1.1 Colorectal Cancer

XELODA is indicated for the:

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

1.2 Breast Cancer

XELODA is indicated for the:

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

1.3 Gastric, Esophageal, or Gastroesophageal Junction Cancer

XELODA is indicated for the:

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

1.4 Pancreatic Cancer

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

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

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

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

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

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

2.4 Recommended Dosage for Pancreatic Cancer

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

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

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

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 in patients 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

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 patients taking XELODA concomitantly with vitamin K antagonists, such as warfarin.

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

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

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 of serious, including fatal, adverse reactions.

XELODA is not recommended for use in patients known to have certain homozygous or compound heterozygous DPYD variants that result in complete DPD deficiency.

Withhold or permanently discontinue XELODA based on clinical assessment of the onset, duration, and severity of the observed adverse reactions in patients with evidence of acute early-onset 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 of serious 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.

An FDA-authorized test for the detection of genetic variants of DPYD to identify patients at risk of 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 and design (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 patients with a prior history of coronary artery disease.

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

5.4 Diarrhea

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

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

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.

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 based on 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 × 109/L or platelet count <100 × 109/L. For grade 3 to 4 myelosuppression, withhold XELODA and then resume at same or reduced dose, or permanently discontinue, based on occurrence [see Dosage and Administration (2.5)].

5.10 Hyperbilirubinemia

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

In the 596 patients who received XELODA for metastatic colorectal cancer, the incidence of grade 3 or 4 hyperbilirubinemia was similar to that observed for the pooled population of patients with metastatic breast and colorectal cancer. The median time to onset for grade 3 or 4 hyperbilirubinemia was 64 days and median total bilirubin increased from 8 µm/L at baseline to 13 µm/L during treatment with XELODA. Of the 136 patients with grade 3 or 4 hyperbilirubinemia, 49 patients had grade 3 or 4 hyperbilirubinemia as their last measured value, of which 46 had liver metastases at baseline.

In the 251 patients with metastatic breast cancer who received XELODA with docetaxel, grade 3 hyperbilirubinemia occurred in 7% and grade 4 hyperbilirubinemia occurred in 2%.

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

5.11 Embryo-Fetal Toxicity

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

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

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 been reported: eye irritation and swelling, skin rash, diarrhea, paresthesia, headache, gastric irritation, vomiting and nausea. Advise patients not to cut or crush tablets.

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

6.1 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 trials of another drug and may not reflect the rates observed in practice.

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 not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Eye: lacrimal duct stenosis, corneal disorders including keratitis

Hepatobiliary: hepatic failure

Immune System Disorders: angioedema

Nervous System: toxic leukoencephalopathy

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

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

7.1 Effect of Other Drugs on XELODA

7.2 Effect of Xeloda on Other Drugs

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 with nephrotoxic drugs (e.g. platinum salts, irinotecan, methotrexate, intravenous bisphosphonates).

8.1 Pregnancy

8.2 Lactation

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)].

8.4 Pediatric Use

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

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 concomitantly with 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 treated with 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 with colorectal 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 to younger 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 in patients 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 and Administration (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.

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 of thymidylate from 2'-deoxyuridylate. Thymidylate is the necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, so that a deficiency of this compound can inhibit cell division. Second, nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis.

12.2 Pharmacodynamics

Population-based exposure-effect analyses demonstrated a positive association between AUC of fluorouracil 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 greater than proportional to the dose. The interpatient variability in the Cmax and AUC of fluorouracil was greater than 85%.

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 no function 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 is available 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 at increased 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 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 in individuals 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)].

13.1 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 to human peripheral blood lymphocytes but not clastogenic in vivo to mouse bone marrow (micronucleus test). Fluorouracil causes mutations in bacteria and yeast. Fluorouracil also causes chromosomal abnormalities in the mouse micronucleus test in vivo.

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 a decrease in fertility. In mice that became pregnant, no fetuses survived this dose. The disturbance in estrus was reversible. In males, this dose caused degenerative changes in the testes, including decreases in the number of spermatocytes and spermatids. In separate pharmacokinetic studies, this dose in mice produced 5'-DFUR AUC values about 0.7 times the corresponding values in patients administered the recommended daily dose.

14.1 Colorectal Cancer

14.2 Metastatic Breast Cancer

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 REAL-2, a randomized non-inferiority, 2×2 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 for metastatic 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.

Storage and Handling

Store 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

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 of severe 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 their healthcare 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 of severe 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 and Precautions (5.3)].

Diarrhea

Inform patients experiencing grade 2 diarrhea (an increase of 4 to 6 stools/day or nocturnal stools) or greater or experiencing severe bloody diarrhea with severe abdominal pain and fever to stop taking XELODA. Advise patients on the use of antidiarrheal treatments (e.g., loperamide) to manage diarrhea [see Warnings and Precautions (5.4)].

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 to stop 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 to loss 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 or suspected 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 last dose [see Use in Specific Populations (8.2)].

Infertility

Advise males and females of reproductive potential that XELODA may impair fertility [see Use in Specific Populations (8.3)].

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 inform their 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) to stop 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 to stop taking XELODA immediately and to contact their healthcare provider for management of vomiting [see Adverse Reactions (6.1)].

Stomatitis

Inform patients experiencing grade 2 stomatitis (painful erythema, edema or ulcers of the mouth or tongue, but able to eat) or greater to stop taking XELODA immediately and to contact their healthcare 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 if they 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 patients to inform their healthcare provider of all prescription or nonprescription medications, vitamins or herbal products [see Drug Interactions (7.1, 7.2, 7.3)].