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:

Capecitabine is a white to off-white crystalline powder with an aqueous solubility of 26 mg/mL at 20°C.

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 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.

Last updated on RxList: 6/25/2008

Colorectal Cancer

• XELODA is indicated as a single agent for adjuvant treatment in patients with Dukes' C colon cancer who have undergone complete resection of the primary tumor when treatment with fluoropyrimidine therapy alone is preferred. XELODA was non-inferior to 5-fluorouracil and leucovorin (5-FU/LV) for disease-free survival (DFS). Although neither XELODA nor combination chemotherapy prolongs overall survival (OS), combination chemotherapy has been demonstrated to improve disease-free survival compared to 5-FU/LV. Physicians should consider these results when prescribing single-agent XELODA in the adjuvant treatment of Dukes' C colon cancer.
• XELODA is indicated as first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred. Combination chemotherapy has shown a survival benefit compared to 5-FU/LV alone. A survival benefit over 5-FU/LV has not been demonstrated with XELODA monotherapy. Use of XELODA instead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of the survival advantage.

Breast Cancer

• XELODA in combination with docetaxel is indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.
• XELODA monotherapy is also indicated for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated, eg, patients who have received cumulative doses of 400 mg/m² of doxorubicin or doxorubicin equivalents. Resistance is 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 regimen.

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. In combination with docetaxel, the recommended dose of XELODA is 1250 mg/m² twice daily for 2 weeks followed by a 1-week rest period, combined with docetaxel at 75 mg/m² as a 1-hour intravenous infusion every 3 weeks. Pre-medication, according to the docetaxel labeling, should be started prior to docetaxel administration for patients receiving the XELODA plus docetaxel combination. Table 17 displays the total daily dose by body surface area and the number of tablets to be taken at each dose.

Adjuvant treatment in patients with Dukes' C colon cancer is recommended for a total of 6 months, ie, XELODA 1250 mg/m² orally twice daily for 2 weeks followed by a 1-week rest period, given as 3-week cycles for a total of 8 cycles (24 weeks).

Table 17: XELODA Dose Calculation According to Body Surface Area

Dose Level 1250 mg/m2 Twice a Day		Number of Tablets to be Taken at Each Dose (Morning and Evening)
Surface Area (m2)	Total DailyDose* (mg)	150 mg	500 mg
≤ 1.25	3000	0	3
1.26-1.37	3300	1	3
1.38-1.51	3600	2	3
1.52-1.65	4000	0	4
1.66-1.77	4300	1	4
1.78-1.91	4600	2	4
1.92-2.05	5000	0	5
2.06-2.17	5300	1	5
≥ 2.18	5600	2	5
*Total Daily Dose divided by 2 to allow equal morning and evening doses

Dose Management Guidelines

XELODA dosage may need to be individualized to optimize patient management. Patients should be carefully monitored for toxicity and doses of XELODA should be modified as necessary to accommodate individual patient tolerance to treatment (see Clinical Studies). 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 coumarin-derivative anticoagulants may need to be reduced when either drug is administered concomitantly with XELODA (see PRECAUTIONS: Drug-Drug Interactions).

XELODA dose modification scheme as described below (see Table 18 and Table 19) is recommended for the management of adverse events.

Table 18: XELODA in Combination With Docetaxel Dose Reduction Schedule

Toxicity NCIC Grades*	Grade 2	Grade 3	Grade 4
1st appearance	Grade 2 occurring during the 14 days of XELOD Atreatment: interrupt XELODA treatment until resolved to grade 0-1. Treatment may be resumed during the cycle at the samedose of XELODA. Doses of XELODA missed during a treatment cycle are not to be replaced. Prophylaxis for toxicities should be implemented where possible.	Grade 3 occurring during the 14 days of XELODA treatment: interrupt the XELODA treatment until resolved to grade 0-1. Treatment may be resumed during the cycle at 75% ofthe XELODA dose. Doses of XELODA missed duringa treatment cycle are not to be replaced. Prophylaxis for toxicities should be implemented where possible.	Discontinue treatment unless treating physician considers it to be in the best interest of the patient to continue with XELODA at 50% of original dose.
	Grade 2 persisting at the time the next XELODA/docetaxe ltreatment is due: delay treatment until resolved to grade 0-1, then continue at 100% of the original XELODA and docetaxel dose. Prophylaxis fortoxicities should be implemented where possible.	Grade 3 persisting at the time the next XELODA/docetaxel treatment is due: delay treatment until resolved to grade 0-1.
		For patients developing grade 3 toxicity at any timeduring the treatment cycle, upon resolution to grade 0-1, subsequent treatment cycles should be continued at 75% of the original XELODA dose and at 55 mg/m2 of docetaxel. Prophylaxis for toxicities should be implemented where possible.
2nd appearance of same toxicity	Grade 2 occurring during the 14 days of XELOD Atreatment: interrupt XELODA treatment untilresolved to grade 0-1. Treatment may be resumed during the cycle at 75% of original XELODA dose. Doses of XELODA missed during a treatment cycle are not to be replaced. Prophylaxis for toxicities should be implementedw here possible.	Grade 3 occurring during the 14 days of XELODA treatment: interrupt the XELODA treatment untilresolved to grade 0-1. Treatment may be resumed during the cycle at 50% ofthe XELODA dose. Doses of XELODA missed duringa treatment cycle are not to be replaced. Prophylaxis for toxicities should be implemented where possible.	Discontinue treatment.
	Grade 2 persisting at the time the next XELODA/docetaxel treatment is due: delay treatment until resolved tograde 0-1.	Grade 3 persisting at the time the next XELODA/docetaxel treatment is due: delay treatment until resolved tograde 0-1.
	For patients developing 2nd occurrence of grade 2 toxicity at any time duringthe treatment cycle, upon resolution to grade 0-1, subsequent treatment cycles should be continued at 75 % of the original XELODA dose and at 55 mg/m2 of docetaxel. Prophylaxis for toxicities should be implemented where possible.	For patients developing grade 3 toxicity at any time during the treatment cycle, upon resolution to grade 0-1, subsequent treatment cycles should be continued at 50% of the original XELODA dose and the docetaxel discontinued. Prophylaxis for toxicities should be implemented where possible.
3rd appearance of same toxicity	Grade 2 occurring during the 14 days of XELODAt reatment: interrupt XELODA treatment untilresolved to grade 0-1. Treatment may be resumed during the cycle at 50% ofthe original XELODA dose. Doses of XELODA missed during a treatment cycle are not to be replaced.	Discontinue treatment.
	Prophylaxis for toxicities should be implemented where possible.
	Grade 2 persisting at the time the next XELODA/docetaxel treatment is due: delay treatment until resolved to grade 0-1.
	For patients developing 3rd occurrence of grade 2 toxicity at any time during the treatment cycle, upon resolution to grade 0-1, subsequent treatment cycles should be continued at 50%of the original XELODA dose and the docetaxel discontinued. Prophylaxis for toxicities should be implemented where possible.
4th appearance of same toxicity	Discontinue treatment.
*National Cancer Institute of Canada Common Toxicity Criteria were used except for hand-and-foot syndrome (see PRECAUTIONS).

Dose modification for the use of XELODA as monotherapy is shown in Table 19.

Table 19: Recommended Dose Modifications With XELODA Monotherapy

Toxicity NCIC Grades*	During a Course of Therapy	Dose Adjustment for Next Treatment (% of starting dose)
•Grade 1	Maintain dose level	Maintain dose level
•Grade 2
-1st appearance	Interrupt until resolved to grade 0-1	100%
-2nd appearance	Interrupt until resolved to grade 0-1	75%
-3rd appearance	Interrupt until resolved to grade 0-1	50%
-4th appearance	Discontinue treatment permanently
•Grade 3
-1st appearance	Interrupt until resolved to grade 0-1	75%
-2nd appearance	Interrupt until resolved to grade 0-1	50%
-3rd appearance	Discontinue treatment permanently
•Grade4
-1st appearance	Discontinue permanently OR If physician deems it to be in the patient's best interest to continue, interrupt until resolved to grade 0-1	50%
*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 Table 18 and Table 19. 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 to 80 mL/min [Cockroft and Gault, as shown below]). In patients with moderate renal impairment (baseline creatinine clearance = 30 to 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 18 and Table 19 if a patient develops a grade 2 to 4 adverse event (see WARNINGS). The starting dose adjustment recommendations for patients with moderate renal impairment apply both to XELODA monotherapy and XELODA in combination use with docetaxel.

Cockroft and Gault Equation: Creatinine clearance for males = (140 - age [yrs]) (body wt [kg])/(72) (serum creatinine [mg/dL])
Creatinine clearance for females = 0.85 x male value

Geriatrics

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

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

150 mg

color: light peach
engraving: XELODA on one side, 150 on the other 150 mg tablets are packaged in bottles of 60 (NDC 0004-1100-20).

500 mg

color: peach
engraving: XELODA on one side, 500 on the other 500 mg tablets are packaged in bottles of 120 (NDC 0004-1101-50).

Storage Conditions

Store at 25 C (77 F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature]. KEEP TIGHTLY CLOSED.

Distributed by: Roche Laboratories Inc. 340 Nutley St, New Jersey, NJ 07110 - 1199. Revised: April 2006. FDA Rev date: 6/15/2005

Last updated on RxList: 6/25/2008

Adjuvant Colon Cancer

Table 11 shows the adverse events occurring in ≥ 5% of patients from one phase 3 trial in patients with Dukes' C colon cancer who received at least one dose of study medication and had at least one safety assessment. A total of 995 patients were treated with 1250 mg/m² twice a day of XELODA administered for 2 weeks followed by a 1-week rest period, and 974 patients were administered 5-FU and leucovorin (20 mg/m² leucovorin IV followed by 425 mg/m² IV bolus 5-FU, on days 1-5, every 28 days). The median duration of treatment was 164 days for capecitabine-treated patients and 145 days for 5-FU/LV-treated patients. A total of 112 (11%) and 73 (7%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse events. A total of 18 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 8 (0.8%) patients randomized to XELODA and 10 (1.0%) randomized to 5-FU/LV.

Table 12 shows grade 3/4 laboratory abnormalities occurring in ≥ 1% of patients from one phase 3 trial in patients with Dukes' C colon cancer who received at least one dose of study medication and had at least one safety assessment.

Table 11: Percent Incidence of Adverse Events Reported in ≥ 5% of Patients Treated With XELODA or 5-FU/LV for Colon Cancer in the Adjuvant Setting (Safety Population)

	Adjuvant Treatment for Colon Cancer (N=1969)
	XELODA (N=995)		5-FU/LV (N=974)
Body System/Adverse Event	All Grades	Grade 3/4	All Grades	Grade 3/4
Gastrointestinal Disorders
Diarrhea	47	12	65	14
Nausea	34	2	47	2
Stomatitis	22	2	60	14
Vomiting	15	2	21	2
Abdominal Pain	14	3	16	2
Constipation	9	-	11	<1
Upper Abdominal Pain	7	<1	7	<1
Dyspepsia	6	<1	5	-
Skin and Subcutaneous Tissue Disorders
Hand-and-Foot Syndrome	60	17	9	<1
Alopecia	6	-	22	<1
Rash	7	-	8	-
Erythema	6	1	5	<1
General Disorders and Administration
Site Conditions
Fatigue	16	<1	16	1
Pyrexia	7	<1	9	<1
Asthenia	10	<1	10	1
Lethargy	10	<1	9	<1
Nervous System Disorders
Dizziness	6	<1	6	-
Headache	5	<1	6	<1
Dysgeusia	6	-	9	-
Metabolism and Nutrition Disorders
Anorexia	9	<1	11	<1
Eye Disorders
Conjunctivitis	5	<1	6	<1
Blood and Lymphatic System Disorders
Neutropenia	2	<1	8	5
Respiratory Thoracic and Mediastinal Disorders
Epistaxis	2	-	5	-

Table 12: Percent Incidence of Grade 3/4 Laboratory Abnormalities Reported in ≥ 1% of Patients Receiving XELODA Monotherapy for Adjuvant Treatment of Colon Cancer (Safety Population)

	XELODA (n=995)	IV 5-FU/LV (n=974)
Adverse Event	Grade 3/4 %	Grade 3/4 %
Increased ALAT (SGPT)	1.6	0.6
Increased calcium	1.1	0.7
Decreased calcium	2.3	2.2
Decreased hemoglobin	1.0	1.2
Decreased lymphocytes	13.0	13.0
Decreased neutrophils*	2.2	26.2
Decreased neutrophils/granulocytes	2.4	26.4
Decreased platelets	1.0	0.7
Increased bilirubin**	20	6.3
*The incidence of grade 3/4 white blood cell abnormalities was 1.3% in the XELODA arm and 4.9% in the IV 5-FU/LV arm. **It should be noted that grading was according to NCIC CTC Version 1 (May,1994). In the NCIC-CTC Version 1, hyperbilirubinemia grade 3 indicates abilirubin value of 1.5 to3.0 × upper limit of normal (ULN) range, and grade 4 a value of > 3.0 × ULN. The NCI CTC Version 2 andabove define a grade 3 bilirubin value of >3.0 to 10.0 × ULN, and grade 4 values >10.0 × ULN.

Metastatic Colorectal Cancer

Table 13 shows the adverse events occurring in ≥ 5% of patients from pooling the two phase 3 trials in first line metastatic colorectal cancer. A total of 596 patients with metastatic colorectal cancer were treated with 1250 mg/m² twice a day of XELODA administered for 2 weeks followed by a 1-week rest period, and 593 patients were administered 5-FU and leucovorin in the Mayo regimen (20 mg/m² leucovorin IV followed by 425 mg/m² IV bolus 5-FU, on days 1-5, every 28 days). In the pooled colorectal database the median duration of treatment was 139 days for capecitabine-treated patients and 140 days for 5-FU/LV-treated patients. A total of 78 (13%) and 63 (11%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse events/intercurrent illness. A total of 82 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 50 (8.4%) patients randomized to XELODA and 32 (5.4%) randomized to 5-FU/LV.

Table 13: Pooled Phase 3 Colorectal Trials: Percent Incidence of Adverse Events in ≥ 5% of Patients Breast Cancer Combination

Adverse Event	XELODA (n=596)			5-FU/LV (n=593)
	Total %	Grade 3 %	Grade 4 %	Total %	Grade 3 %	Grade 4 %
Number of Patients With > One Adverse Event	96	52	9	94	45	9
Body System/Adverse Event
GI
Diarrhea	55	13	2	61	10	2
Nausea	43	4	-	51	3	<1
Vomiting	27	4	<1	30	4	<1
Stomatitis	25	2	<1	62	14	1
Abdominal Pain	35	9	<1	31	5	-
Gastrointestinal Motility Disorder	10	<1	-	7	<1	-
Constipation	14	1	<1	17	1	-
Oral Discomfort	10	-	-	10	-	-
Upper GI Inflammatory Disorders	8	<1	-	10	1	-
Gastrointestinal Hemorrhage	6	1	<1	3	1	-
Ileus	6	4	1	5	2	1
Skin and Subcutaneous
Hand-and-Foot Syndrome	54	17	NA	6	1	NA
Dermatitis	27	1	-	26	1	-
Skin Discoloration	7	<1	-	5	-	-
Alopecia	6	-	-	21	<1	-
General
Fatigue/Weakness	42	4	-	46	4	-
Pyrexia	18	1	-	21	2	-
Edema	15	1	-	9	1	-
Pain	12	1	-	10	1	-
Chest Pain	6	1	-	6	1	<1
Neurological
Peripheral Sensory Neuropathy	10	-	-	4	-	-
Headache	10	1	-	7	-	-
Dizziness*	8	<1	-	8	<1	-
Insomnia	7	-	-	7	-	-
Taste Disturbance	6	1	-	11	<1	1
Metabolism
Appetite Decreased	26	3	<1	31	2	<1
Dehydration	7	2	<1	8	3	1
Eye
Eye Irritation	13	-	-	10	<1	-
Vision Abnormal	5	-	-	2	-	-
Respiratory
Dyspnea	14	1	-	10	<1	1
Cough	7	<1	1	8	-	-
Pharyngeal Disorder	5	-	-	5	-	-
Epistaxis	3	<1	-	6	-	-
Sore Throat	2	-	-	6	-	-
Musculoskeletal
Back Pain	10	2	-	9	<1	-
Arthralgia	8	1	-	6	1	-
Vascular
Venous Thrombosis	8	3	<1	6	2	-
Psychiatric
Mood Alteration	5	-	-	6	<1	-
Depression	5	-	-	4	<1	-
Infections
Viral	5	<1	-	5	<1	-
Blood and Lymphatic
Anemia	80	2	<1	79	1	<1
Neutropenia	13	1	2	46	8	13
Hepatobiliary
Hyperbilirubinemia	48	18	5	17	3	3
- Not observed * Excluding vertigo NA = Not Applicable

Breast Cancer Combination

The following data are shown for the combination study with XELODA and docetaxel in patients with metastatic breast cancer in Table 14 and Table 15. In the XELODA and docetaxel combination arm the treatment was XELODA administered orally 1250 mg/m² twice daily as intermittent therapy (2 weeks of treatment followed by 1 week without treatment) for at least 6 weeks and docetaxel administered as a 1-hour intravenous infusion at a dose of 75 mg/m² on the first day of each 3-week cycle for at least 6 weeks.

In the monotherapy arm docetaxel was administered as a 1-hour intravenous infusion at a dose of 100 mg/m² on the first day of each 3-week cycle for at least 6 weeks. The mean duration of treatment was 129 days in the combination arm and 98 days in the monotherapy arm. A total of 66 patients (26%) in the combination arm and 49 (19%) in the monotherapy arm withdrew from the study because of adverse events. The percentage of patients requiring dose reductions due to adverse events was 65% in the combination arm and 36% in the monotherapy arm. The percentage of patients requiring treatment interruptions due to adverse events in the combination arm was 79%. Treatment interruptions were part of the dose modification scheme for the combination therapy arm but not for the docetaxel monotherapy-treated patients.

Table 14: Percent Incidence of Adverse Events Considered Related or Unrelated to Treatment in ≥ 5% of Patients Participating in the XELODA and Docetaxel Combination vs Docetaxel Monotherapy Study

Adverse Event	XELODA 1250 mg/m2/bid With Docetaxel 75 mg/m2/3 weeks (n=251)			Docetaxel 100 mg/m2/3 weeks (n=255)
	Total %	Grade 3 %	Grade 4 %	Total %	Grade 3 %	Grade 4 %
Number of Patients With at Least One Adverse Event	99	76.5	29.1	97	57.6	31.8
Body System/Adverse Event
GI
Diarrhea	67	14	<1	48	5	<1
Stomatitis	67	17	<1	43	5	-
Nausea	45	7	-	36	2	-
Vomiting	35	4	1	24	2	-
Constipation	20	2	-	18	-	-
Abdominal Pain	30	<3	<1	24	2	-
Dyspepsia	14	-	-	8	1	-
Dry Mouth	6	<1	-	5	-	-
Skin and Subcutaneous
Hand-and-Foot Syndrome	63	24	NA	8	1	NA
Alopecia	41	6	-	42	7	-
Nail Disorder	14	2	-	15	-	-
Dermatitis	8	-	-	11	1	-
Rash Erythematous	9	<1	-	5	-	-
Nail Discoloration	6	-	-	4	<1	-
Onycholysis	5	1	-	5	1	-
Pruritus	4	-	-	5	-	-
General
Pyrexia	28	2	-	34	2	-
Asthenia	26	4	<1	25	6	-
Fatigue	22	4	-	27	6	-
Weakness	16	2	-	11	2	-
Pain in Limb	13	<1	-	13	2	-
Lethargy	7	-	-	6	2	-
Pain	7	<1	-	5	1	-
Chest Pain (non-cardiac)	4	<1	-	6	2	-
Influenza-like Illness	5	-	-	5	-	-
Neurological
Taste Disturbance	16	<1	-	14	<1	-
Headache	15	3	-	15	2	-
Paresthesia	12	<1	-	16	1	-
Dizziness	12	-	-	8	<1	-
Insomnia	8	-	-	10	<1	-
Peripheral Neuropathy	6	-	-	10	1	-
Hypoaesthesia	4	<1	-	8	<1	-
Metabolism
Anorexia	13	1	-	11	<1	-
Appetite Decreased	10	-	-	5	-	-
Weight Decreased	7	-	-	5	-	-
Dehydration	10	2	-	7	<1	<1
Eye
Lacrimation Increased	12	-	-	7	<1	-
Conjunctivitis	5	-	-	4	-	-
Eye Irritation	5	-	-	1	-	-
Musculoskeletal
Arthralgia	15	2	-	24	3	-
Myalgia	15	2	-	25	2	-
Back Pain	12	<1	-	11	3	-
Bone Pain	8	<1	-	10	2	-
Cardiac
Edema	33	<2	-	34	<3	1
Blood
Neutropenic Fever	16	3	13	21	5	16
Respiratory
Dyspnea	14	2	<1	16	2	-
Cough	13	1	-	22	<1	-
Sore Throat	12	2	-	11	<1	-
Epistaxis	7	<1	-	6	-	-
Rhinorrhea	5	-	-	3	-	-
Pleural Effusion	2	1	-	7	4	-
Infection
Oral Candidiasis	7	<1	-	8	<1	-
Urinary Tract Infection	6	<1	-	4	-	-
Upper Respiratory Tract	4	-	-	5	1	-
Vascular
Flushing	5	-	-	5	-	-
Lymphoedema	3	<1	-	5	1	-
Psychiatric
Depression	5	-	-	5	1	-
- Not observed NA = Not Applicable

Table 15: Percent of Patients With Laboratory Abnormalities Participating in the XELODA and Docetaxel Combination vs Docetaxel Monotherapy Study

Adverse Event	XELODA 1250 mg/m2/bid With Docetaxe l75 mg/m2/3 weeks (n=251)			Docetaxel 100 mg/m2/3 weeks (n=255)
Body System/Adverse Event	Total %	Grade 3 %	Grade 4 %	Total %	Grade 3 %	Grade 4 %
Hematologic
Leukopenia	91	37	24	88	42	33
Neutropenia/Granulocytopenia	86	20	49	87	10	66
Thrombocytopenia	41	2	1	23	1	2
Anemia	80	7	3	83	5	<1
Lymphocytopenia	99	48	41	98	44	40
Hepatobiliary
Hyperbilirubinemia	20	7	2	6	2	2

Breast Cancer XELODA Monotherapy

The following data are shown for the study in stage IV breast cancer patients who received a dose of 1250 mg/m² administered twice daily for 2 weeks followed by a 1-week rest period. The mean duration of treatment was 114 days. A total of 13 out of 162 patients (8%) discontinued treatment because of adverse events/intercurrent illness.

Table 16: Percent Incidence of Adverse Events Considered Remotely, Possibly or Probably Related to Treatment in ≥ 5% of Patients Participating in the Single Arm Trial in Stage IV Breast Cancer

Adverse Event	Phase 2 Trialin Stage IV Breast Cancer (n=162)
Body System/Adverse Event	Total %	Grade 3 %	Grade 4 %
GI
Diarrhea	57	12	3
Nausea	53	4	-
Vomiting	37	4	-
Stomatitis	24	7	-
Abdominal Pain	20	4	-
Constipation	15	1	-
Dyspepsia	8	-	-
Skin and Subcutaneous
Hand-and-Foot Syndrome	57	11	NA
Dermatitis	37	1	-
Nail Disorder	7	-	-
General
Fatigue	41	8	-
Pyrexia	12	1	-
Pain in Limb	6	1	-
Neurological
Paresthesia	21	1	-
Headache	9	1	-
Dizziness	8	-	-
Insomnia	8	-	-
Metabolism
Anorexia	23	3	-
Dehydration	7	4	1
Eye
Eye Irritation	15	-	-
Musculoskeletal
Myalgia	9	-	-
Cardiac
Edema	9	1	-
Blood
Neutropenia	26	2	2
Thrombocytopenia	24	3	1
Anemia	72	3	1
Lymphopenia	94	44	15
Hepatobiliary
Hyperbilirubinemia	22	9	2
- Not observed NA = Not Applicable

XELODA and Docetaxel in Combination

Shown below by body system are the clinically relevant adverse events in < 5% of patients in the overall clinical trial safety database of 251 patients (Study Details) reported as related to the administration of XELODA in combination with docetaxel and that were clinically at least remotely relevant. In parentheses is the incidence of grade 3 and 4 occurrences of each adverse event.

It is anticipated that the same types of adverse events observed in the XELODA monotherapy studies may be observed in patients treated with the combination of XELODA plus docetaxel.

Gastrointestinal: ileus (0.39), necrotizing enterocolitis (0.39), esophageal ulcer (0.39), hemorrhagic diarrhea (0.80)

Neurological: ataxia (0.39), syncope (1.20), taste loss (0.80), polyneuropathy (0.39), migraine (0.39)

Cardiac: supraventricular tachycardia (0.39)

Infection: neutropenic sepsis (2.39), sepsis (0.39), bronchopneumonia (0.39) Blood and Lymphatic: agranulocytosis (0.39), prothrombin decreased (0.39)

Vascular: hypotension (1.20), venous phlebitis and thrombophlebitis (0.39), postural hypotension (0.80)

Renal: renal failure (0.39)

Hepatobiliary: jaundice (0.39), abnormal liver function tests (0.39), hepatic failure (0.39), hepatic coma (0.39), hepatotoxicity (0.39)

Immune System: hypersensitivity (1.20)

XELODA Monotherapy Metastatic Breast and Colorectal Cancer

Shown below by body system are the clinically relevant adverse events in < 5% of patients in the overall clinical trial safety database of 875 patients (phase 3 colorectal studies - 596 patients, phase 2 colorectal study - 34 patients, phase 2 breast cancer studies - 245 patients) reported as related to the administration of XELODA and that were clinically at least remotely relevant. In parentheses is the incidence of grade 3 or 4 occurrences of each adverse event.

Gastrointestinal: abdominal distension, dysphagia, proctalgia, ascites (0.1), gastric ulcer (0.1), ileus (0.3), toxic dilation of intestine, gastroenteritis (0.1)

Skin and Subcutaneous: nail disorder (0.1), sweating increased (0.1), photosensitivity reaction (0.1), skin ulceration, pruritus, radiation recall syndrome (0.2)

General: chest pain (0.2), influenza-like illness, hot flushes, pain (0.1), hoarseness, irritability, difficulty in walking, thirst, chest mass, collapse, fibrosis (0.1), hemorrhage, edema, sedation

Neurological: insomnia, ataxia (0.5), tremor, dysphasia, encephalopathy (0.1), abnormal coordination, dysarthria, loss of consciousness (0.2), impaired balance

Metabolism: increased weight, cachexia (0.4), hypertriglyceridemia (0.1), hypokalemia, hypomagnesemia

Eye: conjunctivitis

Respiratory: cough (0.1), epistaxis (0.1), asthma (0.2), hemoptysis, respiratory distress (0.1), dyspnea

Cardiac: tachycardia (0.1), bradycardia, atrial fibrillation, ventricular extrasystoles, extrasystoles, myocarditis (0.1), pericardial effusion

Infections: laryngitis (1.0), bronchitis (0.2), pneumonia (0.2), bronchopneumonia (0.2), keratoconjunctivitis, sepsis (0.3), fungal infections (including candidiasis) (0.2)

Musculoskeletal: myalgia, bone pain (0.1), arthritis (0.1), muscle weakness

Blood and Lymphatic: leukopenia (0.2), coagulation disorder (0.1), bone marrow depression (0.1), idiopathic thrombocytopenia purpura (1.0), pancytopenia (0.1)

Vascular: hypotension (0.2), hypertension (0.1), lymphoedema (0.1), pulmonary embolism (0.2), cerebrovascular accident (0.1)

Psychiatric: depression, confusion (0.1) Renal: renal impairment (0.6) Ear: vertigo

Hepatobiliary: hepatic fibrosis (0.1), hepatitis (0.1), cholestatic hepatitis (0.1), abnormal liver function tests

Immune System: drug hypersensitivity (0.1)

Postmarketing: hepatic failure, lacrimal duct stenosis

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 BOXED WARNING 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 1 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 coadministered 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 Management 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).

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.

Last updated on RxList: 6/25/2008

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 18 in DOSAGE AND ADMINISTRATION.

Coagulopathy

See BOXED 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 875 patients with either metastatic breast or colorectal cancer who received XELODA monotherapy, 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 ≥ 10 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 ≥ 80 years old may experience a greater incidence of grade 3 or 4 adverse events (see PRECAUTIONS: Geriatric Use). In 875 patients with either metastatic breast or colorectal cancer who received XELODA monotherapy, 62% of the 21 patients ≥ 80 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.

Among the 67 patients ≥ 60 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 than in the < 60 years of age patient group.

In 995 patients receiving XELODA as adjuvant therapy for Dukes' C colon cancer after resection of the primary tumor, 41% of the 398 patients ≥ 65 years of age treated with XELODA experienced a treatment-related grade 3 or 4 adverse event: hand-and-foot syndrome in 75 (18.8%), diarrhea in 52 (13.1%), stomatitis in 12 (3.0%), neutropenia/granulocytopenia in 11 (2.8%), vomiting in 6 (1.5%), and nausea in 5 (1.3%) patients. In patients ≥ 65 years of age (all randomized population; capecitabine 188 patients, 5-FU/LV 208 patients) treated for Dukes' C colon cancer after resection of the primary tumor, the hazard ratios for disease-free survival and overall survival for XELODA compared to 5-FU/LV were 1.01 (95% C.I. 0.80 - 1.27) and 1.04 (95% C.I. 0.79 - 1.37), respectively.

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.

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 was 79 days (range from 11 to 360 days) with a severity range of grades 1 to 3 for patients receiving XELODA monotherapy in the metastatic setting. 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).

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.

Dihydropyrimidine Dehydrogenase Deficiency

Rarely, unexpected, severe toxicity (eg, stomatitis, diarrhea, neutropenia and neurotoxicity) associated with 5-fluorouracil has been attributed to a deficiency of dihydropyrimidine dehydrogenase (DPD) activity. A link between decreased levels of DPD and increased, potentially fatal toxic effects of 5-fluorouracil therefore cannot be excluded.

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 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, grade 3 (1.5-3 x ULN) hyperbilirubinemia occurred in 15.2% (n=133) of patients and grade 4 ( > 3 x ULN) hyperbilirubinemia occurred in 3.9% (n=34) of patients. 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 prebaseline and postbaseline 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 m/L at baseline to 13 m/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 to 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 to 3 x normal and grade 4 hyperbilirubinemia as > 3 x normal. (See recommended dose modifications under DOSAGE AND ADMINISTRATION.)

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.

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 100.5°F or greater or other evidence of potential infection should be instructed to call their physician.

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).

Last updated on RxList: 6/25/2008

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).

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

Last updated on RxList: 6/25/2008

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.

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, N^5-10-methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a covalently bound ternary complex. This binding inhibits the formation of thymidylate from 2'-deoxyuridylate. Thymidylate is the necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, so that a deficiency of this compound can inhibit cell division. Second, nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis.

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 ¾ of an hour. The inter-patient variability in the Cmax and AUC of 5-FU was greater than 85%.

Following oral administration of 825 mg/m² capecitabine twice daily for 14 days, Japanese patients (n=18) had about 36% lower Cmax and 24% lower AUC for capecitabine than the Caucasian patients (n=22). Japanese patients had also about 25% lower Cmax and 34% lower AUC for FBAL than the Caucasian patients. The clinical significance of these differences is unknown. No significant differences occurred in the exposure to other metabolites (5'-DFCR, 5'-DFUR, and 5-FU).

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 AUC_0-∞ decreased by 60% and 35%, respectively. The Cmax and AUC_0-∞ 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, β-ureido-propionase cleaves FUPA to α-fluoro-β-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 1 study evaluating the effect of XELODA on the pharmacokinetics of docetaxel (Taxotere ) 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 (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 metastatic 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 AUC_0-&inifn; and Cmax of capecitabine increased by 60% in patients with hepatic dysfunction compared to patients with normal hepatic function (n=14). The AUC_0-&inifn; and Cmax of 5-FU were 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 to 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 BOXED WARNING and PRECAUTIONS: Drug-Drug Interactions).

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 (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

General

The recommended dose of XELODA was determined in an 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.

Adjuvant Colon Cancer

A multicenter randomized, controlled phase 3 clinical trial in patients with Dukes' C colon cancer provided data concerning the use of XELODA for the adjuvant treatment of patients with colon cancer. The primary objective of the study was to compare disease-free survival (DFS) in patients receiving XELODA to those receiving IV 5-FU/LV alone. In this trial, 1987 patients were randomized either to treatment with XELODA 1250 mg/m² orally twice daily for 2 weeks followed by a 1-week rest period, given as 3-week cycles for a total of 8 cycles (24 weeks) or IV bolus 5-FU 425 mg/m² and 20 mg/m² IV leucovorin on days 1 to 5, given as 4-week cycles for a total of 6 cycles (24 weeks). Patients in the study were required to be between 18 and 75 years of age with histologically-confirmed Dukes' stage C colon cancer with at least one positive lymph node and to have undergone (within 8 weeks prior to randomization) complete resection of the primary tumor without macroscopic or microscopic evidence of remaining tumor. Patients were also required to have no prior cytotoxic chemotherapy or immunotherapy (except steroids), and have an ECOG performance status of 0 or 1 (KPS ≥ 70%), ANC ≥ 1.5x10⁹/L, platelets ≥ 100x10⁹/L, serum creatinine ≤ 1.5 ULN, total bilirubin ≤ 1.5 ULN, AST/ALT ≤ 2.5 ULN and CEA within normal limits at time of randomization.

The baseline demographics for XELODA and 5-FU/LV patients are shown in Table 1. The baseline characteristics were well-balanced between arms.

Table 1: Baseline Demographics

	XELODA (n=1004)	5-FU/LV (n=983)
Age (median, years)	62	63
Range	(25-80)	(22-82)
Gender
Male (n, %)	542 (54)	532 (54)
Female (n, %)	461 (46)	451 (46)
ECOG PS
0 (n, %)	849 (85)	830 (85)
1 (n, %)	152 (15)	147 (15)
Staging - Primary Tumor
PT1 (n, %)	12 (1)	6 (0.6)
PT2 (n, %)	90 (9)	92 (9)
PT3 (n, %)	763 (76)	746 (76)
PT4 (n, %)	138 (14)	139 (14)
Other (n, %)	1 (0.1)	0 (0)
Staging - Lymph Node
pN1 (n, %)	695 (69)	694 (71)
pN2 (n, %)	305 (30)	288 (29)
Other (n, %)	4 (0.4)	1 (0.1)

All patients with normal renal function or mild renal impairment began treatment at the full starting dose of 1250 mg/m² orally twice daily. The starting dose was reduced in patients with moderate renal impairment (calculated creatinine clearance 30 to 50 mL/min) at baseline (see DOSAGE AND ADMINISTRATION). Subsequently, for all patients, doses were adjusted when needed according to toxicity. Dose management for XELODA included dose reductions, cycle delays and treatment interruptions (see Table 2).

Table 2: Summary of Dose Modifications in X-ACT Study

	XELODA N = 995	5-FU/LV N = 974
Median relative dose intensity (%)	93	92
Patients completing full course of treatment (%)	83	87
Patients with treatment interruption (%)	15	5
Patients with cycle delay (%)	46	29
Patients with dose reduction (%)	42	44
Patients with treatment interruption, cycle delay, or dose reduction (%)	57	52

The median follow-up at the time of the analysis was 53 months. The hazard ratio for DFS for XELODA compared to 5-FU/LV was 0.87 (95% C.I. 0.76 - 1.00). Because the upper 2-sided 95% confidence limit of hazard ratio was less than 1.20, XELODA was non-inferior to 5-FU/LV. The choice of the non-inferiority margin of 1.20 corresponds to the retention of approximately 75% of the 5-FU/LV effect on DFS.

Survival data were not mature at the time of the analysis with a median follow-up of 53 months. The comparison of overall survival did not reach statistical significance for the test of difference (HR 0.88, 95% C.I. 0.74 - 1.05; p = 0.169).

Table 3: Efficacy of XELODA vs 5-FU/LV in Adjuvant Treatment of Colon Cancer^a

All Randomized Population	XELODA (n=1004)	5-FU/LV (n=983)
Median follow-up (months)	53	53
3-year Disease-free Survival Rates	66.0	62.9
Hazard Ratio
(XELODA/5-FU/LV)	0.87
(95% C.I. for Hazard Ratio),	(0.76-1.00)
p-valueb	p=0.055
a Approximately 85 % had 3-year DF Sinformation b Log-rank test for differences of XELODA vs 5-FU/LV

Figure 1: Kaplan-Meier Estimates of Disease-Free Survival (All Randomized Population)^a

Metastatic Colorectal Cancer

Data from two 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 4.

Table 4: Baseline Demographics of Controlled Colorectal Trials

	Study1		Study2
	XELODA (n=302)	5-FU/LV (n=303)	XELODA (n=301)	5-FU/LV (n=301)
Age (median, years)	64	63	64	64
Range	(23-86)	(24-87)	(29-84)	(36-86)
Gender
Male (%)	181 (60)	197 (65)	172 (57)	173 (57)
Female (%)	121 (40)	106 (35)	129 (43)	128 (43)
Karnofsky PS (median)	90	90	90	90
Range	(70-100)	(70-100)	(70-100)	(70-100)
Colon (%)	222 (74)	232 (77)	199 (66)	196 (65)
Rectum (%)	79 (26)	70 (23)	101 (34)	105 (35)
Prior radiation therapy (%)	52 (17)	62 (21)	42 (14)	42 (14)
Prior adjuvant 5-FU (%)	84 (28)	110 (36)	56 (19)	41 (14)

The efficacy endpoints for the two phase 3 trials are shown in Table 5 and Table 6.

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

	XELODA (n=302)	5-FU/LV (n=303)
Overall Response Rate
(%, 95% C.I.)	21 (16-26)	11 (8-15)
(p-value)	0.0014
Time to Progression
(Median, days, 95% C.I.)	128 (120-136)	131 (105-153)
Hazard Ratio (XELODA/5-FU/LV) 95% C.I. for Hazard Ratio	0.99 (0.84-1.17)
Survival
(Median, days, 95% C.I.)	380 (321-434)	407 (366-446)
Hazard Ratio (XELODA/5-FU/LV) 95% C.I. for Hazard Ratio	1.00 (0.84-1.18)

Table 6: Efficacy of XELODA vs 5-FU/LV in Colorectal Cancer (Study 2)

	XELODA (n=301)	5-FU/LV (n=301)
Overall Response Rate
(%, 95% C.I.)	21 (16-26)	14 (10-18)
(p-value)	0.027
Time to Progression
(Median, days, 95% C.I.)	137 (128-165)	131 (102-156)
Hazard Ratio (XELODA/5-FU/LV) 95% C.I. for Hazard Ratio	0.97 (0.82-1.14)
Survival
(Median, days, 95% C.I.)	404 (367-452)	369 (338-430)
Hazard Ratio (XELODA/5-FU/LV) 95% C.I. for Hazard Ratio	0.92 (0.78-1.09)

Figure 2 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 Table 5, Table 6, and Figure 2).

Breast Cancer

XELODA has been evaluated in clinical trials in combination with docetaxel (Taxotere ) and as monotherapy.

Breast Cancer Combination Therapy

The dose of XELODA used in the phase 3 clinical trial in combination with docetaxel was based on the results of a phase 1 study, where a range of doses of docetaxel administered in 3-week cycles in combination with an intermittent regimen of XELODA (14 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 2 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 1 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 7.

Table 7: Baseline Demographics and Clinical Characteristics XELODA and Docetaxel Combination vs Docetaxel in Breast Cancer Trial

	XELODA + Docetaxel (n=255)	Docetaxel (n=256)
Age (median, years)	52	51
Karnofsky PS (median)	90	90
Site of Disease
Lymph nodes	121 (47%)	125 (49%)
Liver	116 (45%)	122 (48%)
Bone	107 (42%)	119 (46%)
Lung	95 (37%)	99 (39%)
Skin	73 (29%)	73 (29%)
Prior Chemotherapy
Anthracycline1	255 (100%)	256 (100%)
5-FU	196 (77%)	189 (74%)
Paclitaxel	25 (10%)	22 (9%)
Resistance to an Anthracycline
No resistance	19 (7%)	19 (7%)
Progression on anthracycline therapy	65 (26%)	73 (29%)
Stable disease after 4 cycles of anthracycline therapy	41 (16%)	40 (16%)
Relapsed within 2 years of completion of anthracycline-adjuvant therapy	78 (31%)	74 (29%)
Experienced a brief response to anthracycline therapy, with subsequent progression while on therapy or within 12 months after last dose	51 (20%)	50 (20%)
No. of Prior Chemotherapy Regimens for Treatment of Metastatic Disease
0	89 (35%)	80 (31%)
1	123 (48%)	135 (53%)
2	43 (17%)	39 (15%)
3	0 (0%)	2 (1%)
1Includes 10 patients in combination and 18 patients in monotherapy arms treated with an anthracenedione

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 8, Figure 3, and Figure 4.

Table 8: Efficacy of XELODA and Docetaxel Combination vs Docetaxel Monotherapy

Efficacy Parameter	Combination Therapy	Monotherapy	p-value	Hazard Ratio
Time to Disease Progression
Median Days	186	128	0.0001	0.643
95% C.I.	(165-198)	(105-136)
Overall Survival
Median Days	442	352	0.0126	0.775
95% C.I.	(375-497)	(298-387)
Response Rate1	32%	22%	0.009	NA2
1The response rate reported represents a reconciliation of the investigator and IRC assessments performed by the sponsor according to a predefined algorithm. 2 NA = Not Applicable

Figure 3: Kaplan-Meier Estimates for Time to Disease Progression XELODA and Docetaxel vs Docetaxel

Figure 4: Kaplan-Meier Estimates of Survival XELODA and Docetaxel vs Docetaxel

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 ≥ 50% 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 9. 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 9: Baseline Demographics and Clinical Characteristics Single-Arm Breast Cancer Trial

	Patients With Measurable Disease (n=135)	All Patients (n=162)
Age (median, years)	55	56
Karnofsky PS	90	90
No. Disease Sites
1-2	43 (32%)	60 (37%)
3-4	63 (46%)	69 (43%)
>5	29 (22%)	34 (21%)
Dominant Site of Disease
Visceral1	101 (75%)	110 (68%)
Soft Tissue	30 (22%)	35 (22%)
Bone	4 (3%)	17 (10%)
Prior Chemotherapy
Paclitaxel	135 (100%)	162 (100%)
Anthracycline2	122 (90%)	147 (91%)
5-FU	110 (81%)	133 (82%)
Resistance to Paclitaxel	103 (76%)	124 (77%)
Resistance to an Anthracycline2	55 (41%)	67 (41%)
Resistance to both Paclitaxel and an Anthracycline2	43 (32%)	51 (31%)
1Lung, pleura, liver, peritoneum 2Includes 2 patients treated withan anthracenedione

Antitumor responses for patients with disease resistant to both paclitaxel and an anthracycline are shown in Table 10.

Table 10: Response Rates in Doubly-Resistant Patients Single-Arm Breast Cancer Trial

	Resistance to Both Paclitaxel andan Anthracycline (n=43)
CR	0
PR1	11
CR + PR1	11
Response Rate1 (95% C.I.)	25.6% (13.5, 41.2)
Duration of Response,1 Median in days2 (Range)	154 (63-233)
1Includes 2 patients treated with an anthracenedione 2From 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 9). The median time to progression was 90 days and the median survival was 306 days.

Last updated on RxList: 6/25/2008

Read this leaflet before you start taking XELODA [zeh-LOE-duh] and each time you refill your prescription in case the information has changed. This leaflet contains important information about XELODA. However, this information does not take the place of talking with your doctor. This information cannot cover all possible risks and benefits of XELODA. Your doctor should always be your first choice for discussing your medical condition and this medicine.

What is XELODA?

XELODA is a medicine you take by mouth (orally). XELODA is changed in the body to 5-fluorouracil (5-FU). In some patients with colon, rectum or breast cancer, 5-FU stops cancer cells from growing and decreases the size of the tumor.

XELODA is used to treat:

• cancer of the colon after surgery
• cancer of the colon or rectum (colorectal cancer) that has spread to other parts of the body (metastatic colorectal cancer). You should know that in studies, other medicines showed improved survival when they were taken together with 5-FU and leucovorin. In studies, XELODA was no worse than 5-FU and leucovorin taken together but did not improve survival compared to these two medicines.
• breast cancer that has spread to other parts of the body (metastatic breast cancer) together with another medicine called docetaxel (Taxotere )
• breast cancer that has spread to other parts of the body and has not improved after treatment with other medicines such as paclitaxel (Taxol ) and anthracycline-containing medicine such as Adriamycin and doxorubicin

What is the most important information about XELODA?

XELODA may increase the effect of other medicines used to thin your blood such as warfarin (Coumadin ). It is very important that your doctor knows if you are taking a blood thinner such as warfarin because XELODA may increase the effect of this medicine and could lead to serious side effects. If you are taking blood thinners and XELODA, your doctor needs to check more often how fast your blood clots and change the dose of the blood thinner, if needed.

Who should not take XELODA?

1. DO NOT TAKE XELODA IF YOU

• are nursing a baby. Tell your doctor if you are nursing. XELODA may pass to the baby in your milk and harm the baby.
• are allergic to 5-fluorouracil
• are allergic to capecitabine or to any of the ingredients in XELODA
• have been told that you lack the enzyme DPD (dihydropyrimidine dehydrogenase)

2. TELL YOUR DOCTOR IF YOU

• take a blood thinner such as warfarin (Coumadin). This is very important because XELODA may increase the effect of the blood thinner. If you are taking blood thinners and XELODA, your doctor needs to check more often how fast your blood clots and change the dose of the blood thinner, if needed.
• take phenytoin (Dilantin). Your doctor needs to test the levels of phenytoin in your blood more often or change your dose of phenytoin.
• are pregnant or think you may be pregnant. XELODA may harm your unborn child.
• have kidney problems. Your doctor may prescribe a different medicine or lower the XELODA dose.
• have liver problems. You may need to be checked for liver problems while you take XELODA.
• have heart problems because you could have more side effects related to your heart.
• take the vitamin folic acid. It may affect how XELODA works.

How should I take XELODA?

Take XELODA exactly as your doctor tells you to. Your doctor will prescribe a dose and treatment plan that is right for you. Your doctor may want you to take both 150 mg and 500 mg tablets together for each dose. If so, you must be able to identify the tablets. Taking the wrong tablets could cause an overdose (too much medicine) or underdose (too little medicine). The 150 mg tablets are light peach in color with 150 on one side. The 500 mg tablets are peach in color with 500 on one side. Your doctor may change the amount of medicine you take during your treatment. Your doctor may prescribe XELODA Tablets with Taxotere or docetaxel injection.

• XELODA is taken in 2 daily doses, a morning dose and an evening dose
• Take XELODA tablets within 30 minutes after the end of a meal (breakfast and dinner)
• Swallow XELODA tablets with water
• If you miss a dose of XELODA, do not take the missed dose at all and do not double the next dose. Instead, continue your regular dosing schedule and check with your doctor.
• XELODA is usually taken for 14 days followed by a 7-day rest period (no drug), for a 21-day cycle. Your doctor will tell you how many cycles of treatment you will need.
• If you take too much XELODA, contact your doctor or local poison control center or emergency room right away.

What should I avoid while taking XELODA?

• Women should not become pregnant while taking XELODA. XELODA may harm your unborn child. Use effective birth control while taking XELODA. Tell your doctor if you become pregnant.
• Do not breast-feed. XELODA may pass through your milk and harm your baby.
• Men should use birth control while taking XELODA

What are the most common side effects of XELODA?

The most common side effects of XELODA are:

• diarrhea, nausea, vomiting, sores in the mouth and throat (stomatitis), stomach area pain (abdominal pain), upset stomach, constipation, loss of appetite, and too much water loss from the body (dehydration). These side effects are more common in patients age 80 and older.
• hand-and-foot syndrome (palms of the hands or soles of the feet tingle, become numb, painful, swollen or red), rash, dry, itchy or discolored skin, nail problems, and hair loss
• tiredness, weakness, dizziness, headache, fever, pain (including chest, back, joint, and muscle pain), trouble sleeping, and taste problems

These side effects may differ when taking XELODA with Taxotere. Please consult your doctor for possible side effects that may be caused by taking XELODA with Taxotere.

If you are concerned about these or any other side effects while taking XELODA, talk to your doctor.

Stop taking XELODA immediately and contact your doctor right away if you have the side effects listed below, or other side effects that concern you. Your doctor can then adjust XELODA to a dose that is right for you or stop your XELODA treatment for a while. This should help to reduce the side effects and stop them from getting worse.

• Diarrhea: if you have an additional 4 bowel movements each day beyond what is normal or any diarrhea at night
• Vomiting: if you vomit more than once in a 24-hour time period
• Nausea: if you lose your appetite, and the amount of food you eat each day is much less than usual
• Stomatitis: if you have pain, redness, swelling or sores in your mouth
• Hand-and-Foot Syndrome: if you have pain, swelling or redness of your hands or feet that prevents normal activity
• Fever or Infection: if you have a temperature of 100.5 F or greater, or other signs of infection

Your doctor may tell you to lower the dose or to 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 your side effects have improved, your doctor will tell you whether to start taking XELODA again and what dose to take. Adjusting the dose of XELODA to be right for each patient is an important part of treatment.

How should I store and use XELODA?

• Never share XELODA with anyone
• Store XELODA at normal room temperature (about 65 to 85 F)
• Keep XELODA and all other medicines out of the reach of children
• If you take too much XELODA by mistake, contact your doctor or local poison control center or emergency room right away

General advice about prescription medicines:

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use XELODA for a condition for which it was not prescribed. Do not give XELODA to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about XELODA. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about XELODA that is written for health professionals.

ADRIAMYCIN is a trademark of Pharmacia & Upjohn Company. COUMADIN is a registered trademark of Bristol-Myers Squibb Pharma Company. DILANTIN is a registered trademark of Warner-Lambert Company LLC. TAXOL is a registered trademark of Bristol-Myers Squibb Company. TAXOTERE is a registered trademark of Aventis Pharma S.A.

Last updated on RxList: 6/25/2008

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

CAPECITABINE - ORAL

(cap-eh-SIT-uh-bean)

COMMON BRAND NAME(S): Xeloda

WARNING: Capecitabine may interact with "blood thinners" (anticoagulants such as warfarin or phenprocoumon) and cause serious, rarely fatal bleeding. In some cases, this bleeding has occurred up to one month after stopping capecitabine as well as during treatment.

If you are using an anticoagulant, your laboratory tests (INR/PT) will be closely monitored. Report any signs of bleeding or bruising (such as black stools) to your doctor immediately.

USES: Capecitabine is used alone or with other treatments/medications to treat certain types of cancer (e.g., of the breast, colon, rectum). It works by slowing or stopping cancer cell growth and by decreasing tumor size.

HOW TO USE: Read the Patient Information Leaflet provided by your pharmacist before you start taking capecitabine and each time you get a refill. If you have any questions regarding the information, consult your doctor or pharmacist.

Take this medication by mouth, usually twice daily in the morning and evening or as directed by your doctor. It is best to take this with a full glass of water (8 ounces or 240 milliliters) within 30 minutes after the end of a meal. Capecitabine is usually taken every day for 2 weeks, then stopped for 1 week. This course of treatment may be repeated as directed by your doctor.

If you take any antacid products that contain aluminum or magnesium, take capecitabine 2 hours before or after taking any antacids because these products may change the way your body absorbs capecitabine.

The dosage is based on your medical condition, body size, and response to therapy. You may be taking a combination of different tablet sizes. Pay close attention to your dose and tablet sizes to avoid over- or under-dosing.

Do not increase your dose or take this medication more often than directed without your doctor's approval. Your condition will not improve any faster, and the risk of serious side effects may increase.

Since this drug can be absorbed through the skin, women who are pregnant or who may become pregnant should not handle this medication.

SIDE EFFECTS: Nausea, vomiting, loss of appetite, constipation, tiredness, weakness, back/joint/muscle pain, headache, dizziness, trouble sleeping, skin darkening, or dry/itchy skin may occur. Nausea and vomiting can be severe. Changes in diet and lifestyle, such as eating several small meals or limiting activity, may lessen some of these effects. If any of these effects continue or worsen, notify your doctor.

Temporary hair loss may occur. Normal hair growth should return after treatment has ended. Temporary nail changes may occur, which may rarely include fungal infections in the nail beds.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Diarrhea is a common side effect of this medication. It may become very severe (possibly fatal). To decrease this side effect, your doctor may prescribe medication (e.g., loperamide) to control your symptoms, replace lost fluids by vein, or stop treatment with capecitabine. Drink plenty of fluids to prevent serious problems due to a loss of too much body water (dehydration). If you experience signs of severe diarrhea (e.g., 4 or more stools per day, diarrhea at night, bloody stools), or if you experience signs of dehydration (e.g., dizziness, decreased amount of urine), stop taking this drug and tell your doctor immediately.

Stop taking capecitabine and tell your doctor immediately if you have any of these serious side effects: severe nausea/vomiting (vomiting 2 or more times per day, inability to eat or keep food/fluids in your stomach), painful redness/swelling/sores in mouth or throat.

If any of the above symptoms occur, your doctor may lower your dose when you start taking capecitabine again or may stop treatment with this drug.

Treatment with capecitabine may sometimes cause your hands/feet to develop a skin reaction called hand-foot syndrome (palmar-plantar erythrodysesthesia). You can prevent or reduce these problems by protecting your hands and feet from a great deal of heat or pressure. Avoid unnecessary exposure to heat (e.g., hot dishwater, long hot baths). Avoid pressure on elbows, knees, and soles of feet (e.g., leaning on elbows, kneeling, long walks). Wear loose clothing. Depending on how severe your hand-foot syndrome is, your doctor may prescribe a medication to reduce the symptoms or decrease/delay your next dose of capecitabine. If you experience pain/swelling/redness, blisters, or numbness of the hands/feet that affects your usual activities, stop taking this medication and tell your doctor immediately.

This medication can lower your ability to fight an infection. Stop taking this medication and call your doctor promptly if you develop any signs of an infection such as high fever, chills, or persistent sore throat.

Tell your doctor immediately if you have any of these unlikely but serious side effects: abdominal/stomach pain, unusual bruising or bleeding, extreme tiredness, mental/mood changes (e.g., depression), swelling of the ankles/feet, vision changes, shortness of breath, change in the amount of urine, dark urine, yellowing of the eyes/skin, fast/irregular heartbeat.

Seek immediate medical attention if any of these rare but very serious side effects occur: chest pain, fainting, jaw/left arm pain.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other side effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking capecitabine, tell your doctor or pharmacist if you are allergic to it; or to 5-fluorouracil; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: severe kidney disease, a certain enzyme deficiency (dihydropyrimidine dehydrogenase deficiency).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: blood disorders (e.g., bone marrow suppression), heart problems (e.g., coronary artery disease, heart failure), kidney problems, liver problems.

Wash your hands well to prevent the spread of infections.

Do not have immunizations/vaccinations without the consent of your doctor, and avoid contact with people who have recently received oral polio vaccine.

This medication may make you more sensitive to the sun. Avoid prolonged sun exposure, tanning booths, and sunlamps. Use an effective sunscreen and wear protective clothing when outdoors. This will also help protect you from problems related to heat (hand/foot syndrome). See Side Effects section for more information.

To lower the chance of getting cut, bruised or injured, use caution with sharp objects like safety razors and nail cutters, and avoid activities such as contact sports. Use a soft-bristle toothbrush to lower the risk of bleeding gums.

Caution is advised when this drug is used in the elderly because they may be more sensitive to the side effects of this medication, especially nausea, vomiting, and diarrhea.

This drug is not recommended for use during pregnancy. It may harm an unborn baby. Consult your doctor for more details and to discuss reliable forms of birth control. It is recommended that men and women use two effective forms of birth control (e.g., condoms and birth control pills) while taking this medication.

It is not known if this drug passes into breast milk. Because of possible harm to the nursing infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop or change the dosage of any medicine before checking with them first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially: folic acid (including multivitamins with folic acid), leucovorin, metronidazole, tinidazole.

This drug can change the removal of other drugs from your body by affecting certain liver enzymes. These affected drugs include: "blood thinners" (e.g., warfarin), fosphenytoin, phenytoin.

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting capecitabine.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., bilirubin levels, complete blood counts, kidney and liver function tests) should be performed regularly to monitor your progress and check for side effects.

MISSED DOSE: If you miss a dose, do not take the missed dose and do not double the next dose. Continue your regular dosing schedule and check with your doctor.

STORAGE: Store at room temperature at 77 degrees F (25 degrees C) in a tightly closed container away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information call MedicAlert at 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.