Introduction
Xeloda (capecitabine) is an oral chemotherapeutic agent belonging to the class of fluoropyrimidine carbamates. It is a prodrug that undergoes enzymatic conversion to fluorouracil (5-FU) within the body, providing a targeted approach to cancer treatment with the convenience of oral administration. Xeloda is widely used in the management of various gastrointestinal and breast malignancies.
Mechanism of Action
Capecitabine is sequentially converted to 5-FU through a three-step enzymatic process: 1. Hepatic carboxylesterase converts capecitabine to 5'-deoxy-5-fluorocytidine (5'-DFCR) 2. Cytidine deaminase converts 5'-DFCR to 5'-deoxy-5-fluorouridine (5'-DFUR) 3. Thymidine phosphorylase (dThdPase) converts 5'-DFUR to the active drug 5-fluorouracil
The final conversion occurs preferentially in tumor tissues due to higher concentrations of thymidine phosphorylase, providing selective tumor targeting. 5-FU then exerts its cytotoxic effects through multiple mechanisms:
- Inhibition of thymidylate synthase, disrupting DNA synthesis
- Incorporation of fraudulent nucleotides into RNA, impairing RNA processing and function
- Incorporation into DNA, causing DNA damage and strand breaks
Indications
Xeloda is FDA-approved for:
- Adjuvant treatment of Dukes' C colon cancer after complete resection of primary tumor
- First-line treatment of metastatic colorectal cancer
- Metastatic breast cancer resistant to both paclitaxel and anthracycline-containing chemotherapy regimens, or resistant to paclitaxel in patients where further anthracycline therapy is not indicated
- First-line treatment of metastatic gastric cancer (in combination with platinum-based chemotherapy)
- Advanced or metastatic pancreatic cancer (in combination with other agents)
Dosage and Administration
Standard dosing:- 1250 mg/m² orally twice daily (total daily dose 2500 mg/m²) for 14 days followed by 7 days rest, repeated every 21 days
- Renal impairment: CrCl 30-50 mL/min - reduce dose by 25%
- CrCl <30 mL/min - contraindicated
- Hepatic impairment: Mild to moderate impairment (Child-Pugh A and B) - caution advised
- Severe impairment (Child-Pugh C) - not recommended
- Take with water within 30 minutes after a meal
- Tablets should not be crushed, cut, or chewed
- Doses should be approximately 12 hours apart
- Missed doses should not be replaced; continue with next scheduled dose
Pharmacokinetics
Absorption: Rapidly and extensively absorbed from the GI tract; bioavailability is approximately 70-80% Distribution: Protein binding is low (<60%); widely distributed throughout body tissues Metabolism: Extensive hepatic metabolism via carboxylesterase and cytidine deaminase; final conversion to 5-FU occurs in tumor and liver tissues Elimination: Primarily renal excretion (95% of dose); elimination half-life approximately 0.5-1.0 hours Special populations: Elderly patients may have increased exposure; renal impairment significantly affects clearanceContraindications
- Known hypersensitivity to capecitabine, fluorouracil, or any component of the formulation
- Severe renal impairment (CrCl <30 mL/min)
- Known dihydropyrimidine dehydrogenase (DPD) deficiency
- Pregnancy
- Concurrent administration with sorivudine or brivudine
Warnings and Precautions
Black Box Warnings:- Coagulation parameters and/or bleeding should be monitored in patients receiving concomitant Xeloda and oral coumarin-derivative anticoagulants
- Diarrhea: May be severe; interrupt therapy for severe diarrhea and resume at reduced dose
- Cardiotoxicity: Myocardial infarction/ischemia, angina, arrhythmias, and cardiac arrest have occurred
- DPD deficiency: May lead to severe, life-threatening toxicity
- Hand-foot syndrome (palmar-plantar erythrodysesthesia): May require dose modification or discontinuation
- Hyperbilirubinemia: Monitor liver function tests
- Hematologic toxicity: Neutropenia, thrombocytopenia, and anemia may occur
- Embryo-fetal toxicity: Can cause fetal harm; advise women of reproductive potential to use effective contraception
Drug Interactions
Major interactions:- Warfarin: Increased anticoagulant effect; monitor INR closely
- Phenytoin: Increased phenytoin levels; monitor levels and adjust dose
- Leucovorin: Enhanced toxicity of fluorouracil
- Allopurinol: May decrease efficacy of capecitabine
- Sorivudine/brivudine: Contraindicated due to risk of severe and fatal toxicity
- Antacids: May increase capecitabine concentrations
- Drugs affecting CYP2C9: Potential interactions
- Nephrotoxic drugs: May exacerbate renal impairment and affect capecitabine clearance
Adverse Effects
Very common (≥10%):- Diarrhea (50%)
- Hand-foot syndrome (53%)
- Nausea (43%)
- Vomiting (26%)
- Fatigue (42%)
- Anorexia (26%)
- Stomatitis (25%)
- Hyperbilirubinemia (48%)
- Dermatitis
- Constipation
- Pyrexia
- Edema
- Headache
- Dizziness
- Insomnia
- Dyspnea
- Abdominal pain
- Severe diarrhea leading to dehydration and renal failure
- Cardiotoxicity (myocardial infarction, ischemia)
- Severe neutropenia and thrombocytopenia
- Severe hand-foot syndrome requiring dose reduction
- DPD deficiency-related toxicity (severe mucositis, diarrhea, neutropenia)
- Hepatotoxicity
Monitoring Parameters
Baseline assessment:- Complete blood count with differential
- Renal function (serum creatinine, CrCl calculation)
- Liver function tests
- DPD deficiency testing (consider in high-risk populations)
- Pregnancy test in women of reproductive potential
- CBC weekly during first two cycles, then prior to each cycle
- Renal function before each cycle
- LFTs before each cycle
- Signs/symptoms of hand-foot syndrome at each visit
- Diarrhea assessment at each visit
- INR monitoring weekly for patients on warfarin
- Cardiac monitoring for patients with cardiac risk factors
- Diarrhea frequency and severity
- Oral mucositis symptoms
- Hand-foot syndrome symptoms
- Nausea/vomiting assessment
Patient Education
Key points for patients:- Take exactly as prescribed with water within 30 minutes after a meal
- Do not crush, chew, or break tablets
- Report any missed doses to your healthcare provider
- Maintain adequate hydration, especially if experiencing diarrhea
- Diarrhea: Report if >4 bowel movements/day or nocturnal diarrhea; maintain hydration
- Hand-foot syndrome: Use moisturizing creams, avoid hot water, wear comfortable shoes
- Nausea/vomiting: Take antiemetics as prescribed; eat small, frequent meals
- Oral care: Use soft toothbrush, avoid alcohol-containing mouthwashes
- Use effective contraception during treatment and for 6 months after
- Inform all healthcare providers about Xeloda therapy
- Avoid sunlight exposure and use sunscreen (photosensitivity risk)
- Monitor for signs of bleeding if taking blood thinners
- Carry identification card indicating chemotherapy treatment
- Severe diarrhea (>4-6 stools/day) or dehydration symptoms
- Fever ≥100.5°F or signs of infection
- Chest pain, shortness of breath, or palpitations
- Unusual bleeding or bruising
- Severe hand-foot syndrome with blistering or peeling
References
1. Xeloda® (capecitabine) prescribing information. Genentech USA, Inc. Revised January 2023. 2. Miwa M, et al. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer. 1998;34(8):1274-1281. 3. Twelves C, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005;352(26):2696-2704. 4. Blum JL, et al. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol. 1999;17(2):485-493. 5. Cassidy J, et al. Randomized trial of capecitabine plus oxaliplatin versus fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008;26(12):2006-2012. 6. NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. Version 2.2023. 7. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 4.2023. 8. FDA Drug Safety Communication: Capecitabine and fluorouracil may mimic heart attack symptoms. August 2013.