Version May 2024
Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking capecitabine concomitantly with oral vitamin K antagonists, such as warfarin. Clinically significant increases in prothrombin time (PT) and international normalized ratio (INR) have been reported in patients who were on stable doses of a vitamin K antagonist at the time capecitabine was introduced. These events occurred within several days and up to several months after initiating capecitabine and, in a few cases, within 1 month after stopping capecitabine. 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.
Note: Baseline platelets should be ≥100,000/mm3 and neutrophils should be ≥1,500/mm3 prior to capecitabine initiation. Optimize hydration prior to capecitabine initiation. The capecitabine dose should be rounded to the nearest 150 mg to provide the dose as whole tablets.
Anal carcinoma (off-label use): Oral: 825 mg/m2 twice daily 5 days/week (Monday through Friday) (in combination with mitomycin [on day 1 only]) during radiation therapy; radiation therapy occurred over 5 to 6 weeks (Ref) or 825 mg/m2 twice daily on radiation therapy days (in combination with mitomycin [on day 1 only] and radiation therapy) (Ref).
Biliary tract cancer, adjuvant therapy (off-label use):
Monotherapy (adjuvant): Oral: 1,250 mg/m2 twice daily on days 1 to 14 of a 21-day treatment cycle for 8 cycles (Ref). Per the American Society of Clinical Oncology guideline for adjuvant therapy for resected biliary tract cancer, the capecitabine dose may be determined by institutional and regional practices (Ref).
Chemoradiotherapy (adjuvant): Oral: 750 mg/m2 twice daily on days 1 to 14 of a 21-day treatment cycle (in combination with gemcitabine) for 4 cycles, followed by capecitabine 665 mg/m2 twice daily (in combination with concurrent radiotherapy) (Ref). Refer to protocol for specific details.
Biliary tract cancers, advanced (off-label use): Oral: 650 mg/m2 twice daily on days 1 to 14 of a 3-week cycle (in combination with gemcitabine) until disease progression or unacceptable toxicity (Ref) or 1,000 mg/m2 twice daily on days 1 to 14 of a 3-week cycle (in combination with oxaliplatin) until disease progression or unacceptable toxicity (Ref) or 1,250 mg/m2 twice daily on days 1 to 14 of a 3-week cycle (in combination with cisplatin) until disease progression or unacceptable toxicity (Ref).
Breast cancer, adjuvant therapy, triple-negative, with residual disease after neoadjuvant therapy and surgery (off-label use): Oral: 1,250 mg/m2 twice daily on days 1 to 14 of a 21-day treatment cycle for 6 to 8 cycles (Ref).
Breast cancer, advanced or metastatic:
Single-agent therapy: Oral: 1,000 or 1,250 mg/m2 twice daily on days 1 to 14 every 21 days until disease progression or unacceptable toxicity (Ref).
Capecitabine/docetaxel: Oral: 1,000 or 1,250 mg/m2 twice daily on days 1 to 14 every 21 days (in combination with docetaxel) until disease progression or unacceptable toxicity (Ref).
Breast cancer, metastatic (off-label dosing): Adults ≥65 years of age: Oral: 1,000 mg/m2 twice daily on days 1 to 14 of a 21-day treatment cycle for at least 2 and up to 6 cycles or longer (Ref).
Breast cancer, metastatic (off-label combination): Oral: 1,000 mg/m2 twice daily on days 1 to 14 of a 3-week cycle (in combination with ixabepilone) until disease progression or unacceptable toxicity (Ref).
Breast cancer, metastatic, HER2+ (off-label combinations): Oral: 1,000 mg/m2 twice daily on days 1 to 14 of a 3-week cycle (in combination with lapatinib) until disease progression or unacceptable toxicity (Ref) or 1,250 mg/m2 twice daily on days 1 to 14 of a 3-week cycle (in combination with trastuzumab) (Ref) or 1,000 mg/m2 twice daily on days 1 to 14 of a 3-week cycle (in combination with tucatinib and trastuzumab) until disease progression or unacceptable toxicity (Ref) or 750 mg/m2 twice daily on days 1 to 14 of a 3-week cycle (in combination with neratinib) until disease progression or unacceptable toxicity (Ref) or 1,000 mg/m2 twice daily on days 1 to 14 of a 3-week cycle (in combination with margetuximab) until disease progression or unacceptable toxicity (Ref).
Breast cancer, metastatic, HER2+ with brain metastases, first-line therapy (off-label combination): Oral: 1,000 mg/m2 twice daily on days 1 to 14 of a 3-week cycle (in combination with lapatinib) until disease progression or unacceptable toxicity (Ref).
Colorectal cancer:
Colon cancer, stage 3, adjuvant therapy:
Single-agent therapy: Oral: 1,250 mg/m2 twice daily on days 1 to 14 of a 21-day treatment cycle for a maximum of 8 cycles (Ref). Note : Capecitabine toxicities, particularly hand-foot syndrome, may be higher in North American populations; in some patients, therapy initiation at doses of 1,000 mg/m2 twice daily (on days 1 to 14 every 21 days) may be considered (Ref).
XELOX/CAPOX regimen: Oral: 1,000 mg/m2 twice daily on days 1 to 14 of a 21-day treatment cycle (in combination with oxaliplatin) for a maximum of 8 cycles (Ref).
Colorectal cancer, unresectable or metastatic:
Single-agent therapy: Oral: 1,250 mg/m2 twice daily on days 1 to 14 of a 21-day treatment cycle; continue until disease progression or unacceptable toxicity. Note: Capecitabine toxicities, particularly hand-foot syndrome, may be higher in North American populations; therapy initiation at doses of 1,000 mg/m2 twice daily (on days 1 to 14 every 21 days) may be considered (Ref).
XELOX/CAPOX regimen: Oral: 1,000 mg/m2 twice daily on days 1 to 14 of a 21-day treatment cycle (in combination with oxaliplatin); continue until disease progression or unacceptable toxicity. Some studies administered for a duration of 8 or 16 cycles (Ref). A retrospective evaluation of a modified schedule (eg, days 1 to 7 and days 15 to 21 of a 28-day cycle) found improved tolerability and no difference in efficacy outcomes (Ref).
CAPOX/panitumumab: Oral: 1,000 mg/m2 twice daily on days 1 to 14 every 3 weeks (in combination with oxaliplatin and panitumumab) for at least 6 cycles or until disease progression or unacceptable toxicity (Ref).
Rectal cancer, locally advanced, perioperative treatment: Note: Refer to protocol for additional/full details.
When administered with concomitant radiation therapy: Oral: 825 mg/m2 twice daily throughout radiotherapy (as part of a perioperative combination regimen) (Ref).
When administered without concomitant radiation therapy: Oral: 1,250 mg/m2 twice daily on days 1 to 14 of a 21-day treatment cycle (as part of a perioperative combination regimen) (Ref).
Esophageal, gastric, and gastroesophageal cancers:
Esophageal, gastric, or gastroesophageal junction cancer, locally advanced (unresectable) or metastatic: Oral: 625 mg/m2 twice daily on days 1 to 21 every 3 weeks (in combination with platinum-based chemotherapy) for a maximum of 8 cycles (Ref) or 850 or 1,000 mg/m2 twice daily on days 1 to 14 every 3 weeks (in combination with oxaliplatin) until disease progression or unacceptable toxicity; individualize capecitabine dose based on risk factors and tolerance (Ref) or (off-label combination) 1,000 mg/m2 twice daily on days 1 to 14 of a 3-week cycle (in combination with oxaliplatin and nivolumab) until disease progression or unacceptable toxicity (Ref).
Esophageal or gastroesophageal cancers: Preoperative or definitive chemoradiation: Oral: 800 mg/m2 twice daily on days 1 to 5 weekly (in combination with cisplatin and radiation) for 5 weeks (Ref) or 625 mg/m2 twice daily on days 1 to 5 weekly (in combination with oxaliplatin and radiation) for 5 weeks (Ref).
Gastric cancer: Postoperative chemoradiation: Oral: 625 to 825 mg/m2 twice daily during radiation therapy (Ref).
Gastric or gastroesophageal junction cancer, metastatic, HER2 overexpressing: Oral: 1,000 mg/m2 twice daily on days 1 to 14 every 21 days for 6 cycles (in combination with cisplatin and trastuzumab) (Ref) or 1,000 mg/m2 twice daily on days 1 to 14 every 21 days (in combination with oxaliplatin, pembrolizumab, and trastuzumab) until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Ref).
Gastric or gastroesophageal junction cancer: Locally advanced or metastatic (chemoradiation not indicated): Oral: 1,250 mg/m2 twice daily on days 1 to 14 of a 3-week cycle (as a single agent) for up to 6 cycles (Ref) or 1,000 mg/m2 twice daily on days 1 to 14 of a 3-week cycle (in combination with cisplatin) until disease progression or unacceptable toxicity (Ref).
Gastroesophageal cancer, advanced, palliative treatment: Frail and/or elderly patients: Oral: A dose optimization study that examined 60%, 80%, or 100% of a 625 mg/m2 twice daily dose (on days 1 to 21 of a 21-day cycle; in combination with oxaliplatin) found that the 60% dose was not inferior (for progression-free survival) and had less toxicity compared to the full dose (Ref).
Gastric cancer, adjuvant therapy (off-label use): Oral: 1,000 mg/m2 twice daily on days 1 to 14 every 3 weeks for 8 cycles (in combination with oxaliplatin) following D2 gastrectomy in patients who did not receive preoperative therapy (Ref).
Head and neck cancer: Nasopharyngeal carcinoma, locally advanced (off-label use):
Induction therapy: Oral: 1,000 mg/m2 twice daily on days 1 to 14 of a 3-week cycle (in combination with concurrent radiation therapy and cisplatin); refer to protocol for details (Ref).
Adjuvant therapy: Oral: 1,000 mg/m2 twice daily on days 1 to 14 of a 3-week cycle for 8 cycles beginning 4 weeks after concurrent chemoradiotherapy (Ref) or (metronomic dosing) 650 mg/m2 twice daily for 1 year (Ref).
Head and neck cancer, squamous cell, recurrent or metastatic; palliative treatment (off-label use; based on limited data): Oral: 1,250 mg/m2 twice daily on days 1 to 14 of a 21-day treatment cycle for at least 3 cycles; continue until disease progression or unacceptable toxicity (Ref).
Neuroendocrine tumors: GI/carcinoid, refractory (off-label use): Oral: 1,000 mg/m2 twice daily on days 2 to 15 of a 3-week cycle (in combination with oxaliplatin) for up to 6 cycles (Ref).
Neuroendocrine tumors: Pancreatic/islet cell, metastatic or unresectable (off-label use) Based on limited data: Oral: 750 mg/m2 twice daily on days 1 to 14 of a 4-week cycle (in combination with temozolomide) until disease progression (Ref).
Ovarian, fallopian tube, or peritoneal cancer, platinum-refractory (off-label use): Oral: 1,000 mg/m2 twice daily on days 1 to 14 of a 3-week cycle until disease progression or unacceptable toxicity (Ref).
Pancreatic cancer, locally advanced or metastatic (off-label use): Oral: 1,250 mg/m2 twice daily on days 1 to 14 of a 3-week cycle (as a single agent) until disease progression or up to 1 year (Ref) or 830 mg/m2 twice daily on days 1 to 21 of a 4-week cycle (in combination with gemcitabine) until disease progression or unacceptable toxicity (Ref) or 1,000 mg/m2 twice daily (750 mg/m2 twice daily for patients >65 years of age) on days 1 to 14 of a 3-week cycle (in combination with oxaliplatin) until disease progression or unacceptable toxicity (Ref).
Pancreatic cancer, potentially curable, adjuvant therapy (alternative therapy): Note: American Society of Clinical Oncology guidelines for potentially curable pancreatic cancer recommend 6 months of adjuvant therapy if recovery is complete; while first-line therapy with another regimen is preferred, the capecitabine/gemcitabine regimen is an option if toxicity/tolerance are concerns with the preferred therapy (Ref).
Oral: 830 mg/m2 twice daily on days 1 to 21 every 28 days beginning within 12 weeks of resection (in combination with gemcitabine) until disease progression or unacceptable toxicity or for a maximum of 6 cycles (Ref).
Small bowel adenocarcinoma, advanced unresectable or metastatic (off-label use): CAPOX regimen: Oral: 750 mg/m2 twice daily on days 1 to 14 every 3 weeks (in combination with oxaliplatin) until disease progression or unacceptable toxicity (Ref).
Thymic malignancies, refractory (off-label use): CAP-GEM regimen: Oral: 650 mg/m2 twice daily on days 1 to 14 every 21 days (in combination with gemcitabine) until disease progression (Ref).
Unknown primary cancer (off-label use): Oral: 1,000 mg/m2 twice daily on days 1 to 14 of a 3-week cycle (in combination with oxaliplatin) for up to 6 cycles or until disease progression (Ref) or 800 mg/m2 twice daily on days 1 to 14 of a 3-week cycle (in combination with carboplatin and gemcitabine) for up to 8 cycles or until disease progression or unacceptable toxicity (Ref).
Missed doses: Do not replace missed doses, instead resume with the next planned capecitabine dose. If a dose is vomited, continue with the next scheduled dose; do not administer an additional dose.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Kidney impairment prior to treatment initiation:
Altered kidney function:
Note: Capecitabine and its metabolites are primarily (>95%) excreted by the kidneys (Ref). An increased incidence of drug-limiting toxicity has been observed with declining kidney function, including in patients with eGFR 60 to 90 mL/minute/1.73 m2 as compared to eGFR >90 mL/minute/1.73 m2 (Ref), although another study did not find a difference in toxicity based on CrCl using dose-adjusted capecitabine in patients with breast cancer (Ref). As such, monitoring for adverse effects (eg, diarrhea, hematologic, mucositis, hand-foot syndrome/palmar-plantar erythrodysesthesia) is warranted even in mild kidney impairment, and toxicity-related dose reductions may be required. Kidney function may be estimated using the Cockcroft-Gault formula for dosage adjustment purposes.
CrCl >50 mL/minute: No dosage adjustment necessary.
CrCl 30 to 50 mL/minute: Administer 75% of the usual indication-specific daily dose (Ref).
CrCl <30 mL/minute: A dose has not been established (manufacturer's labeling), and use is generally not recommended (Ref). If no treatment alternative exists, capecitabine treatment can be considered on an individual basis utilizing a reduced starting dose with close monitoring and dose modification guided by adverse reactions (Ref). There are limited case reports demonstrating tolerability in this population following dose reductions of up to 80% (Ref).
Augmented renal clearance (measured urinary CrCl ≥130 mL/minute/1.73 m2):
Note: Augmented renal clearance (ARC) is a condition that occurs in certain critically ill patients without organ dysfunction and with normal serum creatinine concentrations. Younger patients (<55 years of age) admitted post-trauma or post-major surgery are at highest risk for ARC, as well as those with sepsis, burns, or hematologic malignancies. An 8- to 24-hour measured urinary CrCl is necessary to identify these patients (Ref).
No dosage adjustment necessary (Ref).
Hemodialysis, intermittent (thrice weekly): Use is generally not recommended (Ref). If no treatment alternative exists, capecitabine treatment can be considered on an individual basis utilizing a reduced starting dose with close monitoring and dose modification guided by adverse reactions (Ref). Tolerability following dose reduction has been observed in several case reports in hemodialysis patients (Ref); however, due to the paucity of data, no specific dosage recommendation can be suggested (Ref).
Peritoneal dialysis: Use not recommended (has not been studied) (Ref).
CRRT: Use not recommended (has not been studied) (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): Use not recommended (has not been studied) (Ref).
Kidney toxicity during treatment:
Capecitabine does not directly damage the kidney (Ref). However, its ability to cause diarrhea and dehydration can impact kidney function. Monitor, intensify supportive care, and correct dehydration. Withhold capecitabine and then resume at the same or at a reduced dose or permanently discontinue based on severity and occurrence. Refer to "Dosing: Adjustment for Toxicity" for dosage adjustment levels.
Hepatic impairment at treatment initiation:
Mild to moderate impairment: No initial dose adjustment necessary (Ref); however, carefully monitor patients with hepatic dysfunction due to liver metastases.
Severe hepatic impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Hepatotoxicity during treatment: Hyperbilirubinemia: Withhold capecitabine and then resume at the same or at a reduced dose or permanently discontinue based on severity and occurrence. For grade 3 or 4 hyperbilirubinemia, interrupt treatment until resolved to ≤ grade 2 (bilirubin ≤3 times ULN). Refer to “Dosing: Adjustment for Toxicity” for dosage adjustment levels.
American Society of Clinical Oncology guidelines for appropriate chemotherapy dosing in adults with cancer with a BMI ≥30 kg/m2: Utilize patient's actual body weight for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for patients with a BMI <30 kg/m2; if a dose reduction is utilized due to toxicity, may consider resumption of full weight-based dosing (or previously tolerated dose level) with subsequent cycles only if dose escalations are allowed in the prescribing information, if contributing underlying factors (eg, hepatic or kidney impairment) are sufficiently resolved, AND if performance status has markedly improved or is considered adequate (Ref).
Monitor carefully for toxicity and adjust dose as necessary. Doses reduced for toxicity should not be increased at a later time. For combination therapy, also refer to docetaxel product labeling for docetaxel dose modifications. If treatment delay is required for either capecitabine or docetaxel, withhold both agents until appropriate to resume combination treatment. Other concomitant anticancer therapies may also require dosage modification.
|
Toxicity Grades |
During a Course of Therapy |
Dose Adjustment for Next Cycle (% of starting dose) |
|---|---|---|
|
a When capecitabine is administered in combination with docetaxel, withhold both capecitabine and docetaxel until the requirements for resuming both medications are met. | ||
|
b Also refer to dose modification recommendations based on toxicity grade listed above. | ||
|
Grade 2 | ||
|
1st appearance |
Interrupt until resolved to grade 0 to 1 |
100% |
|
2nd appearance |
Interrupt until resolved to grade 0 to 1 |
75% |
|
3rd appearance |
Interrupt until resolved to grade 0 to 1 |
50% |
|
4th appearance |
Discontinue treatment permanently |
|
|
Grade 3 | ||
|
1st appearance |
Interrupt until resolved to grade 0 to 1 |
75% |
|
2nd appearance |
Interrupt until resolved to grade 0 to 1 |
50% |
|
3rd appearance |
Discontinue treatment permanently |
|
|
Grade 4 | ||
|
1st appearance |
Discontinue permanently |
|
|
or |
||
|
If in the patient's best interest to continue, interrupt until resolved to grade 0 to 1 |
50% | |
|
Management o f specific capecitabine toxicitiesb | ||
|
Adverse reaction |
Severity |
Capecitabine dosage modification |
|
Cardiotoxicity |
n/a |
Withhold capecitabine as appropriate; the safety of resuming capecitabine following cardiotoxicity has not been established. |
|
Dehydration |
≥ grade 2 |
Optimize hydration before restarting. Withhold capecitabine and then resume at the same or at a reduced dose or permanently discontinue based on severity and occurrence. |
|
Dermatologic toxicity: Cutaneous adverse reactions |
Severe |
Permanently discontinue capecitabine. |
|
GI toxicity: Diarrhea |
≥ grade 2 |
Withhold capecitabine and then resume at the same or at a reduced dose or permanently discontinue based on severity and occurrence. Antidiarrheal therapy (eg, loperamide) is recommended to manage diarrhea. |
|
Hematologic toxicity |
Grade 3 or 4 |
Withhold capecitabine and then resume at the same or at a reduced dose or permanently discontinue based on the occurrence. |
|
Palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome) |
≥ grade 2 |
Withhold capecitabine and then resume at the same or at a reduced dose or permanently discontinue based on severity and occurrence. |
|
Evidence of acute early-onset or unusually severe toxicity indicative of dihydropyrimidine dehydrogenase deficiency |
Any |
Withhold or permanently discontinue capecitabine depending on the onset, duration, and severity of toxicity. |
Capecitabine dosage adjustments for hematologic toxicity when used in combination therapy with ixabepilone:
Neutrophils <500/mm3 for ≥7 days or neutropenic fever: Hold capecitabine for concurrent diarrhea or stomatitis until neutrophils recover to >1,000/mm3, then continue at same dose.
Platelets <25,000/mm3 (or <50,000/mm3 with bleeding): Hold capecitabine for concurrent diarrhea or stomatitis until platelets recover to >50,000/mm3, then continue at same dose.
Refer to adult dosing.
Bone marrow depression may occur, including anemia, neutropenia, and thrombocytopenia. Genetic variants in the DPYD gene (ie, poor metabolizers) increase risk for acute early-onset or severe toxicity due to total or near total absence of dihydropyrimidine dehydrogenase (DPD) enzyme activity (Ref). Patients with partial DPD activity are also at risk. No capecitabine dose has been shown safe in patients with total DPD deficiency; data are insufficient to recommend a dose in patients with partial DPD activity (Ref).
Mechanism: Related to mechanism of action; directly toxic to rapidly replicating cells, including bone marrow (Ref).
Risk factors:
• Genetic variants in the DPYD gene, resulting in total or partial absence of DPD enzyme activity
• Concurrent cytotoxic medications
Cardiotoxicity has been observed with fluoropyrimidine therapy, including capecitabine. Adverse events include acute myocardial infarction, angina pectoris, ischemic heart disease, cardiac arrhythmia, cardiomyopathy, and heart failure (Ref).
Mechanism: Not clearly established; coronary vasospasm is a potential mechanism (Ref). Other proposed mechanisms include endothelial damage, oxidative stress, Krebs cycle disturbances and toxic metabolites (Ref).
Onset: Rapid; fluoropyrimidine cardiotoxicity typically occurs several hours after initiation (Ref).
Risk factors:
• Preexisting cardiac disease (Ref)
• Hypercholesterolemia (Ref)
• Tobacco smoking (Ref)
• Concurrent bevacizumab (Ref)
• Prior or concurrent radiation therapy to the chest (Ref)
• High levels of exertion during therapy (Ref)
Capecitabine may cause hand-and-foot syndrome (HFS) (palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema), characterized by numbness, dysesthesia/paresthesia, tingling, painless or painful swelling, erythema, desquamation, blistering, and severe pain (Ref). Post-inflammatory hyperpigmentation is common (Ref). Persistent HFS (grade ≥2) could eventually lead to fingerprint loss (Ref). Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported (some fatal) (Ref).
Mechanism: HFS: Dose-related; may be caused by cyclooxygenase inflammatory-type reaction, accumulation of capecitabine metabolites, and effects of enzymes and transporters in the skin (Ref). SJS/TEN: Non–dose-related, immunologic. Delayed hypersensitivity reactions, including SJS and TEN, are T-cell mediated (Ref).
Onset: Varied; HFS median time to onset was ~2.6 months (range: 11 days to ~1 year) (Ref). Severe cutaneous adverse reactions, such as SJS/TEN usually occur 1 to 8 weeks after initiation, with cases associated with capecitabine occurring 10 days after initiation (Ref).
Risk factors (HFS):
• Higher doses (Ref)
• Early onset (ie, within 21 days) of grade 1 HFS (Ref)
• Concurrent bevacizumab or docetaxel (Ref)
• History of fluorinated pyrimidine administration (Ref)
• Elevation of serum or red blood cell folate levels, or folate supplementation (Ref)
• Genetic variants, including DPYD (Ref)
• Diabetes (Ref)
Capecitabine may cause GI toxicity, leading to diarrhea and stomatitis, which may be severe. Genetic variants in the DPYD gene (ie, poor metabolizers) increase risk for acute early-onset or severe toxicity due to total or near total absence of dihydropyrimidine dehydrogenase (DPD) enzyme activity (Ref). Dehydration may occur rapidly in patients with diarrhea, nausea, vomiting, and anorexia. Necrotizing enterocolitis (typhlitis) has also been reported.
Mechanism: Dose-related; related to mechanism of action. Directly toxic to fast replicating cells, including those of the GI tract. Thymidine phosphorylase, the enzyme responsible for conversion to active drug, is expressed at higher levels in the GI tract (Ref). Destruction of the epithelium leads to mucositis throughout the GI tract, leading to diarrhea, stomatitis, nausea/vomiting and typhlitis (Ref).
Onset: Varied; median time to first occurrence of grade 2 to 4 diarrhea is 34 days (range: 1 day to 1 year) with a duration of 5 days.
Risk factors:
• Higher doses (Ref)
• Genetic variants in DPYD, resulting in partial or total absence of DPD enzyme activity
• Concurrent radiation therapy (Ref)
• Females (Ref)
• Patients ≥65 years of age (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.
>10%:
Cardiovascular: Edema (≤15%)
Dermatologic: Dermatitis (27% to 37%), palmar-plantar erythrodysesthesia (54% to 60%)
Gastrointestinal: Abdominal pain (14% to 35%), anorexia (≤23%), constipation (≤15%), decreased appetite (26%), diarrhea (47% to 57%; grades 3/4: 2% to 13%), nausea (34% to 53%; grades 3/4: 2% to 4%), stomatitis (22% to 25%; grades 3/4: ≤7%), vomiting (15% to 37%; grades 3/4: ≤4%)
Hematologic & oncologic: Anemia (72% to 80%, grades 3/4: ≤3%) (table 1), lymphocytopenia (94%; grades 3/4: 15% to 44%), neutropenia (13% to 26%; grades 3/4: 1% to 3%) (table 2), thrombocytopenia (24%; grades 3/4: 1% to 3%)
|
Drug (Capecitabine) |
Comparator (5-FU and Leucovorin) |
Dose |
Indication |
Number of Patients (Capecitabine) |
Number of Patients (5-FU and Leucovorin) |
|---|---|---|---|---|---|
|
All grades: 72% |
N/A |
1,250 mg/m2 twice a day for 2 weeks followed by a 1-week rest period |
Breast cancer |
162 |
N/A |
|
Grade 3: 3% |
N/A |
1,250 mg/m2 twice a day for 2 weeks followed by a 1-week rest period |
Breast cancer |
162 |
N/A |
|
Grade 4: 1% |
N/A |
1,250 mg/m2 twice a day for 2 weeks followed by a 1-week rest period |
Breast cancer |
162 |
N/A |
|
All grades: 80% |
79% |
1,250 mg/m2 twice a day for 2 weeks followed by a 1-week rest period |
Metastatic colorectal cancer |
596 |
593 |
|
Grade 3: 2% |
1% |
1,250 mg/m2 twice a day for 2 weeks followed by a 1-week rest period |
Metastatic colorectal cancer |
596 |
593 |
|
Grade 4: <1% |
<1% |
1,250 mg/m2 twice a day for 2 weeks followed by a 1-week rest period |
Metastatic colorectal cancer |
596 |
593 |
|
Drug (Capecitabine) |
Comparator (5-FU and Leucovorin) |
Dose |
Indication |
Number of Patients (Capecitabine) |
Number of Patients (5-FU and Leucovorin) |
|---|---|---|---|---|---|
|
All grades: 26% |
N/A |
1,250 mg/m2 twice a day for 2 weeks followed by a 1-week rest period |
Breast cancer |
162 |
N/A |
|
Grade 3: 2% |
N/A |
1,250 mg/m2 twice a day for 2 weeks followed by a 1-week rest period |
Breast cancer |
162 |
N/A |
|
Grade 4: 2% |
N/A |
1,250 mg/m2 twice a day for 2 weeks followed by a 1-week rest period |
Breast cancer |
162 |
N/A |
|
All grades: 13% |
46% |
1,250 mg/m2 twice a day for 2 weeks followed by a 1-week rest period |
Metastatic colorectal cancer |
596 |
593 |
|
Grade 3: 1% |
8% |
1,250 mg/m2 twice a day for 2 weeks followed by a 1-week rest period |
Metastatic colorectal cancer |
596 |
593 |
|
Grade 4: 2% |
13% |
1,250 mg/m2 twice a day for 2 weeks followed by a 1-week rest period |
Metastatic colorectal cancer |
596 |
593 |
Hepatic: Hyperbilirubinemia (22% to 48%)
Nervous system: Asthenia (≤42%), fatigue (≤42%), pain (≤12%), paresthesia (21%; grade 3: 1%)
Ophthalmic: Eye irritation (13% to 15%)
Respiratory: Dyspnea (≤14%)
Miscellaneous: Fever (≤18%)
1% to 10%:
Cardiovascular: Atrial fibrillation, bradycardia, chest pain, hypertension, hypotension, myocarditis, pulmonary embolism, tachycardia, venous thrombosis
Dermatologic: Alopecia, dermal ulcer, diaphoresis, erythema of skin, nail disease, pruritus, skin discoloration, skin photosensitivity, skin rash
Endocrine & metabolic: Cachexia, decreased serum calcium (grades 3/4: 2%), dehydration, hot flash, hypertriglyceridemia, hypokalemia, hypomagnesemia, increased serum calcium (grades 3/4: 1%), increased thirst
Gastrointestinal: Abdominal distention, dysgeusia, dyspepsia, dysphagia, gastric ulcer, gastroenteritis, gastrointestinal hemorrhage, gastrointestinal inflammation (upper), gastrointestinal motility disorder (10%), intestinal obstruction, oral discomfort (10%), rectal pain, upper abdominal pain
Hematologic & oncologic: Bone marrow depression, disorder of hemostatic components of blood, granulocytopenia (grades 3/4: ≤2%), hemorrhage, leukopenia, lymphedema, pancytopenia
Hepatic: Abnormal hepatic function tests, cholestatic hepatitis, hepatic fibrosis, hepatitis, increased serum alanine aminotransferase (grades 3/4: 2%)
Hypersensitivity: Hypersensitivity reaction
Infection: Fungal infection, sepsis, viral infection
Nervous system: Ataxia, balance impairment, confusion, depression, dizziness, dysarthria, dysphasia, encephalopathy, headache, insomnia, lethargy (10%), mood changes, myasthenia, peripheral sensory neuropathy (10%), tremor, vertigo
Neuromuscular & skeletal: Arthralgia, arthritis, back pain (10%), limb pain, myalgia
Ophthalmic: Conjunctivitis, keratoconjunctivitis, visual disturbance
Renal: Renal insufficiency
Respiratory: Bronchitis, cough, epistaxis, flu-like symptoms, pharyngeal disease, pneumonia, respiratory distress
Miscellaneous: Fibrosis, radiation recall phenomenon
Postmarketing:
Cardiovascular: Acute myocardial infarction (Dyhl-Polk 2020), angina pectoris (Dyhl-Polk 2020), cardiac arrhythmia (Dyhl-Polk 2020), cardiomyopathy (Dyhl-Polk 2020), ECG changes (Dyhl-Polk 2020), heart failure (Dyhl-Polk 2020), ischemic heart disease (Dyhl-Polk 2020)
Dermatologic: Cutaneous lupus erythematosus (Rocha 2019), Stevens-Johnson syndrome (Karthikeyan 2022), toxic epidermal necrolysis
Gastrointestinal: Necrotizing enterocolitis
Hepatic: Hepatic failure
Hypersensitivity: Angioedema
Nervous system: Leukoencephalopathy (Yoshimura 2019)
Ophthalmic: Corneal disease (including keratitis), lacrimal stenosis
Known hypersensitivity to capecitabine, fluorouracil, or any component of the formulation.
Canadian labeling: Additional contraindications (not in the US labeling): Known complete absence of dihydropyrimidine dehydrogenase (DPD) activity; concomitant administration with sorivudine or chemically related analogues (eg, brivudine).
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Concerns related to adverse effects:
• Hepatotoxicity: Grade 3 and 4 hyperbilirubinemia have been observed in patients with and without hepatic metastases at baseline (median onset: 64 days). Transaminase and alkaline phosphatase elevations have also been reported.
Disease-related concerns:
• Kidney impairment: Dehydration may occur, resulting in acute kidney failure (may be fatal); concomitant use with nephrotoxic agents and baseline kidney dysfunction may increase the risk.
Concurrent drug therapy issues:
• Fluorouracil/leucovorin (FU/LV): In patients with colorectal cancer, treatment with capecitabine immediately following 6 weeks of FU/LV therapy has been associated with an increased incidence of grade ≥3 toxicity, when compared to patients receiving the reverse sequence, capecitabine (two 3-week courses) followed by FU/LV (Hennig 2008).
• Proton pump inhibitors: Concomitant use of proton pump inhibitors (PPIs) and capecitabine may alter capecitabine dissolution and absorption due to higher gastric pH levels. Secondary analysis of a large, phase 3 study comparing capecitabine and oxaliplatin with or without lapatinib for the treatment of gastroesophageal cancer showed decreased overall survival in patients who received concurrent PPIs (Chu 2017). Similar concern was raised by a retrospective evaluation of capecitabine monotherapy for early-stage colorectal cancer that found worse relapse-free survival in patients receiving a concurrent PPI (Sun 2016). In contrast, a systematic review (Lin 2022) found similar survival among patients with colorectal cancer treated with capecitabine-based regimens with or without a concurrent PPI. Although disease progression was more common among patients with early-stage disease receiving capecitabine monotherapy and a concurrent PPI, there was no difference in all-cause mortality and PPI use did not affect survival among patients receiving capecitabine combination therapy. Similarly, a retrospective evaluation of patients receiving capecitabine with concomitant radiation as neoadjuvant treatment for early-stage rectal cancer found no adverse pathologic or oncologic outcome based on PPI use (Menon 2021). Consider avoiding PPIs (if possible) in patients receiving capecitabine and routinely assess need for continued PPI use with concurrent capecitabine. Potential drug interaction may be more clinically relevant with capecitabine monotherapy. Use of other acid-suppressing medications (eg, H2 antagonists or antacids) may provide sufficient relief of acid reflux symptoms among PPI users and can be more effectively dose-spaced with capecitabine.
Special populations:
• Dihydropyrimidine dehydrogenase deficiency: Patients with certain homozygous or compound heterozygous mutations of the dihydropyrimidine dehydrogenase (DPD) gene (DPYD) are at increased risk for acute early-onset (potentially severe, life-threatening, or fatal) toxicity due to total or near total absence of DPD activity. Toxicity may include mucositis/stomatitis, diarrhea, neutropenia, and neurotoxicity. Capecitabine is not recommended in patients known to have certain homozygous or compound heterozygous DPYD variants that result in complete DPD deficiency. Patients with partial DPD activity are also at risk for severe, life-threatening, or fatal toxicity. May require therapy interruption, reduced doses, and/or permanent discontinuation, depending on the onset, duration, and severity of toxicity observed. No capecitabine dose has been shown to be safe in patients with complete DPD deficiency; data are insufficient to recommend a dose in patients with partial DPD activity according to the prescribing information. The Clinical Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenetics Working Group both offer guidance for capecitabine dosing in patients with known reduced DPD activity (CPIC [Amstutz 2018], DPWG [Lunenburg 2020]). Consider testing for genetic variants of DPYD prior to capecitabine initiation to reduce the risk of serious adverse reactions if the patient’s clinical status permits and based on clinical judgement. Serious adverse reactions may still occur even if DPYD variants are not identified.
• Older adults: Older adults experienced increased GI toxicity (compared to younger patients). Deaths due to severe enterocolitis, diarrhea, and dehydration have been reported in older adults receiving fluorouracil/leucovorin.
Other warnings/precautions:
• Fluoropyrimidine overdose: Uridine triacetate has been studied in cases of fluoropyrimidine overdose. In a clinical study of 98 patients who received uridine triacetate for fluorouracil toxicity (due to overdose, accidental capecitabine ingestion, or possible DPD deficiency), 96 patients recovered fully (Bamat 2013). Of 17 patients receiving uridine triacetate beginning within 8 to 96 hours after fluorouracil overdose, all patients fully recovered (von Borstel 2009). An additional case report describes accidental capecitabine ingestion by a 22-month-old child; uridine triacetate was initiated approximately 7 hours after exposure. The patient received uridine triacetate every 6 hours for a total of 20 doses through nasogastric tube administration; he was asymptomatic throughout his course and was discharged with normal laboratory values (Kanie 2011). Refer to Uridine Triacetate monograph.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Xeloda: 150 mg, 500 mg
Generic: 150 mg, 500 mg
Yes
Tablets (Capecitabine Oral)
150 mg (per each): $3.30 - $11.85
500 mg (per each): $6.50 - $39.94
Tablets (Xeloda Oral)
150 mg (per each): $16.27
500 mg (per each): $54.22
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet, Oral:
Xeloda: 150 mg [DSC], 500 mg [DSC]
Generic: 150 mg, 500 mg
Oral: Administer doses at approximately the same times each day, ~12 hours apart. Administer with water within 30 minutes after a meal. Swallow tablets whole; do not cut, chew, or crush. If a dose is missed or vomited, continue with the next scheduled dose; do not administer an additional dose.
Hazardous agent (NIOSH 2016 [group 1]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Breast cancer, advanced or metastatic:
Monotherapy: Treatment of advanced or metastatic breast cancer (as a single agent) if an anthracycline- or taxane-containing chemotherapy is not indicated.
Combination therapy: Treatment of advanced or metastatic breast cancer (in combination with docetaxel) after disease progression on a prior anthracycline-containing regimen.
Colorectal cancer:
Adjuvant treatment of stage 3 colon cancer, either as a single agent or as a component of a combination chemotherapy regimen.
Perioperative treatment of locally advanced rectal cancer in adults, as a component of chemoradiotherapy.
Treatment of unresectable or metastatic colorectal cancer, either as a single agent or as a component of a combination chemotherapy regimen.
Gastric, esophageal, or gastroesophageal junction cancer:
Treatment of unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer in adults, as a component of a combination chemotherapy regimen.
Treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma in adults who have not received prior treatment for metastatic disease, as a component of a combination regimen.
Pancreatic cancer, adjuvant therapy: Adjuvant treatment of pancreatic adenocarcinoma in adults, as a component of a combination chemotherapy regimen.
Guideline recommendations: According to American Society of Clinical Oncology (ASCO) guidelines for potentially curable pancreatic cancer, while first-line adjuvant therapy with another regimen is preferred, capecitabine (in combination with gemcitabine) is an alternate adjuvant therapy option (in the absence of contraindications) if toxicity or tolerance are concerns with the preferred therapy (ASCO [Khorana 2019]).
Anal carcinoma; Biliary tract cancer, adjuvant therapy; Biliary tract cancers, advanced; Breast cancer, adjuvant therapy, triple-negative, with residual disease after neoadjuvant therapy and surgery; Gastric cancer, adjuvant treatment; Head and neck cancer: Nasopharyngeal carcinoma, locally advanced; Head and neck cancer, squamous cell, recurrent or metastatic; palliative treatment; Neuroendocrine tumors: GI/carcinoid, refractory; Neuroendocrine tumors: Pancreatic/islet cell, metastatic or unresectable; Ovarian, fallopian tube, or peritoneal cancers, refractory; Pancreatic cancer, locally advanced or metastatic; Small bowel adenocarcinoma, advanced unresectable or metastatic; Thymic malignancies, refractory; Unknown primary cancer
Capecitabine may be confused with cabozantinib, capmatinib
Xeloda may be confused with Xenical, Xpovio
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
Inhibits CYP2C9 (weak)
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Allopurinol: May decrease serum concentrations of the active metabolite(s) of Fluorouracil Products. Risk X: Avoid combination
Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Risk X: Avoid combination
Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Risk C: Monitor therapy
Amisulpride (Oral): May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk C: Monitor therapy
Antithymocyte Globulin (Equine): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Antithymocyte Globulin (Equine). Specifically, these effects may be unmasked if the dose of cytotoxic chemotherapy is reduced. Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Antithymocyte Globulin (Equine). Specifically, infections may occur with greater severity and/or atypical presentations. Risk C: Monitor therapy
Baricitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
BCG Products: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination
Bisphosphonate Derivatives: May enhance the nephrotoxic effect of Capecitabine. Risk C: Monitor therapy
Brincidofovir: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy
Brivudine: May enhance the adverse/toxic effect of Fluorouracil Products. Risk X: Avoid combination
CARBOplatin: May enhance the nephrotoxic effect of Capecitabine. Risk C: Monitor therapy
Cedazuridine: May increase the serum concentration of Cytidine Deaminase Substrates. Risk X: Avoid combination
Chikungunya Vaccine (Live): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Chikungunya Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Chikungunya Vaccine (Live). Risk X: Avoid combination
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy
Chloramphenicol (Systemic): Myelosuppressive Agents may enhance the myelosuppressive effect of Chloramphenicol (Systemic). Risk X: Avoid combination
Cimetidine: May increase the serum concentration of Fluorouracil Products. Risk C: Monitor therapy
CISplatin: May enhance the nephrotoxic effect of Capecitabine. Risk C: Monitor therapy
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination
Cladribine: Agents that Undergo Intracellular Phosphorylation may diminish the therapeutic effect of Cladribine. Risk X: Avoid combination
Cladribine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy
CloZAPine: Fluorouracil Products may enhance the myelosuppressive effect of CloZAPine. CloZAPine may enhance the QTc-prolonging effect of Fluorouracil Products. Management: Monitor for QTc interval prolongation and ventricular arrhythmias, including torsades de pointes when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Coccidioides immitis Skin Test: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing cytotoxic chemotherapy several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification
COVID-19 Vaccine (Adenovirus Vector): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector). Management: Administer a 2nd dose using an mRNA COVID-19 vaccine (at least 4 weeks after the primary vaccine dose) and a bivalent booster dose (at least 2 months after the additional mRNA dose or any other boosters). Risk D: Consider therapy modification
COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy
COVID-19 Vaccine (mRNA): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA). Management: Give a 3-dose primary series for all patients aged 6 months and older taking immunosuppressive medications or therapies. Booster doses are recommended for certain age groups. See CDC guidance for details. Risk D: Consider therapy modification
COVID-19 Vaccine (Subunit): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). Risk C: Monitor therapy
COVID-19 Vaccine (Virus-like Particles): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Virus-like Particles). Risk C: Monitor therapy
Dabrafenib: Fluorouracil Products may enhance the QTc-prolonging effect of Dabrafenib. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification
Dengue Tetravalent Vaccine (Live): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination
Denosumab: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and cytotoxic chemotherapy. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modification
Deucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination
Domperidone: QT-prolonging Agents (Moderate Risk) may enhance the QTc-prolonging effect of Domperidone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Etrasimod: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination
Fexinidazole: Fluorouracil Products may enhance the myelosuppressive effect of Fexinidazole. Fexinidazole may enhance the QTc-prolonging effect of Fluorouracil Products. Risk X: Avoid combination
Filgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Fluorouracil Products: May enhance the QTc-prolonging effect of other Fluorouracil Products. Management: Monitor for QTc interval prolongation and ventricular arrhythmias, including torsades de pointes when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Folic Acid: May enhance the adverse/toxic effect of Fluorouracil Products. Risk C: Monitor therapy
Fosphenytoin-Phenytoin: CYP2C9 Inhibitors (Weak) may increase the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy
Gimeracil: May increase the serum concentration of Fluorouracil Products. Risk X: Avoid combination
Haloperidol: May enhance the QTc-prolonging effect of Fluorouracil Products. Management: Monitor for QTc interval prolongation and ventricular arrhythmias, including torsades de pointes when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Inebilizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy
Influenza Virus Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating chemotherapy if possible. If vaccination occurs less than 2 weeks prior to or during chemotherapy, revaccinate at least 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification
Inhibitors of the Proton Pump (PPIs and PCABs): May diminish the therapeutic effect of Capecitabine. Risk C: Monitor therapy
Interferons (Alfa): May increase the serum concentration of Fluorouracil Products. Risk C: Monitor therapy
Irinotecan Products: May enhance the nephrotoxic effect of Capecitabine. Risk C: Monitor therapy
Leflunomide: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents, such as cytotoxic chemotherapy. Risk D: Consider therapy modification
Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modification
Leucovorin Calcium-Levoleucovorin: May enhance the adverse/toxic effect of Fluorouracil Products. Risk C: Monitor therapy
Levoketoconazole: QT-prolonging Agents (Moderate Risk) may enhance the QTc-prolonging effect of Levoketoconazole. Risk X: Avoid combination
Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modification
Methotrexate: May enhance the nephrotoxic effect of Capecitabine. Risk C: Monitor therapy
Methoxsalen (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Methoxsalen (Systemic). Risk C: Monitor therapy
MetroNIDAZOLE (Systemic): May increase the serum concentration of Fluorouracil Products. Risk C: Monitor therapy
Mumps- Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination
Nadofaragene Firadenovec: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Nadofaragene Firadenovec. Specifically, the risk of disseminated adenovirus infection may be increased. Risk X: Avoid combination
Natalizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination
Ocrelizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy
Ofatumumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy
Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. Risk C: Monitor therapy
Ondansetron: May enhance the QTc-prolonging effect of Fluorouracil Products. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Oxaliplatin: May enhance the nephrotoxic effect of Capecitabine. Oxaliplatin may enhance the neurotoxic (peripheral) effect of Capecitabine. Oxaliplatin may enhance the QTc-prolonging effect of Capecitabine. Risk C: Monitor therapy
Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Risk D: Consider therapy modification
Pentamidine (Systemic): May enhance the QTc-prolonging effect of Fluorouracil Products. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Pidotimod: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy
Pimecrolimus: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Pimozide: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk X: Avoid combination
Pneumococcal Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy
Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination
Polymethylmethacrylate: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification
Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Risk C: Monitor therapy
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
QT-prolonging Agents (Highest Risk): May enhance the QTc-prolonging effect of Fluorouracil Products. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
QT-prolonging Antidepressants (Moderate Risk): Fluorouracil Products may enhance the QTc-prolonging effect of QT-prolonging Antidepressants (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias, including torsades de pointes when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Antipsychotics (Moderate Risk): May enhance the QTc-prolonging effect of Fluorouracil Products. Management: Monitor for QTc interval prolongation and ventricular arrhythmias, including torsades de pointes when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Class IC Antiarrhythmics (Moderate Risk): May enhance the QTc-prolonging effect of Fluorouracil Products. Management: Monitor for QTc interval prolongation and ventricular arrhythmias, including torsades de pointes when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-Prolonging Inhalational Anesthetics (Moderate Risk): May enhance the QTc-prolonging effect of Fluorouracil Products. Management: Monitor for QTc interval prolongation and ventricular arrhythmias, including torsades de pointes when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Kinase Inhibitors (Moderate Risk): Fluorouracil Products may enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Miscellaneous Agents (Moderate Risk): May enhance the QTc-prolonging effect of Fluorouracil Products. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of Fluorouracil Products. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Quinolone Antibiotics (Moderate Risk): May enhance the QTc-prolonging effect of Fluorouracil Products. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of Fluorouracil Products. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Rabies Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modification
Ritlecitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ritlecitinib. Risk X: Avoid combination
Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification
Ruxolitinib (Topical): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination
Sertindole: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk X: Avoid combination
Sipuleucel-T: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants, such as cytotoxic chemotherapy, prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification
Sphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk C: Monitor therapy
Tacrolimus (Topical): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination
Talimogene Laherparepvec: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination
Telotristat Ethyl: May decrease serum concentrations of the active metabolite(s) of Capecitabine. Risk C: Monitor therapy
Tofacitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Tofacitinib. Risk X: Avoid combination
TOLBUTamide: CYP2C9 Inhibitors (Weak) may increase the serum concentration of TOLBUTamide. Risk C: Monitor therapy
Typhoid Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination
Ublituximab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ublituximab. Risk C: Monitor therapy
Upadacitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination
Vaccines (Inactivated/Non-Replicating): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of chemotherapy when possible. Patients vaccinated less than 14 days before initiating or during chemotherapy should be revaccinated at least 3 months after therapy is complete. Risk D: Consider therapy modification
Vaccines (Live): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Vaccines (Live) may diminish the therapeutic effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Fluorouracil Products may increase the serum concentration of Vitamin K Antagonists. Management: Monitor INR and for signs/symptoms of bleeding closely when a fluorouracil product is combined with a vitamin K antagonist (eg, warfarin). Anticoagulant dose adjustment will likely be necessary. Risk D: Consider therapy modification
Yellow Fever Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination
Food reduced the rate and extent of absorption of capecitabine. Following administration of a meal (breakfast; medium-rich in fat and carbohydrates), the mean capecitabine Cmax and AUC0-INF were reduced by 60% and 34%, respectively, and the mean fluorouracil Cmax and AUC0-INF were reduced by 37% and 12%, respectively. The time to peak of both capecitabine and fluorouracil was delayed by 1.5 hours. Management: Administer within 30 minutes after a meal.
Verify pregnancy status prior to treatment initiation. Patients who could become pregnant should use effective contraception during treatment and for 6 months after the last dose of capecitabine. Patients with partners who could become pregnant should use effective contraception during treatment and for 3 months after the last capecitabine dose.
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to capecitabine may cause fetal harm.
Outcome data following maternal use of capecitabine during pregnancy are limited (Cardonick 2010; Castellanos 2020; Sharma 2016).
The European Society for Medical Oncology (ESMO) has published guidelines for diagnosis, treatment, and follow-up of cancer during pregnancy. The guidelines recommend referral to a facility with expertise in cancer during pregnancy and encourage a multidisciplinary team (obstetrician, neonatologist, oncology team) approach. In general, if chemotherapy is indicated, it should be avoided in the first trimester and there should be a 3-week time period between the last chemotherapy dose and anticipated delivery (for adequate maternal and fetal bone marrow recovery), and chemotherapy should not be administered beyond week 33 of gestation (ESMO [Peccatori 2013]).
A long-term observational research study is collecting information about the diagnosis and treatment of cancer during pregnancy. For additional information about the pregnancy and cancer registry or to become a participant, contact Cooper Health (1-877-635-4499).
It is not known if capecitabine is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during treatment and for 1 week after the last capecitabine dose. Other guidance suggests waiting at least 24 hours after the last dose of capecitabine and feeding with breast milk; however, actual recommendations should be individualized. Patients may maintain milk supply by expressing during treatment; however, milk supply is expected to be decreased by systemic chemotherapy (ABM [Johnson 2020]).
CBC with differential (at baseline and prior to each cycle), hepatic function (as clinically indicated; more frequently if hepatotoxicity occurs), and kidney function (at baseline and as clinically indicated). Monitor INR closely/more frequently if receiving a concomitant vitamin K antagonist. Evaluate pregnancy status prior to treatment initiation (in patients who could become pregnant). Monitor hydration status at baseline and as clinically indicated. Monitor for signs/symptoms of diarrhea, dehydration, hand-foot syndrome, new or worsening serious skin reactions (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis), stomatitis, hepatotoxicity, nephrotoxicity, and cardiotoxicity. Promptly evaluate any symptoms suggestive of cardiotoxicity. Consider monitoring ECG in patients on concomitant QT-prolonging medications. Monitor adherence.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Consider testing for genetic variants of the dihydropyrimidine dehydrogenase gene (DPYD) prior to capecitabine initiation.
Cardiovascular monitoring: Comprehensive assessment prior to treatment including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking (ASCO [Armenian 2017]). Obtain baseline blood pressure, electrocardiogram, lipid profile, hemoglobin A1c, and assess cardiovascular risk score; obtain a baseline echocardiography (transthoracic preferred) in patients with a history of symptomatic cardiovascular disease (ESC [Lyon 2022]).
Capecitabine is a prodrug of fluorouracil. It undergoes hydrolysis in the liver and tissues to form fluorouracil which is the active moiety. Fluorouracil is a fluorinated pyrimidine antimetabolite that inhibits thymidylate synthetase, blocking the methylation of deoxyuridylic acid to thymidylic acid, interfering with DNA, and to a lesser degree, RNA synthesis. Fluorouracil appears to be phase specific for the G1 and S phases of the cell cycle.
Absorption: Rapid and extensive (rate and extent reduced by food).
Protein binding: <60%; ~35% to albumin.
Metabolism:
Hepatic: Inactive metabolites: 5′-deoxy-5-fluorocytidine, 5′-deoxy-5-fluorouridine.
Tissue: Enzymatically metabolized to fluorouracil, which is then metabolized to active metabolites, 5-fluoroxyuridine monophosphate (F-UMP) and 5-5-fluoro-2’-deoxyuridine-5’-O-monophosphate (F-dUMP).
Half-life elimination: ~0.75 hour.
Time to peak: Capecitabine: 1.5 hours; Fluorouracil: 2 hours.
Excretion: Urine (96%, 57% as α-fluoro-β-alanine; <3% as unchanged drug); feces (<3%).
Altered kidney function: In moderate to severe kidney function impairment, there is increased exposure to inactive metabolites (FBAL and 5’-DFUR) and a 25% increase in exposure to capecitabine.
Hepatic function impairment: In mild to moderate hepatic dysfunction due to liver metastases, capecitabine AUC0-INF and Cmax increased 60%; 5-FU was not affected. The effect of severe hepatic dysfunction is not known.
Older adult: In a study of patients ranging from ages 27 to 86 years, age had no significant influence on the pharmacokinetics of 5’-DFUR, 5-FU; a 20% increase in age resulted in a 15% increase in the AUC of alpha-fluoro-beta-alanine (FBAL).
Race/ethnicity: Following oral administration of 825 mg/m2 capecitabine twice daily for 14 days, Japanese patients (n = 18) had about 36% lower Cmax and 24% lower AUC for capecitabine compared to White patients (n = 22). Japanese patients had also about 25% lower Cmax and 34% lower AUC for alpha-fluoro-beta-alanine than White patients, although the clinical significance of these differences is unknown.
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