CAPECITABINE
Clinical safety rating: avoid
Contraindicated (not allowed)
Capecitabine is a prodrug that is enzymatically converted to 5-fluorouracil (5-FU) in the body, which inhibits thymidylate synthase and incorporates into RNA and DNA, leading to cytotoxic effects.
| Metabolism | Metabolized primarily by hepatic carboxylesterase and cytidine deaminase to 5'-deoxy-5-fluorouridine (5'-DFUR), which is then converted to 5-FU by thymidine phosphorylase. 5-FU is catabolized by dihydropyrimidine dehydrogenase (DPD). |
| Excretion | Capecitabine is predominantly eliminated renally. Approximately 95.5% of the administered dose is recovered in urine, with 61% as unchanged capecitabine and its metabolites. Fecal excretion accounts for about 2.6%. Biliary elimination is minimal (<1%). |
| Half-life | The terminal elimination half-life of capecitabine is approximately 0.75 hours. For its active metabolite 5-fluorouracil, the half-life is about 0.7 hours. Clinically, this short half-life necessitates twice-daily dosing to maintain therapeutic levels. |
| Protein binding | Capecitabine is approximately 54% bound to plasma proteins, primarily albumin. The active metabolite 5-FU is about 10% bound. |
| Volume of Distribution | The apparent volume of distribution (Vd/F) for capecitabine is about 25.0 L/m² (approximately 0.5-1.0 L/kg). This suggests extensive distribution into total body water, including tissues. |
| Bioavailability | Capecitabine has an oral bioavailability of approximately 60% (range 50-70%) under fed conditions. It is administered orally as a prodrug that undergoes enzymatic conversion to 5-FU. |
| Onset of Action | After oral administration, peak plasma concentrations of capecitabine are reached in 1.5 hours. Maximal concentrations of 5-FU occur at about 2 hours. Antitumor activity is typically observed within 2-4 weeks of continuous dosing. |
| Duration of Action | The effect of capecitabine persists as long as therapy continues. With continuous dosing (2 weeks on, 1 week off), steady-state is achieved by day 21. Adverse effects like hand-foot syndrome may persist for several weeks after discontinuation. |
Oral, 1250 mg/m2 twice daily for 2 weeks followed by a 1-week rest period.
| Dosage form | TABLET |
| Renal impairment | For CrCl 30-50 mL/min: reduce dose to 75% of standard; CrCl <30 mL/min: contraindicated. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: insufficient data, use caution; Child-Pugh C: not recommended. |
| Pediatric use | Not established; safety and efficacy not determined. |
| Geriatric use | No specific dose adjustment; monitor renal function and toxicity more frequently in elderly (≥65 years). |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Warfarin interaction can lead to serious bleeding and death Patients with DPD deficiency are at risk for severe toxicity.
| Breastfeeding | No data on capecitabine or its metabolites in human milk. Due to potential for serious adverse reactions (e.g., myelosuppression, gastrointestinal toxicity) in the breastfed infant, breastfeeding is contraindicated during therapy and for at least 2 weeks after the last dose. M/P ratio is unknown. |
| Teratogenic Risk | Capecitabine, a prodrug of 5-fluorouracil, is contraindicated in pregnancy. First trimester: high risk of major congenital malformations, including central nervous system, cardiovascular, and skeletal defects, based on its antimetabolite mechanism and data from 5-FU. Second and third trimesters: risk of fetal growth restriction, preterm birth, and neonatal myelosuppression. It is classified as FDA Category D (positive evidence of human fetal risk). |
■ FDA Black Box Warning
Capecitabine may cause severe or fatal hemorrhagic gastroenteropathy, necrotizing enterocolitis, and enteric fistulas. It can also cause severe or fatal anemia, neutropenia, and thrombocytopenia. Patients with low or absent dihydropyrimidine dehydrogenase (DPD) activity are at increased risk for severe or fatal adverse reactions.
| Common Effects | colorectal cancer |
| Serious Effects |
Known hypersensitivity to capecitabine or 5-FU, known DPD deficiency, severe renal impairment (CrCl <30 mL/min), pregnancy.
| Precautions | Cardiotoxicity (including myocardial infarction, angina, arrhythmias), severe diarrhea (monitor and manage), hand-foot syndrome (palmar-plantar erythrodysesthesia), hyperbilirubinemia, renal impairment (dose adjustment required), coagulation disorders (e.g., warfarin interaction), DPD deficiency (contraindicated in known deficiency). |
| Food/Dietary |
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| Fetal Monitoring | Monitor complete blood counts (CBC) weekly during therapy due to risk of myelosuppression. Assess liver function tests (LFTs) and renal function (creatinine) at baseline and periodically. Fetal monitoring includes serial ultrasound for growth restriction and anatomy survey if exposure occurs in first trimester. For neonatal monitoring, assess CBC and bilirubin after delivery if exposure near term. |
| Fertility Effects | Capecitabine may impair fertility in both males and females. In females, it can cause ovarian suppression, amenorrhea, and premature ovarian failure, which may be irreversible. In males, it may cause oligospermia, azoospermia, and testicular atrophy. Fertility preservation counseling should be considered prior to therapy. |
| Take with food (within 30 minutes after a meal) to reduce GI side effects. Avoid grapefruit juice (may alter absorption). Alcohol may worsen GI effects. Maintain consistent diet to minimize variability in absorption. |
| Clinical Pearls | Capecitabine is an oral prodrug of 5-FU, requiring intracellular activation. Hand-foot syndrome (palmar-plantar erythrodysesthesia) is common; manage with dose interruption and pyridoxine. Avoid concurrent use with warfarin – INR monitoring is essential. Renal impairment reduces clearance; dose adjustment needed for CrCl 30-50 mL/min (25-50% reduction). Contraindicated if CrCl <30 mL/min. |
| Patient Advice | Take capecitabine within 30 minutes after a meal with water, at the same times daily. · Do not crush or break tablets; if missed dose, skip it and resume next scheduled dose. · Report severe diarrhea (≥4 loose stools/day), vomiting, or hand-foot syndrome (redness, swelling, pain on palms/soles). · Use effective contraception during treatment and for 6 months after stopping. · Avoid grapefruit juice and alcohol; maintain adequate hydration. |