AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• Capecitabine

Capecitabine, a prodrug that has little pharmacologic activity until it is converted to fluorouracil (an antimetabolite) in tumor tissue, is an antineoplastic agent.1

Breast Cancer

Capecitabine is used in combination with docetaxel for the treatment of advanced or metastatic breast cancer after disease progression on prior anthracycline-containing chemotherapy.1 Capecitabine is also used for the treatment of advanced or metastatic breast cancer as a single agent if an anthracycline- or taxane-containing chemotherapy is not indicated.1

Combination Therapy

The efficacy of capecitabine as a component of combination chemotherapy in patients with metastatic breast cancer is based principally on the results of an open-label, multicenter, randomized trial (Study SO14999).1,37 The study included 511 patients with metastatic breast cancer resistant to or recurring during or following anthracycline-containing therapy, or relapsing during or recurring within 2 years of completion of anthracycline-containing adjuvant therapy.1,37

Patients received either combination therapy with capecitabine 1250 mg/m² twice daily for 14 days followed by 1 week without treatment and docetaxel 75 mg/m²as a 1-hour IV infusion administered on the first day of each 3-week cycle or monotherapy with docetaxel 100 mg/m² as a 1-hour IV infusion administered on the first day of each 3-week cycle.1,37 The median patient age was 52 and 51 years in the capecitabine/docetaxel combination group and docetaxel monotherapy group, respectively; the median Karnofsky performance status score was 90 in both treatment groups.1 The median time to disease progression was 6.1 and 4.2 months, median overall survival was 14.5 and 11.6 months, and response rate was 32 and 22% for the capecitabine/docetaxel and docetaxel groups, respectively.1

Monotherapy

The efficacy of capecitabine monotherapy in the treatment of metastatic breast cancer is based principally on the results of a multicenter, open-label, single-arm, phase 2 trial (SO14697) in 162 patients (135 patients with measurable disease) with previously treated stage IV breast cancer resistant to both paclitaxel and an anthracycline or resistant to paclitaxel and where further anthracycline therapy was not indicated.1,15 Patients received capecitabine 1255 mg/m² twice daily for 2 weeks followed by a 1-week rest period in each 3-week treatment cycle.1,15 The median patient age was 55—56 years, and the Karnofsky Performance Status score was 90 in all patients.1

For the subgroup of 43 patients whose disease was resistant to both paclitaxel and an anthracycline, response rate was 25.6%, with a median duration of response of 5.1 months, median time to progression of 3.4 months, and median survival of 8.4 months.1 For the 135 patients with measurable disease, the objective response rate was 18.5%, median time to progression was 3 months, and median survival was 10.1 months.1

Clinical Perspective

According to the National Cancer Institute, treatment options for locally advanced breast cancer include surgery, chemotherapy, radiation therapy, and hormone therapy, with targeted therapies (e.g., trastuzumab) added for locoregional recurrent disease.12000 For metastatic disease, treatment options include surgery for metastases, hormone therapy, targeted therapies, chemotherapy, immunotherapy, and radiation.12000 Various chemotherapy agents have been used for metastatic disease, including anthracyclines, taxanes, capecitabine or fluorouracil, vinca alkaloids, and platinum agents.12000

Colorectal Cancer

Capecitabine is used as adjuvant treatment of patients with stage III colon cancer alone or as part of a combination chemotherapy regimen.1 The drug is also used as perioperative treatment for adults with locally advanced rectal cancer as part of a combination chemoradiotherapy regimen.1 Capecitabine is also is used for treatment of patients with unresectable or metastatic colorectal cancer as a single agent or as part of a combination chemotherapy regimen.1

Adjuvant Treatment of Colon Cancer

Monotherapy

The efficacy of capecitabine as a single-agent adjuvant therapy in patients with stage III colon cancer is based principally on the results of a multicenter, randomized, controlled, phase 3 clinical study (X-ACT).1,42,47

In this study, 1987 patients were randomized to receive either capecitabine 1250 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 IV on days 1—5 of each 28-day cycle for a total of 6 cycles.1 The primary outcome was disease-free survival; secondary outcomes included relapse-free survival and overall survival.42

The median age of patients was 62 and 63 years for the capecitabine and fluorouracil/leucovorin groups, respectively; 54% of patients were male, 85% had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, and 76% had a primary tumor staging of 3.1 Median follow-up was 6.9 years.1 The 5-year disease-free survival rate was 60.8% for patients receiving capecitabine and 56.7% for patients receiving fluorouracil/leucovorin, demonstrating noninferiority of capecitabine to fluorouracil/leucovorin.47 The 5-year overall survival was 71.4 and 68.4% for the capecitabine and fluorouracil/leucovorin groups, respectively.1,47 The 5-year relapse-free survival rate was 63.2 and 59.8% for the capecitabine and fluorouracil/leucovorin groups, respectively.47

Combination Therapy

The efficacy of capecitabine as a component of an adjuvant combination chemotherapy regimen for stage III colon cancer is based on several published studies, including a randomized, open-label, phase 3 clinical study (NO16968).1,10002 In this study, patients were randomly assigned to treatment with either oxaliplatin 130 mg/m² on day 1 plus capecitabine 1000 mg/m² twice daily on days 1—14 of a 3-week cycle for a total of 8 cycles or a fluorouracil/leucovorin regimen.10002 A total of 1886 patients were enrolled.10002 At a median follow-up of 74 months, 33.9% of patients who received capecitabine experienced a relapse, developed a new colon cancer, or died versus 40.2% of patients who received fluorouracil/leucovorin.10002 Overall survival was also higher with the capecitabine regimen versus fluorouracil/leucovorin; at a median follow-up of 83 months, deaths occurred in 25.6% and 30.4% of patients in the respective treatment groups.10002

Perioperative Treatment of Rectal Cancer

The efficacy of capecitabine as perioperative treatment of adults with locally advanced rectal cancer is based on several published studies, including an open-label, phase 3 trial comparing fluorouracil with capecitabine (Rektum-III).1,12001 In Rektum-III, patients were randomized (1:1 ratio) to preoperative treatment with either capecitabine- or fluorouracil-based chemoradiotherapy.12001 The 5-year overall survival was 76 and 67% with capecitabine and fluorouracil, respectively, with capecitabine found to be noninferior to fluorouracil.12001

Metastatic or Unresectable Colorectal Cancer

Monotherapy

The efficacy of capecitabine monotherapy in patients with metastatic colorectal cancer is based principally on the results of 2 open-label, randomized trials (SO14695 and SO14796).1,31,32 Enrolled patients were randomized to treatment with either capecitabine 1250 mg/m²twice daily for 14 days of a 21-day cycle or leucovorin 20 mg/m² IV followed by fluorouracil 425 mg/m² as an IV bolus on days 1-5 of each 28-day cycle.1 Outcomes assessed were overall survival, time to progression, and response rate (complete plus partial response).1

A total of 1207 patients were enrolled in the 2 trials; the median age of patients was 63 or 64 years; 57—65% were male, the median Karnofsky performance status score was 90, 65—77% of patients had disease in the colon, and 23-35% had disease in the rectum.1 In Study SO14695, the overall response rate was 24.8 and 15.5%, median time to progression was 4.3 and 4.7 months, and overall median survival was 12.5 and 13.3 months for the capecitabine and fluorouracil/leucovorin groups, respectively.32 In Study SO14796, the overall response rate was 18.9 and 15%, median time to progression was 5.2 and 4.7 months, and overall median survival was 13.2 or 12.1 months for the capecitabine and fluorouracil/leucovorin groups, respectively.31

Combination Therapy

The efficacy of capecitabine in the treatment of unresectable or metastatic colorectal cancer as part of a combination chemotherapy regimen is based on several published trials, including Study NO16966, a randomized, noninferiority, 2-arm study evaluating capecitabine in combination with oxaliplatin versus FOLFOX-4 (fluorouracil/folinic acid/oxaliplatin).1,12002 The protocol was later revised to include 4 treatment arms (capecitabine/oxaliplatin/placebo; capecitabine/oxaliplatin/bevacizumab; FOLFOX-4/placebo; or FOLFOX-4/bevacizumab).12002 Treatment was continued until disease progression or for 48 weeks, whichever came first.12002 A total of 2034 patients were enrolled.12002 Median progression-free survival was 8 and 8.5 months for the capecitabine-containing and FOLFOX-4 based regimens, respectively.12002 Results for secondary outcomes (overall response rate, median overall survival, and median duration of response) were similar between treatment groups.12002

Clinical Perspective

According to the National Cancer Institute, surgery is the first-line treatment for patients with any stage of colon or rectal cancer.12003 The use of chemotherapy or other systemic therapy after surgery is recommended for recurrent, late-stage, or metastatic disease.12003 Various chemotherapy regimens have been used, including folic acid/fluorouracil/irinotecan, capecitabine/oxaliplatin, and fluorouracil/oxaliplatin.12003 For stage IV or recurrent colon or rectal cancer, surgical resection (based on site of metastasis) and/or systemic therapy (e.g., targeted therapies, palliative chemotherapy) is recommended.12003

The American Society of Clinical Oncology (ASCO) guideline on metastatic colorectal cancer recommends the use of a chemotherapy (doublet or triplet) backbone as first-line therapy for previously untreated, unresectable microsatellite stable (MSS) or proficient mismatch repair (pMMR) metastatic colorectal cancer, in combination with anti-vascular endothelial growth factor (VEGF) antibodies (e.g., bevacizumab).12004 Doublet chemotherapy regimens include folinic acid/fluorouracil/oxaliplatin and folinic acid/fluorouracil/irinotecan.12004 Capecitabine plus oxaliplatin may be used as a substitute for folinic acid/fluorouracil/oxaliplatin.12004 Triplet chemotherapy includes folinic acid/fluorouracil/oxaliplatin/irinotecan.12004

Gastric, Esophageal, or Gastroesophageal Junction Cancer

Capecitabine is used for the treatment of adults with unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer as part of a combination chemotherapy regimen.1 Capecitabine is also used for treatment of adults with human epidermal growth factor receptor (HER)2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not been previously treated for metastatic disease as part of a combination regimen.1

Unresectable or Metastatic Gastric, Esophageal, or Gastroesophageal Junction Cancer

The efficacy of capecitabine in the treatment of unresectable or metastatic gastric, esophageal, or gastroesophageal cancer was derived from several published studies, including REAL-2, a randomized noninferiority trial.1,44 A total of 1002 patients were randomized to treatment with 1 of 4 combination regimens (epirubicin/cisplatin/fluorouracil [ECF]; epirubicin/cisplatin/capecitabine [ECX]; epirubicin/oxaliplatin/fluorouracil [EOF]; or epirubicin/oxaliplatin/capecitabine [EOX]).44 The primary endpoint was overall survival.44 At a median follow-up of 17.1 months, median overall survival was 9.9, 9.9, 9.3, and 11.2 months for ECF, ECX, EOF, and EOX, respectively, demonstrating noninferiority of capecitabine to oxaliplatin.44

HER2-overexpressing Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma

The efficacy of capecitabine in the treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma was derived from several published studies, including ToGA, a phase 3, open-label, randomized trial.1,12005 A total of 594 patients with HER2-overexpressing metastatic cancer were randomized (1:1 ratio) to treatment with trastuzumab plus chemotherapy (capecitabine plus cisplatin or fluorouracil plus cisplatin) or chemotherapy alone.12005 Median overall survival was 13.8 or 11.1 months for trastuzumab plus chemotherapy and chemotherapy alone, respectively.12005

Clinical Perspective

According to the National Cancer Institute, therapies for the treatment of stage IV or recurrent gastric cancers include a combination of chemotherapy, targeted therapies, immunotherapies, and palliative treatment.12006 First-line palliative systemic therapies for HER2-negative tumors include chemotherapy with or without immunotherapy (e.g., fluorouracil or capecitabine with oxaliplatin and nivolumab), triplet chemotherapy regimens (e.g., fluorouracil and either epirubicin and cisplatin, etoposide and leucovorin, or doxorubicin and methotrexate), doublet regimens (e.g., a taxane and either cisplatin or carboplatin, or capecitabine plus oxaliplatin), or single agents (e.g., fluorouracil or capecitabine).12006 For HER-2 positive tumors, first-line palliative systemic therapy includes immunotherapy with chemotherapy (nivolumab or trastuzumab with chemotherapy, including cisplatin plus fluorouracil, or capecitabine plus oxaliplatin).12006

The National Cancer Institute guidelines for esophageal cancer include surgery, endoscopic resection, chemotherapy (including capecitabine and fluorouracil), chemoradiation, and immunotherapies as treatment options, based on stage and extent of disease.12007

Pancreatic Cancer

Capecitabine is used as adjuvant treatment of adults with pancreatic adenocarcinoma as part of a combination chemotherapy regimen.1

Clinical Experience

The efficacy of capecitabine in the treatment of pancreatic adenocarcinoma was derived from ESPAC-4, an open-label, randomized trial.1,12008 A total of 732 patients were randomized to treatment (1:1 ratio) with either capecitabine plus gemcitabine or gemcitabine alone, with a primary outcome of overall survival.12008 At a median follow-up of 43.2 months, median overall survival with capecitabine plus gemcitabine was 28 months versus 25.5 months with gemcitabine alone, with results favoring the combination regimen.12008

Clinical Perspective

According to the National Cancer Institute, treatment options for pancreatic cancer are based on clinical stage of the disease and include surgery, chemotherapy, radiation, and chemotherapy with targeted therapy.12009 For patients with resectable or borderline resectable pancreatic cancer, postoperative chemotherapy includes adjuvant FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) or gemcitabine plus capecitabine.12009 For both locally advanced and metastatic or recurrent pancreatic cancer, chemotherapy with or without targeted therapy is a primary treatment option.12009 Evidence for several chemotherapy regimens is discussed, including FOLFIRINOX, gemcitabine-based regimens, fluorouracil/leucovorin/oxaliplatin, and capecitabine-based regimens.12009

General

Pretreatment Screening

• Consider testing for genetic variants of dihydropyrimidine dehydrogenase (DPYD), the gene encoding dihydropyrimidine dehydrogenase (DPD), prior to initiating treatment with capecitabine.1
• Obtain complete blood count (CBC) at baseline.1 Do not initiate capecitabine therapy if baseline neutrophil count <1500/mm³ and/ or baseline platelet count <100,000/mm³.1
• Assess renal function and hydration status prior to initiating treatment with capecitabine.1 Optimize hydration prior to initiating treatment.1
• Verify pregnancy status in females of reproductive potential prior to initiating treatment with capecitabine.1

Patient Monitoring

• Obtain CBC prior to each treatment cycle.1
• Monitor renal function and hydration status as clinically indicated during treatment with capecitabine.1 Promptly correct dehydration, which can develop rapidly in patients with anorexia, asthenia, nausea, vomiting, or diarrhea, and can result in acute renal failure; patients with preexisting renal impairment and those receiving concomitant therapy with nephrotoxic agents are at increased risk.1
• Monitor for new or worsening serious skin reactions during treatment with capecitabine.1
• If capecitabine is used in patients receiving a coumarin-derivative anticoagulant, prothrombin time (PT) or international normalized ratio (INR) should be monitored frequently, and the anticoagulant dosage should be adjusted accordingly.1
• Liver function should be monitored carefully during capecitabine therapy in patients with mild to moderate hepatic impairment.1

Premedication and Prophylaxis

• If used concomitantly with docetaxel, administer premedication prior to docetaxel administration.1 Consult docetaxel manufacturer's labeling for specific information.1

Dispensing and Administration Precautions

• Based on the Institute for Safe Medication Practices (ISMP), capecitabine is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.772

Handling and Disposal

• Procedures for proper handling and disposal of antineoplastic drugs should be followed when preparing or administering capecitabine.1
• Capecitabine should be used under the supervision of a qualified clinician experienced in therapy with cytotoxic agents.1

Administration

Capecitabine is administered orally.1 Capecitabine tablets should be swallowed whole with water within 30 minutes after the end of a meal.1 The recommended dose should be rounded to the nearest 150-mg dose so that whole tablets are administered.1 Capecitabine tablets should not be chewed, cut, or crushed.1 If a dose is missed or vomited, skip the missed/vomited dose and continue with the next scheduled dose.1

Capecitabine tablets should be stored in tightly closed containers at 20-25°C; excursions are permitted to 15-30°C.1

Pharmacogenomic Considerations in Dosing

Patients who are intermediate or poor metabolizers of dihydropyrimidine dehydrogenase (DPYD) may be at an increased risk for severe and sometimes fatal adverse effects with fluoropyrimidines (5-fluorouracil and capecitabine).700 Genetic DPYD variants associated with reduced DPD enzyme activity (particularly DPYD c.1905+1G>A and c.1679T>G) have been linked to decreased 5-fluorouracil clearance and increased risk for 5-fluorouracil toxicity.700 The Clinical Pharmacogenetics Implementation Consortium (CPIC) provides recommendations for fluoropyrimidine dosing guided by DPYD phenotype.700 For patients who are DPYD intermediate metabolizers (i.e., DPYD activity score of 1 or 1.5), the starting dose should be reduced based on the enzyme activity score; when the activity score is 1, the dose should be reduced by 50% and when the score is 1.5, the dose should be reduced by 25—50%.700 Further dose titration should be guided by toxicity or therapeutic drug monitoring (if available).700 For patients who are DPYD poor metabolizers (i.e., DPYD activity score of 0 or 0.5), it is strongly recommended to avoid use of fluoropyrimidines.700 In patients with an activity score of 0.5 who do not have suitable alternative therapeutic options, fluoropyrimidines should be administered at a markedly reduced dose (i.e., estimated via phenotyping test or <25% of the normal starting dose), with therapeutic drug monitoring completed as early as possible.700 Consult the CPIC guideline for additional details.700

Dosage

Breast Cancer

Combination Therapy

When used in combination with docetaxel for the treatment of advanced or metastatic breast cancer in patients with disease that failed to respond to or recurred following anthracycline-containing chemotherapy, the recommended dosage of capecitabine is 1000 or 1250 mg/m² twice daily (morning and evening), for the first 14 days of a 21-day cycle until disease progression or unacceptable toxicity occurs, in combination with docetaxel.1 Docetaxel 75 mg/m² is administered as an IV infusion on the first day of each 21-day cycle.1

Monotherapy

For the treatment of advanced or metastatic breast cancer in patients who are not candidates for anthracycline- or taxane-containing chemotherapy, the recommended initial dosage of capecitabine is 1000 or 1250 mg/m² twice daily (morning and evening), for the first 14 days of a 21-day cycle until disease progression or unacceptable toxicity occurs.1 Individualize the dosing schedule based on patient-specific factors (i.e., risk factors, adverse reactions).1

Colorectal Cancer

Adjuvant Therapy for Colon Cancer

For adjuvant therapy following the complete resection of the primary tumor in patients with stage III colon cancer when treatment with fluoropyrimidine therapy alone is preferred, the recommended dosage of capecitabine is 1250 mg/m² twice daily (morning and evening) for the first 14 days of each 21-day cycle for a maximum of 8 cycles.1

When used in combination with oxaliplatin-containing regimens as adjuvant therapy following the complete resection of the primary tumor in patients with stage III colon cancer, the dosage of capecitabine is 1000 mg/m² given twice daily (morning and evening) for the first 14 days of each 21-day cycle for a maximum of 8 cycles in combination with oxaliplatin 130 mg/m² administered IV on day 1 of each cycle.1

Perioperative Treatment of Rectal Cancer

When used as a component of chemoradiotherapy for the perioperative treatment of locally advanced rectal cancer, the recommended dosage of capecitabine is 825 mg/m² twice daily (morning and evening) when administered with concomitant radiation therapy or 1250 mg/m² twice daily when administered as part of a perioperative combination regimen that does not include radiation therapy.1

Unresectable or Metastatic Colorectal Cancer

When used as monotherapy for the treatment of unresectable or metastatic colorectal cancer, the recommended dosage of capecitabine is 1250 mg/m² twice daily (morning and evening) for the first 14 days of a 21-day cycle until disease progression or unacceptable toxicity occurs.1

When used in combination with oxaliplatin for the treatment of unresectable or metastatic colorectal cancer, the recommended dosage of capecitabine is 1000 mg/m² twice daily for the first 14 days of each 21-day cycle.1 Continue treatment until disease progression or unacceptable toxicity occurs.1 Oxaliplatin 130 mg/m² is administered as an IV infusion on day 1 of each cycle.1

Gastric, Esophageal, or Gastroesophageal Junction Cancer

Unresectable or Metastatic Gastric, Esophageal, or Gastroesophageal Junction Cancer

When used in combination with platinum-containing chemotherapy for the treatment of unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer, the recommended dosage of capecitabine is 625 mg/m² twice daily (morning and evening) on days 1—21 of each 21-day cycle for a maximum of 8 cycles.1 Alternately, a capecitabine dosage of 850 or 1000 mg/m² twice daily (morning and evening) for the first 14 days of each 21-day cycle can be administered in combination with oxaliplatin 130 mg/m² IV given on day 1 of each cycle.1 Continue treatment until disease progression or unacceptable toxicity occurs.1

Human Epidermal Growth Factor Receptor (HER)2-overexpressing Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma

For treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma, the recommended dosage of capecitabine is 1000 mg/m² twice daily (morning and evening), for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity occurs.1 Capecitabine is given in combination with cisplatin and trastuzumab for this indication.1 Refer to the prescribing information for dosing recommendations for combination agents.1

Pancreatic Adenocarcinoma

For adjuvant therapy patients with pancreatic adenocarcinoma (as a component of a combination chemotherapy regimen), the recommended dosage of capecitabine is 830 mg/m² twice daily (morning and evening) for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity occurs.1 If used in combination with gemcitabine 1000 mg/m² IV, given on days 1, 8, and 15 of each cycle, administer capecitabine for a maximum of 6 cycles.1

Dosage Modification for Toxicity

Monitor patients for adverse reactions during treatment with capecitabine and modify dosages as indicated in Table 1 below.1 When capecitabine is administered in combination with docetaxel, withhold both capecitabine and docetaxel until the requirements for resuming both agents are met.1 Refer to the prescribing information for docetaxel for additional dosing information.

Table 1. Recommended Capecitabine Dosage Modifications for Adverse Reactions1

Severity	Dosage Modification	Resume at Same or Reduce Dose (Percent of Current Dose)
Grade 2 toxicity
First appearance	Withhold therapy until resolved to grade 0 or 1	100%
Second appearance	Withhold therapy until resolved to grade 0 or 1	75%
Third appearance	Withhold therapy until resolved to grade 0 or 1	50%
Fourth appearance	Permanently discontinue capecitabine
Grade 3 toxicity
First appearance	Withhold therapy until resolved to grade 0 or 1	75%
Second appearance	Withhold therapy until resolved to grade 0 or 1	50%
Third appearance	Permanently discontinue capecitabine
Grade 4 toxicity
First appearance	Permanently discontinue capecitabine OR withhold until resolved to grade 0 or 1	50%

If patients develop grade 3 or 4 hyperbilirubinemia during treatment with capecitabine, withhold treatment and resume once the event is grade 2 or less (i.e., bilirubin level below 3 times the upper limit of normal); use the percent of current dose column of Table 1 to determine the appropriate dose of capecitabine to resume therapy.1

Special Populations

Hepatic Impairment

The manufacturer makes no specific dosage recommendations for patients with hepatic impairment; however, more frequent monitoring of such patients is recommended.1

Renal Impairment

In patients with mild to moderate renal impairment (i.e., creatinine clearance of 30—50 mL/min as determined by the Cockroft-Gault equation), reduce the dose of capecitabine by 25%.1 The manufacturer states that a dosage has not been established for patients with severe renal impairment (creatinine clearance <30 mL/min).1 If no alternative treatment exists for such patients, capecitabine can be administered on an individual basis using a reduced starting dose, close monitoring, and dosage modifications guided by adverse events.1

Geriatric Patients

The manufacturer makes no specific dosage recommendations for geriatric patients.1

Contraindications

• History of severe hypersensitivity reactions to fluorouracil or capecitabine.1

Warnings/Precautions

Warnings

Increased Risk of Bleeding with Concomitant Use of Vitamin K Antagonists

A boxed warning about an increased risk of bleeding with concomitant use of vitamin K antagonists is included in the prescribing information for capecitabine.1 Altered coagulation and/or bleeding parameters, including fatal cases of bleeding, have been reported in patients taking capecitabine concomitantly with vitamin K antagonists such as warfarin.1 There have been reports of clinically significant increases in the prothrombin time and international normalized ratio (INR) following initiation of capecitabine in patients on stable therapy with oral vitamin K antagonists.1 These events have occurred anywhere from several days to several months after initiation of capecitabine, with a few cases occurring within 1 month following discontinuation of capecitabine.1 Such bleeding events have occurred in patients with and without liver metastases.1 In patients receiving capecitabine with concomitant vitamin K antagonist therapy, monitor INR more frequently and adjust the dose of the vitamin K antagonist as appropriate.1

Other Warnings and Precautions

Cardiotoxicity

Cardiotoxicity can occur with capecitabine.1 Myocardial infarction or ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy have been reported in patients taking capecitabine.1 Patients with a past history of coronary artery disease may be more likely to experience these adverse reactions.1 If cardiotoxicity occurs, withhold capecitabine as appropriate.1 The safety of resuming capecitabine therapy in patients with resolution of symptoms after development of cardiotoxicity has not been established.1

Diarrhea

Diarrhea, sometimes severe, can occur with capecitabine.1 In clinical trials including 875 patients with metastatic breast or colorectal cancer who received treatment with capecitabine monotherapy, grade 2 to 4 diarrhea first occurred after a median of 34 days (range, 1 day to 1 year).1 Grade 3 to 4 diarrhea lasted for a median of 5 days.1 If diarrhea occurs, withhold treatment; dosage modification or permanent discontinuation of capecitabine may be necessary upon resumption depending on the frequency and severity of symptoms.1

Dehydration

Dehydration can occur with capecitabine.1 Patients with anorexia, asthenia, nausea, vomiting, or diarrhea may be more likely to develop dehydration during treatment with capecitabine.1 Prior to treatment with capecitabine, optimize hydration.1 Monitor hydration status and kidney function at baseline and during treatment as clinically indicated.1 If dehydration occurs, withhold treatment; dosage modification or permanent discontinuation of capecitabine may be necessary upon resumption depending on the frequency and severity of symptoms.1

Renal Toxicity

Serious and sometimes fatal renal failure can occur with capecitabine.1 Patients with renal impairment or who are receiving concomitant therapy with capecitabine and other drugs that are known to cause renal toxicity may increase this risk.1 Prior to treatment with capecitabine, optimize hydration.1 Monitor renal function at baseline and during treatment as clinically indicated.1 If renal toxicity occurs, withhold treatment; dosage modification or permanent discontinuation of capecitabine may be necessary upon resumption depending on the frequency and severity of symptoms.1

Serious Skin Toxicities

Serious, sometimes fatal severe cutaneous adverse reactions, including Stevens-Johnson Syndrome and toxic epidermal necrolysis, can occur with capecitabine.1 Monitor for new or worsening skin reactions during treatment with capecitabine and permanently discontinue treatment if such reactions occur.1

Palmar-Plantar Erythrodysesthesia Syndrome

Palmar-plantar erythrodysesthesia syndrome can occur with capecitabine.1 Among patients who developed grade 1 to 3 palmar-plantar erythrodysesthesia syndrome in clinical trials of capecitabine monotherapy for treatment of metastatic breast or colorectal cancer, the median time to onset was 2.6 months (range, 11 days to 1 year).1 If palmar-plantar erythrodysesthesia syndrome occurs, withhold treatment; dosage modification or permanent discontinuation of capecitabine may be necessary upon resumption depending on the frequency and severity of symptoms.1

Myelosuppression

Myelosuppression can occur with capecitabine.1 In clinical trials including 875 patients with metastatic breast or colorectal cancer who received treatment with capecitabine monotherapy, grade 3 or 4 neutropenia, thrombocytopenia, and anemia occurred in 3.2, 1.7, and 2.4% of patients, respectively.1 In 251 patients with metastatic breast cancer who received combination therapy with capecitabine and docetaxel, grade 3 or 4 neutropenia, thrombocytopenia, and anemia occurred in 68, 2.8, and 10% of patients, respectively.1 Necrotizing enterocolitis (typhlitis) has also been reported with capecitabine.1 Consider a diagnosis of typhlitis in patients taking capecitabine who experience fever, neutropenia, and abdominal pain.1

Monitor CBC at baseline and prior to each capecitabine treatment cycle.1 Treatment with capecitabine is not recommended if the neutrophil count is below 1500/mm³ or the platelet count is below 100,000/mm³ at baseline.1 If grade 3 or 4 myelosuppression occurs during treatment with capecitabine, withhold treatment; dosage modification or permanent discontinuation of capecitabine may be necessary upon resumption depending on the frequency of symptoms.1

Hyperbilirubinemia

Hyperbilirubinemia can occur with capecitabine.1 In clinical trials including 875 patients with metastatic breast or colorectal cancer who received treatment with capecitabine monotherapy, grade 3 and 4 hyperbilirubinemia occurred in 15 and 3.9% of patients, respectively.1 Grade 3 or 4 hyperbilirubinemia occurred more frequently in the 566 patients with hepatic metastases at baseline (23%) compared to 309 without hepatic metastases at baseline (12%).1 Among the 167 patients who developed grade 3 or 4 hyperbilirubinemia, post-baseline increases in alkaline phosphatase and transaminases at any time (not necessarily concurrent) occurred in 19 and 28% of patients, respectively; most patients who experienced these increases had liver metastases at baseline.1 Of the patients who developed grade 3 or 4 hyperbilirubinemia, pre- and post-baseline values of alkaline phosphatase and transaminases were elevated in 58 and 35% of patients, respectively.1 Grade 3 or 4 elevations of alkaline phosphatase and transaminases occurred in 8 and 3% of patients, respectively.1

Among 596 patients with metastatic colorectal cancer who were treated with capecitabine, grade 3 or 4 hyperbilirubinemia occurred at a similar rate as seen for the pooled population described above.1 The median time to onset of grade 3 or 4 hyperbilirubinemia was 64 days; median total bilirubin levels increased from a median of 8 µm/L at baseline to 13 µm/L during treatment with capecitabine.1

Of the 251 patients with metastatic breast cancer who received combination therapy with capecitabine and docetaxel, grade 3 and 4 hyperbilirubinemia occurred in 7 and 2% of patients, respectively.1

If hyperbilirubinemia develops, withhold treatment; dosage modification or permanent discontinuation of capecitabine may be necessary upon resumption depending on the frequency of symptoms.1 If grade 3 or 4 hyperbilirubinemia occurs, capecitabine may be resumed once the event is classified as grade 2 or less than 3 times the upper limit of normal.1

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

Eye irritation and swelling, skin rash, diarrhea, paresthesia, headache, gastric irritation, nausea, and vomiting have occurred following exposure to crushed capecitabine tablets.1 Advise patients not to cut or crush capecitabine tablets.1 If the tablets must be cut or crushed, this should be done by a professional who is trained in the safe handling of cytotoxic drugs using appropriate equipment and safety procedures.1 Safety and effectiveness of administering crushed capecitabine tablets have not been established.1

Pharmacogenomics of Capecitabine-Induced Serious Adverse Reactions Due to Dihydropyrimidine Dehydrogenase (DPD) Deficiency

Dihydropyrimidine dehydrogenase, encoded by the DPYD gene, is responsible for catabolism of >80% of fluorouracil.1 Capecitabine is metabolized to fluorouracil in vivo.1 Capecitabine should be withheld or permanently discontinued in patients experiencing acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of dihydropyrimidine dehydrogenase (DPD) activity.1 Patients with certain homozygous or certain compound heterozygous mutations in the DPYD gene resulting in complete or near complete absence of DPD activity (i.e., DPYD poor metabolizers) are at increased risk for acute early-onset toxicity and severe, life-threatening, or fatal toxicity (e.g., mucositis, diarrhea, neutropenia, neurotoxicity) caused by capecitabine; patients with partial DPD activity (i.e., DPYD intermediate metabolizers) also may be at increased risk for severe, life-threatening, or fatal toxicity.1,700 No dosage of capecitabine has been proven safe for patients with complete absence of DPD activity, and there are insufficient data to support dosage recommendations for those with partial DPD activity.1 Consider testing patients for genetic variants of DPYD prior to initiating treatment with capecitabine.1 However, serious adverse reactions can still occur even if no variants are identified.1

Genetic DPYD variants associated with reduced DPD enzyme activity (particularly DPYD c.1905+1G>A and c.1679T>G) have been linked to decreased 5-fluorouracil clearance and increased risk for 5-fluorouracil toxicity.700 The Clinical Pharmacogenetics Implementation Consortium (CPIC) provides recommendations for fluoropyrimidine dosing guided by DPYD phenotype.700 Dosage adjustments are recommended for patients who are DPYD intermediate metabolizers, and fluoropyrimidines should be avoided in patients who are DPYD poor metabolizers.700 (See Pharmacogenomic Considerations in Dosing under Dosage and Administration.) Consult the CPIC guideline for more details and definitions of DPYD phenotypes based on genotype.700

Fetal/Neonatal Morbidity and Mortality

Based on its mechanism of action and animal findings, capecitabine can cause fetal harm when administered to a pregnant patient.1 Human data are not sufficient to inform the drug-associated risk of capecitabine use in pregnancy.1 In animal studies, administration of capecitabine during the period of organogenesis at 0.2 times the human exposure in patients receiving the recommended dose of 1250 mg/m² twice daily in pregnant mice and 0.6 times the human exposure in pregnant monkeys led to embryolethality and teratogenicity in mice and embryolethality in monkeys.1 Additionally, animal studies have shown that capecitabine may impair fertility in females and males of reproductive potential.1

Verify pregnancy status in female patients of reproductive potential prior to initiating treatment with capecitabine and advise pregnant patients of the potential risk to a fetus.1 Advise females of reproductive potential to use effective contraception during treatment with capecitabine and for 6 months following discontinuation.1 Advise male partners of such females to use effective contraception during treatment with capecitabine and for 3 months following discontinuation.1

Specific Populations

Pregnancy

Based on its mechanism of action and animal findings, capecitabine can cause fetal harm when administered to a pregnant patient.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.) Advise pregnant patients of the potential risk to a fetus.1

Lactation

In lactating mice receiving a single dose of capecitabine, significant amounts of capecitabine metabolites were distributed into milk.1 It is not known whether capecitabine or its metabolites are distributed into human milk.1 The effects of the drug on nursing infants or on milk production are unknown.1 Because of the potential for serious adverse reactions to capecitabine in nursing infants, women should be advised to discontinue nursing during capecitabine therapy and for 1 week after discontinuance of therapy.1

Females and Males of Reproductive Potential

Based on animal studies, capecitabine may impair fertility in females and males of reproductive potential.1 Verify pregnancy status in female patients of reproductive potential prior to initiating treatment with capecitabine.1 Advise females of reproductive potential to use effective contraception during treatment with capecitabine and for 6 months following discontinuation.1 Advise male partners of such females to use effective contraception during treatment with capecitabine and for 3 months following discontinuation.1

Pediatric Use

The manufacturer states that safety and efficacy of capecitabine in children younger than 18 years of age have not been established.1

Geriatric Use

In clinical trials of patients with colorectal cancer (N=7938), metastatic breast cancer (N=4536), gastric, esophageal, or gastrointestinal junction cancer (N=1951), or pancreatic cancer (N=364) who were treated with capecitabine, 33, 18, 26, and 47% of patients, respectively, were ≥65 years of age.1 No differences in efficacy were noted in geriatric patients compared to younger patients in these trials.1 However, geriatric patients experienced increased GI toxicity from capecitabine.1 Deaths have been reported from severe enterocolitis, diarrhea, and dehydration in geriatric patients treated with weekly leucovorin and fluorouracil.1

Hepatic Impairment

In pharmacokinetic studies, systemic exposure and maximum serum concentrations of fluorouracil (the active principle of capecitabine) were not affected in patients with mild or moderate hepatic impairment compared to patients with normal hepatic function.1 The maximum serum concentration and systemic exposure of capecitabine increased by 60%.1 The effect of severe hepatic impairment on the pharmacokinetics of capecitabine and its metabolites are not known.1

Renal Impairment

The effect of renal impairment on the elimination of capecitabine has been evaluated in cancer patients.1 Renal impairment causes increased systemic exposure to capecitabine and its metabolites.1 Following oral administration of capecitabine 1250 mg/m² twice daily, systemic exposure to the FBAL metabolite on day 1 was 85% higher in patients with moderate renal impairment (creatinine clearance of 30-50 mL/min) and 258% higher in patients with severe renal impairment (creatinine clearance <30 mL/min) than in patients with normal renal function (creatinine clearance >80 mL/min).1 Systemic exposure to the 5'-DFUR metabolite was 42 or 71% greater in patients with moderate or severe renal impairment, respectively, than in those with normal renal function.1 Systemic exposure to 5-fluorouracil did not increase in patients with moderate renal impairment, but increased by 24% in patients with severe renal impairment, compared to those with normal renal function.1 Systemic exposure to capecitabine was about 25% greater in patients with moderate or severe renal impairment than in those with normal renal function.1

The effect of dialysis on the elimination of capecitabine has not been determined; however, the manufacturer reports that dialysis may reduce circulating concentrations of 5'-DFUR, a low molecular weight metabolite of the drug.1

Common Adverse Effects

Adverse effects reported in ≥30% of patients receiving capecitabine monotherapy for adjuvant treatment of colon cancer include palmar-plantar erythrodysesthesia syndrome, diarrhea, and nausea.1

Adverse effects reported in ≥30% of patients receiving capecitabine monotherapy for metastatic colorectal cancer include anemia, diarrhea, palmar-plantar erythrodysesthesia syndrome, hyperbilirubinemia, nausea, fatigue, and abdominal pain.1

Adverse effects reported in ≥30% of patients receiving capecitabine monotherapy for metastatic breast cancer include lymphopenia, anemia, diarrhea, hand-and-foot syndrome, nausea, fatigue, vomiting, and dermatitis.1

Adverse effects reported in ≥30% of patients receiving capecitabine in combination with docetaxel for metastatic breast cancer include lymphocytopenia, leukopenia, neutropenia, anemia, diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, nausea, alopecia, thrombocytopenia, vomiting, edema, and abdominal pain.1

Capecitabine is not metabolized by cytochrome P-450 (CYP) isoenzymes.1 In vitro studies indicate that capecitabine and its metabolites do not inhibit CYP isoenzymes 1A2, CYP2A6, CYP3A4, CYP2C19, CYP2D6, or CYP2E1.1

Drugs Affecting Hepatic Microsomal Enzymes

Capecitabine increases exposure of CYP2C9 substrates, which may increase the likelihood for development of adverse events from such substrates.1 Concomitant administration of celecoxib (a sensitive CYP2C9 substrate) with capecitabine 1000 mg/m² twice daily for 14 days increased systemic exposure to celecoxib and its maximum serum concentration by 28 and 24%, respectively.1

In patients receiving concomitant therapy with capecitabine and CYP2C9 substrates where minimal concentration changes may lead to serious adverse reactions (e.g., anticoagulants, antidiabetic drugs), closely monitor for adverse events.1

Nephrotoxic Drugs

Due to the additive pharmacologic effect, concomitant use of capecitabine with other drugs that are known to cause renal toxicity may increase the risk of renal toxicity.1 When capecitabine is used concomitantly with nephrotoxic drugs (e.g., platinum salts, irinotecan, methotrexate, IV bisphosphonates), closely monitor for signs of renal toxicity.1

Allopurinol

Concomitant use of allopurinol and capecitabine may decrease conversion of capecitabine to the active metabolites, 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP), and result in reduced capecitabine efficacy.1 Concomitant use of capecitabine with allopurinol should be avoided.1

Antacids

In a small number of patients, administration of an antacid containing aluminum hydroxide and magnesium hydroxide immediately following capecitabine (1250 mg/m²) resulted in an increased rate and extent of absorption of capecitabine; AUC and peak plasma concentration increased by 16 and 35%, respectively, for capecitabine and by 18 and 22%, respectively, for the 5'-DFCR metabolite.1 Antacid administration had no effect on the other 3 major metabolites of capecitabine (i.e., 5'-DFUR, fluorouracil, and FBAL).1

Anticoagulants

Capecitabine increases exposure of vitamin K antagonists (i.e., warfarin), which may alter coagulation parameters and/or bleeding and could result in death.1 Such events may occur within days after initiation of treatment with capecitabine, and up to 1 month following its discontinuation.1 In 4 patients receiving chronic administration of capecitabine 1250 mg/m² twice daily with a single dose of warfarin 20 mg, the mean AUC of S-warfarin was increased by 57% and clearance was decreased by 37%.1 The baseline corrected AUC of INR in these patients increased by 2.8-fold, and the maximum observed mean international normalized ratio (INR) increased by 91%.1

In patients receiving concomitant treatment with capecitabine and a vitamin K antagonist, monitor the INR more frequently; reduction in the dosage of the vitamin K antagonist may be necessary.1

Docetaxel

When used in combination, capecitabine had no impact on the pharmacokinetics of docetaxel and docetaxel did not affect the pharmacokinetics of capecitabine or its metabolite 5'-DFUR.1

Leucovorin

Leucovorin potentiates the antineoplastic activity of fluorouracil (the active drug of capecitabine) and also may increase its toxicity.1 Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in geriatric patients receiving a weekly regimen of combination therapy with leucovorin and fluorouracil.1 Instruct patients to avoid taking products that contain folic acid or folate analog products unless directed to do so by their healthcare provider.1

Phenytoin

Concomitant use of phenytoin and capecitabine may result in toxicity from increased serum phenytoin concentrations.1 In patients receiving capecitabine, serum concentrations of phenytoin must be monitored carefully, and reduction in the phenytoin dosage may be necessary.1

Description

Capecitabine, a fluoropyrimidine carbamate, is an antineoplastic agent.1 Capecitabine is a prodrug of 5'-deoxy-5-fluorouridine (doxifuridine, 5'-DFUR) and has little pharmacologic activity until it is converted to fluorouracil, a fluorinated pyrimidine antagonist, in tumor tissue.1,5,6,7 Because capecitabine is converted to fluorouracil by enzymes that are expressed at higher concentrations in many tumors than in adjacent normal tissues or plasma, it is thought that high tumor concentrations of the active drug may be achieved with less systemic toxicity.1,4,5,14 Fluorouracil is metabolized in both normal and tumor cells to 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP).1,4 The main mechanism of fluorouracil is via the binding of the deoxyribonucleotide of the drug (FdUMP) and the folate cofactor (N5-10-methylenetetrahydrofolate) to thymidylate synthase (TS) to form a covalently bound ternary complex, which inhibits the formation of thymidylate from 2'-deoxyuridylate, thereby interfering with DNA synthesis.1,4 In addition, FUTP can be incorporated into RNA in place of uridine triphosphate (UTP), producing a fraudulent RNA and interfering with RNA processing and protein synthesis.1,4 Capecitabine has been shown to be active in xenograft tumors that are resistant to fluorouracil indicating incomplete cross-resistance between the drugs.8,9

Over a dosage range of 500-3500 mg/m² daily, the pharmacokinetics of capecitabine and its metabolite, 5'-deoxy-5-fluorocytidine (5'-DFCR), were dose proportional and did not change over time.1 However, the manufacturer reports that increases in area under the concentration-time curves (AUCs) of metabolites 5'-DFUR and fluorouracil were greater than proportional to the increase in dose.1 Considerable interindividual variations (i.e., exceeding 85%) in peak plasma concentrations and AUCs have been reported following oral administration of capecitabine.1 According to the manufacturer, peak plasma concentrations of capecitabine occur in about 1.5 hours, and peak plasma concentrations of fluorouracil, its active metabolite, occur at 2 hours.1

Administration of capecitabine after a breakfast that is medium-rich in fat and carbohydrates resulted in decreases in the peak plasma concentration and AUC of capecitabine by 60 and 34%, respectively.1 The peak plasma concentration and AUC of fluorouracil were also decreased by 37 and 12%, respectively.1 The time to maximum concentration of both capecitabine and fluorouracil were delayed by 1.5 hours.1 Plasma protein binding (mainly to albumin) of capecitabine and its metabolites is less than 60% and is not concentration dependent.1 Capecitabine is extensively metabolized in the liver and tumors.1,7 The plasma elimination half-life of capecitabine and fluorouracil is about 45 minutes.1

In the liver, capecitabine is largely hydrolyzed to 5'-DFCR by carboxylesterase.1 5'-DFCR subsequently is converted to another noncytotoxic intermediate, 5'-deoxy-5-fluorouridine (5'-DFUR), by cytidine deaminase.1 Hydrolysis of 5'-DFUR to the active drug fluorouracil is catalyzed by thymidine phosphorylase.1 Once capecitabine is converted to the active drug fluorouracil, mainly in tumor tissue, fluorouracil is anabolized to 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP), the active metabolites of the drug.1,4,8 Fluorouracil is catabolized to dihydrofluorouracil (FUH₂), by dihydropyrimidine dehydrogenase.1 Dihydropyrimidinase cleaves the pyrimidine ring of FUH₂, yielding 5-fluoro-ureido-propionic acid (FUPA), which is then cleaved by β-ureido-propionase to form α-fluoro-β-alanine (FBAL).1 Capecitabine and its metabolites are excreted predominantly in urine (96%); fecal excretion is minimal (2.6%).1 Most of the capecitabine dose is excreted in urine as metabolites, principally FBAL, a catabolite of fluorouracil (57% of an administered dose); about 3% of an administered dose is excreted in urine as unchanged drug.1

Following therapeutic doses of capecitabine, no clinically meaningful differences in the pharmacokinetics of 5'-DFUR, fluorouracil, or FBAL were observed based on sex and race; additionally, no clinically meaningful differences of 5'-DFUR and fluorouracil were observed based on age (range, 27—86 years).1 The exposure to FBAL increased by 15% following a 20% increase in age.1 Data from a study in Japanese and white patients receiving capecitabine 825 mg/m² twice daily for 14 days showed differences in the pharmacokinetic disposition of capecitabine and its catabolite, FBAL.1 Peak plasma concentration and the AUC of capecitabine were reduced by about 36 and 24%, respectively, and peak plasma concentration and AUC of FBAL were about 25 and 34% lower, respectively, in the Japanese patients than in the white patients.1 The clinical importance of these differences is not known.1 No clinically significant differences in the pharmacokinetics of 5'-DFCR, 5'-DFUR, or fluorouracil were observed.1

Advice to Patients

• Stress importance of reading the manufacturer's patient information.1
• Advise patients on vitamin K antagonists, such as warfarin, that they are at an increased risk of severe bleeding while taking capecitabine.1 Advise these patients that the international normalized ratio (INR) should be monitored more frequently, and dosage modifications of the vitamin K antagonist may be required, while taking and after discontinuation of capecitabine.1 Advise these patients to immediately contact their healthcare provider if signs or symptoms of bleeding occur.1
• Inform patients of the potential for serious and life-threatening adverse reactions due to dihydropyrimidine dehydrogenase (DPD) deficiency and discuss whether they should be tested for genetic variants that are associated with an increased risk of serious adverse reactions from the use of capecitabine.1 Advise patients to immediately contact their healthcare provider if symptoms of severe mucositis, diarrhea, neutropenia, and neurotoxicity occur.1
• 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.1
• 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 capecitabine.1 Advise patients on the use of antidiarrheal treatments (e.g., loperamide) to manage diarrhea.1
• Instruct patients experiencing grade 2 or greater dehydration to stop taking capecitabine immediately and to contact their healthcare provider.1 Advise patients to not restart capecitabine until rehydrated and any precipitating causes have been corrected or controlled.1
• Instruct patients experiencing decreased urinary output or other signs and symptoms of renal toxicity to immediately contact their healthcare provider.1
• Instruct patients with skin rash, blistering, or peeling to immediately contact their healthcare provider.1
• Instruct patients experiencing grade 2 or greater palmar-plantar erythrodysesthesia syndrome to stop taking capecitabine immediately and to contact their healthcare provider.1 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.1
• Inform patients who develop a fever of 100.5°F or greater or other evidence of potential infection to immediately contact their healthcare provider.1
• Inform patients who develop jaundice or icterus to immediately contact their healthcare provider.1
• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.1 Advise pregnant women and females of reproductive potential of the potential risk to a fetus.1 Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy.1 Advise females not to breast-feed during treatment with capecitabine and for 1 week after the last dose.1
• Advise males and females of reproductive potential that capecitabine may impair fertility.1 Advise females of reproductive potential to use effective contraception during treatment with capecitabine and for 6 months after the last dose.1 Advise males with female partners of reproductive potential to use effective contraception during treatment with capecitabine and for 3 months after the last dose.1
• Advise patients that capecitabine may cause severe hypersensitivity reactions and angioedema.1 Advise patients who have known hypersensitivity to capecitabine or 5-fluorouracil to inform their healthcare provider.1 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 capecitabine and immediately contact their healthcare provider or go to an emergency room.1
• Instruct patients experiencing grade 2 nausea (food intake significantly decreased but able to eat intermittently) or greater to stop taking capecitabine and to immediately contact their healthcare provider for management of nausea.1 Instruct patients experiencing grade 2 vomiting (2 to 5 episodes in a 24-hour period) or greater to stop taking capecitabine immediately and to contact their healthcare provider for management of vomiting.1
• 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 capecitabine immediately and to contact their healthcare provider.1
• Advise patients to swallow capecitabine tablets whole with water within 30 minutes after a meal.1 Advise patients and caregivers not to chew, crush, or cut capecitabine tablets.1 Advise patients if they cannot swallow capecitabine tablets whole to inform their healthcare provider.1
• 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.1 Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses.1
• Inform patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

Only references cited for selected revisions after 1984 are available electronically.

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