FLUOROURACIL
Clinical safety rating: avoid
Contraindicated (not allowed)
Fluorouracil is a pyrimidine analog that inhibits thymidylate synthase, blocking DNA synthesis. It is metabolized to active nucleotides (FdUMP, FUTP) which incorporate into RNA and inhibit thymidylate synthase, leading to cell cycle arrest and apoptosis.
| Metabolism | Primarily catabolized by dihydropyrimidine dehydrogenase (DPD) in the liver to dihydrofluorouracil, then further to fluoro-beta-alanine and other metabolites. Approximately 80% of the drug is eliminated via the urine as metabolites. |
| Excretion | Renal: 60-80% as intact drug and metabolites (primarily urea, CO2, α-fluoro-β-alanine). Fecal: <10%. Biliary: minor. |
| Half-life | Biphasic: initial α-phase 10-20 min; terminal β-phase 16-20 min (no accumulation). For continuous infusion, functional half-life ~20 min. Clinically, rapid clearance necessitates infusion schedules. |
| Protein binding | 10-15%, primarily to albumin. |
| Volume of Distribution | 0.1-0.2 L/kg (approximates extracellular fluid volume, indicating limited tissue distribution). |
| Bioavailability | Oral: variable (10-50%) due to first-pass metabolism; not used orally. Topical: minimal systemic absorption (<5%). |
| Onset of Action | IV: immediate; topical: 2-3 weeks for visible effect. |
| Duration of Action | IV: short (minutes to hours) due to rapid metabolism; topical: treatment often 2-4 weeks for actinic keratosis, longer for superficial basal cell carcinoma. |
| Molecular Weight | 130.08 |
425 mg/m² IV bolus on days 1-5 every 28 days (Mayo regimen) or 400 mg/m² IV bolus on day 1, then 2400 mg/m² continuous IV infusion over 46 hours (FOLFOX regimen). For topical use, 5% cream applied twice daily for 2-4 weeks.
| Dosage form | CREAM |
| Renal impairment | CrCl 30-50 mL/min: reduce dose by 25%. CrCl <30 mL/min: avoid use (no data). Hemodialysis: administer after dialysis, reduce dose by 50%. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: reduce dose by 50% (limited data). Child-Pugh C: avoid use due to risk of severe toxicity. |
| Pediatric use | 20 mg/kg IV once weekly as bolus (max 1 g) or 10-15 mg/kg IV daily for 5 days every 28 days. Dose based on ideal body weight, not total body weight. Adjust for toxicity. |
| Geriatric use | Age ≥65 years: reduce initial dose by 20-30% due to increased myelosuppression and mucositis risk. Monitor renal function and adjust accordingly. |
| 1st trimester | Avoid. Teratogenic; risk of miscarriage and fetal malformations. |
| 2nd trimester | Avoid. Risk of fetal harm; may cause low birth weight. |
| 3rd trimester | Avoid. Risk of neonatal myelosuppression and other adverse effects. |
Clinical note
Leucovorin enhances the toxicity and efficacy Can cause severe myelosuppression and mucositis.
| Placental transfer | Rapidly crosses placenta; concentrations in fetal plasma similar to maternal. |
| Breastfeeding | Excreted in breast milk; potential for severe toxicity in infant. Contraindicated during breastfeeding. |
| Lactation Rating | L5 - Avoid |
■ FDA Black Box Warning
Boxed Warning: Fluorouracil should be administered under the supervision of a qualified physician experienced in cancer chemotherapy. Severe toxicities including myelosuppression, mucositis, and gastrointestinal toxicity may occur. Patients with dihydropyrimidine dehydrogenase (DPD) deficiency are at increased risk for severe or fatal toxicity. Women of childbearing potential should be advised to avoid pregnancy.
| Common Effects | Myelosuppression |
| Serious Effects |
PregnancyBreastfeedingSevere bone marrow depressionDihydropyrimidine dehydrogenase (DPD) deficiency
| Precautions | Monitor for severe myelosuppression (neutropenia, thrombocytopenia, anemia), mucositis, diarrhea, and hand-foot syndrome. Do not use in patients with DPD deficiency unless dose adjustment. Caution in patients with impaired renal or hepatic function. Avoid live vaccines during treatment. |
| Food/Dietary |
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| Teratogenic Risk | FDA Pregnancy Category D. First trimester: High risk of major malformations (neural tube defects, craniofacial anomalies) and spontaneous abortion. Second and third trimesters: Fetal growth restriction, microcephaly, and neurodevelopmental deficits. Contraindicated in pregnancy. |
| Fetal Monitoring | Maternal: Complete blood count (CBC) with differential, hepatic and renal function tests weekly during therapy; monitor for stomatitis, diarrhea, myelosuppression, and neurotoxicity. Fetal: Ultrasound for growth and anatomy if exposure occurs; consider fetal echocardiography. |
| Fertility Effects | May cause reversible or irreversible ovarian failure in females, leading to reduced fertility; in males, oligospermia or azoospermia with potential for permanent infertility. |
| Avoid folic acid supplements (including multivitamins) due to potential increased toxicity when combined with leucovorin. Limit consumption of foods rich in vitamin K (e.g., spinach, kale, broccoli) if on anticoagulants; maintain consistent intake. St. John's wort may reduce efficacy; avoid concomitant use. Grapefruit juice may increase toxicity via CYP450 inhibition; avoid excessive intake. Ensure adequate hydration to prevent dehydration from diarrhea. |
| Clinical Pearls | Fluorouracil is an antimetabolite that inhibits thymidylate synthase. It is cell-cycle phase-specific (S-phase). Administer IV push or infusion; extravasation can cause severe tissue necrosis. Monitor for cardiotoxicity (angina, ECG changes) especially in patients with coronary artery disease. Hand-foot syndrome (palmar-plantar erythrodysesthesia) is dose-dependent and managed with dose reduction, pyridoxine, or topical emollients. Dihydropyrimidine dehydrogenase (DPD) deficiency increases toxicity risk; screen for DPD variants before starting therapy. Leucovorin potentiates fluorouracil activity by stabilizing the ternary complex with thymidylate synthase. Adjust dose in renal impairment (CrCl <30 mL/min reduce by 20%). Avoid live vaccines during therapy. |
| Patient Advice | Report any chest pain, shortness of breath, or irregular heartbeat immediately. · Hand-foot syndrome: redness, swelling, pain on palms/soles; keep hands/feet cool, avoid excessive friction. · Diarrhea is common; stay hydrated and notify your doctor if severe or bloody. · Mouth sores: use soft toothbrush, avoid spicy/acidic foods, use salt-water rinses. · Avoid sun exposure; use sunscreen and protective clothing. · Do not receive live vaccines (e.g., MMR, flu mist) during treatment. · Women should avoid pregnancy during therapy and for up to 6 months after. · Take anti-nausea medication as prescribed; avoid large meals before infusion. |