Fluorouracil

Fluorouracil is indicated alone or in combination for carcinoma of the colon or rectum, carcinoma of the stomach and exocrine pancreas, carcinoma of the liver, carcinoma of the breast, carcinoma of the bladder, carcinoma of the lung, epithelial ovarian carcinoma, and cervical carcinoma.

Fluorouracil is inactive as such in mammalian cells but is converted into the active 5-fluorodeoxyuridine monophosphate (FdUMP) by a variety of different metabolic pathways. The drug works by inhibiting the enzyme thymidylate kinase which results in reduced formation of thymidine and thus of DNA.

• Carcinoma of the colon or rectum
• Carcinoma of the stomach and exocrine pancreas
• Carcinoma of the liver
• Carcinoma of the breast
• Carcinoma of the bladder
• Carcinoma of the lung
• Epithelial ovarian carcinoma
• Cervical carcinoma

Cytotoxic Chemotherapy

Antimetabolite (Pyrimidine Analog)

Fluorouracil is inactive as such in mammalian cells but is converted into the active 5-fluorodeoxyuridine monophosphate (FdUMP) by a variety of different metabolic pathways. The drug works by inhibiting the enzyme thymidylate kinase which results in reduced formation of thymidine and thus of DNA. The active metabolite FdUMP appears to form a stable complex with the folate cofactor N-5, 10-methylene tetrahydrofolate which inactivates thymidylate kinase.

Fluorouracil inhibits thymidylate kinase to prevent DNA synthesis and incorporates into RNA to cause cell death.

Adult Dose (IV):

• Bolus Injection: 12-13.5 mg/kg (500 mg/m2) daily for 5 days, repeated every 4 weeks.
• Slow IV Infusion: Dilute in 500 mL dextrose 5% solution, infuse over 2-3 hr for 5 successive days.
• Palliative Management: Initial: 12 mg/kg IV once daily for 4 days (max 800 mg/day); if no toxicity, 6 mg/kg on days 6,8,10,12.
• Poor risk patients: Initial: 6 mg/kg/day for 3 days (max 400 mg/day).
• Maintenance: 10-15 mg/kg/week (max 1 g/week) or repeat first course every 30 days.

Administered as IV bolus injection or slow IV infusion. Should be administered under the supervision of a physician experienced in cancer chemotherapy.

If you miss a dose of Fluorouracil, please consult your doctor.

Serious Side Effects:

• Cardiac effects (ischemic cardiac events)
• Hematological effects (leukopenia, thrombocytopenia) - potentially fatal
• Neurological effects (cerebral ataxia, myelopathy)
• Stomatitis (signal for stopping treatment)
• Severe diarrhea, gastrointestinal ulceration and bleeding
• Hand-foot syndrome

Other Side Effects: Nausea, vomiting, loss of appetite, balance problems, confusion, rash, itching, temporary hair loss, conjunctivitis.

Precautions:

• 5-fluorouracil is a highly toxic drug with a narrow margin of safety; therapeutic response is unlikely without some evidence of toxicity.
• Daily dose should not exceed 1 gram.
• Discontinue treatment promptly if leukopenia (WBC <3500/mm3), thrombocytopenia (platelet <100000/mm3), stomatitis, severe diarrhea, gastrointestinal ulceration and bleeding appear.
• Special, trained personnel should reconstitute the drug.
• Pregnant women must avoid handling cytotoxic agents.

Contraindications:

• Severely debilitated patients
• Bone marrow suppression due to radiotherapy or chemotherapy
• Pregnant or breastfeeding women
• Patients with non-malignant illnesses

Drug Interactions:

• Cimetidine: Pre-treatment increases plasma concentrations of fluorouracil (due to hepatic enzyme inhibition and reduced hepatic blood flow).

Food Interactions: It is not known whether it is safe to consume alcohol with Fluorouracil; consult your doctor.

Use in Pregnancy: Category D; contraindicated throughout pregnancy; first trimester use has been reported to cause multiple congenital abnormalities.

Use in Lactation: It is not known whether fluorouracil is excreted in human milk; because fluorouracil inhibits DNA, RNA and protein synthesis, mothers should not nurse while receiving this drug.

Pediatric Use: Safety and effectiveness in children have not been established; has been used following adult guidelines.

Geriatric Use: Doses being adjusted for the patient's weight and height; no special precautions required.

Renal Impairment: Limited information available; use with caution.

Hepatic Impairment: Use with caution in patients with liver disease.

Overdose: Cases of deliberate overdose are unknown; excessive toxicity because of hematological effects; no specific antidote; supportive care.

Storage: Store in original carton not exceeding 25 degree C. Do not refrigerate. Protect from light.

Fluorouracil