Xeloda
Xeloda (Capecitabine)
Generic Name
Xeloda (Capecitabine)
Mechanism
* Prodrug activation – Xeloda is metabolized intracellularly to 5‑FU in a catalytic, dose‑dependent manner.
* Enzymatic steps –
1. Carboxylesterase → 3′-deoxy‑5′‑deoxy‑l‑xylofuranosyl‑5‑FU (DXP).
2. Thymidine phosphorylase (TP) (highly expressed in tumor tissues) → 5‑deoxy‑L‑thymidylate (5‑DMT).
3. Dihydropyrimidine dehydrogenase (DPD) → 5‑FU.
* Molecular target – The resulting 5‑FU inhibits thymidylate synthase, impairing DNA synthesis and inducing apoptosis in rapidly dividing tumor cells.
* Tumor‑selective activation – TP‑driven conversion preferentially occurs in malignant tissues, reducing systemic toxicity relative to IV 5‑FU.
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Pharmacokinetics
| Parameter | Typical value / notes |
| Absorption | Rapid oral absorption; peak plasma concentration (tmax) ≈ 0.5–1 h after a single dose. |
| Bioavailability | ~79 % (after first‑pass metabolism). |
| Distribution | Extensive tissue distribution; protein binding ≈ 3 %. |
| Metabolism | Sequential activation (carboxylesterase → TP → DPD). Major metabolite 5‑FU. |
| Elimination | Renally excreted (∼ 70 % urinary), hepatic fraction < 30 %. |
| Half‑life | 1–2 h for capecitabine; 1–12 h for 5‑FU depending on dose. |
| Clearance | Linear with renal function; 25 % dose reduction per CrCl < 60 mL/min; 50 % reduction or discontinuation. |
| Drug interactions | ↓ 5‑FU clearance with CYP2J2/3A inhibitors: carbamazepine, rifampin, phenobarbital. ↑ 5‑FU with potent DPD inhibitors (e.g., fluconazole). |
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Indications
| Condition | Typical regimen | Notes |
| Metastatic colorectal cancer | 10 mg/kg/day oral × 14 days → 7‑day rest (2‑cycle regimen) | Dual regimen with oxaliplatin or irinotecan (CAPOX / CAPIRI). |
| Adjuvant colorectal cancer | Same as metastatic | 12 cycles over 6 months. |
| Salvage therapy for metastatic breast cancer (HER2‑negative) | 10 mg/kg/day bid for 10 days → 14‑day rest | Advantage over IV 5‑FU for work‑place convenience. |
| Locally advanced or metastatic gastric/GEJ carcinoma | 10 mg/kg/day bid for 14 days × 7‑day rest (CAPOX) | Often combined with oxaliplatin. |
| Synchronous tumors | Combination regimens; e.g., CAPOX + bevacizumab. |
*Consideration: Capecitabine is not recommended in patients with MTHFR deficiency (C677T homozygous).*
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Contraindications
| Category | Key Points |
| Contraindications |
• Known hypersensitivity to capecitabine or 5‑FU. • Severe hepatic or renal impairment (CrCl < 30 mL/min). • Pregnancy (high‑dose teratogenicity). |
| Warnings |
• Hand–foot syndrome (HFS). • Cardiac: Dyspnea, chest pain, especially in pre‑existing heart disease. • Severe mucositis and diarrhea leading to dehydration. • Neutropenia & thrombocytopenia. |
| Precautions |
• Patients with MTHFR polymorphisms may have increased toxicity. • Concurrent use of anti‑VEGF agents or radiation enhances HFS risk. • Avoid prescribing with high‑dose alcohol. |
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Dosing
| Patient factor | Standard dose | Renal adjustment | Note |
| Body surface area (BSA) ≥ 1.2 m² | 10 mg/kg/day (≈ 1250 mg/m²) orally, BID (11 a.m. & 4–5 p.m.) | Reduce 25 % per 20 mL/min drop in CrCl; > 60 mL/min → standard dose. | Max daily dose 2 500 mg. |
| BSA < 1.2 m² | 10 mg/kg/day (≈ 850 mg/m²) | Same adjustments. | |
| Renal impairment (CrCl 30–60 mL/min) | 7 500 mg/day (7.5 mg/kg/day) | 25 % dose reduction. | |
| CrCl < 30 mL/min | 5 000 mg/day (5 mg/kg/day) | 50 % dose reduction. | Consider discontinuation if < 20 mL/min. |
*Schedule (typical)*
• Cycle 1–12 (colorectal) or 1–6 (breast) – 14 days on, 7 days off.
• Over‑the‑counter: Take with a full meal; avoid alcohol.
• Palmer/soluble: Swallow whole; do not crush.
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Adverse Effects
Common (≥ 20 % incidence)
* Hand–foot syndrome (HFS)
* Diarrhea, nausea, vomiting
* Oral mucositis
* Myelosuppression (neutropenia, thrombocytopenia)
Serious (≤ 10 %)
* Severe HFS → blistering, ulceration
* Cardiotoxicity (pericarditis, arrhythmia)
* Severe mucositis / dysphagia
* Gastrointestinal perforation
* Severe myelosuppression → infection risk
* Hypersensitivity reactions (anaphylaxis)
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Monitoring
| Parameter | Timing | Rationale |
| CBC with differential | Before each 3‑cycle block and during dose adjustments | Detect neutropenia, thrombocytopenia |
| Renal function (CrCl, BUN/Creatinine) | Prior to initiation and every 2 cycles | Dose adjustment necessity |
| Liver enzymes (ALT, AST, bilirubin) | Baseline, then every 3 cycles | Hepatic toxicity |
| Electrolytes | Every 2 cycles | Diarrhea‑associated electrolyte loss |
| Cardiac evaluation (EKG/echo) | Prior and when symptomatic | Detect arrhythmia, ischemia |
| Patient diary (diarrhea, HFS) | Continuous | Early intervention |
| Drug‑drug interaction screening | Prior to start | Avoid potent DPD inhibitors |
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Clinical Pearls
1. Hand–foot syndrome as a surrogate for adequate drug exposure – Early HFS may predict therapeutic efficacy; consider dose escalation if HFS is mild (grade 1) after cycle 1.
2. MTHFR polymorphisms (C677T) = ↑ toxicity – Genotype testing prior to treatment can identify patients likely to suffer severe myelosuppression or HFS.
3. Renal dosing is paramount – Capecitabine is largely renally cleared; failure to adjust dose in CrCl < 60 mL/min significantly increases cardiotoxic and cumulative toxicity risk.
4. “High‑dose” capecitabine (10 mg/kg/day) is the standard – Many clinicians mistakenly dose by mg/m² and under‑dosing occurs.
5. HFS community – Avoid mechanical pressure (tight shoes, prolonged standing) and use emollients; early topical steroids help prevent progression.
6. Combination safety – When combined with oxaliplatin or irinotecan, monitor for overlapping neurotoxicity.
7. Patient education – Stress the importance of reporting mucositis and gastrointestinal symptoms promptly to avoid severe dehydration or infections.
Key take‑away: Capecitabine’s tumor‑selective activation offers a convenient oral alternative to IV 5‑FU while demanding vigilant renal dosing, HFS surveillance, and patient‐centered toxicity management.