may prescribe XELODA either alone or in combination with a chemotherapy drug called Taxotere(r) (also known as docetaxel). XELODA is also used to treat metastatic colorectal cancer that has spread outside of the colon and/or rectum. Adjuvant therapy, stage III colon cancer XELODA is used to treat cancer of the colon following complete surgical removal. The intent of treatment with XELODA is to prevent or delay the recurrence of cancer (cure).

What should you tell your doctor before you start taking XELODA?

Before beginning treatment with XELODA, make sure your doctor knows if: you ever had a bad reaction to capecitabine, 5-fluorouracil or any of the non-medicinal ingredients. you are allergic to other medications, food and dyes. you are taking any other medications, including those not prescribed by your doctor. tell your doctor if you are taking warfarin (Coumadin(r)). Your doctor may need to check the clotting time of your blood more often. tell your doctor if you are taking phenytoin (Dilantin(r)) or fosphenytoin (Cerebyx(r)). Your doctor may need to check the levels of phenytoin in your blood more often. you have any other illnesses or diseases affecting your kidneys, liver or heart. you are pregnant, plan to become pregnant or are breastfeeding. This information will help your doctor and you decide whether you should use XELODA and what extra care may need to be taken while you are on the medication.

How should XELODA be taken?

Your doctor prescribed XELODA after carefully studying your condition. Other people may not benefit from taking this medicine, even though their problems may seem similar to yours. Do not give your XELODA to anyone else. The usual dose of XELODA depends on your body surface size. Your doctor will calculate the dose for you. You may need to take a combination of 150 mg and 500 mg tablets. To get the right dose it

is very important that you identify the tablets correctly each time you take XELODA.

Taking the wrong tablets could result in an overdose (too much medication) or underdose (too little medication). Swallow the XELODA tablets whole, with water. Take the tablets within 30 minutes after the end of a meal (breakfast and dinner). Take the tablets twice a day (morning and evening doses) as your doctor prescribed. Do not take more than your prescribed dose, do not take it more often or for a longer time than your doctor ordered. XELODA is taken in 21 day cycles. This means you take XELODA for 14 days and then stop taking it for 7 days. It is important to have this rest period. Your doctor will decide how many cycles of treatment you will need. For the treatment of colon cancer following complete surgical removal, XELODA is usually taken for eight 21-day cycles (i.e. for a total of 24 weeks or ~6 months).

What should you do if you forget a dose of XELODA?

If you forget a dose of XELODA do not take the missed dose at all. Take your next dose at the usual time and check with your doctor. Do not take a double dose.

What should you do in case of an overdose or XELODA is taken accidentally?

Call your doctor or the Poison Control Centre immediately if you think you have taken an overdose or someone has accidentally taken your XELODA. If you are not able to contact them, go to the nearest hospital emergency department for medical help.

What else should you remember while you are taking XELODA?

Practice contraception: If you are of childbearing age you should avoid becoming pregnant while taking XELODA. No research studies have been done with pregnant women. However, studies with animals suggest that XELODA may cause serious harm to an unborn child. Practice contraception: If you are a male, you are advised not to father a child during treatment. You should stop breastfeeding if you start treatment with XELODA. If you are over 65 years old or have a history of heart disease, you may be more sensitive to XELODA. Watch more carefully for possible unwanted effects. If you are over 80 years old, your stomach may be more sensitive to XELODA. Watch more carefully for possible unwanted effects.

What are the possible unwanted effects of XELODA?

Unwanted effects are possible with all medicines. Tell your doctor, nurse or pharmacist as soon as possible if you do not feel well while you are taking XELODA. The most common unwanted effects are: diarrhea nausea vomiting sores in the mouth and throat (called stomatitis) tiredness or fatigue tingling, numbness, pain, swelling, redness or blisters of the palms of the hands or feet (called hand-and-foot syndrome) Less common unwanted effects are: reduced white blood cells, red blood cells and platelets in the blood increased chance of infection increased chance of unusual bleeding

What possible unwanted effects require immediate medical attention?

Stop taking XELODA and call your doctor immediately if you notice any of the following side effects. Your doctor can then adjust XELODA to a dose that is right for you. This should help to reduce the side effects and stop them from getting worse. Diarrhea

• an additional 4 bowel movements a day beyond what is normal or any diarrhea at night

• if you have a colostomy, an increase in loose, watery fluid in your colostomy bag

• any diarrhea in conjunction with soreness of the mouth affecting your ability to drink enough fluids

Vomiting:

• vomiting more than once in 24 hours, especially if in association with diarrhea

Nausea:

• loss of appetite or eating less food than usual each day

Stomatitis:

• painful sores, redness or swelling in the mouth or throat

Hand-and-foot Syndrome:

• pain, redness, swelling, ulcers or blisters on the hands and feet

Infection:

• fever; a temperature of 38.0degC or higher

• signs of infection such as sore throat, cough, or pain when you pass urine

Heart problems: chest pains, abnormal heart rate, edema of extremities Your doctor may tell you to decrease the dose or stop XELODA treatment for a while. If caught early, most of these side effects usually improve after you stop taking XELODA. If they do not improve within 2 to 3 days, call your doctor again. After side effects have improved, your doctor will tell you whether to start taking XELODA again and what is the right dose for you. These unwanted effects may differ when taking XELODA in combination with Taxotere(r) (docetaxel). For example, in addition to the unwanted effects mentioned above which may occur with XELODA alone, the following unwanted effects may occur when XELODA is taken in combination with Taxotere(r): hair loss, weakness, fluid retention, nail changes and peripheral neuropathy (numbness, tingling, and burning of the hands and feet), constipation, abdominal pain, indigestion, dry mouth, rash, weakness, pain, taste disturbance, headache, dizziness, inability to sleep, loss or decreased appetite, dehydration, back pain. Please consult your doctor for more information on the possible unwanted effects that may occur when taking XELODA in combination with Taxotere(r) (docetaxel). If you are concerned about these or any other unexpected effects while taking XELODA, talk with your doctor, nurse or pharmacist.

How should XELODA be stored?

Keep out of reach of children. Store at room temperature (15 to 30degC), in the original labelled container. Store away from heat and direct light. This leaflet does not provide all known information about XELODA. If you have any questions or concerns about your treatment, please speak with your doctor, nurse or pharmacist.

(r)

Taxotere, Registered Trademark of Sanofi-aventis Inc

(r)

Coumadin, Registered Trademark of Bristol Myers Squibb Company.

(r)

Dilantin and Cerebyx are Registered Trademarks of Pfizer Inc.

Animal Pharmacology:

PHARMACOLOGY

Capecitabine administration of doses up to 300 mg/kg (p.o.) in mice and rats and up to 30 mg/kg (i.v.) in anesthetized dogs, produced no biologically significant pharmacodynamic effects on the mammalian nervous, cardiovascular, respiratory, and gastrointestinal systems. At the highest doses [1,000 mg/kg (p.o.) in mice and rats and 100 mg/kg (i.v.) in dogs], capecitabine caused minimal changes in some of the above parameters. In anaesthetized cynomolgus monkeys, capecitabine infused i.v. at 10 and 30 mg/kg did not affect the parameters relating to cardiovascular and respiratory function. At 100 mg/kg (i.v. ), it caused slight and transient hypotension and suppressed cardiac function. These effects were not considered critical.

Metabolic Conversion of Capecitabine in Animals:

The cynomolgus monkey is the most predictive model of the toxicity that may occur in humans as the activity and distribution of the metabolizing enzymes carboxylesterase and cytidine deaminase are similar in this species to those seen in humans. In the mouse, as in humans and monkeys, conversion of the parent drug occurs via 5'-DFCR to 5'-DFUR. However, the efficiency of this conversion is less than that of the monkey. In contrast to monkey and mouse, the rat has minimal cytidine deaminase activity in major organs. Therefore, in the latter species, capecitabine is metabolized to 5'-DFCR; however, its subsequent conversion to 5'-DFUR is poor. The low activity of cytidine deaminase in the rat, which results in high plasma levels of 5'-DFCR relative to monkey and man, allowed the toxicity of 5'-DFCR to be investigated. For these reasons, the teratology and reproductive toxicity studies were conducted in the mouse and the monkey.

Mechanism of Action:

5-FU is further metabolized to 5-fluoro-2'-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP) and causes cell injury by two primary mechanisms. First, FdUMP binds covalently to thymidylate synthase (TS) and prevents formation of thymidylate, the precursor of thymidine triphosphate that is required for DNA synthesis, thereby inhibiting cell proliferation. The second mechanism results from the incorporation of FUTP into RNA in place of UTP, thereby preventing the correct nuclear processing of ribosomal RNA and messenger RNA. These effects are most marked on rapidly proliferating cells, such as tumour cells, which utilize 5-FU at a higher rate.

Clinical Pharmacokinetics:

Absorption:

The gastrointestinal absorption of capecitabine and its metabolites (5'-DFCR, 5'- DFUR and 5-FU) was rapid (median 2 hours; range 0.5 to 5 hours). Capecitabine is extensively absorbed since at least 70% of the dose was recovered in urine with low variability (CV of 30%).

Distribution: Binding of 14C-capecitabine, 14C-5'-DFCR and 3H-5'-DFUR to human plasma proteins were determined in vitro by ultrafiltration. The concentration ranges used (0.2/0.5 to 200/500 ugmL) encompassed the concentrations observed in plasma species in vivo. Plasma protein binding of capecitabine is low (54%, 10% and 60% for capecitabine, 5'-DFCR and 5'- DFUR, respectively) and is not concentration-dependent. Capecitabine was primarily bound to human albumin (approximately 35%).

Excretion:

In three studies, concentrations of capecitabine and its metabolites (5'-DFCR, 5'- DFUR, 5-FU, FUH2, FUPA and FBAL) were measured in urine. Over 70% of the capecitabine dose was recovered in urine as drug-related material. The majority of the dose was recovered as FBAL (approximately 50%).

Pharmacokinetic Parameters: Table 15 shows the pharmacokinetic parameters of capecitabine, 5'-DFCR, 5'-DFUR and 5-FU in plasma at steady-state (day 14) following administration of the recommended dose (1255 mg/m2 b.i.d.) in 8 cancer patients. The peak of plasma concentrations of intact drug, 5'-DFCR, 5'-DFUR and 5-FU is reached rapidly and then concentrations decline with a short half-life for all species.

Table 15: Descriptive Statistics on the Pharmacokinetic Parameters Estimated on Day 14 after Administration of Capecitabine (1255 mg/m2) in 8 Cancer Patients

Geometric means (CV) are reported for Cmax, AUC0-t and AUC0-[?] . Median values (min-max) are reported for tmax. Arithmetic means (CV) are reported for t1/2. After oral administration, plasma data indicate an extensive and rapid conversion to the first two metabolites in plasma, 5'-DFCR and 5'-DFUR. The peak plasma concentrations for the drug and its two first metabolites occurs shortly (median tmax of 1.50 to 2.0 h) after capecitabine administration. Concentrations then decline exponentially with half-lives of 0.85 h (arithmetic mean), 1.11 h and 0.66 h for intact drug, 5'-DFCR and 5'-DFUR, respectively. Following administration of 1255 mg/m2, a high AUC0- [?] is obtained for 5'-DFUR (geometric mean = 21.7

mg *h/mL, CV = 63%, n = 8). On day 14, the systemic exposure (AUC) to 5-FU is approximately 13 times lower than the systemic exposure to 5'-DFUR. In plasma, the peak of FBAL concentration occurred approximately 3 h after drug intake. The decline in FBAL concentration is characterized by a half-life of 3.23 +- 1.29 h. Plasma concentrations of FBAL are high (1.6 times those of 5'-DFUR and 22 times those of 5-FU), which probably reflects the extensive formation of 5-FU in the tumour and other tissues.

TOXICOLOGY

The tables presented on the following pages provide the findings of the main toxicology, mutagenicity/genotoxicity and reproduction/teratology studies performed with capecitabine:

Acute Toxicity

:

500 mg/kg (day 1), 1000 mg/kg (day 4), 2000 mg/kg (day 7)

Subchronic and Chronic (Long-Term) Toxicology Studies:

1. 10 for 13 week dosing, 5 for recovery.

2. The high dose was changed from 791 mg/kg/day to 593 mg/kg/day on day 37.

Days 0-31:215 mg/kg/day; days 32-34: cessation of administration; days 35-90: 162 mg/kg/day

Carcinogenicity Study:

Mutagenicity and Genotoxicity Studies:

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