Capecitabine is a nucleoside metabolic inhibitor. The chemical name is 5'-deoxy-5-fluoro-N-[(pentyloxy) carbonyl]-cytidine and has a molecular formula of C 15 H 22 FN 3 O 6 and a molecular weight of 359.35. Capecitabine has the following structural formula: Capecitabine is a white to off-white crystalline powder with an aqueous solubility of 26 mg/mL at 20°C. XELODA (capecitabine) is supplied as biconvex, oblong film-coated tablets for oral use. Each light peach-colored tablet contains 150 mg capecitabine and each peach-colored tablet contains 500 mg capecitabine. The inactive ingredients in XELODA include: anhydrous lactose, croscarmellose sodium, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium stearate and purified water. The peach or light peach film coating contains hydroxypropyl methylcellulose, talc, titanium dioxide, and synthetic yellow and red iron oxides. Chemical Structure

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. 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. Breast Cancer treatment of patients with advanced or metastatic breast cancer as a single agent if an anthracycline- or taxane-containing chemotherapy is not indicated. treatment of patients with advanced or metastatic breast cancer in combination with docetaxel after disease progression on prior anthracycline-containing chemotherapy. 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. 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. Pancreatic Cancer adjuvant treatment of adults with pancreatic adenocarcinoma as a component of a combination chemotherapy regimen

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

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

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

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

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 Tablets: 150 mg and 500 mg

Adjuvant Treatment of Colon Cancer Single agent: 1,250 mg/m 2 twice daily orally for the first 14 days of each 21-day cycle for a maximum of 8 cycles. In combination with Oxaliplatin-Containing Regimens: 1,000 mg/m 2 orally twice daily for the first 14 days of each 21-day cycle for a maximum of 8 cycles in combination with oxaliplatin 130 mg/m 2 administered intravenously on day 1 of each cycle. Perioperative Treatment of Rectal Cancer With Concomitant Radiation Therapy: 825 mg/m 2 orally twice daily Without Radiation Therapy: 1,250 mg/m 2 orally twice daily Unresectable or Metastatic Colorectal Cancer: Single agent: 1,250 mg/m 2 twice daily orally for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity. In Combination with Oxaliplatin: 1,000 mg/m 2 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/m 2 administered intravenously on day 1 of each cycle. Advanced or Metastatic Breast Cancer: Single agent: 1,000 mg/m 2 or 1,250 mg/m 2 twice daily orally for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity. In combination with docetaxel: 1,000 mg/m 2 or 1,250 mg/m 2 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/m 2 administered intravenously on day 1 of each cycle Unresectable or Metastatic Gastric, Esophageal, or Gastroesophageal Junction Cancer 625 mg/m 2 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/m 2 or 1,000 mg/m 2 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/m 2 administered intravenously on day 1 of each cycle. HER2-overexpressing metastatic adenocarcinoma of the gastroesophageal junction or stomach 1,000 mg/m 2 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. Pancreatic cancer 830 mg/m 2 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/m 2 administered intravenously on days 1, 8, and 15 of each cycle. 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 )

Evaluation and Testing for DPD Deficiency Before Initiating XELODA Prior to initiating XELODA, test patients for genetic variants of the DPYD gene unless immediate treatment is necessary. An FDA-authorized test for the detection of the DPYD gene to identify patients at risk of serious adverse reactions with XELODA is not currently available. Currently available tests used to identify DPYD variants may vary in accuracy and design (e.g., which DPYD variant(s) they identify). Avoid use of XELODA in patients known to have certain homozygous or compound heterozygous DPYD variants that result in complete DPD deficiency. No XELODA dose has been proven safe for patients with complete DPD deficiency. For patients with partial DPD deficiency, individualize the dosage and modify based on tolerability and intent of treatment

Recommended Dosage for Colorectal Cancer Adjuvant Treatment of Colon Cancer Single Agent The recommended dosage of XELODA is 1,250 mg/m 2 orally twice daily for the first 14 days of each 21-day cycle for a maximum of 8 cycles. In Combination with Oxaliplatin-Containing Regimens The recommended dosage of XELODA is 1,000 mg/m 2 orally twice daily for the first 14 days of each 21-day cycle for a maximum of 8 cycles in combination with oxaliplatin 130 mg/m 2 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/m 2 orally twice daily when administered with concomitant radiation therapy and 1,250 mg/m 2 orally twice daily when administered without radiation therapy as part of a peri-operative combination regimen. Unresectable or Metastatic Colorectal Cancer Single Agent The recommended dosage of XELODA is 1,250 mg/m 2 orally twice daily for the first 14 days of a 21-day cycle until disease progression or unacceptable toxicity. In Combination with Oxaliplatin The recommended dosage of XELODA is 1,000 mg/m 2 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/m 2 administered intravenously on day 1 of each cycle. Refer to the Prescribing Information for oxaliplatin for additional dosing information as appropriate

Recommended Dosage for Breast Cancer Advanced or Metastatic Breast Cancer Single Agent The recommended dosage of XELODA is 1,000 mg/m 2 or 1,250 mg/m 2 orally twice daily for the first 14 days of a 21-day cycle until disease progression or unacceptable toxicity. Individualize the dose and dosing schedule of XELODA based on patient risk factors and adverse reactions. In Combination with Docetaxel The recommended dosage of XELODA is 1,000 mg/m 2 or 1,250 mg/m 2 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/m 2 administered intravenously on day 1 of each cycle. Refer to the Prescribing Information for docetaxel for additional dosing information as appropriate

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/m 2 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/m 2 or 1,000 mg/m 2 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/m 2 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/m 2 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

Recommended Dosage for Pancreatic Cancer The recommended dosage of XELODA is 830 mg/m 2 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/m 2 administered intravenously on days 1, 8, and 15 of each cycle. Refer to Prescribing Information for gemcitabine for additional dosing information as appropriate

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. Table 1 Recommended Dosage Modifications for Adverse Reactions Severity Dosage Modification Resume at Same or Reduced Dose (Percent of Current Dose) Grade 2 1st appearance Withhold until resolved to grade 0-1. 100% 2nd appearance 75% 3rd appearance 50% 4th appearance Permanently discontinue. - Grade 3 1st appearance Withhold until resolved to grade 0-1. 75% 2nd appearance 50% 3rd appearance Permanently discontinue. - Grade 4 1st appearance Permanently discontinue OR Withhold until resolved to grade 0-1. 50% Hyperbilirubinemia Patients with Grade 3-4 hyperbilirubinemia may resume treatment once the event is Grade 2 or less (less than three times the upper limit of normal), using the percent of current dose as shown in column 3 of Table 1

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)

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 . 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

Cardiotoxicity : May be more common in patients with a prior history of coronary artery disease. Withhold XELODA for cardiotoxicity as appropriate. The safety of resumption of XELODA in patients with cardiotoxicity that has resolved has not been established. Diarrhea : Withhold XELODA and then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence. (2.5, 5.4) Dehydration : Optimize hydration before starting XELODA. Monitor hydration status and kidney function at baseline and as clinically indicated. Withhold XELODA and then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence. Renal Toxicity : Monitor renal function at baseline and as clinically indicated. Optimize hydration before starting XELODA. Withhold XELODA and then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence. Serious Skin Toxicities : Monitor for new or worsening serious skin reactions. Permanently discontinue XELODA in patients who experience a severe cutaneous adverse reaction. Palmar-Plantar Erythrodysesthesia Syndrome : Withhold XELODA then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence. Myelosuppression : Monitor complete blood count at baseline and before each cycle. XELODA is not recommended in patients with baseline neutrophil counts <1.5 × 10 9 /L or platelet counts <100 × 10 9 /L. For grade 3 or 4 myelosuppression, withhold XELODA and then resume at same or reduced dose, or permanently discontinue, based on occurrence. Hyperbilirubinemia : Patients with Grade 3-4 hyperbilirubinemia may resume treatment once the event is Grade 2 or less (≤3 × ULN), using the percent of current dose as shown in column 3 of Table 1 ( 2.5 , 5.10 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.11 , 8.1 , 8.3 ) 5.1 Serious Adverse Reactions or Death 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 or fatal, adverse reactions. Prior to initiating XELODA, test patients for genetic variants of the DPYD gene unless immediate treatment is necessary . Serious adverse reactions may still occur even if no DPYD variants are identified. Avoid use of XELODA in patients with certain homozygous or compound heterozygous DPYD variants that result in complete DPD deficiency. Withhold or permanently discontinue XELODA based on clinical assessment of the onset, duration, and severity of adverse reactions in patients with evidence of acute early-onset or unusually severe reactions. No XELODA dose has been proven safe for patients with complete DPD deficiency. There are insufficient data to recommend a specific dose in patients with partial DPD deficiency. For patients with partial DPD deficiency, individualize the dosage and modify based on tolerability and intent of treatment. An FDA-authorized test for the detection of genetic variants of the DPYD gene to identify patients at risk of serious adverse reactions with XELODA treatment is not currently available. Currently available tests used to identify DPYD variants may vary in accuracy and design (e.g., which DPYD variant(s) they identify)

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

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 . The safety of resumption of XELODA in patients with cardiotoxicity that has resolved have not been established

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

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

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 . 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

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

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

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 × 10 9 /L or platelet count <100 × 10 9 /L. For grade 3 to 4 myelosuppression, withhold XELODA and then resume at same or reduced dose, or permanently discontinue, based on occurrence

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 . 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

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/m 2 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

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 . The safety and effectiveness have not been established for the administration of crushed XELODA tablets.

Allopurinol: Avoid concomitant use of allopurinol with XELODA. Leucovorin: Closely monitor for toxicities when XELODA is coadministered with leucovorin. CYP2C9 substrates: Closely monitor for adverse reactions when CYP2C9 substrates are coadministered with XELODA. 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. Nephrotoxic drugs: Closely monitor for signs of renal toxicity when XELODA is used concomitantly with nephrotoxic drugs

Effect of Other Drugs on XELODA Allopurinol Concomitant use with allopurinol may decrease concentration of capecitabine's active metabolites , 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 unless directed to do so by their healthcare provider

Effect of Xeloda on Other Drugs CYP2C9 Substrates XELODA increased exposure of CYP2C9 substrates , which may increase the risk of adverse reactions related to these substrates. Closely monitor for adverse 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 , which m ay alter coagulation parameters and/or bleeding and could result in death . 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 with vitamin 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 used concomitantly with phenytoin

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 . Closely monitor for signs of renal toxicity when XELODA is used concomitantly with nephrotoxic drugs (e.g. platinum salts, irinotecan, methotrexate, intravenous bisphosphonates).