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. |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Leucovorin enhances the toxicity and efficacy Can cause severe myelosuppression and mucositis.
| Breastfeeding | Excreted in breast milk; M/P ratio not established. Contraindicated due to potential serious adverse effects in nursing infants (e.g., myelosuppression, gastrointestinal toxicity). |
| 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 |
■ 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 |
Absolute: Hypersensitivity to fluorouracil. Severe infection. Bone marrow depression (e.g., WBC < 3500/mm3, platelets < 100,000/mm3). Dihydropyrimidine dehydrogenase (DPD) deficiency. Pregnancy and lactation.
| 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. |
Loading safety data…
| 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. |