HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
XELODA® safely and effectively. See full prescribing information for
XELODA®.
XELODA® (capecitabine) tablets, for oral use
Initial U.S. Approval: 1998
WARNING: INCREASED RISK OF BLEEDING WITH
CONCOMITANT USE OF VITAMIN K ANTAGONISTS
See full prescribing information for complete boxed warning.
Altered coagulation parameters and/or bleeding, including death, havebeen reported in patients taking XELODA concomitantly with oralvitamin K antagonists. (5.1, 7.2)
Monitor international normalized ratio (INR) more frequently and adjust
the dose of the vitamin K antagonist as appropriate. (7.2)--------------------------- RECENT MAJOR CHANGES --------------------------Boxed Warning(12/2022)
Indications and Usage, Colorectal Cancer (1.1)(12/2022)
Indications and Usage, Breast Cancer (1.2)(12/2022)
Indications and Usage, Gastric, Esophageal, or Gastroesophageal Junction
Cancer (1.3)(12/2022)
Indications and Usage, Pancreatic Cancer (1.4)(12/2022)
Dosage and Administration (2.1-2.7)(12/2022)
Contraindications (4)(12/2022)
Warnings and Precautions (5.1-5.12)(12/2022)--------------------------- INDICATIONS AND USAGE---------------------------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 asingle 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 prioranthracycline-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 acomponent of a combination chemotherapy regimen. (1.4)●-----------------------DOSAGE AND ADMINISTRATION ----------------------Adjuvant Treatment of Colon Cancer• Single agent: 1,250 mg/m2 twice daily orally for the first 14 days of each21-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 incombination 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 (2.1)• Without Radiation Therapy: 1,250 mg/m2 orally twice daily (2.1)
Unresectable or Metastatic Colorectal Cancer:• Single agent: 1,250 mg/m2 twice daily orally for the first 14 days of each21-day cycle until disease progression or unacceptable toxicity. (2.1)

Reference ID: 5093808

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. (2.1)
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 unacceptabletoxicity. (2.2)• 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 (2.2)
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. (2.3)
OR• 850 mg/m2 or 1,000 mg/m2 orally twice daily for the first 14 days of each21-day cycle until disease progression or unacceptable toxicity in
combination with oxaliplatin 130 mg/m2 administered intravenously on
day 1 of each cycle. (2.3)
HER2-overexpressing metastatic adenocarcinoma of thegastroesophageal 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 withcisplatin and trastuzumab. (2.3)
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. (2.4)
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).
•--------------------- DOSAGE FORMS AND STRENGTHS---------------------Tablets: 150 mg and 500 mg (3)------------------------------ CONTRAINDICATIONS -----------------------------History of severe hypersensitivity reactions to fluorouracil or capecitabine (4)----------------------- WARNINGS AND PRECAUTIONS ----------------------•
Serious Adverse Reactions from Dihydropyrimidine Dehydrogenase(DPD) Deficiency: Patients with certain homozygous or compound
heterozygous variants in the DPYD gene are at increased risk for acuteearly-onset toxicity and serious, including fatal, adverse reactions due to
XELODA (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity).
XELODA is not recommended for use in patients known to have certain
homozygous or compound heterozygous DPYD variants that result incomplete absence of DPD activity. Withhold or permanently discontinue
based on clinical assessment. No XELODA dose has been proven safe inpatients with complete absence of DPD activity. (5.2)•
Cardiotoxicity: May be more common in patients with a prior history ofcoronary artery disease. Withhold XELODA for cardiotoxicity as
appropriate. The safety of resumption of XELODA in patients withcardiotoxicity 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 clinicallyindicated. 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 clinicallyindicated. 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 skinreactions. Permanently discontinue XELODA in patients who
experience a severe cutaneous adverse reaction. (5.7)•
Palmar-Plantar Erythrodysesthesia Syndrome: Withhold XELODA thenresume 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 x 109/L or platelet counts <100 x 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 x 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 thepotential risk to a fetus and to use effective contraception. (5.11, 8.1,
8.3)------------------------------ ADVERSE REACTIONS------------------------------•
Most common adverse reactions in patients who received XELODA as asingle agent for the adjuvant treatment for colon cancer (>30%) werepalmar-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 werelymphopenia, anemia, diarrhea, hand-and-foot syndrome, nausea,
fatigue, vomiting, and dermatitis. (6.1)

Reference ID: 5093808

To report SUSPECTED ADVERSE REACTIONS, contact Genentech at
1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
------------------------------ DRUG INTERACTIONS------------------------------•
Allopurinol: Avoid concomitant use of allopurinol with XELODA. (7.1)•
Leucovorin: Closely monitor for toxicities when XELODA is
coadministered with leucovorin. (7.1)•
CYP2C9 substrates: Closely monitor for adverse reactions when
CYP2C9 substrates are coadministered with XELODA. (7.2)•
Vitamin K antagonists: Monitor INR more frequently and dose adjust
oral vitamin K antagonist as appropriate•
Phenytoin: Closely monitor phenytoin levels in patients taking
XELODA concomitantly with phenytoin and adjust the phenytoin dose
as appropriate. (7.2)•
Nephrotoxic drugs: Closely monitor for signs of renal toxicity when
XELODA is used concomitantly with nephrotoxic drugs. (7.3)----------------------- USE IN SPECIFIC POPULATIONS ----------------------•
Lactation: Advise not to breastfeed. (8.2)•
Hepatic Impairment: Monitor patients with hepatic impairment more
frequently for adverse reactions. (8.7)
See 17 for PATIENT COUNSELING INFORMATION and FDAapproved patient labeling
Revised: 12/2022

FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: INCREASED RISK OF BLEEDING WITH
CONCOMITANT USE OF VITAMIN K ANTAGONISTS
1 INDICATIONS AND USAGE
1.1 Colorectal Cancer
1.2 Breast Cancer
1.3 Gastric, Esophageal, or Gastroesophageal Junction Cancer
1.4 Pancreatic Cancer
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage for Colorectal Cancer
2.2 Recommended Dosage for Breast Cancer
2.3 Recommended Dosage for Gastric, Esophageal, or
Gastroesophageal Junction Cancer
2.4 Recommended Dosage for Pancreatic Cancer
2.5 Dosage Modifications for Adverse Reactions
2.6 Dosage Modification For Renal Impairment
2.7 Administration
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Increased Risk of Bleeding With Concomitant Use of Vitamin K
Antagonists
5.2 Serious Adverse Reactions from Dihydropyrimidine Dehydrogenase(DPD) Deficiency
5.3 Cardiotoxicity
5.4 Diarrhea
5.5 Dehydration
5.6 Renal Toxicity
5.7 Serious Skin Toxicities
5.8 Palmar-Plantar Erythrodysesthesia Syndrome
5.9 Myelosuppression
5.10 Hyperbilirubinemia
5.11 Embryo-Fetal Toxicity
5.12 Eye Irritation, Skin Rash and Other Adverse Reactions from
Exposure to Crushed Tablets

Reference ID: 5093808

6
7

8

10
11
12

13
14

15
16
17

ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
DRUG INTERACTIONS
7.1 Effect of Other Drugs on XELODA
7.2 Effect of Xeloda on Other Drugs
7.3 Nephrotoxic Drugs
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
OVERDOSAGEDESCRIPTION
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
12.5 Pharmacogenomics
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
CLINICAL STUDIES
14.1 Colorectal Cancer
14.2 Metastatic Breast Cancer
14.3 Gastric, Esophageal, or Gastroesophageal Junction Cancer
14.4 Pancreatic Cancer
REFERENCES
HOW SUPPLIED/STORAGE AND HANDLINGPATIENT COUNSELING INFORMATION*Sections or subsections omitted from the full prescribing information
are not listed.

FULL PRESCRIBING INFORMATIONWARNING: INCREASED RISK OF BLEEDING WITH CONCOMITANT USE OF
VITAMIN K ANTAGONISTS
Altered coagulation parameters and/or bleeding, including death, have been reported inpatients taking XELODA concomitantly with oral vitamin K antagonists, such as warfarin[see Warnings and Precautions (5.1), Drug Interactions (7.2)].
Clinically significant increases in prothrombin time (PT) and international normalized ratio(INR) have been reported in patients who were on stable doses of a vitamin K antagonist 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 (7.2)].
1

INDICATIONS AND USAGE

1.1

Colorectal Cancer

XELODA is indicated for the:•adjuvant treatment of patients with Stage III colon cancer as a single agent or as acomponent of a combination chemotherapy regimen.

•

perioperative treatment of adults with locally advanced rectal cancer as a component ofchemoradiotherapy.

•

treatment of patients with unresectable or metastatic colorectal cancer as a single agent or
as a component of a combination chemotherapy regimen.

1.2

Breast Cancer

XELODA is indicated for the:•treatment of patients with advanced or metastatic breast cancer as a single agent if ananthracycline- or taxane-containing chemotherapy is not indicated.

•

treatment of patients with advanced or metastatic breast cancer in combination withdocetaxel after disease progression on prior anthracycline-containing chemotherapy.

1.3

Gastric, Esophageal, or Gastroesophageal Junction Cancer

XELODA is indicated for the:Reference ID: 5093808•

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.

1.4

Pancreatic Cancer

XELODA is indicated for the adjuvant treatment of adults with pancreatic adenocarcinoma as acomponent of a combination chemotherapy regimen.
2

DOSAGE AND ADMINISTRATION

2.1

Recommended Dosage for Colorectal Cancer

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 ofeach 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 ofeach 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 administeredwith concomitant radiation therapy and 1,250 mg/m2 orally twice daily when administeredwithout 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 ofa 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 ofeach 21-day cycle until disease progression or unacceptable toxicity in combination withoxaliplatin 130 mg/m2 administered intravenously on day 1 of each cycle.
Refer to the Prescribing Information for oxaliplatin for additional dosing information as
appropriate.
2.2

Recommended Dosage for Breast Cancer

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.

Reference ID: 5093808

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.
2.3

Recommended Dosage for Gastric, Esophageal, or Gastroesophageal Junction
Cancer

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 anddosing 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 daysof each 21-day cycle until disease progression or unacceptable toxicity in combination withcisplatin and trastuzumab.
Refer to the Prescribing Information for agents used in combination for additional dosing
information as appropriate.
2.4

Recommended Dosage for Pancreatic Cancer

The recommended dosage of XELODA is 830 mg/m2 orally twice daily for the first 21 days ofeach 28-day cycle until disease progression, unacceptable toxicity, or for a maximum 6 cycles incombination with gemcitabine 1,000 mg/m2 administered intravenously on days 1, 8, and 15 ofeach cycle.
Refer to Prescribing Information for gemcitabine for additional dosing information as
appropriate.
2.5

Dosage Modifications for Adverse Reactions

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 therequirements for resuming both XELODA and docetaxel are met. Refer to the Prescribing
Information for docetaxel for additional dosing information as appropriate.

Reference ID: 5093808

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
2nd appearance

100%
Withhold until resolved to grade 0-1.

3rd appearance
4th appearance

75%
50%

Permanently discontinue.

-

Grade 3
1st appearance
2nd appearance
3rd appearance

Withhold until resolved to grade 0-1.
Permanently discontinue.

75%
50%
-

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 orless (less than three times the upper limit of normal), using the percent of current dose as shownin column 3 of Table 1 [see Warnings and Precautions (5.10)].
2.6

Dosage Modification For Renal Impairment

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 inpatients with severe renal impairment (CLcr <30 mL/min) [see Use in Specific Populations(8.6)].
2.7

Administration

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

Reference ID: 5093808

3

DOSAGE FORMS AND STRENGTHS

Tablets, film-coated:•

150 mg: biconvex, oblong, light-peach colored, with “XELODA” on one side and “150” on
the other•

500 mg: biconvex, oblong, peach colored, with “XELODA on one side and “500” on the
other

4

CONTRAINDICATIONSXELODA is contraindicated in patients with history of severe hypersensitivity reaction to
fluorouracil or capecitabine [see Adverse Reactions (6.1)].
5

WARNINGS AND PRECAUTIONS

5.1

Increased Risk of Bleeding With Concomitant Use of Vitamin K Antagonists

Altered coagulation parameters and/or bleeding, including death, have been reported in patientstaking 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 [seeDrug Interactions (7.1)].
5.2

Serious Adverse Reactions from Dihydropyrimidine Dehydrogenase (DPD)
Deficiency

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 ofserious, including fatal, adverse reactions.
XELODA is not recommended for use in patients known to have certain homozygous orcompound 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 the observed adverse reactions in patients with evidence of acute earlyonset or unusually severe reactions, which may indicate complete DPD deficiency. 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.
Consider testing for genetic variants of DPYD prior to initiating XELODA to reduce the risk ofserious adverse reactions if the patient’s clinical status permits and based on clinical judgement[see Clinical Pharmacology (12.5)]. Serious adverse reactions may still occur even if no DPYD
variants are identified.

Reference ID: 5093808

An FDA-authorized test for the detection of genetic variants of DPYD to identify patients at riskof serious adverse reactions due to increased systemic exposure to XELODA is not currently
available. Currently available tests used to identify DPYD variants may vary in accuracy anddesign (e.g., which DPYD variant(s) they identify).
5.3

Cardiotoxicity

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 patientswith 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 notbeen established.
5.4

Diarrhea

Diarrhea, sometimes severe, can occur with XELODA. In 875 patients with metastatic breast orcolorectal cancer who received XELODA as a single agent, the median time to first occurrenceof 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 basedon severity and occurrence [see Dosage and Administration (2.5)].
5.5

Dehydration

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)].
5.6

Renal Toxicity

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)].
5.7

Serious Skin Toxicities

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.

Reference ID: 5093808

5.8

Palmar-Plantar Erythrodysesthesia Syndrome

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 basedon severity and occurrence [see Dosage and Administration (2.5)].
5.9

Myelosuppression

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 x 109/L or platelet count <100 x 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)].
5.10

Hyperbilirubinemia

Hyperbilirubinemia can occur with XELODA. In the 875 patients with metastatic breast orcolorectal cancer who received XELODA as a single agent, grade 3 hyperbilirubinemia occurredin 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 patientswith grade 3 or 4 hyperbilirubinemia, 19% had postbaseline increased alkaline phosphatase and28% 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 ofgrade 3 or 4 hyperbilirubinemia was similar to that observed for the pooled population ofpatients 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.

Reference ID: 5093808

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 theupper limit of normal, using the percent of current dose as shown in Table 1 [see Dosage andAdministration (2.5)].
5.11

Embryo-Fetal Toxicity

Based on findings from animal reproduction studies and its mechanism of action, XELODA cancause 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 thelast 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 Usein Specific Populations (8.1, 8.3)].
5.12

Eye Irritation, Skin Rash, and Other Adverse Reactions from Exposure to Crushed
Tablets

In instances of exposure to crushed XELODA tablets, the following adverse reactions have beenreported: 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 andAdministration (2.7)]. The safety and effectiveness have not been established for theadministration of crushed XELODA tablets.
6

ADVERSE REACTIONS

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)]

Reference ID: 5093808

•

6.1

Hyperbilirubinemia [see Warnings and Precautions (5.10)]

Clinical Trials Experience

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 trialsof 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 followedby 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 occurredin 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 2Adverse Reactions (>10%) in Patients Who Received XELODA for Adjuvant
Treatment of Colon Cancer in X-ACTXELODA(N=995)Adverse Reaction

All Grades

Fluorouracil + Leucovorin(N=974)All Grades(%)

Grade 3 or 4
(%)

(%)

Grade 3 or 4
(%)

60

17

9

<1

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

Skin and Subcutaneous Tissue
Palmar-plantar
erythrodysesthesia syndrome
Gastrointestinal

Reference ID: 5093808

XELODA(N=995)Adverse Reaction

All Grades

Fluorouracil + Leucovorin(N=974)All Grades(%)

Grade 3 or 4
(%)

(%)

Grade 3 or 4(%)

Fatigue

16

<1

16

1

Asthenia

10

<1

10

1

Lethargy

10

<1

9

<1

GeneralClinically 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

Reference ID: 5093808

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 XACTXELODA

Fluorouracil + Leucovorin(N=995)(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 decreased1

1.2

Platelets decreased

1

0.7

Laboratory Abnormality

In Combination with Oxaliplatin-Containing Regimens
The safety of XELODA for the perioperative treatment of adults with Stage III colon cancer as acomponent of a combination chemotherapy regimen was derived from published literature [seeClinical 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 ClinicalStudies (14.1)]. The safety of XELODA for the perioperative treatment of adults with locallyadvanced rectal cancer as a component of chemoradiotherapy was similar to those in patientstreated with XELODA as a single agent, with the exception of an increased incidence of
diarrhea.

Reference ID: 5093808

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 boluson days 1 to 5 of each 28-day cycle (N=593). Among the patients who received XELODA, themedian 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 orintercurrent 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 4Adverse Reactions (>10%) in Patients Who Received XELODA in Pooled
Metastatic Colorectal Cancer Population (Study SO14695 and Study
SO14796)
Fluorouracil +Leucovorin

XELODA(N=596)Adverse Reaction(N=593)

Grade 3 GradeAll Grade Grade
All
3
4
(%)
4
GradesGrades
(%)
(%)
(%)
(%)
(%)

Blood and Lymphatic System
Anemia

80

2

<1

79

1

<1

Neutropenia

13

1

2

46

8

13

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

–

Gastrointestinal

Reference ID: 5093808

Fluorouracil +Leucovorin

XELODA(N=596)Adverse Reaction

Oral discomfort(N=593)All Grade GradeAll
Grade 3 Grade
3
4
GradesGrades
(%)
4
(%)
(%)
(%)
(%)
(%)
10

–

–

10

–

–

Palmar-plantar erythrodysesthesia syndrome

54

17

NA

6

1

NA

Dermatitis

27

1

–

26

1

–

48

18

5

17

3

3

Fatigue*

42

4

–

46

4

–

Pyrexia

18

1

–

21

2

–

Edema

15

1

–

9

1

–

Pain

12

1

–

10

1

–

26

3

<1

31

2

<1

14

1

–

10

<1

1

13

–

–

10

<1

–

Peripheral sensory neuropathy

10

–

–

4

–

–

Headache

10

1

–

7

–

–

10

2

–

9

<1

–

Skin and Subcutaneous Tissue

Hepatobiliary
Hyperbilirubinemia
GeneralMetabolism and Nutrition
Decreased appetite
Respiratory Thoracic and Mediastinal
Dyspnea
Eye
Eye irritation
Nervous System

Musculoskeletal
Back pain– Not observed* Includes weakness
NA = Not Applicable

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

Reference ID: 5093808

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 publishedliterature [see Clinical Studies (14.1)]. The safety of XELODA for the treatment of patients withunresectable 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 1hour 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.

Reference ID: 5093808

Table 5

Adverse Reactions (≥10%) in Patients Who Received XELODA with
Docetaxel for Metastatic Breast Cancer in Study SO14999
XELODA with Docetaxel(N=251)Adverse Reaction

All
Grades(%)

Grade 3(%)

Diarrhea

67

Stomatitis

Docetaxel(N=255)

Grade 4(%)

All
Grades(%)

Grade 3(%)

Grade 4
(%)

14

<1

48

5

<1

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

–

Palmar-plantar erythrodysesthesia
syndrome

63

24

NA

8

1

NA

Alopecia

41

6

–

42

7

–

Nail disorder

14

2

–

15

–

–

33

<2

–

34

<3

1

Gastrointestinal

Skin and Subcutaneous Tissue

Cardiac
Edema

Reference ID: 5093808

XELODA with Docetaxel(N=251)Adverse Reaction

All
Grades(%)

Grade 3(%)

Pyrexia28

Asthenia

Docetaxel(N=255)

Grade 4(%)

All
Grades(%)

Grade 3(%)

Grade 4
(%)

2

–

34

2

–

26

4

<1

25

6

–

Fatigue

22

4

–

27

6

–

Weakness

16

2

–

11

2

–

Pain in Limb

13

<1

–

13

2

–

16

3

13

21

5

16

Taste disturbance

16

<1

–

14

<1

–

Headache

15

3

–

15

2

–

Paresthesia

12

<1

–

16

1

–

Dizziness

12

–

–

8

<1

–

GeneralBlood and Lymphatic System
Neutropenic fever
Nervous System

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

–

Anorexia

13

<1

–

11

<1

–

Appetite decreased

10

–

–

5

–

–

Dehydration

10

2

–

7

<1

<1

Metabolism and Nutrition

Reference ID: 5093808

XELODA with Docetaxel(N=251)Adverse Reaction

All
Grades(%)

Grade 3(%)

12–Docetaxel(N=255)

Grade 4(%)

All
Grades(%)

Grade 3(%)

Grade 4
(%)

–

7

<1

–

Eye
Lacrimation increased– Not observed
NA = Not Applicable

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, drymouthGeneral: 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.

Reference ID: 5093808

Table 6

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

XELODA with Docetaxel(N=251)

Laboratory Abnormality

All Grades Grade 3(%)(%)(N=255)

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

20

7

2

6

2

2

Hepatobiliary
Hyperbilirubinemia

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-footsyndrome, nausea, fatigue, vomiting, and dermatitis.
Table 7 summarizes the adverse reactions in Study SO14697.
Table 7Adverse Reactions (>10%) in Patients Who Received XELODA for
Metastatic Breast Cancer in Study SO14697
All Grades(%)

XELODA(n=162)
Grade 3(%)

Grade 4(%)

Lymphopenia

94

44

15

Anemia72

3

1

Adverse Reaction

Blood and Lymphatic System

Reference ID: 5093808

All Grades(%)

XELODA(n=162)
Grade 3(%)

Grade 4(%)

Neutropenia

26

2

2

Thrombocytopenia

24

3

1

Diarrhea

57

12

3

Nausea53

4–

Vomiting

37

4–

Stomatitis

24

7

–

Abdominal pain

20

4

–

Constipation

15

1

–

Hand-and-foot syndrome

57

11

NA

Dermatitis

37

1

–

Fatigue

41

8–

Pyrexia

12

1

–

23

3

–

22

9

2

21

1

–

15

–

–

Adverse Reaction

Gastrointestinal

Skin and Subcutaneous Tissue

GeneralMetabolism and Nutrition
Anorexia
Hepatobiliary
Hyperbilirubinemia
Nervous System
Paresthesia
Eye
Eye irritation– = Not observed
NA = Not Applicable

Reference ID: 5093808

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, impairedbalance, 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, skinulceration, 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 wasconsistent 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 formetastatic disease as a component of a combination regimen was derived from the published

Reference ID: 5093808

literature [see Clinical Studies (14.3)]. The safety of XELODA for the treatment of patients with
HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma wasconsistent with the known safety profile of XELODA.
Pancreatic Cancer
The safety of XELODA for the adjuvant treatment of adults with pancreatic adenocarcinoma as acomponent 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 withpancreatic adenocarcinoma as a component of a combination chemotherapy regimen wasconsistent with the known safety profile of XELODA.
6.2

Postmarketing Experience

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 notalways 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
7

DRUG INTERACTIONS

7.1

Effect of Other Drugs on XELODA

Allopurinol
Concomitant use with allopurinol may decrease concentration of capecitabine’s active
metabolites [see Clinical Pharmacology (12.3)], which may decrease efficacy. Avoid
concomitant use of allopurinol with XELODA.
Leucovorin
The concentration of fluorouracil is increased and its toxicity may be enhanced by leucovorin,
folic acid, or folate analog products. Deaths from severe enterocolitis, diarrhea, and dehydration
have been reported in elderly patients receiving weekly leucovorin and fluorouracil.
Instruct patients not to take products containing folic acid or folate analog products unlessdirected to do so by their healthcare provider.
7.2

Effect of Xeloda on Other Drugs

CYP2C9 Substrates
XELODA increased exposure of CYP2C9 substrates [see Clinical Pharmacology (12.3)], which
may increase the risk of adverse reactions related to these substrates. Closely monitor for adverse

Reference ID: 5093808

reactions of CYP2C9 substrates where minimal concentration changes may lead to serious
adverse reactions when used concomitantly with XELODA (e.g., anticoagulants, antidiabetic
drugs).
Vitamin K Antagonists
XELODA increases exposure of vitamin K antagonist [see Clinical Pharmacology (12.3)],
which may alter coagulation parameters and/or bleeding and could result in death [see Warning
and Precautions (5.1)]. These events may occur within days of treatment initiation and up to 1
month after discontinuation of XELODA.
Monitor INR more frequently and refer to the prescribing information of oral vitamin K
antagonist for dosage adjustment, as appropriate, when XELODA is used concomitantly withvitamin K antagonist.
Phenytoin
XELODA may increases exposure of phenytoin, which may increase the risk of adverse
reactions related to phenytoin. Closely monitor phenytoin levels and refer to the prescribing
information of phenytoin for dosage adjustment, as appropriate, when XELODA is usedconcomitantly with phenytoin.
7.3

Nephrotoxic Drugs

Due of the additive pharmacologic effect, concomitant use of XELODA with other drugs known
to cause renal toxicity may increase the risk of renal toxicity [see Warnings and Precautions(5.6)]. Closely monitor for signs of renal toxicity when XELODA is used concomitantly withnephrotoxic drugs (e.g. platinum salts, irinotecan, methotrexate, intravenous bisphosphonates).
8

USE IN SPECIFIC POPULATIONS

8.1

Pregnancy

Risk Summary
Based on findings in animal reproduction studies and its mechanism of action [see ClinicalPharmacology (12.1)], XELODA can cause fetal harm when administered to a pregnant woman.
Available human data with XELODA use in pregnant women is not sufficient to inform thedrug-associated risk. In animal reproduction studies, administration of capecitabine to pregnant
animals during the period of organogenesis caused embryolethality and teratogenicity in miceand embryolethality in monkeys at 0.2 and 0.6 times the exposure (AUC) in patients receiving
the recommended dose of 1,250 mg/m2 twice daily, respectively (see Data). Advise pregnant
women of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicatedpopulation is unknown. All pregnancies have a background risk of birth defect, loss, or otheradverse outcomes. In the U.S. general population, the estimated background risk of major birthdefects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%,
respectively.
Data
Animal Data

Reference ID: 5093808

Oral administration of capecitabine to pregnant mice during the period of organogenesis at adose of 198 mg/kg/day caused malformations and embryo lethality. In separate pharmacokinetic
studies, this dose in mice produced 5’-DFUR AUC values that were approximately 0.2 times the
AUC 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. Oral administration of capecitabine to pregnant
monkeys during the period of organogenesis at a dose of 90 mg/kg/day, caused fetal lethality.
This dose produced 5’-DFUR AUC values that were approximately 0.6 times the AUC values inpatients administered the recommended daily dose.
8.2

Lactation

Risk Summary
There is no information regarding the presence of capecitabine or its metabolites in human milk,or on its effects on milk production or the breastfed child. Capecitabine metabolites were present
in the milk of lactating mice (see Data). Because of the potential for serious adverse reactions ina breastfed child, advise women not to breastfeed during treatment with XELODA and for 1
week after the last dose.
Data
Lactating mice given a single oral dose of capecitabine excreted significant amounts ofcapecitabine metabolites into the milk.
8.3

Females and Males of Reproductive Potential

XELODA can cause fetal harm when administered to a pregnant woman [see Use in Specific
Populations (8.1)].
Pregnancy Testing
Verify pregnancy status in females of reproductive potential prior to initiating XELODA.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with
XELODA and for 6 months after the last dose.
Males
Based on genotoxicity findings, advise males with female partners of reproductive potential touse effective contraception during treatment with XELODA and for 3 months after the last dose[see Nonclinical Toxicology (13.1)].
Infertility
Based on animal studies, XELODA may impair fertility in females and males of reproductive
potential [see Nonclinical Toxicology (13.1)].
8.4

Pediatric Use

The safety and effectiveness of XELODA in pediatric patients have not been established.

Reference ID: 5093808

Safety and effectiveness were assessed, but not established in two single arm studies in 56
pediatric patients aged 3 months to <17 years with newly diagnosed gliomas. In both trials,
pediatric patients received an investigational pediatric formulation of capecitabine concomitantlywith and following completion of radiation therapy (total dose of 5580 cGy in 180 cGy
fractions). The relative bioavailability of the investigational formulation to XELODA was
similar.
The adverse reaction profile was consistent with that of adults, with the exception of laboratory
abnormalities which occurred more commonly in pediatric patients. The most frequently
reported laboratory abnormalities (per-patient incidence ≥ 40%) were increased ALT (75%),
lymphocytopenia (73%), hypokalemia (68%), thrombocytopenia (57%), hypoalbuminemia(55%), neutropenia (50%), low hematocrit (50%), hypocalcemia (48%), hypophosphatemia(45%) and hyponatremia (45%).
8.5

Geriatric Use

Of 7938 patients with colorectal cancer who were treated with XELODA, 33% were older than
65 years. Of the 4536 patients with metastatic breast cancer who were treated with XELODA,
18% were older than 65 years.
Of 1951 patients with gastric, esophageal, or gastrointestinal junction cancer who were treatedwith XELODA, 26% were older than 65 years.
Of 364 patients with pancreatic cancer who received adjuvant treatment with XELODA, 47%
were 65 years or older.
No overall differences in efficacy were observed comparing older versus younger patients withcolorectal cancer, gastric, esophageal or gastrointestinal junction cancer, or pancreatic cancer
using the approved recommended dosages and treatment regimens.
Older patients experience increased gastrointestinal toxicity due to XELODA compared toyounger patients. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported
in elderly patients receiving weekly leucovorin and fluorouracil [see Drug Interactions (7.1)].
8.6

Renal Impairment

The exposure of capecitabine and its inactive metabolites (5-DFUR and FBAL) increases inpatients with CLcr <50 mL/min as determined by Cockcroft-Gault [see Clinical Pharmacology(12.3)]. Reduce the dosage for patients with CLcr of 30 to 50 mL/min [see Dosage andAdministration (2.6)]. There is limited experience with XELODA in patients with CLcr <30
mL/min, and a dosage has not been established in those patients. If no treatment alternative
exists, XELODA could be administered to such patients on an individual basis applying a
reduced starting dose, close monitoring of a patient's clinical and biochemical data and dose
modifications guided by observed adverse reactions.
8.7

Hepatic Impairment

The exposure of capecitabine increases in patients with mild to moderate hepatic impairment.
The effect of severe hepatic impairment on the safety and pharmacokinetics of XELODA is
unknown [see Clinical Pharmacology (12.3)]. Monitor patients with hepatic impairment more
frequently for adverse reactions.

Reference ID: 5093808

10

OVERDOSAGE

Administer uridine triacetate within 96 hours for management of XELODA overdose.
Although no clinical experience using dialysis as a treatment for XELODA overdose has beenreported, dialysis may be of benefit in reducing circulating concentrations of 5’-DFUR, a low–
molecular-weight metabolite of the parent compound.
11

DESCRIPTION

Capecitabine is a nucleoside metabolic inhibitor. The chemical name is 5’-deoxy-5-fluoro-N[(pentyloxy) carbonyl]-cytidine and has a molecular formula of C15H22FN3O6 and a molecularweight 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 20ºC.
XELODA (capecitabine) is supplied as biconvex, oblong film-coated tablets for oral use. Eachlight 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.
12

CLINICAL PHARMACOLOGY

12.1

Mechanism of Action

Capecitabine is metabolized to fluorouracil in vivo. Both normal and tumor cells metabolize
fluorouracil to 5-fluoro-2’-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine
triphosphate (FUTP). These metabolites cause cell injury by two different mechanisms. First,
FdUMP and the folate cofactor, N5-10-methylenetetrahydrofolate, bind to thymidylate synthase(TS) to form a covalently bound ternary complex. This binding inhibits the formation ofthymidylate 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.

Reference ID: 5093808

12.2

Pharmacodynamics

Population-based exposure-effect analyses demonstrated a positive association between AUC offluorouracil and grade 3-4 hyperbilirubinemia.
12.3

Pharmacokinetics

The AUC of capecitabine and its metabolite 5’-DFCR increases proportionally over a dosage
range of 500 mg/m2/day to 3,500 mg/m2/day (0.2 to 1.4 times the approved recommended
dosage). The AUC of capecitabine’s metabolites 5’-DFUR and fluorouracil increased greaterthan proportional to the dose. The interpatient variability in the Cmax and AUC of fluorouracil
was greater than 85%.
Absorption
Following oral administration of XELODA 1,255 mg/m2 orally twice daily (the recommended
dosage when used as single agent), the median Tmax of capecitabine and its metabolite
fluorouracil was approximately 1.5 hours and 2 hours, respectively.
Effect of Food
Following administration of a meal (breakfast medium-rich in fat and carbohydrates), the mean
Cmax and AUC0-INF of capecitabine was decreased by 60% and 34%, respectively. The mean Cmax
and AUC0-INF of fluorouracil were also decreased by 37 % and 12%, respectively. The Tmax ofboth capecitabine and fluorouracil was delayed by 1.5 hours.
Distribution
Plasma protein binding of capecitabine and its metabolites is less than 60% and is notconcentration-dependent. Capecitabine was primarily bound to human albumin (approximately
35%).
Following oral administration of XELODA 7 days before surgery in patients with colorectal
cancer, the median ratio of concentration for the active metabolite fluorouracil in colorectal
tumors to adjacent tissues was 2.9 (range: 0.9 to 8.0).
Elimination
The elimination half-lives of capecitabine and fluorouracil were approximately 0.75 hour.
Metabolism
Capecitabine undergoes metabolism by carboxylesterase and is hydrolyzed to 5’-DFCR. 5’DFCR is subsequently converted to 5’-DFUR by cytidine deaminase. 5’-DFUR is thenhydrolized by thymidine phosphorylase (dThdPase) enzymes to the active metabolite
fluorouracil.
Fluorouracil is subsequently metabolized by dihydropyrimidine dehydrogenase to 5-fluoro-5, 6dihydro-fluorouracil (FUH2). The pyrimidine ring of FUH2 is cleaved by dihydropyrimidinase toyield 5-fluoro-ureido-propionic acid (FUPA). Finally, FUPA is cleaved by β-ureido-propionaseto α-fluoro-β-alanine (FBAL).

Reference ID: 5093808

Excretion
Following administration of radiolabeled capecitabine, 96% of the administered capecitabine
dose was recovered in urine (3% unchanged and 57% as metabolite FBAL) and 2.6% in feces.
Specific Populations
Following therapeutic doses of XELODA, no clinically meaningful difference in thepharmacokinetics of 5’-DFUR, fluorouracil or FBAL were observed based on sex (202 females
and 303 males) and race (455 White, 22 Black, and 28 Other). No clinically meaningful
difference on the pharmacokinetics of 5’-DFUR and fluorouracil were observed based on age(range: 27 to 86 years); however, the AUC of FBAL increased by 15% following a 20% increasein age.
Racial or Ethnic Groups
Following administration of XELODA 825 mg/m2 orally twice daily for 14 days (0.66 times therecommended dosage), the Cmax and AUC of capecitabine decreased by 36% and 24%,
respectively in Japanese patients (n=18) compared to White patients (n=22). The Cmax and AUC
of FBAL decreased by approximately 25% and 34%, respectively in Japanese patients comparedto White patients; however, the clinical significance of these differences is unknown. No
clinically significant differences in the pharmacokinetics of 5’-DFCR, 5’-DFUR or fluorouracil
were observed.
Patients with Renal Impairment
Table 8 Effect of Renal Impairment on the Pharmacokinetics of Capecitabine, 5’-DFUR, and FBAL
Renal Impairment a
CLcr 30 to 50
mL/minCLcr <30 mL/min

Capecitabine
Increased by 25%

Changes in AUC b
5’-DFURc
FBALc
Increased by 42% Increased by 85%

Increased by 25%

Increased by 71%

Increased by
258%

5-FU
No relevantchangeIncreased by 24%

Compared to patients with CLcr >80 mL/min
Following administration of XELODA 1,250 mg/m2 orally twice daily; day 1 observationscCapecitabine metabolite
CLcr= Creatine Clearance, AUC= Area under the plasma concentration-time curveabPatients with Hepatic Impairment
AUC0-INF and Cmax of capecitabine’s active principle, fluorouracil, were not affected in patientswith mild or moderate hepatic impairment compared to patients with normal hepatic function.
The AUC0-INF and Cmax of capecitabine increased by 60%. The effect of severe hepatic
impairment on the pharmacokinetics of capecitabine and its metabolites are unknown.

Reference ID: 5093808

Drug Interaction Studies
Clinical Studies
Effect of Capecitabine on Warfarin: In four patients with cancer, chronic administration of
XELODA 1,250 mg/m2 twice daily with a single dose of warfarin 20 mg 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 wasincreased by 91%.
Effect of Capecitabine on Celecoxib: Concomitant administration of multiple doses ofcapecitabine (XELODA 1,000 mg/m2 twice daily for 14 days) increased celecoxib (sensitive
CYP2C9 substrate) AUC by 28%, Cmax by 24% and Ctrough by 30%.
Effect of Antacids on Capecitabine: When an aluminum hydroxide- and magnesium hydroxidecontaining antacid was administered immediately after a XELODA dose of 1,250 mg/m2 inpatients with cancer, AUC and Cmax increased by 16% and 35%, respectively, for capecitabineand by 18% and 22%, respectively, for 5’-DFCR. No effect was observed on the other threemajor metabolites (5’-DFUR, fluorouracil, FBAL) of XELODA.
Effect of Allopurinol on Capecitabine: Concomitant use with allopurinol may decrease
conversion of capecitabine to the active metabolites, FdUMP and FUTP.
Effect of Capecitabine on Docetaxel and Effect of Docetaxel on Capecitabine: XELODA had noeffect on the pharmacokinetics of docetaxel (Cmax and AUC) and docetaxel has no effect on thepharmacokinetics of capecitabine and the fluorouracil precursor 5’-DFUR.
In Vitro Studies
Cytochrome P450 (CYP) Enzymes: Capecitabine and its metabolites (5’-DFUR, 5’-DFCR,
fluorouracil, and FBAL) did not inhibit CYP1A2, CYP2A6, CYP3A4, CYP2C19, CYP2D6, or
CYP2E1 in vitro.
12.5

Pharmacogenomics

The DPYD gene encodes the enzyme DPD, which is responsible for the catabolism of >80% of
fluorouracil. Approximately 3-5% of White populations have partial DPD deficiency and 0.2%
of White populations have complete DPD deficiency, which may be due to certain genetic nofunction or decreased function variants in DPYD resulting in partial to complete or near complete
absence of enzyme activity. DPD deficiency is estimated to be more prevalent in Black or
African American populations compared to White populations. Insufficient information isavailable to estimate the prevalence of DPD deficiency in other populations.
Patients who are homozygous or compound heterozygous for no function DPYD variants (i.e.,
carry two no function DPYD variants) or are compound heterozygous for a no function DPYD
variant plus a decreased function DPYD variant have complete DPD deficiency and are atincreased risk for acute early-onset of toxicity and serious life-threatening, or fatal adverse
reactions due to increased systemic exposure to XELODA. Partial DPD deficiency can result
from the presence of either two decreased function DPYD variants or one normal function plus

Reference ID: 5093808

either a decreased function or a no function DPYD variant. Patients with partial DPD deficiency
may also be at an increased risk for toxicity from XELODA.
Four DPYD variants have been associated with impaired DPD activity in White populations,especially when present as homozygous or compound heterozygous variants: c.1905+1G>A(DPYD *2A), c.1679T>G (DPYD *13), c.2846A>T, and c.1129-5923C>G (Haplotype
B3). DPYD*2A and DPYD*13 are no function variants, and c.2846A>T and c.1129-5923C>G are
decreased function variants. The decreased function DPYD variant c.557A>G is observed inindividuals of African ancestry. This is not a complete listing of all DPYD variants that may
result in DPD deficiency [see Warnings and Precautions (5.2)].
13

NONCLINICAL TOXICOLOGY

13.1

Carcinogenesis, Mutagenesis, Impairment of Fertility

Adequate studies investigating the carcinogenic potential of capecitabine have not been
conducted. Capecitabine was not mutagenic in vitro to bacteria (Ames test) or mammalian cells(Chinese hamster V79/HPRT gene mutation assay). Capecitabine was clastogenic in vitro tohuman peripheral blood lymphocytes but not clastogenic in vivo to mouse bone marrow(micronucleus test). Fluorouracil causes mutations in bacteria and yeast. Fluorouracil also causes
chromosomal abnormalities in the mouse micronucleus test in vivo.
In studies of fertility and general reproductive performance in female mice, oral capecitabine
doses of 760 mg/kg/day (about 2,300 mg/m2/day) disturbed estrus and consequently caused adecrease in fertility. In mice that became pregnant, no fetuses survived this dose. The disturbancein 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 inpatients administered the recommended daily dose.
14

CLINICAL STUDIES

14.1

Colorectal Cancer

Adjuvant Treatment of Colon Cancer
Single Agent
The efficacy of XELODA was evaluated in X-ACT (NCT00009737), a multicenter, randomized,
controlled clinical trial. Eligible patients were between 18 and 75 years of age withhistologically-confirmed Dukes’ Stage C colon cancer with at least one positive lymph node andto have undergone (within 8 weeks prior to randomization) complete resection of the primarytumor without macroscopic or microscopic evidence of remaining tumor. Patients were also
required to have no prior cytotoxic chemotherapy or immunotherapy (except steroids) and havean 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.
Patients (n=1987) were randomized to XELODA 1,250 mg/m2 orally twice daily for the first 14
days of a 21-day cycle for a total of 8 cycles or fluorouracil 425 mg/m2 and leucovorin 20 mg/m2
intravenously on days 1 to 5 of each 28-day cycle for a total of 6 cycles. The XELODA dose wasReference ID: 5093808

reduced in patients with baseline CLcr of 30 to 50 mL/min. The major efficacy outcome measure
was disease-free survival (DFS).
The baseline demographics are shown in Table 9. The baseline characteristics were wellbalanced between arms.
Table 9Baseline Demographics in X-ACTXELODA(N=1004)

Fluorouracil + Leucovorin(N=983)62

63(25-80)(22-82)

Male, %

54

54

Female, %

46

46

0, %

85

85

1, %

15

15

PT1, %

1

0.6

PT2, %

9

9

PT3, %

76

76

PT4, %

14

0

Other, %0.1

14pN1, %

69

71

pN2, %

30

29

Other, %0.4

0.1

Age (median, years)
Range
Sex

ECOG Performance Status

Staging – Primary Tumor

Staging – Lymph Node

Efficacy results are summarized in Table 10 and Figures 1 and 2. The median follow-up at thetime of the analysis was 6.9 years. Because the upper 2-sided 95% confidence limit of hazard
ratio for DFS was less than 1.20, XELODA was non-inferior to fluorouracil + leucovorin. The
choice of the non-inferiority margin of 1.20 corresponds to the retention of approximately 75%of the fluorouracil + leucovorin effect on DFS. The hazard ratio for XELODA compared tofluorouracil + leucovorin with respect to overall survival was 0.86 (95% CI 0.74, 1.01). The 5year overall survival rates were 71% for XELODA and 68% for fluorouracil + leucovorin.

Reference ID: 5093808

Table 10

Efficacy Results in X-ACTa (All Randomized Population)
Fluorouracil +Leucovorin

XELODA

Efficacy Parameters(N=1004)

5-year Disease-free Survival Rateb(N=983)59%

55%

Hazard Ratio

0.88(95% CI)(0.77, 1.01)

p-valuecp = 0.068

Approximately 93.4% had 5-year DFS information
Based on Kaplan-Meier estimatesc
Wald chi-square testab

Figure 1

Kaplan-Meier Estimates of Disease-Free Survival in X-ACT(All Randomized Population)
1.0
0.9

0.8
0.7
0.6 -

O.!l
0.4

0.3
0.2 ·

REA

Ell GROUP- - - ·- - ·- - 5.RJ

I.E\JCO\l'ORIN

o., .
0.0
I

0
, al li!sk
5afU + l.BJOO'i'ORIN 933

CAPEm/lBI -Reference ID: 5093808

6

12

18

24

30

Ji6

42

48

GO

66

72'

78

002 801 720 64-0 500 562 522 492 453 373 301 221 136'1004 926 8c36 748 696 658 GOO 57-1 5~ 49t7 432' 332 228 '137

84

90

96

Moi'llJW;:SaicooomlialiCil
13
10
2
li(j,
8
3

Figure 2

Kaplan-Meier Estimates of Overall Survival in X-ACT(All Randomized Population)n.rival1.0 0.9
0.8 O.J 0.6
0.5

o...;
0.3

0.2

TAEMMEiNT GflOOP - ·- - - ·- - - 5-FU

- - - -CAPECITABI E

LBJCOYo:RIN

0.1 0.0
0

6

12

18

24

30

3'6

42

48

!i4

00

66

72

78

00

96

Moottls Si11Cij R:andomizalion

ri at rlsk

5-R.I

84

LEUC()V(IRIN 983 9

CARECITABI E

93•1 003 650 795 753 724 700 659 614 5-50 417 25'8

85

6

26

434- 200

74

55

36

004 983 9641 929 888 84'9 808 769 735 702 665 58

In Combination with Oxaliplatin-Containing Regimens
The efficacy of XELODA in combination with oxaliplatin for the adjuvant treatment of patientswith Stage III colon cancer as a component of a combination chemotherapy regimen was derived
from studies in the published literature, including NO16968 [NCT00069121], a multicenter,
open-label, randomized trial, where the major efficacy outcome measure was disease freesurvival.
Perioperative Treatment of Rectal Cancer
The efficacy of XELODA for the perioperative treatment of adults with locally advanced rectal
cancer as a component of chemoradiotherapy was derived from studies in the publishedliterature, including Rektum-III [NCT01500993], a randomized, open-label, multicenter, noninferiority trial, where the major efficacy outcome measure was overall survival.
Metastatic Colorectal Cancer
The efficacy of XELODA as a single agent was evaluated in two open-label, multicenter,randomized, controlled clinical trials (Study SO14695 and Study SO14796). Eligible patients
received first-line treatment for metastatic colorectal cancer. Patients were randomized to
XELODA 1,250 mg/m2 twice daily for first 14 days of a 21-day cycle or leucovorin 20 mg/m2
intravenously followed by fluorouracil 425 mg/m2 as an intravenous bolus on days 1 to 5 of each28-day cycle.
The efficacy outcome measures were overall survival, time to progression and response rate(complete plus partial responses). Responses were defined by the World Health Organization
criteria and submitted to a blinded independent review committee (IRC). Differences inassessments between the investigator and IRC were reconciled by the sponsor, blinded toReference ID: 5093808

treatment arm, according to a specified algorithm. Survival was assessed based on a noninferiority analysis.
The baseline demographics are shown in Table 11.
Table 11Baseline Demographics for Study SO14695 and Study SO14796
Study SO14695
XELODA

Study SO14796
XELODA(N=302)

Fluorouracil +Leucovorin(N=303)(N=301)

Fluorouracil +Leucovorin(N=301)

64

63

64

64

(23-86)(24-87)(29-84)(36-86)

Male, %

60

65

57

57

Female, %

40

35

43

43

90

90

90

90

Range

(70-100)(70-100)(70-100)(70-100)

Colon, %

74

77

66

65

Rectum, %

26

23

34

35

Prior radiation therapy, %

17

21

14

14

Prior adjuvant
fluorouracil, %

28

36

19

14

Age (median, years)
Range
Sex

Karnofsky PS (median)

Efficacy results for Study SO14695 and Study SO14796 are shown in Table 12 and Table 13.

Reference ID: 5093808

Table 12

Efficacy Results for First-Line Treatment of Metastatic Colorectal Cancer(Study SO14695)
XELODA(N=302)

Fluorouracil + Leucovorin(N=303)21 (16, 26)

11 (8, 15)Overall Response Rate
% (95% CI)

0.0014p-valueTime to Progression
Median, months (95% CI)

4.2 (3.9, 4.5)

Hazard Ratio

4.3 (3.4, 5.0)
0.99

95% CI(0.84, 1.17)

Overall Survival
Median, months (95% CI)

12.5 (10.5, 14.3)

Hazard Ratio

1.00

95% CI

Table 1313.4 (12.0, 14.7)(0.84, 1.18)

Efficacy Results for First-Line Treatment of Metastatic Colorectal Cancer(Study SO14796)
XELODA(N=301)

Fluorouracil + Leucovorin(N=301)21 (16, 26)

14 (10, 18)

Overall Response Rate
% (95% CI)
p-value

0.027

Time to Progression
Median, months (95% CI)

4.5 (4.2, 5.5)

Hazard Ratio

4.3 (3.4, 5.1)
0.97

95% CI(0.82, 1.14)

Overall Survival
Median, months (95% CI)
Hazard Ratio
95% CI

Reference ID: 5093808

13.3 (12.1, 14.8)

12.1 (11.1,14.1)
0.92(0.78, 1.09)

Efficacy results of the pooled population from Study SO14695 and Study SO14796 are shown in
Figure 3. Statistical analyses were performed to determine the percent of the survival effect offluorouracil + leucovorin that was retained by XELODA. The estimate of the survival effect offluorouracil + leucovorin was derived from a meta-analysis of ten randomized studies from thepublished literature comparing fluorouracil to regimens of fluorouracil + leucovorin that weresimilar to the control arms used in these Studies SO14695 and SO14796. The method forcomparing the treatments was to examine the worst case (95% confidence upper bound) for thedifference between fluorouracil + leucovorin and XELODA, and to show that loss of more than
50% of the fluorouracil + leucovorin survival effect was ruled out. It was demonstrated that thepercent of the survival effect of fluorouracil + leucovorin maintained was at least 61% for Study
SO14796 and 10% for Study SO14695. The pooled result is consistent with a retention of at least
50% of the effect of fluorouracil + leucovorin. It should be noted that these values for preserved
effect are based on the upper bound of the fluorouracil + leucovorin vs XELODA difference.
Figure 3

Kaplan-Meier Curve for Overall Survival of Pooled Data (Studies SO14695
and SO14796)

ti in ated
Prnba~ iIity

1.0,-----------------------------,
Group

OJ!

- - - - - - - 5~1Ftl + l eucovo rin !Mayo Heg frnen)
.
.
.
.

.

- - - - Xel oda 1250 {ill g/s~m ti.' loe da11~r lnter;rnttent

0.8
0.7
iO.G

0.5

OA
0.3

0.2
0.1
0.0
0

300

t
3911.0392..0

61)0

'900

11200

1500
Ti me ([) ays ,In Combination with Oxaliplatin
The efficacy of XELODA for the treatment of patients with unresectable or metastatic colorectal
cancer as a component of a combination chemotherapy regimen was derived from studies in the
published literature, including NO16966 [NCT00069095], a randomized, non-inferiority, 2x2
factorial trial, where the major efficacy outcome measure was progression free survival.

Reference ID: 5093808

14.2

Metastatic Breast Cancer

In Combination With Docetaxel
The efficacy of XELODA in combination with docetaxel was evaluated in an open-label,multicenter, randomized trial (Study SO14999). Eligible patients had 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 wereenrolled. Patients were randomized to XELODA 1,250 mg/m2 twice daily for the first 14 days ofa 21-day cycle and docetaxel 75 mg/m2 as a 1-hour intravenous infusion on day 1 of day of a 21day cycle or docetaxel 100 mg/m2 as a 1-hour intravenous infusion on day 1 of a 21-day cycle.
The efficacy outcome measures were time to disease progression, overall survival, and response
rate.
Patient demographics are provided in Table 14.

Reference ID: 5093808

Table 14

Baseline Demographics in Metastatic Breast Cancer (Study SO14999)
XELODA +Docetaxel(N=255)Docetaxel(N=256)Age (median, years)

52

51

Karnofsky Performance Status (median)90

90

Lymph nodes, %47

49

Liver, %45

48

Bone, %

42

46

Lung, %

37

39

Skin, %

29

29

Anthracycline1, %

100

100

Fluorouracil, %77

74

Paclitaxel, %10

9No resistance, %7

7Progression on anthracycline therapy, %26

29

Stable disease after 4 cycles of anthracycline
therapy, %16

16

Relapsed within 2 years of completion ofanthracycline-adjuvant therapy, %31

29

Experienced a brief response to anthracycline
therapy, with subsequent progression while on
therapy or within 12 months after last dose, %20

20

Site of Disease

Prior Chemotherapy

Resistance to an Anthracycline

No. of Prior Chemotherapy Regimens for Treatment of Metastatic Disease

1

0, %

35

31

1, %

48

53

2, %

17

15

3, %

0

1

Includes 10 patients in combination and 18 patients in single agent arms treated with an anthracenedione

Efficacy results are shown in Table 15, Figure 4 and Figure 5.

Reference ID: 5093808

Table 15

Efficacy Results in Metastatic Breast Cancer (Study SO14999)

Efficacy Parameter

XELODA + Docetaxel

Docetaxel(N=255)(N=256)

6.1

4.2(5.4, 6.5)

(3.5, 4.5)

Time to Disease Progression
Median, months
95% CI
Hazard Ratio

0.643

p-value

0.0001

Overall Survival
Median, months
95% CI

14.5

11.6(12.3, 16.3)(9.8, 12.7)

Hazard Ratio

0.775

p-value

0.0126

Response Rate1

32%

I

22%

The response rate reported represents a reconciliation of the investigator and IRC assessments performed by thesponsor according to a predefined algorithm.

1

Reference ID: 5093808

Figure 4

Kaplan-Meier Estimates for Time to Disease Progression in Metastatic
Breast Cancer (Study SO14999)

stimated
Probability
1.0
Group

0.9

'

0.8

- - - - - - - Docetaxel 100 (mg/sqrn/3 weeks)- - - - Xeloda 1250 (mg/sqm ~.vice daily) intermittent
w/docetaxel 15 (mg/sqm/3 weeks)

'

0.7

0.6
0.5

0.4
0.3
0.2
0.1

--- ------~--

0.0
0

t

200

128.0 ♦
186.0

Reference ID: 5093808

400

600

800
Time (Days)

Figure 5

Kaplan-Meier Estimates of Survival in Metastatic Breast Cancer (Study
SO14999)

sti matedPm!lall ili tyLO~------------------------~Gro up0.9- - - - - - - Doc etaxelmo (m gtsq

3 vreeks, .
,- - - - XIEILODA 1125·0 (in g/sqn twloe da11~~ , l11te rr111Hent

w/clooetaxel 75•, 11 g/s•qn 13. weeks)

o.s:
0.7

0.6
0.5,

0.4

0.3

., _'
- - - - .... "'!! _ _ _ _

0.2

---.

(U

OJ)
0

200

t 400 t351 .5800

111 e (IDa,rs

442..0Single Agent
The efficacy of XELODA as a single agent was evaluated in an open-label single-arm trial(Study SO14697). Eligible patients had metastatic breast cancer resistant to both paclitaxel andan anthracycline-containing chemotherapy regimen or resistant to paclitaxel and for whomfurther anthracycline therapy is not indicated (e.g., patients who have received cumulative dosesof 400 mg/m2 of doxorubicin or doxorubicin equivalents). Resistance was defined as progressive
disease while on treatment, with or without an initial response, or relapse within 6 months ofcompleting treatment with an anthracycline-containing adjuvant chemotherapy regimen. Patients
received XELODA 1,255 mg/m2 orally twice daily for first 14-days of a 21-day treatment cycle.
The major efficacy outcome measure 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.
The baseline demographics are shown in Table 16.

Reference ID: 5093808

Table 16

Baseline Demographics in Metastatic Breast Cancer (Study SO14697)
Patients With
Measurable Disease(N=135)All Patients(N=162)Age (median, years)

55

56

Karnofsky Performance Status

90

90

1-2, %

32

37

3-4, %

46

43

>5, %

22

21

Visceral1, %75

68Soft Tissue, %22

22Bone, %

3

10

Paclitaxel, %

100

100

Anthracycline2, %90

91Fluorouracil, %81

82

Resistance to Paclitaxel, %76

77Resistance to an Anthracycline2, %41

41Resistance to both Paclitaxel and an
Anthracycline2, %32

31

No. Disease Sites

Dominant Site of Disease

Prior Chemotherapy

12Lung, pleura, liver, peritoneum
Includes 2 patients treated with an anthracenedione

Efficacy for Study SO14697 are shown in Table 17.

Reference ID: 5093808

Table 17

Efficacy Results in Metastatic Breast Cancer (Study SO14697)

Efficacy Parameter

Resistance to Both Paclitaxel and an
Anthracycline(N=43)

Response Rate1(95% CI)

25.6%(13.5, 41.2)

Complete Response

0%

Partial Response1

11%

Duration of Response1
Median, months2(Range)12

5.1 (2.1-7.7)

Includes 2 patients treated with an anthracenedione
From date of first response

For the subgroup of 43 patients who were doubly resistant, the median time to progression was
3.4 months and the median survival was 8.4 months. The objective response rate in thispopulation was supported by a response rate of 18.5% (1 CR, 24 PRs) in the overall populationof 135 patients with measurable disease, who were less resistant to chemotherapy (see Table 15).
The median time to progression was 3.0 months and the median survival was 10.1 months.
14.3

Gastric, Esophageal, or Gastroesophageal Junction Cancer

The efficacy of XELODA for treatment of adults with unresectable or metastatic gastric,
esophageal, or gastroesophageal junction cancer as a component of a combination chemotherapy
regimen was derived from studies in the published literature. XELODA was evaluated in REAL2, a randomized non-inferiority, 2x2 factorial trial, where the major efficacy outcome measure
was overall survival, and an additional randomized trial conducted by the North Central Cancer
Treatment Group, where the major efficacy outcome measure was objective response rate.
The efficacy of XELODA for the treatment of adults with HER2-overexpressing metastatic
gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment formetastatic disease as a component of a combination regimen was derived from studies in the
published literature. XELODA was evaluated in the ToGA trial [NCT01041404], an open-label,multicenter, randomized trial where the primary efficacy measure was overall survival.
14.4

Pancreatic Cancer

The efficacy of XELODA for the adjuvant treatment of adults with pancreatic adenocarcinoma
as a component of a combination chemotherapy regimen was derived from a study in the
published literature. XELODA was evaluated in ESPAC-4 trial, a two-group, open-label,multicenter, randomized trial, where the major efficacy outcome measure was overall survival.
15

REFERENCES

1. “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

Reference ID: 5093808

16

HOW SUPPLIED/STORAGE AND HANDLINGXELODA (capecitabine) tablets are supplied as follows:• 150 mg, biconvex, oblong, film-coated, light peach tablets with “XELODA” on one sideand “150” on the other; available in bottles of 60 tablets (NDC 0004-1100-20),
individually packaged in a carton.
•

500 mg, biconvex, oblong, film-coated, peach tablets with “XELODA” on one side and“500” on the other; available in bottles of 120 tablets (NDC 0004-1101-50), individually
packaged in a carton.

Storage and HandlingStore at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP
Controlled Room Temperature]. KEEP TIGHTLY CLOSED.
XELODA is a hazardous drug. Follow applicable special handling and disposal procedures.1
17

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).
Increased Risk of Bleeding with Concomitant Use of Vitamin K Antagonists
Advise patients on vitamin K antagonists, such as warfarin, that they are at an increased risk ofsevere bleeding while taking XELODA. Advise these patients that INR should be monitored
more frequently, and dosage modifications of the vitamin K antagonist may be required, while
taking and after discontinuation of XELODA. Advise these patients to immediately contact theirhealthcare provider if signs or symptoms of bleeding occur [see Warnings and Precautions(5.1)].
Serious Adverse Reactions from Dihydropyrimidine Dehydrogenase (DPD) Deficiency
Inform patients of the potential for serious and life-threatening adverse reactions due to DPD
deficiency and discuss with your patient whether they should be tested for genetic variants of
DPYD that are associated with an increased risk of serious adverse reactions from the use of
XELODA. Advise patients to immediately contact their healthcare provider if symptoms ofsevere mucositis, diarrhea, neutropenia, and neurotoxicity occur [see Warnings and Precautions(5.2) and Clinical Pharmacology (12.5)].
Cardiotoxicity
Advise patients of the risk of cardiotoxicity and to immediately contact their healthcare provider
for new onset of chest pain, shortness of breath, dizziness, or lightheadedness [see Warnings andPrecautions (5.3)].
Diarrhea
Inform patients experiencing grade 2 diarrhea (an increase of 4 to 6 stools/day or nocturnalstools) or greater or experiencing severe bloody diarrhea with severe abdominal pain and fever tostop taking XELODA. Advise patients on the use of antidiarrheal treatments (e.g., loperamide) to
manage diarrhea [see Warnings and Precautions (5.4)].

Reference ID: 5093808

Dehydration
Instruct patients experiencing grade 2 or higher dehydration to stop taking XELODA
immediately and to contact their healthcare provider. Advise patients to not restart XELODA
until rehydrated and any precipitating causes have been corrected or controlled [see Warnings
and Precautions (5.5)].
Renal Toxicity
Instruct patients experiencing decreased urinary output or other signs and symptoms of renal
toxicity to immediately contact their healthcare provider [see Warnings and Precautions (5.6)].
Serious Skin Toxicities
Instruct patients skin rash, blistering, or peeling to immediately contact their healthcare provider[see Warnings and Precautions (5.7)].
Palmar-Plantar Erythrodysesthesia Syndrome
Instruct patients experiencing grade 2 palmar-plantar erythrodysesthesia syndrome or greater tostop taking XELODA immediately and to contact their healthcare provider. Inform patients that
initiation of symptomatic treatment is recommended and hand-and-foot syndrome can lead toloss of fingerprints which could impact personal identification [see Warnings and Precautions(5.8)].
Myelosuppression
Inform patients who develop a fever of 100.5°F or greater or other evidence of potential infection
to immediately contact their healthcare provider [see Warnings and Precautions (5.9)].
Hyperbilirubinemia
Inform patients who develop jaundice or icterus to immediately contact their healthcare provider[see Warnings and Precautions (5.10)].
Embryo-Fetal Toxicity
Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
Advise females of reproductive potential to inform their healthcare provider of a known orsuspected pregnancy [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)].
Advise females of reproductive potential to use effective contraception during treatment with
XELODA and for 6 months after the last dose [see Use in Specific Populations (8.3)].
Advise males with female partners of reproductive potential to use effective contraception during
treatment with XELODA and for 3 months after the last dose [see Use in Specific Populations(8.3)].
Lactation
Advise females not to breastfeed during treatment with XELODA and for 1 week after the lastdose [see Use in Specific Populations (8.2)].
Infertility
Advise males and females of reproductive potential that XELODA may impair fertility [see Usein Specific Populations (8.3)].

Reference ID: 5093808

Hypersensitivity and Angioedema
Advise patients that XELODA may cause severe hypersensitivity reactions and angioedema.
Advise patients who have known hypersensitivity to capecitabine or 5-fluorouracil to informtheir healthcare provider [see Contraindications (4)]. Instruct patients who develop
hypersensitivity reactions or mucocutaneous symptoms (e.g., urticaria, rash, erythema, pruritus,
or swelling of the face, lips, tongue or throat which make it difficult to swallow or breathe) tostop taking XELODA and immediately contact their healthcare provider or to go to an
emergency room. [see Adverse Reactions (6)].
Nausea and Vomiting
Instruct patients experiencing grade 2 nausea (food intake significantly decreased but able to eat
intermittently) or greater to stop taking XELODA and to immediately contact their healthcare
provider for management of nausea [see Adverse Reactions (6.1)].
Instruct patients experiencing grade 2 vomiting (2 to 5 episodes in a 24-hour period) or greater tostop taking XELODA immediately and to contact their healthcare provider for management ofvomiting [see Adverse Reactions (6.1)].
Stomatitis
Inform patients experiencing grade 2 stomatitis (painful erythema, edema or ulcers of the mouthor tongue, but able to eat) or greater to stop taking XELODA immediately and to contact theirhealthcare provider [see Adverse Reactions (6.1)].
Important Administration Instructions
Advise patients to swallow XELODA tablets whole with water within 30 minutes after a meal.
Advise patients and caregivers not to chew, crush, or cut XELODA tablets. Advise patients ifthey cannot swallow XELODA tablets whole to inform their healthcare provider [see Dosage
and Administration (2.7), Warnings and Precautions (5.12)].
Drug interactions
Instruct patients not to take products containing folic acid or folate analog products (e.g.,leucovorin, levoleucovorin) unless directed to do so by their healthcare provider. Advise patientsto inform their healthcare provider of all prescription or nonprescription medications, vitamins or
herbal products [see Drug Interactions (7.1, 7.2, 7.3)].
Distributed by:

Genentech, Inc.
A Member of the Roche Group
1 DNA WaySouth San Francisco, CA 94080-4990
XELODA® is a registered trademark of Hoffmann-La Roche, Inc.
© 2022 Genentech, Inc. All rights reserved.

Reference ID: 5093808

Patient Information
XELODA® (zeh-LOE-duh)(capecitabine)tablets
What is the most important information I should know about XELODA?
XELODA can cause serious side effects, including:• Increased risk of bleeding when taking XELODA with blood thinner medicines, such as warfarin. Taking
XELODA with these medicines can cause changes in how fast your blood clots and can cause bleeding thatcan lead to death. This can happen as soon as a few days after you start taking XELODA, or later during treatment,
and possibly within 1 month after you stop taking XELODA. This can happen in people whose cancer has spread tothe liver (liver metastasis) and in people whose cancer has not spread to the liver.
o Before taking XELODA, tell your healthcare provider if you are taking warfarin or another blood thinner
medicine.
o If you take warfarin or another blood thinner that is like warfarin during treatment with XELODA, your healthcare
provider should do blood tests more often, to check how fast your blood clots during and after you stoptreatment with XELODA. Your healthcare provider may change your dose of the blood thinner medicine if
needed.
o Tell your healthcare provider right away if you develop any signs or symptoms of bleeding.
See “What are the possible side effects of XELODA?” for more information about side effects.
What is XELODA?
XELODA is a prescription medicine used to treat:• A kind of cancer called colon or rectal (colorectal) cancer. XELODA may be used:o alone or in combination with other chemotherapy medicines in people with colon cancer that has spread tolymph nodes in the area close to the colon (Stage III colon cancer), to help prevent your cancer from comingback after you have had surgery.
o adults with rectal cancer, around the time of your surgery, as a part of chemotherapy and radiation(chemoradiation) treatment when your rectal cancer has spread to nearby tissues (locally advanced).
o alone or in combination with other chemotherapy medicines, when your colorectal cancer cannot be removed bysurgery or has spread to other areas of your body (metastatic).
• A kind of cancer called breast cancer. XELODA may be used in people with breast cancer that is advanced or has
spread to other parts of the body (metastatic):o alone if you are not able to receive an anthracycline medicine or taxane-containing chemotherapy.
o in combination with docetaxel when you have received anthracycline containing chemotherapy and it is nolonger working.
• Kinds of cancer called stomach (gastric), esophageal, or gastroesophageal junction (GEJ) cancer. XELODA may be
used in adults:
o in combination with other chemotherapy medicines when your cancer of the stomach, esophagus, or GEJ
cannot be removed by surgery or has spread to other parts of the body (metastatic).
o when your cancer of the stomach, esophagus, or GEJ is metastatic adenocarcinoma, and:
 is HER2-positive, and you have not received treatment with XELODA in combination with other treatments for your metastatic
cancer.
• A kind of cancer called pancreatic cancer. XELODA may be used to treat adults in combination with otherchemotherapy medicines, to help prevent your pancreatic cancer from coming back after you have had surgery.
It is not known if XELODA is safe and effective in children.
Do not take XELODA if you:• have had a severe allergic reaction to fluorouracil or capecitabine. See the end of this leaflet for a complete list ofingredients in XELODA.
Talk to your healthcare provider before taking XELODA if you are not sure.
Before taking XELODA, tell your healthcare provider about all your medical conditions, including if you:See “What is the most important information I should know about XELODA?”• have had heart problems.
• have kidney or liver problems.
• are pregnant or plan to become pregnant. XELODA can harm your unborn baby.
Females who are able to become pregnant:o Your healthcare provider should do a pregnancy test before you start treatment with XELODA.

Reference ID: 5093808

Use an effective method of birth control (contraception) during treatment and for 6 months after your last dose of
XELODA. Talk to your healthcare provider about birth control choices that may be right for you during treatment
with XELODA.
o Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment
with XELODA.
Males who have female partners who are able to become pregnant should use effective birth control during
treatment and for 3 months after your last dose of XELODA.
• are breastfeeding or plan to breastfeed. It is not known if XELODA passes into your breast milk. Do not breastfeed
during treatment with XELODA and for 1 week after your last dose of XELODA.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines,
vitamins, and herbal supplements. XELODA may affect the way other medicines work, and other medicines may affectthe way XELODA works.
How should I take XELODA?
• Take XELODA exactly as your healthcare provider tells you to take it.
• Your healthcare provider will tell you how much XELODA to take and when to take it. The number of days that you
will take XELODA during each treatment cycle and the number of days in each treatment cycle depends on the typeof cancer you are being treated for.
• Take XELODA 2 times a day at the same time each day, about 12 hours apart.
• Take XELODA within 30 minutes after finishing a meal.
• Swallow XELODA tablets whole with water. Do not chew, cut, or crush XELODA tablets. See “Eye irritation, skinrash and other side effects with exposure to crushed XELODA tablets” in the section called “What are the possible
side effects of XELODA?”• If you cannot swallow XELODA tablets whole, tell your healthcare provider.
• Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with XELODA if
you develop side effects.
• Do not take products that contain folic acid or folate analog products, for example, leucovorin or levoleucovorin,
during treatment with XELODA, unless your healthcare provider instructs you to take it.
• If you vomit after taking a dose of XELODA, do not take another dose at that time. Wait and take your next dose of
XELODA at your scheduled time.
• If you miss a dose of XELODA, just skip the dose and then take your next dose at your scheduled time.
• If you take too much XELODA, call your healthcare provider or go to the nearest hospital emergency room rightaway.
What are the possible side effects of XELODA?
XELODA can cause serious side effects including:• See “What is the most important information I should know about XELODA?”• Serious side effects in people with dihydropyrimidine dehydrogenase (DPD) enzyme deficiency. People withcertain changes in a gene called “DPYD” may have a deficiency of the DPD enzyme. Some of these people may not
produce enough DPD enzyme, and some of these people may not produce the DPD enzyme at all.
o People who do not produce any DPD enzyme are at increased risk of sudden side effects that come on early
during treatment with XELODA and can be serious, and sometimes lead to death. Call your healthcare
provider right away if you develop any of the following symptoms and they are severe, including:• sores of the mouth, tongue, throat and esophagus (mucositis)• diarrhea• low white blood cell counts• nervous system problems.
oPeople with some DPD enzyme may have an increased risk of serious side effects with XELODA treatment thatcan sometimes lead to death.
Your healthcare provider should talk with you about DPYD testing to look for DPD deficiency.
• Heart problems. XELODA can cause heart problems including: heart attack and decreased blood flow to the heart,chest pain, irregular heartbeats, changes in the electrical activity of your heart seen on an electrocardiogram (ECG),
problems with your heart muscle, heart failure, and sudden death. You may have an increased risk of heart
problems with XELODA if you have a history of narrowing or blockage of the coronary arteries (coronary arterydisease). Stop taking XELODA and call your healthcare provider or go to the nearest hospital emergency
room right away if you get any new symptoms of a heart problem including:o chest paino dizzinesso shortness of breatho lightheadedness• Diarrhea. Diarrhea is common with XELODA and can sometimes be severe. Stop taking XELODA and call yourhealthcare provider right away if the number of bowel movements you have in a day increases by 4 or more bowel
movements than what is usual for you, or if you have bowel movements at night. Ask your healthcare provider about
what medicines you can take to treat your diarrhea. Stop taking XELODA if you have severe bloody diarrhea withsevere abdominal pain and fever and call you healthcare provider right away.
oReference ID: 5093808

• Loss of too much body fluid (dehydration) and kidney failure. Dehydration can happen with XELODA and may
affect how well your kidneys work. If you take XELODA with certain other medicines that can cause kidney
problems, you may have an increased risk of serious kidney failure that can sometimes lead to death. Your risk ofkidney failure may also be increased if you have kidney problems before taking XELODA.
Nausea, and vomiting are common with XELODA. If you lose your appetite, feel weak, and have nausea, vomiting,or diarrhea, you can quickly become dehydrated.
Stop taking XELODA and call your healthcare provider right away if you:o vomit 2 or more times in a day.
o are only able to eat or drink a little now and then, or not at all due to nausea.
o have diarrhea. See “diarrhea” above.
You may need to receive fluids through your vein (intravenous) to treat your dehydration or receive treatment forkidney failure.
• Severe skin and mouth reactions.
o XELODA can cause severe skin reactions that may lead to death. Tell your healthcare provider right away if you
develop a skin rash, blister and peeling of your skin. Your healthcare provider may tell you to stop taking
XELODA if you have a serious skin reaction. Do not take XELODA again if this happens.
o XELODA can also cause “hand and foot” syndrome. Hand and foot syndrome is common with XELODA and cancause you to have numbness and changes in sensation in your hands and feet, or cause redness, pain, swellingof your hands and feet. Stop taking XELODA and call your healthcare provider right away if you have any ofthese symptoms and you are not able to do your usual activities.
o Hand and foot syndrome can lead to a loss of fingerprints which could impact your identification.
o You may get sores in your mouth or on your tongue when taking XELODA. Stop taking XELODA and call yourhealthcare provider right away if you get painful redness, swelling, or ulcers in your mouth or tongue, or if you
are having problems eating.
• Decreased white blood cells, platelets, and red blood cell counts. Decreased white blood cells, platelets,
and red blood cell counts can happen with XELODA and can sometimes be severe. Your healthcare provider
will do blood tests during treatment with XELODA to check your blood cell counts.
If your white blood cell count is very low, you are at increased risk for infection. Call your healthcare provider rightaway if you develop a fever of 100.5oF or greater or have other signs and symptoms of infection.
• Increased level of bilirubin in your blood and liver problems. Increased bilirubin in your blood is common with
XELODA and can also sometimes be severe. Your healthcare provider will check you for these problems during
treatment with XELODA. Tell your healthcare provider right away if you develop yellowing of your skin or the whitepart of your eyes.
• Eye irritation, skin rash and other side effects with exposure to crushed XELODA tablets. If you come into
contact with (you are exposed to) crushed XELODA tablets, you may develop side effects including:o eye irritation and swellingo feeling like pins and needles in your handso headacheo skin rasho stomach irritationo diarrhea
o nausea and vomiting
Do not chew, cut, or crush XELODA tablets. See “How should I take XELODA tablets.”
If for any reason your tablets must be cut or crushed, this must be done by your pharmacist or healthcare provider.
Your healthcare provider may decide to decrease your dose, or temporarily or permanently stop XELODA if you haveserious side effects with XELODA.
The most common side effects in people with colon cancer who take XELODA alone to help prevent it from comingback include: hand and foot syndrome, diarrhea, and nausea.
The most common side effects in people with metastatic colorectal carcinoma who take XELODA alone include:• decreased red blood cell count• diarrhea• nausea• hand and foot syndrome• tiredness• increased bilirubin level in your blood• stomach-area (abdominal) pain
The most common side effects in people with metastatic breast cancer who take XELODA in combination withdocetaxel include:• hair loss
• diarrhea• swelling• mouth sores or mouth inflammation

Reference ID: 5093808

• hand and foot syndrome• nausea and vomiting• stomach-area (abdominal) pain

The most common side effects in people with metastatic breast cancer who take XELODA alone include:• decreased white blood cell and red blood cell count• nausea and vomiting• diarrhea• tiredness• hand and foot syndrome• skin inflammation, including rash

Severe allergic reactions can happen with XELODA. See “Do not take XELODA if you:” Stop taking XELODA
and call your healthcare provider right away or go to an emergency room if you have any of the following
symptoms of a severe allergic reaction to XELODA:• red itchy welts on your skin (hives)• skin redness• swelling of your face, lips, tongue or throat• rash• itching• trouble swallowing or breathing
XELODA may cause fertility problems in females and males. This may affect the ability to have a child. Talk to yourhealthcare provider if you have concerns about fertility.
These are not all the possible side effects of XELODA.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store XELODA?
• Store XELODA at room temperature between 68°F to 77°F (20°C to 25°C).
• Keep XELODA in a tightly closed container.
• Ask your healthcare provider or pharmacist how to safely throw away any unused XELODA.
Keep XELODA and all medicines out of the reach of children.
General information about the safe and effective use of XELODA.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use
XELODA for a condition for which it was not prescribed. Do not give XELODA to other people, even if they have thesame symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about
XELODA that is written for health professionals.
What are the ingredients in XELODA?
Active ingredient: capecitabine
Inactive ingredients: 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.
Distributed by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990
XELODA® is a registered trademark of Hoffmann-La Roche, Inc.© 2022 Genentech, Inc. All rights reserved.
For more information, go to http://www.gene.com/patients/medicines/xeloda or call 1-877-436-3683.
This Patient Information has been approved by the U.S. Food and Drug Administration.

Reference ID: 5093808

Revised: 12/2022