XELODA (capecitabine) is a nucleoside metabolic inhibitor indicated for:

Colorectal Cancer

• adjuvant treatment of patients with Stage III colon cancer as a single agent or as a component of a combination chemotherapy regimen. (1.1)
• perioperative treatment of adults with locally advanced rectal cancer as a component of chemoradiotherapy. (1.1)
• treatment of patients with unresectable or metastatic colorectal cancer as a single agent or as a component of a combination chemotherapy regimen. (1.1)

Breast Cancer

• treatment of patients with advanced or metastatic breast cancer as a single agent if an anthracycline- or taxane-containing chemotherapy is not indicated. (1.2)
• treatment of patients with advanced or metastatic breast cancer in combination with docetaxel after disease progression on prior anthracycline-containing chemotherapy. (1.2)

Gastric, Esophageal, or Gastroesophageal Junction Cancer

• treatment of adults with unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer as a component of a combination chemotherapy regimen. (1.3)
• treatment of adults with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease as a component of a combination regimen. (1.3)

Pancreatic Cancer

• adjuvant treatment of adults with pancreatic adenocarcinoma as a component of a combination chemotherapy regimen. (1.4)

XELODA is indicated for the:

• adjuvant treatment of patients with Stage III colon cancer as a single agent or as a component of a combination chemotherapy regimen.
• perioperative treatment of adults with locally advanced rectal cancer as a component of chemoradiotherapy.
• treatment of patients with unresectable or metastatic colorectal cancer as a single agent or as a component of a combination chemotherapy regimen.

XELODA is indicated for the:

• treatment of patients with advanced or metastatic breast cancer as a single agent if an anthracycline- or taxane-containing chemotherapy is not indicated.
• treatment of patients with advanced or metastatic breast cancer in combination with docetaxel after disease progression on prior anthracycline-containing chemotherapy.

XELODA is indicated for the:

• treatment of adults with unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer as a component of a combination chemotherapy regimen.
• treatment of adults with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease as a component of a combination regimen.

XELODA is indicated for the adjuvant treatment of adults with pancreatic adenocarcinoma as a component of a combination chemotherapy regimen.

Adjuvant Treatment of Colon Cancer

• Single agent: 1,250 mg/m² twice daily orally for the first 14 days of each 21-day cycle for a maximum of 8 cycles. (2.1) In combination with Oxaliplatin-Containing Regimens: 1,000 mg/m² orally twice daily for the first 14 days of each 21-day cycle for a maximum of 8 cycles in combination with oxaliplatin 130 mg/m² administered intravenously on day 1 of each cycle. (2.1)

Perioperative Treatment of Rectal Cancer

• With Concomitant Radiation Therapy: 825 mg/m² orally twice daily (2.2)
• Without Radiation Therapy: 1,250 mg/m² orally twice daily (2.2)

Unresectable or Metastatic Colorectal Cancer:

• Single agent: 1,250 mg/m² twice daily orally for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity. (2.2)
• In Combination with Oxaliplatin: 1,000 mg/m² orally twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with oxaliplatin 130 mg/m² administered intravenously on day 1 of each cycle. (2.2)

Advanced or Metastatic Breast Cancer:

• Single agent: 1,000 mg/m² or 1,250 mg/m² twice daily orally for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity. (2.3)
• In combination with docetaxel: 1,000 mg/m² or 1,250 mg/m² orally twice daily for the first 14 days of a 21-day cycle, until disease progression or unacceptable toxicity in combination with docetaxel at 75 mg/m² administered intravenously on day 1 of each cycle (2.3)

Unresectable or Metastatic Gastric, Esophageal, or Gastroesophageal Junction Cancer

• 625 mg/m² orally twice daily on days 1 to 21 of each 21-day cycle for a maximum of 8 cycles in combination with platinum-containing chemotherapy. (2.4)
  OR
• 850 mg/m² or 1,000 mg/m² orally twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with oxaliplatin 130 mg/m² administered intravenously on day 1 of each cycle. (2.4)

HER2-overexpressing metastatic adenocarcinoma of the gastroesophageal junction or stomach

• 1,000 mg/m² orally twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with cisplatin and trastuzumab. (2.4)

Pancreatic cancer

• 830 mg/m² orally twice daily for the first 21 days of each 28-day cycle for maximum of 6 cycles in combination with gemcitabine 1,000 mg/m² administered intravenously on days 1, 8, and 15 of each cycle. (2.5)

Refer to Sections 2.5 and 2.6 for information related to dosage modifications for adverse reactions and renal impairment (2.5 and 2.6).

Prior to initiating XELODA, test patients for genetic variants of the DPYD gene unless immediate treatment is necessary. An FDA-authorized test for the detection of the DPYD gene to identify patients at risk of serious adverse reactions with XELODA is not currently available. Currently available tests used to identify DPYD variants may vary in accuracy and design (e.g., which DPYD variant(s) they identify).

Avoid use of XELODA in patients known to have certain homozygous or compound heterozygous DPYD variants that result in complete DPD deficiency. No XELODA dose has been proven safe for patients with complete DPD deficiency. For patients with partial DPD deficiency, individualize the dosage and modify based on tolerability and intent of treatment [see Warnings and Precautions (5.1) ].

Adjuvant Treatment of Colon Cancer

Single Agent

The recommended dosage of XELODA is 1,250 mg/m² orally twice daily for the first 14 days of each 21-day cycle for a maximum of 8 cycles.

In Combination with Oxaliplatin-Containing Regimens

The recommended dosage of XELODA is 1,000 mg/m² orally twice daily for the first 14 days of each 21-day cycle for a maximum of 8 cycles in combination with oxaliplatin 130 mg/m² administered intravenously on day 1 of each cycle.

Refer to the oxaliplatin prescribing information for additional dosing information as appropriate.

Perioperative Treatment of Rectal Cancer

The recommended dosage of capecitabine is 825 mg/m² orally twice daily when administered with concomitant radiation therapy and 1,250 mg/m² orally twice daily when administered without radiation therapy as part of a peri-operative combination regimen.

Unresectable or Metastatic Colorectal Cancer

Single Agent

The recommended dosage of XELODA is 1,250 mg/m² orally twice daily for the first 14 days of a 21-day cycle until disease progression or unacceptable toxicity.

In Combination with Oxaliplatin

The recommended dosage of XELODA is 1,000 mg/m² orally twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with oxaliplatin 130 mg/m² administered intravenously on day 1 of each cycle.

Refer to the Prescribing Information for oxaliplatin for additional dosing information as appropriate.

Advanced or Metastatic Breast Cancer

Single Agent

The recommended dosage of XELODA is 1,000 mg/m² or 1,250 mg/m² orally twice daily for the first 14 days of a 21-day cycle until disease progression or unacceptable toxicity. Individualize the dose and dosing schedule of XELODA based on patient risk factors and adverse reactions.

In Combination with Docetaxel

The recommended dosage of XELODA is 1,000 mg/m² or 1,250 mg/m² orally twice daily for the first 14 days of a 21-day cycle until disease progression or unacceptable toxicity in combination with docetaxel 75 mg/m² administered intravenously on day 1 of each cycle.

Refer to the Prescribing Information for docetaxel for additional dosing information as appropriate.

The recommended dosage of XELODA for unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer is:

• 625 mg/m² orally twice daily on days 1 to 21 of each 21-day cycle for a maximum of 8 cycles in combination with platinum-containing chemotherapy.
  OR
• 850 mg/m² or 1,000 mg/m² orally twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with oxaliplatin 130 mg/m² administered intravenously on day 1 of each cycle. Individualize the dose and dosing schedule of XELODA based on patient risk factors and adverse reactions.

The recommended dosage of XELODA for HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma is 1,000 mg/m² orally twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with cisplatin and trastuzumab.

Refer to the Prescribing Information for agents used in combination for additional dosing information as appropriate.

The recommended dosage of XELODA is 830 mg/m² orally twice daily for the first 21 days of each 28-day cycle until disease progression, unacceptable toxicity, or for a maximum 6 cycles in combination with gemcitabine 1,000 mg/m² administered intravenously on days 1, 8, and 15 of each cycle.

Refer to Prescribing Information for gemcitabine for additional dosing information as appropriate.

Monitor patients for adverse reactions and modify dosages of XELODA as described in Table 1. Do not replace missed doses of XELODA; instead resume XELODA with the next planned dosage.

When XELODA is administered with docetaxel, withhold XELODA and docetaxel until the requirements for resuming both XELODA and docetaxel are met. Refer to the Prescribing Information for docetaxel for additional dosing information as appropriate.

Table 1 Recommended Dosage Modifications for Adverse Reactions

Severity	Dosage Modification	Resume at Same or Reduced Dose (Percent of Current Dose)
Grade 2
1st appearance	Withhold until resolved to grade 0-1.	100%
2nd appearance		75%
3rd appearance		50%
4th appearance	Permanently discontinue.	-
Grade 3
1st appearance	Withhold until resolved to grade 0-1.	75%
2nd appearance		50%
3rd appearance	Permanently discontinue.	-
Grade 4
1st appearance	Permanently discontinue OR Withhold until resolved to grade 0-1.	50%

Hyperbilirubinemia

Patients with Grade 3-4 hyperbilirubinemia may resume treatment once the event is Grade 2 or less (less than three times the upper limit of normal), using the percent of current dose as shown in column 3 of Table 1 [see Warnings and Precautions (5.10)].

Reduce the dose of XELODA by 25% for patients with creatinine clearance (CLcr) of 30 to 50 mL/min as determined by Cockcroft-Gault equation. A dosage has not been established in patients with severe renal impairment (CLcr <30 mL/min) [see Use in Specific Populations (8.6)].

Round the recommended dosage for patients to the nearest 150 mg dose to provide whole XELODA tablets.

Swallow XELODA tablets whole with water within 30 minutes after a meal. Do not chew, cut, or crush XELODA tablets [see Warnings and Precautions (5.12)].

Take XELODA at the same time each day approximately 12 hours apart.

Do not take an additional dose after vomiting and continue with the next scheduled dose.

Do not take a missed dose and continue with the next scheduled dose.

XELODA is a hazardous drug. Follow applicable special handling and disposal procedures.¹

XELODA is contraindicated in patients with history of severe hypersensitivity reaction to fluorouracil or capecitabine [see Adverse Reactions (6.1)].

History of severe hypersensitivity reactions to fluorouracil or capecitabine (4)

• Cardiotoxicity: May be more common in patients with a prior history of coronary artery disease. Withhold XELODA for cardiotoxicity as appropriate. The safety of resumption of XELODA in patients with cardiotoxicity that has resolved has not been established. (2.5, 5.3)
• Diarrhea: Withhold XELODA and then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence. (2.5, 5.4)
• Dehydration: Optimize hydration before starting XELODA. Monitor hydration status and kidney function at baseline and as clinically indicated. Withhold XELODA and then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence. (2.5, 5.5)
• Renal Toxicity: Monitor renal function at baseline and as clinically indicated. Optimize hydration before starting XELODA. Withhold XELODA and then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence. (2.5, 5.6)
• Serious Skin Toxicities: Monitor for new or worsening serious skin reactions. Permanently discontinue XELODA in patients who experience a severe cutaneous adverse reaction. (5.7)
• Palmar-Plantar Erythrodysesthesia Syndrome: Withhold XELODA then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence. (2.5, 5.8)
• Myelosuppression: Monitor complete blood count at baseline and before each cycle. XELODA is not recommended in patients with baseline neutrophil counts <1.5 × 10⁹/L or platelet counts <100 × 10⁹/L. For grade 3 or 4 myelosuppression, withhold XELODA and then resume at same or reduced dose, or permanently discontinue, based on occurrence. (2.5, 5.9)
• Hyperbilirubinemia: Patients with Grade 3-4 hyperbilirubinemia may resume treatment once the event is Grade 2 or less (≤3 × ULN), using the percent of current dose as shown in column 3 of Table 1 (2.5, 5.10)
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. (5.11, 8.1, 8.3)

Patients with certain homozygous or compound heterozygous variants in the DPYD gene known to result in complete or near complete absence of DPD activity (complete DPD deficiency) are at increased risk for acute early-onset toxicity and serious, including fatal, adverse reactions due to XELODA (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity). Patients with partial DPD activity (partial DPD deficiency) may also have increased risk of serious or fatal, adverse reactions.

Prior to initiating XELODA, test patients for genetic variants of the DPYD gene unless immediate treatment is necessary [see Clinical Pharmacology (12.5) ]. Serious adverse reactions may still occur even if no DPYD variants are identified.

Avoid use of XELODA in patients with certain homozygous or compound heterozygous DPYD variants that result in complete DPD deficiency.

Withhold or permanently discontinue XELODA based on clinical assessment of the onset, duration, and severity of adverse reactions in patients with evidence of acute early-onset or unusually severe reactions. No XELODA dose has been proven safe for patients with complete DPD deficiency. There are insufficient data to recommend a specific dose in patients with partial DPD deficiency. For patients with partial DPD deficiency, individualize the dosage and modify based on tolerability and intent of treatment.

An FDA-authorized test for the detection of genetic variants of the DPYD gene to identify patients at risk of serious adverse reactions with XELODA treatment is not currently available. Currently available tests used to identify DPYD variants may vary in accuracy and design (e.g., which DPYD variant(s) they identify).

Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking XELODA concomitantly with vitamin K antagonists, such as warfarin.

Clinically significant increases in PT and INR have been reported in patients who were on stable doses of oral vitamin K antagonists at the time XELODA was introduced. These events occurred within several days and up to several months after initiating XELODA and, in a few cases, within 1 month after stopping XELODA. These events occurred in patients with and without liver metastases.

Monitor INR more frequently and adjust the dose of the vitamin K antagonist as appropriate [see Drug Interactions (7.1)].

Cardiotoxicity can occur with XELODA. Myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy have been reported with XELODA. These adverse reactions may be more common in patients with a prior history of coronary artery disease.

Withhold XELODA for cardiotoxicity as appropriate [see Dosage and Administration (2.5)]. The safety of resumption of XELODA in patients with cardiotoxicity that has resolved have not been established.

Diarrhea, sometimes severe, can occur with XELODA. In 875 patients with metastatic breast or colorectal cancer who received XELODA as a single agent, the median time to first occurrence of grade 2 to 4 diarrhea was 34 days (range: 1 day to 1 year). The median duration of grade 3 to 4 diarrhea was 5 days.

Withhold XELODA and then resume at same or reduced dose or permanently discontinue based on severity and occurrence [see Dosage and Administration (2.5)].

Dehydration can occur with XELODA. Patients with anorexia, asthenia, nausea, vomiting, or diarrhea may be at an increased risk of developing dehydration with XELODA. Optimize hydration before starting XELODA. Monitor hydration status and kidney function at baseline and as clinically indicated. Withhold XELODA and then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence [see Dosage and Administration (2.5)].

Serious renal failure, sometimes fatal, can occur with XELODA. Renal impairment or coadministration of XELODA with other products known to cause renal toxicity may increase the risk of renal toxicity [see Drug Interactions (7.3)].

Monitor renal function at baseline and as clinically indicated. Optimize hydration before starting XELODA. Withhold XELODA and then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence [see Dosage and Administration (2.5)].

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson Syndrome and toxic epidermal necrolysis (TEN), which can be fatal, can occur with XELODA [see Adverse Reactions (6.2)].

Monitor for new or worsening serious skin reactions. Permanently discontinue XELODA for severe cutaneous adverse reactions.

Palmar-plantar erythrodysesthesia syndrome (PPES) can occur with XELODA.

In patients with metastatic breast or colorectal cancer who received XELODA as a single agent, the median time to onset of grades 1 to 3 PPES was 2.6 months (range: 11 days to 1 year).

Withhold XELODA and then resume at same or reduced dose or permanently discontinue based on severity and occurrence [see Dosage and Administration (2.5)].

Myelosuppression can occur with XELODA.

In the 875 patients with metastatic breast or colorectal cancer who received XELODA as a single agent, 3.2% had grade 3 or 4 neutropenia, 1.7% had grade 3 or 4 thrombocytopenia, and 2.4% had grade 3 or 4 anemia.

In the 251 patients with metastatic breast cancer who received XELODA with docetaxel, 68% had grade 3 or 4 neutropenia, 2.8% had grade 3 or 4 thrombocytopenia, and 10% had grade 3 or 4 anemia.

Necrotizing enterocolitis (typhlitis) has been reported. Consider typhlitis in patients with fever, neutropenia and abdominal pain.

Monitor complete blood count at baseline and before each cycle. XELODA is not recommended if baseline neutrophil count <1.5 × 10⁹/L or platelet count <100 × 10⁹/L. For grade 3 to 4 myelosuppression, withhold XELODA and then resume at same or reduced dose, or permanently discontinue, based on occurrence [see Dosage and Administration (2.5)].

Hyperbilirubinemia can occur with XELODA. In the 875 patients with metastatic breast or colorectal cancer who received XELODA as a single agent, grade 3 hyperbilirubinemia occurred in 15% of patients and grade 4 hyperbilirubinemia occurred in 3.9%. Of the 566 patients who had hepatic metastases at baseline and the 309 patients without hepatic metastases at baseline, grade 3 or 4 hyperbilirubinemia occurred in 23% and 12%, respectively. Of these 167 patients with grade 3 or 4 hyperbilirubinemia, 19% had postbaseline increased alkaline phosphatase and 28% had postbaseline increased transaminases at any time (not necessarily concurrent). The majority of these patients with increased transaminases or alkaline phosphatase had liver metastases at baseline. In addition, 58% and 35% of the 167 patients with grade 3 or 4 hyperbilirubinemia had pre- and postbaseline increased alkaline phosphatase or transaminases (grades 1 to 4), respectively. Only 8% (n=13) and 3% (n=5) had grade 3 or 4 increased alkaline phosphatase or transaminases.

In the 596 patients who received XELODA for metastatic colorectal cancer, the incidence of grade 3 or 4 hyperbilirubinemia was similar to that observed for the pooled population of patients with metastatic breast and colorectal cancer. The median time to onset for grade 3 or 4 hyperbilirubinemia was 64 days and median total bilirubin increased from 8 µm/L at baseline to 13 µm/L during treatment with XELODA. Of the 136 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 the 251 patients with metastatic breast cancer who received XELODA with docetaxel, grade 3 hyperbilirubinemia occurred in 7% and grade 4 hyperbilirubinemia occurred in 2%.

Withhold XELODA and then resume at a same or reduced dose, or permanently discontinue, based on occurrence [see Dosage and Administration (2.5)]. Patients with Grade 3-4 hyperbilirubinemia may resume treatment once the event is Grade 2 or less than three times the upper limit of normal, using the percent of current dose as shown in Table 1 [see Dosage and Administration (2.5)].

Based on findings from animal reproduction studies and its mechanism of action, XELODA can cause fetal harm when administered to a pregnant woman. Insufficient data is available on XELODA use in pregnant women to evaluate a drug-associated risk. In animal reproduction studies, administration of capecitabine to pregnant animals during the period of organogenesis caused embryolethality and teratogenicity in mice and embryolethality in monkeys at 0.2 and 0.6 times the human exposure (AUC) in patients who received a dosage of 1,250 mg/m² twice daily, respectively.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with XELODA and for 6 months following the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with XELODA and for 3 months following the last dose [see Use in Specific Populations (8.1, 8.3)].

In instances of exposure to crushed XELODA tablets, the following adverse reactions have been reported: eye irritation and swelling, skin rash, diarrhea, paresthesia, headache, gastric irritation, vomiting and nausea. Advise patients not to cut or crush tablets.

If XELODA tablets must be cut or crushed, this should be done by a professional trained in safe handling of cytotoxic drugs using appropriate equipment and safety procedures [see Dosage and Administration (2.7)]. The safety and effectiveness have not been established for the administration of crushed XELODA tablets.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Cardiotoxicity [see Warnings and Precautions (5.3)]
• Diarrhea [see Warnings and Precautions (5.4)]
• Dehydration [see Warnings and Precautions (5.5)]
• Renal Toxicity [see Warnings and Precautions (5.6)]
• Serious Skin Toxicities [see Warnings and Precautions (5.7)]
• Palmar-Plantar Erythrodysesthesia Syndrome [see Warnings and Precautions (5.8)]
• Myelosuppression [see Warnings and Precautions (5.9)]
• Hyperbilirubinemia [see Warnings and Precautions (5.10)]

• Most common adverse reactions in patients who received XELODA as a single agent for the adjuvant treatment for colon cancer (≥30%) were palmar-plantar erythrodysesthesia syndrome, diarrhea, and nausea. (6.1)
• Most common adverse reactions (≥30%) in patients with metastatic colorectal cancer who received XELODA as a single agent were anemia, diarrhea, palmar-plantar erythrodysesthesia syndrome, hyperbilirubinemia, nausea, fatigue, and abdominal pain. (6.1)
• Most common adverse reactions (≥30%) in patients with metastatic breast cancer who received XELODA with docetaxel were diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, nausea, alopecia, vomiting, edema, and abdominal pain. (6.1)
• Most common adverse reactions (≥30%) in patients with metastatic breast cancer who received XELODA as a single agent were lymphopenia, anemia, diarrhea, hand-and-foot syndrome, nausea, fatigue, vomiting, and dermatitis. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact 1-866-995-4272 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adjuvant Treatment of Colon Cancer

Single Agent

The safety of XELODA as a single agent was evaluated in patients with Stage III colon cancer in X-ACT [see Clinical Studies (14.1)]. Patients received XELODA 1,250 mg/m² orally twice daily for the first 14 days of a 21-day cycle (N=995) or leucovorin 20 mg/m² intravenously followed by fluorouracil 425 mg/m² as an intravenous bolus on days 1 to 5 of each 28-day cycle (N=974). Among patients who received XELODA, the median duration of treatment was 5.4 months.

Deaths due to all causes occurred in 0.8% of patients who received XELODA on study or within 28 days of receiving study drug. Permanent discontinuation due to an adverse reaction occurred in 11% of patients who received XELODA.

Most common adverse reactions (>30%) were palmar-plantar erythrodysesthesia syndrome, diarrhea, and nausea.

Tables 2 and 3 summarize the adverse reactions and laboratory abnormalities in X-ACT.

Table 2 Adverse Reactions (≥10%) in Patients Who Received XELODA for Adjuvant Treatment of Colon Cancer in X-ACT

Adverse Reaction	XELODA (N=995)		Fluorouracil + Leucovorin (N=974)
	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Skin and Subcutaneous Tissue
Palmar-plantar erythrodysesthesia syndrome	60	17	9	<1
Gastrointestinal
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
General
Fatigue	16	<1	16	1
Asthenia	10	<1	10	1
Lethargy	10	<1	9	<1

Clinically relevant adverse reactions in <10% of patients are presented below:

Eye: conjunctivitis

Gastrointestinal: constipation, upper abdominal pain, dyspepsia

General: pyrexia

Metabolism and Nutrition: anorexia

Nervous System: dizziness, dysgeusia, headache

Skin & Subcutaneous Tissue: rash, alopecia, erythema

Table 3 Grade 3 or 4 Laboratory Abnormalities (>1%) in Patients Who Received XELODA as a Single Agent for Adjuvant Treatment of Colon Cancer in X-ACT

Laboratory Abnormality	XELODA (N=995)	Fluorouracil + Leucovorin (N=974)
	Grade 3 or 4	Grade 3 or 4
	(%)	(%)
Bilirubin increased	20	6
Lymphocytes decreased	13	13
Neutrophils/granulocytes decreased	2.4	26
Calcium decreased	2.3	2.2
Neutrophils decreased	2.2	26
ALT increased	1.6	0.6
Calcium increased	1.1	0.7
Hemoglobin decreased	1	1.2
Platelets decreased	1	0.7

In Combination with Oxaliplatin-Containing Regimens

The safety of XELODA for the perioperative treatment of adults with Stage III colon cancer as a component of a combination chemotherapy regimen was derived from published literature [see Clinical Studies (14.1)]. The safety of XELODA for the adjuvant treatment of patients with Stage III colon cancer as a component of a combination chemotherapy regimen was similar to those in patients treated with XELODA as a single agent, with the exception of an increased incidence of neurosensory toxicity.

Perioperative Treatment of Rectal Cancer

The safety of XELODA for the perioperative treatment of adults with locally advanced rectal cancer as a component of chemoradiotherapy was derived from published literature [see Clinical Studies (14.1)]. The safety of XELODA for the perioperative treatment of adults with locally advanced rectal cancer as a component of chemoradiotherapy was similar to those in patients treated with XELODA as a single agent, with the exception of an increased incidence of diarrhea.

Metastatic Colorectal Cancer

Single Agent

The safety of XELODA as a single agent was evaluated in a pooled metastatic colorectal cancer population (Study SO14695 and Study SO14796) [see Clinical Studies (14.1)]. Patients received XELODA 1,250 mg/m² orally twice a day for the first 14 days of a 21-day cycle (N=596) or leucovorin 20 mg/m² intravenously followed by fluorouracil 425 mg/m² as an intravenous bolus on days 1 to 5 of each 28-day cycle (N=593). Among the patients who received XELODA, the median duration of treatment was 4.6 months.

Deaths due to all causes occurred in 8% of patients who received XELODA on study or within 28 days of receiving study drug. Permanent discontinuation due to an adverse reaction or intercurrent illness occurred in 13% of patients who received XELODA.

Most common adverse reactions (>30%) were anemia, diarrhea, palmar-plantar erythrodysesthesia syndrome, hyperbilirubinemia, nausea, fatigue, and abdominal pain.

Table 4 shows the adverse reactions occurring in this pooled colorectal cancer population.

Table 4 Adverse Reactions (≥10%) in Patients Who Received XELODA in Pooled Metastatic Colorectal Cancer Population (Study SO14695 and Study SO14796)

Adverse Reaction	XELODA			Fluorouracil + Leucovorin
	(N=596)			(N=593)
	All Grades (%)	Grade 3 (%)	Grade 4 (%)	All Grades (%)	Grade 3 (%)	Grade 4 (%)
– Not observed NA = Not Applicable
Blood and Lymphatic System
Anemia	80	2	<1	79	1	<1
Neutropenia	13	1	2	46	8	13
Gastrointestinal
Diarrhea	55	13	2	61	10	2
Nausea	43	4	–	51	3	<1
Abdominal pain	35	9	<1	31	5	–
Vomiting	27	4	<1	30	4	<1
Stomatitis	25	2	<1	62	14	1
Constipation	14	1	<1	17	1	–
Gastrointestinal motility disorder	10	<1	–	7	<1	–
Oral discomfort	10	–	–	10	–	–
Skin and Subcutaneous Tissue
Palmar-plantar erythrodysesthesia syndrome	54	17	NA	6	1	NA
Dermatitis	27	1	–	26	1	–
Hepatobiliary
Hyperbilirubinemia	48	18	5	17	3	3
General
FatigueIncludes weakness	42	4	–	46	4	–
Pyrexia	18	1	–	21	2	–
Edema	15	1	–	9	1	–
Pain	12	1	–	10	1	–
Metabolism and Nutrition
Decreased appetite	26	3	<1	31	2	<1
Respiratory Thoracic and Mediastinal
Dyspnea	14	1	–	10	<1	1
Eye
Eye irritation	13	–	–	10	<1	–
Nervous System
Peripheral sensory neuropathy	10	–	–	4	–	–
Headache	10	1	–	7	–	–
Musculoskeletal
Back pain	10	2	–	9	<1	–

Clinically relevant adverse reactions in <10% of patients are presented below:

Eye: abnormal vision

Gastrointestinal: upper gastrointestinal tract inflammatory disorders, gastrointestinal hemorrhage, ileus

General: chest pain

Infections: viral

Metabolism and Nutrition: dehydration

Musculoskeletal: arthralgia

Nervous System: dizziness (excluding vertigo), insomnia, taste disturbance

Psychiatric: mood alteration, depression

Respiratory, Thoracic, and Mediastinal: cough, pharyngeal disorder

Skin and Subcutaneous Tissue: skin discoloration, alopecia

Vascular: venous thrombosis

In Combination with Oxaliplatin

The safety of XELODA for the treatment of patients with unresectable or metastatic colorectal cancer as a component of a combination chemotherapy regimen was derived from published literature [see Clinical Studies (14.1)]. The safety of XELODA for the treatment of patients with unresectable or metastatic colorectal cancer as a component of a combination chemotherapy regimen was similar to those in patients treated with XELODA as a single agent, with the exception of an increased incidence of peripheral neuropathy.

Metastatic Breast Cancer

In Combination with Docetaxel

The safety of XELODA in combination with docetaxel was evaluated in patients with metastatic breast cancer in Study SO14999 [see Clinical Studies (14.2)]. Patients received XELODA 1,250 mg/m² orally twice daily for the first 14 days of a 21-day cycle with docetaxel 75 mg/m² as 1-hour intravenous infusion on day 1 of each 21-day cycle for at least 6 weeks or docetaxel 100 mg/m² as a 1-hour intravenous infusion on day 1 of each 21-day cycle for at least 6 weeks. Among patients who received XELODA, the mean duration of treatment was 4.2 months.

Permanent discontinuation due to an adverse reaction occurred in 26% of patients who received XELODA. Dosage interruptions due to an adverse reaction occurred in 79% of patients who received XELODA and dosage reductions due to an adverse reaction occurred in 65%.

Most common adverse reactions (>30%) were diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, nausea, alopecia, vomiting, edema, and abdominal pain.

Table 5 summarizes the adverse reactions in Study SO14999.

Table 5 Adverse Reactions (≥10%) in Patients Who Received XELODA with Docetaxel for Metastatic Breast Cancer in Study SO14999

Adverse Reaction	XELODA with Docetaxel			Docetaxel
	(N=251)			(N=255)
	All Grades (%)	Grade 3 (%)	Grade 4 (%)	All Grades (%)	Grade 3 (%)	Grade 4 (%)
– Not observed NA = Not Applicable
Gastrointestinal
Diarrhea	67	14	<1	48	5	<1
Stomatitis	67	17	<1	43	5	–
Nausea	45	7	–	36	2	–
Vomiting	35	4	1	24	2	–
Abdominal pain	30	3	<1	24	2	–
Constipation	20	2	–	18	–	–
Dyspepsia	14	–	–	8	1	–
Skin and Subcutaneous Tissue
Palmar-plantar erythrodysesthesia syndrome	63	24	NA	8	1	NA
Alopecia	41	6	–	42	7	–
Nail disorder	14	2	–	15	–	–
Cardiac
Edema	33	<2	–	34	<3	1
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	–
Blood and Lymphatic System
Neutropenic fever	16	3	13	21	5	16
Nervous System
Taste disturbance	16	<1	–	14	<1	–
Headache	15	3	–	15	2	–
Paresthesia	12	<1	–	16	1	–
Dizziness	12	–	–	8	<1	–
Musculoskeletal and Connective Tissue
Arthralgia	15	2	–	24	3	–
Myalgia	15	2	–	25	2	–
Back Pain	12	<1	–	11	3	–
Respiratory, Thoracic and Mediastinal
Dyspnea	14	2	<1	16	2	–
Cough	13	1	–	22	<1	–
Sore Throat	12	2	–	11	<1	–
Metabolism and Nutrition
Anorexia	13	<1	–	11	<1	–
Appetite decreased	10	–	–	5	–	–
Dehydration	10	2	–	7	<1	<1
Eye
Lacrimation increased	12	–	–	7	<1	–

Clinically relevant adverse reactions in <10% of patients are presented below:

Blood and Lymphatic System: agranulocytosis, prothrombin decreased

Cardiac: supraventricular tachycardia

Eye: conjunctivitis, eye irritation

Gastrointestinal: ileus, necrotizing enterocolitis, esophageal ulcer, hemorrhagic diarrhea, dry mouth

General: chest pain (non-cardiac), lethargy, pain, influenza-like illness

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

Immune System: hypersensitivity

Infection: hypoesthesia, neutropenic sepsis, sepsis, bronchopneumonia, oral candidiasis, urinary tract infection

Metabolism and Nutrition: weight decreased

Musculoskeletal and Connective Tissue: bone pain

Nervous System: insomnia, peripheral neuropathy, ataxia, syncope, taste loss, polyneuropathy, migraine

Psychiatric: depression

Renal and Urinary: renal failure

Respiratory, Thoracic and Mediastinal: upper respiratory tract infection, pleural effusion, epistaxis, rhinorrhea

Skin and Subcutaneous Tissue: pruritis, rash erythematous, dermatitis, nail discoloration, onycholysis

Vascular: lymphedema, hypotension, venous phlebitis and thrombophlebitis, postural hypotension, flushing

Table 6 summarizes the laboratory abnormalities in this trial.

Table 6 Laboratory Abnormalities (≥20%) in Patients Who Received XELODA with Docetaxel for Metastatic Breast Cancer in Study SO14999

Laboratory Abnormality	XELODA with Docetaxel			Docetaxel
	(N=251)			(N=255)
	All Grades (%)	Grade 3 (%)	Grade 4 (%)	All Grades (%)	Grade 3 (%)	Grade 4 (%)
Hematologic
Lymphocytopenia	99	48	41	98	44	40
Leukopenia	91	37	24	88	42	33
Neutropenia	86	20	49	87	10	66
Anemia	80	7	3	83	5	<1
Thrombocytopenia	41	2	1	23	1	2
Hepatobiliary
Hyperbilirubinemia	20	7	2	6	2	2

Single Agent

The safety of XELODA as a single agent was evaluated in patients with metastatic breast cancer in Study SO14697 [see Clinical Studies (14.2)]. Patients received XELODA 1,250 mg/m² orally twice daily for the first 14 days of a 21-day cycle. The mean duration of treatment was 3.7 months.

Permanent discontinuation due to an adverse reaction or intercurrent illness occurred in 8% of patients.

Most common adverse reactions (>30%) were lymphopenia, anemia, diarrhea, hand-and-foot syndrome, nausea, fatigue, vomiting, and dermatitis.

Table 7 summarizes the adverse reactions in Study SO14697.

Table 7 Adverse Reactions (≥10%) in Patients Who Received XELODA for Metastatic Breast Cancer in Study SO14697

Adverse Reaction	XELODA (n=162)
	All Grades (%)	Grade 3 (%)	Grade 4 (%)
	– = Not observed     NA = Not Applicable
Blood and Lymphatic System
Lymphopenia	94	44	15
Anemia	72	3	1
Neutropenia	26	2	2
Thrombocytopenia	24	3	1
Gastrointestinal
Diarrhea	57	12	3
Nausea	53	4	–
Vomiting	37	4	–
Stomatitis	24	7	–
Abdominal pain	20	4	–
Constipation	15	1	–
Skin and Subcutaneous Tissue
Hand-and-foot syndrome	57	11	NA
Dermatitis	37	1	–
General
Fatigue	41	8	–
Pyrexia	12	1	–
Metabolism and Nutrition
Anorexia	23	3	–
Hepatobiliary
Hyperbilirubinemia	22	9	2
Nervous System
Paresthesia	21	1	–
Eye
Eye irritation	15	–	–

Pooled Safety Population

Clinically relevant adverse reactions in <10% of patients who received XELODA as a single agent are presented below.

Blood & Lymphatic System: leukopenia, coagulation disorder, bone marrow depression, pancytopenia

Cardiac: tachycardia, bradycardia, atrial fibrillation, myocarditis, edema

Ear: vertigo

Eye: conjunctivitis

Gastrointestinal: abdominal distension, dysphagia, proctalgia, gastric ulcer, ileus, gastroenteritis, dyspepsia

General: chest pain, influenza-like illness, hot flushes, pain, thirst, fibrosis, hemorrhage, edema, pain in limb

Hepatobiliary: hepatic fibrosis, hepatitis, cholestatic hepatitis, abnormal liver function tests

Immune System: drug hypersensitivity

Infections: bronchitis, pneumonia, keratoconjunctivitis, sepsis, fungal infections

Metabolism and Nutrition: cachexia, hypertriglyceridemia, hypokalemia, hypomagnesemia, dehydration

Musculoskeletal and Connective Tissue: myalgia, arthritis, muscle weakness

Nervous System: insomnia, ataxia, tremor, dysphasia, encephalopathy, dysarthria, impaired balance, headache, dizziness

Psychiatric: depression, confusion

Renal and Urinary: renal impairment

Respiratory, Mediastinal and Thoracic: cough, epistaxis, respiratory distress, dyspnea

Skin and Subcutaneous Tissue: nail disorder, sweating increased, photosensitivity reaction, skin ulceration, pruritus, radiation recall syndrome

Vascular: hypotension, hypertension, lymphedema, pulmonary embolism

Unresectable or Metastatic Gastric, Esophageal, or Gastroesophageal Junction Cancer

The safety of XELODA for the treatment of adults with unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer as a component of a combination chemotherapy regimen was derived from published literature [see Clinical Studies (14.3)]. The safety of XELODA for the treatment of adults with unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer as a component of a combination chemotherapy regimen was consistent with the known safety profile of XELODA.

The safety of XELODA for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease as a component of a combination regimen was derived from the published literature [see Clinical Studies (14.3)]. The safety of XELODA for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma was consistent with the known safety profile of XELODA.

Pancreatic Cancer

The safety of XELODA for the adjuvant treatment of adults with pancreatic adenocarcinoma as a component of a combination chemotherapy regimen was derived from the published literature [see Clinical Studies (14.4)]. The safety of XELODA for the adjuvant treatment of adults with pancreatic adenocarcinoma as a component of a combination chemotherapy regimen was consistent with the known safety profile of XELODA.

The following adverse reactions have been identified during post-approval use of XELODA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Eye: lacrimal duct stenosis, corneal disorders including keratitis

Hepatobiliary: hepatic failure

Immune System Disorders: angioedema

Nervous System: toxic leukoencephalopathy

Renal & Urinary: acute renal failure secondary to dehydration including fatal outcome

Skin & Subcutaneous Tissue: cutaneous lupus erythematosus, severe skin reactions such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (TEN), persistent or severe PPES can eventually lead to loss of fingerprints