XELODA(r)

(capecitabine)

TABLETS

WARNING

XELODA Warfarin Interaction: Patients receiving concomitant capecitabine and oral coumarin- derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly. A clinically important XELODA-Warfarin drug interaction was demonstrated in a clinical pharmacology trial(see CLINICAL PHARMACOLOGY AND PRECAUTIONS). Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking XELODA concomitantly with coumarin- derivative anticoagulants such as warfarin and phenprocoumon. Post-marketing reports have shown clinically significant increases in prothrombin time (PT) and INR in patients who were stabilized on anticoagulants at the time XELODA was introduced. 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. Age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy.

DESCRIPTION

XELODA (capecitabine) is a fluoropyrimidine carbamate with antineoplastic activity. It is an orally administered systemic prodrug of 5'-deoxy-5-fluorouridine (5'-DFUR) which is converted to 5- fluorouracil. The chemical name for capecitabine is 5'-deoxy-5-fluoro-N-[(pentyloxy) carbonyl]-cytidine and has a molecular weight of 359.35. Capecitabine has the following structural formula:

O N NH O

H3C O N O F

HO OH

Capecitabine is a white to off-white crystalline powder with an aqueous solubility of 26 mg/mL at 20oC. XELODA is supplied as biconvex, oblong film-coated tablets for oral administration. Each light peach- colored tablet contains 150 mg capecitabine and each peach-colored tablet contains 500 mg

C:\Data\My Documents\NDAs\20896\SE7_010_Phase4\Xeloda_Taxotere PI 090701_clean.doc 1

XELODA(r) (capecitabine)

capecitabine. The inactive ingredients in XELODA include: anhydrous lactose, croscarmellose sodium, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium stearate and purified water. The peach or light peach film coating contains hydroxypropyl methylcellulose, talc, titanium dioxide, and synthetic yellow and red iron oxides.

CLINICAL PHARMACOLOGY

XELODA is relatively non-cytotoxic in vitro. This drug is enzymatically converted to 5-fluorouracil (5- FU) in vivo.

Bioactivation:

Capecitabine is readily absorbed from the gastrointestinal tract. In the liver, a 60 kDa

carboxylesterase hydrolyzes much of the compound to 5'-deoxy-5-fluorocytidine (5'-DFCR). Cytidine deaminase, an enzyme found in most tissues, including tumors, subsequently converts 5'-DFCR to 5'- deoxy-5-fluorouridine (5'-DFUR). The enzyme, thymidine phosphorylase (dThdPase), then hydrolyzes 5'-DFUR to the active drug 5-FU. Many tissues throughout the body express thymidine phosphorylase. Some human carcinomas express this enzyme in higher concentrations than surrounding normal tissues.

Metabolic Pathway of capecitabine to 5-FU

NH-CO-O N F

O

N O

NH2

N

F

O N O

Carboxylesterase

HO OH HO OH

5'-DFCR

H3C O

Cyd deaminase

O HN F

dThdPase O

N H

5'-DFUR

5-FU

Mechanism of Action:

Both normal and tumor cells metabolize 5-FU 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, N5-10- methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a covalently bound ternary

XELODA(r) (capecitabine)

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.

Pharmacokinetics in Colorectal Tumors and Adjacent Healthy Tissue:

Following oral

administration of XELODA 7 days before surgery in patients with colorectal cancer, the median ratio of 5-FU concentration in colorectal tumors to adjacent tissues was 2.9 (range from 0.9 to 8.0). These ratios have not been evaluated in breast cancer patients or compared to 5-FU infusion.

Human Pharmacokinetics:

The pharmacokinetics of XELODA and its metabolites have been

evaluated in about 200 cancer patients over a dosage range of 500 to 3500 mg/m2/day. Over this range, the pharmacokinetics of XELODA and its metabolite, 5'-DFCR were dose proportional and did not change over time. The increases in the AUCs of 5'-DFUR and 5-FU, however, were greater than proportional to the increase in dose and the AUC of 5-FU was 34% higher on day 14 than on day 1. The elimination half-life of both parent capecitabine and 5-FU was about 3/4 of an hour. The inter-patient variability in the Cmax and AUC of 5-FU was greater than 85%.

Absorption, Distribution, Metabolism and Excretion:

Capecitabine reached peak blood levels in

about 1.5 hours (Tmax) with peak 5-FU levels occurring slightly later, at 2 hours. Food reduced both the rate and extent of absorption of capecitabine with mean Cmax and AUC0-Y= decreased by 60% and 35%, respectively. The Cmax and AUC0-Y= of 5-FU were also reduced by food by 43% and 21%, respectively. Food delayed Tmax of both parent and 5-FU by 1.5 hours (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). 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%). Capecitabine is extensively metabolized enzymatically 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. Capecitabine and its metabolites are predominantly excreted in urine; 95.5% of administered capecitabine dose is recovered in urine. Fecal excretion is minimal (2.6%). The major metabolite excreted in urine is FBAL which represents 57% of the administered dose. About 3% of the administered dose is excreted in urine as unchanged drug. A clinical phase I study evaluating the effect of XELODA on the pharmacokinetics of docetaxel (Taxotere(r)) and the effect of docetaxel on the pharmacokinetics of XELODA was conducted in 26 patients with solid tumors. XELODA was found to have no effect on the pharmacokinetics of docetaxel

XELODA(r) (capecitabine)

(Cmax and AUC) and docetaxel has no effect on the pharmacokinetics of capecitabine and the 5-FU precursor 5'-DFUR.

Special Populations:

A population analysis of pooled data from the two large controlled studies in patients with colorectal cancer (n=505) who were administered XELODA at 1250 mg/m2 twice a day indicated that gender (202 females and 303 males) and race (455 white/caucasian patients, 22 black patients, and 28 patients of other race) have no influence on the pharmacokinetics of 5'- DFUR, 5-FU and FBAL. Age has no significant influence on the pharmacokinetics of 5'-DFUR and 5-FU over the range of 27 to 86 years. A 20% increase in age results in a 15% increase in AUC of FBAL (see WARNINGS and DOSAGE AND ADMINISTRATION).

Hepatic Insufficiency:

XELODA has been evaluated in 13 patients with mild to moderate hepatic

dysfunction due to liver metastases defined by a composite score including bilirubin, AST/ALT and alkaline phosphatase following a single 1255 mg/m2 dose of XELODA. Both AUC0-Y= and Cmax of capecitabine increased by 60% in patients with hepatic dysfunction compared to patients with normal hepatic function (n=14). The AUC0-Y= and Cmax of 5-FU was not affected. In patients with mild to moderate hepatic dysfunction due to liver metastases, caution should be exercised when XELODA is administered. The effect of severe hepatic dysfunction on XELODA is not known (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Renal Insufficiency: Following oral administration of 1250 mg/m2 capecitabine twice a day to cancer patients with varying degrees of renal impairment, patients with moderate (creatinine clearance = 30-50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment showed 85% and 258% higher systemic exposure to FBAL on day 1 compared to normal renal function patients (creatinine clearance >80 mL/min). Systemic exposure to 5'-DFUR was 42% and 71% greater in moderately and severely renal impaired patients, respectively, than in normal patients. Systemic exposure to capecitabine was about 25% greater in both moderately and severely renal impaired patients (see CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION).

Drug-Drug Interactions:

Anticoagulants: In four patients with cancer, chronic administration of capecitabine (1250 mg/ m2 bid) with a single 20 mg dose of warfarin increased the mean AUC of S-warfarin by 57% and decreased its clearance by 37%. Baseline corrected AUC of INR in these 4 patients increased by 2.8 fold, and the maximum observed mean INR value was increased by 91% (see Box WARNINGS and PRECAUTIONS: Drug-Drug Interactions).

XELODA(r) (capecitabine)

Drugs Metabolized by Cytochrome P450 Enzymes:

In vitro enzymatic studies with human liver microsomes indicated that capecitabine and its metabolites (5'-DFUR, 5'-DFCR, 5-FU, and FBAL) had no inhibitory effects on substrates of cytochrome P450 for the major isoenzymes such as 1A2, 2A6, 3A4, 2C9, 2C19, 2D6, and 2E1.

Antacid: When Maalox(r) (20 mL), an aluminum hydroxide- and magnesium hydroxide- containing antacid, was administered immediately after XELODA (1250 mg/m2, n=12 cancer patients), AUC and Cmax increased by 16% and 35%, respectively, for capecitabine and by 18% and 22%, respectively, for 5'-DFCR. No effect was observed on the other three major metabolites (5'-DFUR, 5-FU, FBAL) of XELODA. XELODA has a low potential for pharmacokinetic interactions related to plasma protein binding.

CLINICAL STUDIES

Colorectal Carcinoma: The recommended dose of XELODA was determined in a open-label, randomized clinical study, exploring the efficacy and safety of continuous therapy with capecitabine (1331 mg/m2/day in two divided doses, n=39), intermittent therapy with capecitabine (2510 mg/m2/day in two divided doses, n=34), and intermittent therapy with capecitabine in combination with oral leucovorin (LV) (capecitabine 1657 mg/m2/day in two divided doses, n=35; leucovorin 60 mg/day) in patients with advanced and/or metastatic colorectal carcinoma in the first-line metastatic setting. There was no apparent advantage in response rate to adding leucovorin to XELODA; however, toxicity was increased. XELODA, 1250 mg/m2 twice daily for 14 days followed by a 1-week rest, was selected for further clinical development based on the overall safety and efficacy profile of the three schedules studied. Data from 2 open-label, multicenter, randomized, controlled clinical trials involving 1207 patients support the use of XELODA in the first-line treatment of patients with metastatic colorectal carcinoma. The two clinical studies were identical in design and were conducted in 120 centers in different countries. Study 1 was conducted in the US, Canada, Mexico, and Brazil; Study 2 was conducted in Europe, Israel, Australia, New Zealand, and Taiwan. Altogether, in both trials, 603 patients were randomized to treatment with XELODA at a dose of 1250 mg/m2 twice daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles; 604 patients were randomized to treatment with 5-FU and leucovorin (20 mg/m2 leucovorin IV followed by 425 mg/m2 IV bolus 5-FU, on days 1 to 5, every 28 days). In both trials, overall survival, time to progression and response rate (complete plus partial responses) were assessed. Responses were defined by the World Health Organization criteria and submitted to a blinded independent review committee (IRC). Differences in assessments between the investigator and IRC were reconciled by the sponsor, blinded to treatment arm, according to a specified algorithm. Survival was assessed based on a non-inferiority analysis. The baseline demographics for XELODA and 5-FU/LV patients are shown in Table 1.

XELODA(r) (capecitabine)

Table 1. Baseline Demographics of Controlled Colorectal Trials

XELODA(r) (capecitabine)

The efficacy endpoints for the two phase 3 trials are shown in Tables 2 and 3.

Table 2. Efficacy of XELODA vs. 5-FU/LV in Colorectal Cancer (Study 1)

Table 3. Efficacy of XELODA vs. 5-FU/LV in Colorectal Cancer (Study 2)

XELODA(r) (capecitabine)

Figure 1. Kaplan-Meier Curve for Overall Survival of Pooled Data (Studies 1 and 2)

XELODA was superior to 5-FU/LV for objective response rate in Study 1 and Study 2. The similarity of XELODA and 5-FU/LV in these studies was assessed by examining the potential difference between the two treatments. In order to assure that XELODA has a clinically meaningful survival effect, statistical analyses were performed to determine the percent of the survival effect of 5-FU/LV that was retained by XELODA. The estimate of the survival effect of 5-FU/LV was derived from a meta-analysis of ten randomized studies from the published literature comparing 5-FU to regimens of 5-FU/LV that were similar to the control arms used in these Studies 1 and 2. The method for comparing the treatments was to examine the worst case (95% confidence upper bound) for the difference between 5-FU/LV and XELODA, and to show that loss of more than 50% of the 5-FU/LV survival effect was ruled out. It was demonstrated that the percent of the survival effect of 5-FU/LV maintained was at least 61% for Study 2 and 10% for Study 1. The pooled result is consistent with a retention of at least 50% of the effect of 5-FU/LV. It should be noted that these values for preserved effect are based on the upper bound of the 5-FU/LV vs. XELODA difference. These results do not exclude the possibility of true equivalence of XELODA to 5-FU/LV (see Tables 2 and 3 and Kaplan-Meier Figure 1). Breast Carcinoma: XELODA has been evaluated in clinical trials in combination with docetaxel (Taxotere(r)) and as monotherapy.

Breast Cancer Combination Therapy:

The dose of XELODA used in phase 3 clinical trial in combination with docetaxel was based on the results of a phase I study, where a range of doses of docetaxel administered in 3 week cycles in combination with an intermittent regimen of XELODA (14

XELODA(r) (capecitabine)

days of treatment, followed by a 7 day rest period) were evaluated. The combination dose regimen was selected based on the tolerability profile of the 75 mg/m2 administered in 3 week cycles of docetaxel in combination with 1250 mg/m2 twice daily for 14 days of XELODA administered in 3 week cycles. The approved dose of 100 mg/m2 of docetaxel administered in 3 week cycles was the control arm of the phase 3 study. XELODA in combination with docetaxel was assessed in an open-label, multicenter, randomized trial in 75 centers in Europe, North America, South America, Asia, and Australia. A total of 511 patients with metastatic breast cancer resistant to, or recurring during or after an anthracycline-containing therapy, or relapsing during or recurring within two years of completing an anthracycline-containing adjuvant therapy were enrolled. Two hundred and fifty-five (255) patients were randomized to receive XELODA 1250 mg/m2 twice daily for 14 days followed by one week without treatment and docetaxel 75 mg/m2 as a 1 hour intravenous infusion administered in 3 week cycles. In the monotherapy arm, 256 patients received docetaxel 100 mg/m2 as a 1 hour intravenous infusion administered in 3 week cycles. Patient demographics are provided in Table 4.

XELODA(r) (capecitabine)

Table 4. Baseline Demographics and Clinical Characteristics XELODA and Docetaxel Combination vs. Docetaxel in Breast Cancer Trial

Includes 10 patients in combination and 18 patients in monotherapy arms treated with an

anthracenedione

XELODA(r) (capecitabine)

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 as shown in Table 5 and Figures 2 and 3.

Table 5. Efficacy of XELODA and Docetaxel Combination vs. Docetaxel Monotherapy

1. The response rate reported represents a reconciliation of the investigator and IRC assessments

performed by the sponsor according to a predefined algorithm. NA = Not Applicable

XELODA(r) (capecitabine)

Figure 2. Kaplan-Meier Estimates for Time to Disease Progression XELODA and Docetaxel vs. Docetaxel

Figure 3. Kaplan-Meier Estimates of Survival XELODA and Docetaxel vs. Docetaxel

XELODA(r) (capecitabine)

Breast Cancer Monotherapy: The antitumor activity of XELODA as a monotherapy was evaluated in an open-label single-arm trial conducted in 24 centers in the US and Canada. A total of 162 patients with stage IV breast cancer were enrolled. The primary endpoint was tumor response rate in patients with measurable disease, with response defined as a 350% decrease in sum of the products of the perpendicular diameters of bidimensionally measurable disease for at least 1 month. XELODA was administered at a dose of 1255 mg/m2 twice daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles. The baseline demographics and clinical characteristics for all patients (n=162) and those with measurable disease (n=135) are shown in Table 6. Resistance was defined as progressive disease while on treatment, with or without an initial response, or relapse within 6 months of completing treatment with an anthracycline-containing adjuvant chemotherapy regimen.

Table 6. Baseline Demographics and Clinical Characteristics Single Arm Breast Cancer Trial

Lung, pleura, liver, peritoneum

Includes 2 patients treated with an anthracenedione

XELODA(r) (capecitabine)

Antitumor responses for patients with disease resistant to both paclitaxel and an anthracycline are shown in Table 7.

Table 7. Response Rates in Doubly-Resistant Patients Single Arm Breast Cancer Trial

Includes 2 patients treated with an anthracenedione

From date of first response

For the subgroup of 43 patients who were doubly resistant, the median time to progression was 102 days and the median survival was 255 days. The objective response rate in this population was supported by a response rate of 18.5% (1 CR, 24 PRs) in the overall population of 135 patients with measurable disease, who were less resistant to chemotherapy (see Table 6). The median time to progression was 90 days and the median survival was 306 days.

CONTRAINDICATIONS

XELODA is contraindicated in patients who have a known hypersensitivity to 5-fluorouracil. XELODA is also contraindicated in patients with severe renal impairment (creatinine clearance below 30 mL/min [Cockroft and Gault]) (see CLINICAL PHARMACOLOGY: Special Populations).

WARNINGS

Renal Insufficiency:

Patients with moderate renal impairment at baseline require dose reduction (see DOSAGE AND ADMINISTRATION). Patients with mild and moderate renal impairment at baseline should be carefully monitored for adverse events. Prompt interruption of therapy with subsequent dose adjustments is recommended if a patient develops a grade 2 to 4 adverse event as outlined in Table 14 in DOSAGE AND ADMINISTRATION.

Coagulopathy:

See box warning.

Diarrhea: XELODA can induce diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. In the overall clinical trial safety database of XELODA monotherapy (N=875), the median time to first occurrence of grade 2 to 4 diarrhea was 34 days (range from 1 to 369 days). The median duration of grade 3 to 4 diarrhea was 5 days. National Cancer Institute of Canada (NCIC) 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, and grade 4 diarrhea as an increase of 310 stools/day or grossly bloody diarrhea or the need for parenteral support. If grade 2, 3 or 4 diarrhea occurs, administration of XELODA should be immediately interrupted until the diarrhea resolves or decreases in intensity to grade 1. Following a reoccurrence of grade 2 diarrhea or occurrence of any grade 3 or 4 diarrhea, subsequent doses of XELODA should be decreased (see DOSAGE AND ADMINISTRATION). Standard antidiarrheal treatments (eg, loperamide) are recommended. Necrotizing enterocolitis (typhlitis) has been reported. Geriatric Patients: Patients 380 years old may experience a greater incidence of grade 3 or 4 adverse events (see PRECAUTIONS: Geriatric Use). In the overall clinical trial safety database of XELODA monotherapy (N=875), 62% of the 21 patients 380 years of age treated with XELODA experienced a treatment-related grade 3 or 4 adverse event: diarrhea in 6 (28.6%), nausea in 3 (14.3%), hand-and-foot syndrome in 3 (14.3%), and vomiting in 2 (9.5%) patients. Among the 10 patients 70 years of age and greater (no patients were >80 years of age) treated with XELODA in combination with docetaxel, 30% ( 3 out of 10) of patients experienced grade 3 or 4 diarrhea and stomatitis, and 40% (4 out of 10) experienced grade 3 hand-and-foot syndrome.

XELODA(r) (capecitabine)

Among the 67 patients 360 years of age receiving XELODA in combination with docetaxel, the incidence of grade 3 or 4 treatment-related adverse events, treatment-related serious adverse events, withdrawals due to adverse events, treatment discontinuations due to adverse events and treatment discontinuations within the first two treatment cycles was higher then in the <60 years of age patient group.

Pregnancy:

XELODA may cause fetal harm when given to a pregnant woman. Capecitabine at doses of 198 mg/kg/day during organogenesis caused malformations and embryo death in mice. In separate pharmacokinetic studies, this dose in mice produced 5'-DFUR AUC values about 0.2 times the corresponding values in patients administered the recommended daily dose. Malformations in mice included cleft palate, anophthalmia, microphthalmia, oligodactyly, polydactyly, syndactyly, kinky tail and dilation of cerebral ventricles. At doses of 90 mg/kg/day, capecitabine given to pregnant monkeys during organogenesis caused fetal death. This dose produced 5'-DFUR AUC values about 0.6 times the corresponding values in patients administered the recommended daily dose. 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.

PRECAUTIONS

General:

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

Combination With Other Drugs:

Use of XELODA in combination with irinotecan has not been adequately studied.

Hand-and-Foot Syndrome:

Hand-and-foot syndrome (palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema) is a cutaneous toxicity (median time to onset of 79 days, range from 11 to 360 days) with a severity range of grades 1 to 3. Grade 1 is characterized by any of the following: numbness, dysesthesia/paresthesia, tingling, painless swelling 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 and/or discomfort affecting the patient's activities of daily living. Grade 3 hand-and-foot syndrome is defined as moist desquamation, ulceration, blistering or severe pain of the hands and/or feet and/or severe discomfort that causes the patient to be unable to work or perform activities of daily living. 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).

XELODA(r) (capecitabine)

Cardiotoxicity:

The cardiotoxicity observed with XELODA includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy. These adverse events may be more common in patients with a prior history of coronary artery disease.

Hepatic Insufficiency:

Patients with mild to moderate hepatic dysfunction due to liver metastases should be carefully monitored when XELODA is administered. The effect of severe hepatic dysfunction on the disposition of XELODA is not known (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Hyperbilirubinemia: In the overall clinical trial safety database of XELODA monotherapy (N=875), grade 3 (1.5-3 x ULN) hyperbilirubinemia occurred in 15.2% (n=133) and grade 4 (>3 x ULN) hyperbilirubinemia occurred in 3.9% (n=34) of 875 patients with either metastatic breast or colorectal cancer who received at least one dose of XELODA 1250 mg/m2 twice daily as monotherapy for 2 weeks followed by a 1-week rest period. Of 566 patients who had hepatic metastases at baseline and 309 patients without hepatic metastases at baseline, grade 3 or 4 hyperbilirubinemia occurred in 22.8% and 12.3%, respectively. Of the 167 patients with grade 3 or 4 hyperbilirubinemia, 18.6% (n=31) also had postbaseline elevations (grades 1 to 4, without elevations at baseline) in alkaline phosphatase and 27.5% (n=46) had postbaseline elevations in transaminases at any time (not necessarily concurrent). The majority of these patients, 64.5% (n=20) and 71.7% (n=33), had liver metastases at baseline. In addition, 57.5% (n=96) and 35.3% (n=59) of the 167 patients had elevations (grades 1 to 4) at both pre baseline and post baseline in alkaline phosphatase or transaminases, respectively. Only 7.8% (n=13) and 3.0% (n=5) had grade 3 or 4 elevations in alkaline phosphatase or transaminases. In the 596 patients treated with XELODA as first-line therapy for metastatic colorectal cancer, the incidence of grade 3 or 4 hyperbilirubinemia was similar to the overall clinical trial safety database of XELODA monotherapy. The median time to onset for grade 3 or 4 hyperbilirubinemia in the colorectal cancer population was 64 days and median total bilirubin increased from 8 mm/L at baseline to 13 mm/L during treatment with XELODA. Of the 136 colorectal cancer patients with grade 3 or 4 hyperbilirubinemia, 49 patients had grade 3 or 4 hyperbilirubinemia as their last measured value, of which 46 had liver metastases at baseline. In 251 patients with metastatic breast cancer who received a combination of XELODA and docetaxel, grade 3 (1.5-3 x ULN) hyperbilirubinemia occurred in 7% (n=17) and grade 4 (>3 x ULN) hyperbilirubinemia occurred in 2% (n=5). If drug related grade 2 to 4 elevations in bilirubin occur, administration of XELODA should be immediately interrupted until the hyperbilirubinemia resolves or decreases in intensity to grade 1. NCIC grade 2 hyperbilirubinemia is defined as 1.5 x normal, grade 3 hyperbilirubinemia as 1.5-3 x normal and grade 4 hyperbilirubinemia as >3 x normal. (See recommended dose modifications under DOSAGE AND ADMINISTRATION.)

XELODA(r) (capecitabine)

Hematologic: In 875 patients with either metastatic breast or colorectal cancer who received a dose of 1250 mg/m2 administered twice daily as monotherapy for 2 weeks followed by a 1-week rest period, 3.2%, 1.7%, and 2.4% of patients had grade 3 or 4 neutropenia, thrombocytopenia or decreases in hemoglobin, respectively. In 251 patients with metastatic breast cancer who received a dose of 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.

Carcinogenesis, Mutagenesis and Impairment of Fertility:

Adequate studies investigating the carcinogenic potential of XELODA 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.

Impairment of Fertility:

In studies of fertility and general reproductive performance in mice, oral capecitabine doses of 760 mg/kg/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.

Information for Patients (see Patient Package Insert):

Patients and patients' caregivers should be informed of the expected adverse effects of XELODA, particularly nausea, vomiting, diarrhea, and hand-and-foot syndrome, and should be made aware that patient-specific dose adaptations during therapy are expected and necessary (see DOSAGE AND ADMINISTRATION). Patients should be encouraged to recognize the common grade 2 toxicities associated with XELODA treatment.

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 treatments (eg, loperamide) are recommended.

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. Initiation of symptomatic treatment is recommended.

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. Initiation of symptomatic treatment is recommended.

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.

XELODA(r) (capecitabine)

Stomatitis:

Patients experiencing grade 2 stomatitis (painful erythema, edema or ulcers of the mouth or tongue, but able to eat) or greater should be instructed to stop taking XELODA immediately. Initiation of symptomatic treatment is recommended (see DOSAGE AND ADMINISTRATION).

Fever and Neutropenia:

Patients who develop a fever of 100.5degF or greater or other evidence of potential infection should be instructed to call their physician.

Drug-Food Interaction:

In all clinical trials, patients were instructed to administer XELODA within 30 minutes after a meal. Since current safety and efficacy data are based upon administration with food, it is recommended that XELODA be administered with food (see DOSAGE AND ADMINISTRATION).

Drug-Drug Interactions:

Antacid:

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

Anticoagulants: Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored closely with great frequency and the anticoagulant dose should be adjusted accordingly (see BOX WARNINGS and CLINICAL PHARMACOLOGY). 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. 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 of S-warfarin. The maximum observed INR value increased by 91%. This interaction is probably due to an inhibition of cytochrome P450 2C9 by capecitabine and/or its metabolites (see CLINICAL PHARMACOLOGY.)

CYP2C9 substrates:

Other than warfarin, no formal drug-drug interaction studies between XELODA and other CYP2C9 substrates have been conducted. Care should be exercised when XELODA is co- administered with CYP2C9 substrates.

Phenytoin: The level of phenytoin should be carefully monitored in patients taking XELODA and phenytoin dose may need to be reduced (see DOSAGE AND ADMINISTRATION: Dose Modification Guidelines). Postmarketing reports indicate that some patients receiving XELODA and phenytoin had toxicity associated with elevated phenytoin levels. Formal drug-drug interaction studies with phenytoin have not been conducted, but the mechanism of interaction is presumed to be inhibition of the CYP2C9 isoenzyme by capecitabine and/or its metabolites (see PRECAUTIONS: Drug-Drug Interactions: Anticoagulants).

XELODA(r) (capecitabine)

Leucovorin:

The concentration of 5-fluorouracil is increased and its toxicity may be enhanced by leucovorin. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil.

Pregnancy:

Teratogenic Effects:

Category D (see WARNINGS). Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with XELODA.

Nursing Women:

Lactating mice given a single oral dose of capecitabine excreted significant amounts of capecitabine metabolites into the milk. Because of the potential for serious adverse reactions in nursing infants from capecitabine, 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 have not been established.

Geriatric Use: Physicians should pay particular attention to monitoring the adverse effects of XELODA in the elderly (see WARNINGS: Geriatric Patients).

OVERDOSAGE

The manifestations of acute overdose would include nausea, vomiting, diarrhea, gastrointestinal irritation and bleeding, and bone marrow depression. Medical management of overdose should include customary supportive medical interventions aimed at correcting the presenting clinical manifestations. Although no clinical experience using dialysis as a treatment for XELODA overdose has been reported, dialysis may be of benefit in reducing circulating concentrations of 5'-DFUR, a low-molecular weight metabolite of the parent compound. Single doses of XELODA were not lethal to mice, rats, and monkeys at doses up to 2000 mg/kg (2.4, 4.8, and 9.6 times the recommended human daily dose on a mg/m2 basis).

DOSAGE AND ADMINISTRATION

The recommended dose of XELODA is 1250 mg/m2 administered orally twice daily (morning and evening; equivalent to 2500 mg/m2 total daily dose) for 2 weeks followed by a 1-week rest period given as 3-week cycles. XELODA tablets should be swallowed with water within 30 minutes after a meal. Table 12 displays the total daily dose by body surface area and the number of tablets to be taken at each dose.

Table 12. XELODA Dose Calculation According to Body Surface Area

*Total Daily Dose divided by 2 to allow equal morning and evening doses

XELODA(r) (capecitabine)

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.

The dose of phenytoin and the dose of a coumarin-derivative anticoagulants may need to be reduced when either drug is administered concomitantly with XELODA (see PRECAUTIONS: Drug-Drug Interactions). Dose modification for the use of XELODA and docetaxel in combination are shown in Table 13.

Table 13: XELODA in Combination with Docetaxel Dose Reduction Schedule

XELODA(r) (capecitabine)

XELODA(r) (capecitabine)

*National Cancer Institute of Canada Common Toxicity Criteria were used except for hand-foot syndrome (see PRECAUTIONS).

Dose modification for the use of XELODA as monotherapy is shown in Table 14.

Table 14. Recommended Dose Modifications

XELODA(r) (capecitabine)

*National Cancer Institute of Canada Common Toxicity Criteria were used except for the Hand-and- Foot Syndrome (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 the above table. 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. Doses of XELODA omitted for toxicity are not replaced or restored; instead the patient should resume the planned treatment cycles.

Adjustment of Starting Dose in Special Populations:

Hepatic Impairment:

In patients with mild to moderate hepatic dysfunction due to liver metastases, no starting dose adjustment is necessary; however, patients should be carefully monitored. Patients with severe hepatic dysfunction have not been studied.

Renal Impairment: No adjustment to the starting dose of XELODA is recommended in patients with mild renal impairment (creatinine clearance = 51-80 mL/min [Cockroft and Gault, as shown below]). In patients with moderate renal impairment (baseline creatinine clearance = 30-50 mL/min), a dose reduction to 75% of the XELODA starting dose when used as monotherapy or in combination with docetaxel (from 1250 mg/m2 to 950 mg/m2 twice daily) is recommended (see CLINICAL PHARMACOLOGY: Special Populations). Subsequent dose adjustment is recommended as outlined in Table 14 if a patient develops a grade 2 to 4 adverse event (see WARNINGS). Cockroft and Gault Equation: (140 - age [yrs]) (body wt [kg]) Creatinine clearance for males = -------------------------- (72) (serum creatinine [mg/dL]) Creatinine clearance for females = 0.85 x male value

XELODA(r) (capecitabine)

Geriatrics:

Physicians should exercise caution in monitoring the effects of XELODA in the elderly. Insufficient data are available to provide a dosage recommendation.

HOW SUPPLIED

XELODA is supplied as biconvex, oblong film-coated tablets, available in bottles as follows:

mg

color: light peach engraving: XELODA on one side, 150 on the other 150 mg tablets packaged in bottles of 120 (NDC 0004-1100-51)

mg

color: peach engraving: XELODA on one side, 500 on the other 500 mg tablets packaged in bottles of 240 (NDC 0004-1101-16) Storage Conditions: Store at 25degC (77degF); excursions permitted to 15deg to 30degC (59deg to 86degF), keep tightly closed. [See USP Controlled Room Temperature] Maalox is a registered trademark of Novartis. Taxotere is a registered trademark of Aventis Pharmaceuticals Products Inc. For full Taxotere prescribing information, please refer to Taxotere Package Insert.

XELODA(r) (capecitabine)

PATIENT PACKAGE INSERT (text only):