Brand name: Xeloda
Drug class: Antineoplastic Agents
VA class: AN300
Chemical name: Pentyl ester [1-(5-deoxy-β-d-ribofuranosyl)-5-fluoro-1,2-dihydro-2-oxo-4-pyrimidinyl]-carbamic acid
Molecular formula: C₁₅ H₂₂FN₃O₆
CAS number: 154361-50-9

Medically reviewed by Drugs.com on Oct 24, 2022. Written by ASHP.

Introduction

Antineoplastic agent; prodrug of fluorouracil (an antimetabolite).

Uses for Capecitabine

Breast Cancer

Treatment of metastatic breast cancer in combination with docetaxel in patients with disease that failed to respond to, or recurred or relapsed during or following, anthracycline-containing chemotherapy.

Synergistic effect with combination therapy; docetaxel increases the expression of an enzyme found at higher concentrations in many tumor cells that is involved in converting capecitabine to its active moiety, fluorouracil.

Palliative treatment of metastatic breast cancer, as monotherapy, in patients with disease resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or in patients with disease resistant to paclitaxel who are not candidates for further anthracycline therapy (e.g., cumulative doses of 400 mg/m² of doxorubicin or doxorubicin equivalents).

Colorectal Cancer

Used alone as adjuvant therapy following the complete resection of primary tumor in patients with stage III (Dukes’ C) colon cancer when treatment with fluoropyrimidine therapy alone is preferred.

Combined therapy with IV oxaliplatin^{† [off-label]} is a reasonable choice (accepted, treatment option) as adjuvant therapy following complete resection of primary tumor in patients with stage III colon cancer.

Initial (first-line) treatment of metastatic colorectal cancer when fluoropyrimidine therapy alone is preferred.

Gastric Cancer

Has been used in combination regimens for advanced gastric cancer^{† [off-label]}.

Related/similar drugs

Kisqali, Ibrance, Opdivo, Keytruda, Arimidex, pembrolizumab, fluorouracil

Capecitabine Dosage and Administration

General

Pretreatment Screening

• Do not initiate capecitabine therapy if baseline neutrophil count <1500/mm³ and/or baseline platelet count <100,000/mm³.

Patient Monitoring

• Patients receiving capecitabine should be monitored to prevent and 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.

• Because the incidence of adverse cardiovascular effects associated with fluorinated pyrimidines (e.g., myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, ECG changes) may be increased in patients with a history of coronary artery disease, such patients should be monitored carefully during capecitabine therapy (e.g., ECG for patients experiencing chest pain).

• 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.

• If capecitabine is used in patients receiving phenytoin, serum phenytoin concentrations must be monitored carefully; reduction in the phenytoin dosage may be necessary.

• Liver function should be monitored carefully during capecitabine therapy in patients with mild to moderate hepatic impairment secondary to liver metastases.

Premedication and Prophylaxis

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

Dispensing and Administration Precautions

Handling and Disposal

• Procedures for proper handling and disposal of antineoplastic drugs should be followed when preparing or administering capecitabine.

• Capecitabine should be used under the supervision of a qualified clinician experienced in therapy with cytotoxic agents.

Administration

Oral Administration

Administer orally with water twice daily within 30 minutes after the end of a meal, in the morning and evening.

Tablets should be swallowed whole. Tablets should be cut or crushed only by a qualified clinician trained in safe handling of cytotoxic drugs.

Follow procedures for proper handling and disposal of antineoplastic drugs when preparing or administering capecitabine.

Dosage

Adults

Breast Cancer

Combination Therapy

Oral

Initially, 1250 mg/m² twice daily (2500 mg/m² total daily dose) for 2 weeks followed by a 1-week rest period; courses of therapy are given in 3-week cycles. (See Table 1.) Used in combination with docetaxel.

Treatment was continued for at least 6 weeks in a clinical trial.

Consult published protocols for dosages in combination regimens and methods and sequence of administration.

After the initial dose, modify subsequent doses as necessary based on individual patient tolerance with careful monitoring to obtain optimal therapeutic response with minimal toxicity. (See Table 2 and Table 3.)

Monotherapy

Oral

Initially, 1250 mg/m² twice daily (2500 mg/m² total daily dose) for 2 weeks followed by a 1-week rest period; courses of therapy are given in 3-week cycles. (See Table 1.)

Some experts suggest that a trial of 2 cycles (i.e., 6 weeks) of therapy is adequate to assess response. During a clinical trial, onset of response typically occurred within 6–12 weeks.

After the initial dose, modify subsequent doses as necessary based on individual patient tolerance with careful monitoring to obtain optimal therapeutic response with minimal toxicity. (See Table 2.)

Colorectal Cancer

Adjuvant Therapy for Colon Cancer

Oral

Initially, 1250 mg/m² twice daily (2500 mg/m² total daily dose) for 2 weeks followed by a 1-week rest period; courses of therapy are given in 3-week cycles for a total of 8 cycles and a treatment period of 6 months. (See Table 1.)

After the initial dose, modify subsequent doses as necessary based on individual patient tolerance with careful monitoring to obtain optimal therapeutic response with minimal toxicity. (See Table 2.)

Dosage of 1 g/m² twice daily on days 1–14 in combination with oxaliplatin^{† [off-label]} 130 mg/m² IV over 2 hours on day 1 of each 3-week cycle, for a total of 4 or 8 cycles, also has been used; 4 cycles (for a treatment duration of 3 months) has been shown to have comparable efficacy and less toxicity than 8 cycles of therapy (for a treatment duration of 6 months).

First-line Therapy for Metastatic Colorectal Cancer

Oral

Initially, 1250 mg/m² twice daily (2500 mg/m² total daily dose) for 2 weeks followed by a 1-week rest period; courses of therapy are given in 3-week cycles. (See Table 1.)

After the initial dose, modify subsequent doses as necessary based on individual patient tolerance with careful monitoring to obtain optimal therapeutic response with minimal toxicity. (See Table 2.)

Other Dosage Considerations

Recommended Initial Dosage

Divide into 2 equal doses given morning and evening.

Dosage Modification for Toxicity

Adjust capecitabine doses according to the severity and number of appearances of the toxicity. (See Table 2.)

When therapy is interrupted because of toxicity, resume according to planned treatment cycles; capecitabine doses omitted because of toxicity should not be replaced. Once a dosage has been reduced for toxicity, it should not be increased at a later time.

If a patient experiences either no toxicity or NCIC grade 1 toxicity within a course of treatment, maintain the current capecitabine dose for subsequent courses of therapy until more serious toxicity occurs.

When used concomitantly with docetaxel, modification of docetaxel dosage also may be required. (See Table 3.) If either capecitabine or docetaxel toxicity delays initiation of a treatment cycle, delay administration of both drugs until criteria for reinitiating therapy with both drugs are met.

All dose modifications should be based on the worst preceding toxicity.

NCIC Common Toxicity Criteria except for hand-foot syndrome, which is defined according to a grading system incorporated by Roche and accepted by FDA.

Prophylaxis for toxicity should be instituted whenever possible; all dosage modifications should be based on the worst preceding toxicity.

NCIC Common Toxicity Criteria except for hand-foot syndrome, which is defined according to a grading system incorporated by Roche and accepted by FDA.

Special Populations

Hepatic Impairment

No initial dosage adjustment necessary in patients with mild to moderate hepatic dysfunction secondary to liver metastases. Use with caution; monitor patients carefully during therapy.

Renal Impairment

Contraindicated in patients with severe renal impairment (Cl_cr <30 mL/minute).

In patients with moderate renal impairment (Cl_cr 30–50 mL/minute), reduce dosage (as monotherapy or in combination with docetaxel) by 25% of the initial dose (i.e., from 1250 to 950 mg/m² twice daily).

No adjustment in starting dose recommended in patients with mild renal impairment.

Monitor carefully in patients with mild or moderate renal impairment because the frequency and/or severity of adverse effects may be increased. Discontinue treatment promptly if the patient develops a grade 2, 3, or 4 adverse effect; modify dosage for toxicity. (See Table 2.)

Geriatric Patients

Manufacturer states that insufficient data are available to recommend dosage adjustment for age in geriatric patients; however, the greater frequency of decreased hepatic and/or renal function in the elderly should be considered.

Patients >80 years of age receiving monotherapy: Some experts recommend dosage reduction (e.g., reduce initial dosage by up to 20%). (See Geriatric Use under Cautions.)

Patients >60 years of age receiving capecitabine/docetaxel combination: Some experts recommend dosage reduction (reduce initial dose by 25% [to 950 mg/m²]). (See Geriatric Use under Cautions.)

Cautions for Capecitabine

Contraindications

• Severe renal impairment (Cl_cr <30 mL/minute).

• Known hypersensitivity to fluorouracil.

• Known hypersensitivity to capecitabine or any ingredient in the formulation.

Warnings/Precautions

Warnings

Coagulopathy

Altered coagulation parameters and/or bleeding, sometimes fatal, reported in patients receiving capecitabine concomitantly with coumarin anticoagulants (e.g., warfarin, phenprocoumon [no longer commercially available in the US]). Generally occurs within several days to months following initiation of therapy; similar events reported in at least a few patients within 1 month following discontinuance of therapy.

Alterations in anticoagulant effect associated with capecitabine therapy reported in patients with or without liver metastases. Age >60 years and diagnosis of cancer are independent variables predisposing patients to an increased risk of coagulopathy.

Monitor anticoagulant response (PT or INR) frequently, and adjust the anticoagulant dose accordingly in patients receiving concomitant therapy. (See Specific Drugs under Interactions.)

Other Warnings and Precautions

GI Effects

Possible diarrhea, sometimes severe or life-threatening.

If grade 2, 3, or 4 diarrhea occurs, immediately discontinue administration until the diarrhea resolves or decreases in intensity to grade 1. Decrease subsequent doses in patients who have experienced grade 3 or 4 diarrhea or recurring episodes of grade 2 diarrhea. (See Table 2.)

Median time to onset of grade 2 to 4 diarrhea was 34 days (range: 1–369 days) following initiation of therapy; median duration of grade 3 to 4 diarrhea was 5 days.

Manufacturer recommends treatment with standard antidiarrheal therapy (e.g., loperamide). Monitor patients with severe diarrhea closely and give fluid and electrolyte replacement for dehydration as indicated.

Severe adverse GI effects may occur more frequently in geriatric patients. (See Geriatric Use under Cautions.)

Necrotizing enterocolitis (typhlitis) reported.

Cardiotoxicity

Risk of MI/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, ECG changes, and cardiomyopathy. Increased incidence in patients with a history of CAD.

Pharmacogenomics: Dihydropyrimidine Dehydrogenase (DPD) Activity Deficiency

Acute early-onset or unusually severe capecitabine toxicity may indicate near complete or total absence of DPD activity; withhold or permanently discontinue capecitabine in such patients.

Certain homozygous or compound heterozygous mutations in the DPD gene result in complete or near complete absence of DPD activity. Patients with such mutations are at increased risk for acute early-onset and severe, life-threatening, or fatal capecitabine toxicity (e.g., mucositis, diarrhea, neutropenia, neurotoxicity). Patients with partial DPD activity also may have increased risk of severe, life-threatening, or fatal toxicity.

No dosage of capecitabine has been proven safe for patients with complete absence of DPD activity; data insufficient to support dosage recommendations for those with partial DPD activity.

Dehydration and Renal Failure

Dehydration can develop rapidly in patients with anorexia, asthenia, nausea, vomiting, or diarrhea.

Risk of acute renal failure secondary to dehydration, which can be fatal; patients with preexisting renal impairment and those receiving concomitant therapy with nephrotoxic agents are at increased risk.

Monitor patients receiving capecitabine to prevent and promptly correct dehydration (i.e., at its onset).

If grade 2 or greater dehydration occurs, immediately interrupt capecitabine therapy. Do not restart treatment until patient is rehydrated and any precipitating causes have been corrected or controlled; make any necessary dosage modifications for the precipitating adverse event. (See Table 2.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on mechanism of action and animal findings; embryotoxicity and teratogenicity demonstrated in animals.

Confirmation of pregnancy status recommended prior to initiating therapy. Avoid pregnancy during therapy. Women of reproductive potential should use effective contraceptive methods while receiving capecitabine and for 6 months after the drug is discontinued. Men who are partners of such women should use effective contraceptive methods while receiving the drug and for 3 months after the drug is discontinued. Apprise patients of potential fetal hazard if the drug is used during pregnancy.

Severe Mucocutaneous Reactions

Severe, sometimes fatal, mucocutaneous reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) reported. If such reactions occur and are potentially related to capecitabine, permanently discontinue therapy.

Hand-foot Syndrome

Palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema (hand-foot syndrome) occurs in 54–63% of patients and is severe (grade 3) in 11–24% of patients. Median time to onset is 79 days (range: 11–360 days).

Persistent or severe hand-foot syndrome (grade 2 or greater) may result in loss of fingerprints and affect fingerprint identification.

If grade 2 or 3 hand-foot syndrome occurs, withhold administration of capecitabine until manifestations resolve or decrease in intensity to grade 1. Decrease subsequent doses in patients experiencing grade 3 hand-foot syndrome or recurring episodes of grade 2 hand-foot syndrome. (See Table 2.)

Topical emollients (e.g., hand creams, udder balm) or oral pyridoxine therapy may ameliorate the manifestations of hand-foot syndrome.

Hyperbilirubinemia

Risk of severe, possibly life-threatening hyperbilirubinemia, occurring alone or in combination with docetaxel.

If grade 2, 3, or 4 elevations in serum bilirubin concentration occur, discontinue administration of capecitabine until the hyperbilirubinemia resolves or decreases in intensity to grade 1.

Severe or life-threatening hyperbilirubinemia associated with capecitabine therapy occurs more frequently in patients with hepatic metastases. Monitor liver function carefully during therapy in patients with mild to moderate hepatic impairment secondary to liver metastases.

Hematologic Effects

Possible lymphopenia, neutropenia, thrombocytopenia, or anemia.

Impairment of Fertility

Results of animal studies suggest that capecitabine may impair female and male fertility.

Specific Populations

Pregnancy

May cause fetal harm.

Lactation

Distributed into milk in mice. Not known whether capecitabine is distributed into milk in humans or affects milk production or nursing infants.

Women should not breast-feed during therapy and for 2 weeks following the last dose.

Pediatric Use

Safety and efficacy not established in children <18 years of age.

Geriatric Use

Safety and efficacy in geriatric patients not specifically studied to date; however, geriatric individuals may experience increased frequency and severity of toxicity (e.g., grade 3 or 4 diarrhea, nausea, or vomiting; severe hand-foot syndrome). (See GI Effects and also see Hand-foot Syndrome under Cautions.)

Possible increased risk of coagulopathy in patients >60 years receiving concomitant anticoagulant therapy. (See Coagulopathy under Cautions.)

Monitor geriatric patients closely for the number of appearances of capecitabine-induced adverse effects.

Hepatic Impairment

Monitor carefully in patients with mild to moderate hepatic impairment due to liver metastases. Safety and efficacy not studied in patients with severe hepatic impairment.

Renal Impairment

Contraindicated in patients with severe renal impairment (Cl_cr <30 mL/minute).

Frequency and/or severity of adverse effects may be increased in patients with mild or moderate renal impairment. Monitor carefully. Discontinue treatment promptly if the patient develops a grade 2, 3, or 4 adverse effect; modify dosage for toxicity. (See Table 2.)

Common Adverse Effects

Abdominal pain, diarrhea, nausea, vomiting, stomatitis, constipation, fatigue/weakness, anemia, lymphopenia, dermatitis, hand-foot syndrome.

Potential inhibition of CYP2C9.

Does not inhibit CYP isoenzymes 1A2, 2A6, 3A4, 2C9, 2C19, 2D6, or 2E1 in vitro.

Drugs Metabolized by Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (decreased warfarin metabolism) probably through inhibition of CYP2C9. (See Specific Drugs under Interactions.)

No formal drug interaction studies between capecitabine and CYP2C9 substrates other than warfarin have been performed.

Specific Drugs

Capecitabine Pharmacokinetics

Absorption

Bioavailability

Readily absorbed from the GI tract; about 70% is absorbed.

Peak plasma concentrations of capecitabine occur in about 1.5 hours, and peak plasma concentrations of fluorouracil occur slightly later at 2 hours.

Onset

For treatment of breast cancer, onset of response to monotherapy typically occurred within 6–12 weeks.

Food

Food decreases the rate and extent of absorption and, to a lesser extent, decreases the peak plasma concentration and AUC of its metabolites.

Special Populations

Reduced peak plasma concentration and AUC of capecitabine and its catabolite, α-fluoro-β-alanine (FBAL) reported in Japanese patients compared with white patients. Clinical importance of these differences is not known.

Among patients 27–86 years of age, a 20% increase in age is associated with a 15% increase in the AUC of FBAL.

Distribution

Extent

Distributed into tumors, intestinal mucosa, plasma, liver, and other tissues. Not known whether distributed into CSF and brain tissue in humans; does not readily penetrate the blood-brain barrier in animal studies.

Studies have shown a higher concentration of fluorouracil, its active moiety, in tumor than in surrounding normal tissue, plasma, or muscle.

Not known whether capecitabine or its metabolites cross the placenta or are distributed into milk.

Plasma Protein Binding

<60% (mainly albumin); not concentration dependent.

Elimination

Metabolism

Capecitabine is a prodrug of fluorouracil; metabolized to fluorouracil following oral administration.

Extensively metabolized in the liver and tumors to inactive, intermediate metabolites that are hydrolyzed mainly in tumor tissue to the active moiety fluorouracil.

Fluorouracil is anabolized to active metabolites, 5-fluoro-2′-deoxyuridine-5′-monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP).

Fluorouracil is catabolized by dihydropyrimidine dehydrogenase to dihydrofluorouracil (FUH₂), a much less toxic metabolite.

Elimination Route

Excreted principally in urine (95.5%) as metabolites; fecal excretion is minimal (2.6%).

Half-life

About 45–60 minutes for capecitabine and its metabolites, except for FBAL, which has an initial half-life of about 3 hours.

Special Populations

Increased systemic exposure in patients with renal impairment; systemic exposure to capecitabine was about 25% greater in patients with moderate or severe renal impairment than in those with normal renal function.

Dialysis may reduce circulating concentrations of 5′-DFUR, a low molecular weight metabolite of the drug.

Stability

Storage

Oral

Tablets

Tight containers at 25°C (may be exposed to 15–30°C.)

Actions

• Prodrug; has little pharmacologic activity until it is converted to fluorouracil, an antimetabolite.

• Converted to fluorouracil by enzymes that are expressed at higher concentrations in many tumors than in adjacent normal tissues or plasma; high tumor concentrations of the active drug may be achieved with less systemic toxicity.

• Fluorouracil is metabolized in both normal and tumor cells to 5-fluoro-2′-deoxyuridine 5′-monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). The main mechanism of action may be the binding of the deoxyribonucleotide of the drug (FdUMP) and the folate cofactor (N^5–10-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. 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.

• Active in xenograft tumors that are resistant to fluorouracil indicating incomplete cross-resistance between the drugs.

Advice to Patients

• Importance of reading the manufacturer's patient information.

• Importance of informing clinician of any known deficiency in DPD activity.

• Importance of discontinuing the drug and contacting clinician if stool output increases by 4–6 stools or more daily or if nocturnal stools or severe bloody diarrhea with severe abdominal pain and fever occurs.

• Importance of discontinuing the drug and contacting clinician if grade 2 or greater dehydration occurs.

• Importance of discontinuing the drug and contacting clinician if 2–5 or more episodes of vomiting occur in a 24-hour period.

• Importance of discontinuing the drug and contacting clinician if nausea resulting in a substantial decrease in food intake occurs.

• Importance of discontinuing the drug and contacting clinician if pain, redness, swelling, or sores in mouth occur.

• Importance of discontinuing the drug and contacting clinician if pain and swelling or redness of hands or feet that prevents normal activity occur.

• Importance of notifying clinician if fever (≥100.5°F) or other signs of infection occur.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Risk of fetal harm. Necessity of advising women of reproductive potential to use effective contraception during capecitabine therapy and for 6 months after the last dose of the drug. Necessity of advising men who are partners of such women that they should use effective contraception during capecitabine therapy and for 3 months after the last dose of the drug. Importance of women informing clinicians immediately if they are pregnant or become pregnant during therapy. If pregnancy occurs, advise pregnant women of potential risk to the fetus.

• Importance of advising women to avoid breast-feeding while receiving capecitabine and for 2 weeks following the last dose of the drug.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Reload page with references included

Frequently asked questions

• Why do you need to take Xeloda with food?

Medical Disclaimer