5 FU PhaRes

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
• 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. The active metabolite FdUMP appears to form a stable complex with the folate cofactor N-5, 10-methylene tetrahydrofolate which inactivates thymidylate kinase. Fluorouracil as FdUMP is also incorporated into RNA which results in fluorination of RNA. The effect of fluorouracil on living cells is limited mainly to those in the proliferative phase but while cells in the G2 and S phase are most affected there may be effects at any stage of the cell cycle.

Pre-treatment with cimetidine for 4 weeks led to increased plasma concentrations of fluorouracil following intravenous and oral administration in 6 patients. The effect was probably due to a combination of hepatic enzyme inhibition and reduced hepatic blood flow.

Potentially life-threatening effects: Severe effects from 5-fluorouracil are related to the dosage and duration of therapy.

Cardiac effects: Occasional case reports associating 5-fluorouracil therapy with ‘ischemic cardiac events’ evidence against the autoimmune phenomenon is the fact that in several cases cardiotoxicity occurred within several hours of the first dose.

Hematological effects: Potentially lethal effects caused by severe hematological toxicity may develop within the first 10 days of treatment being instituted but generally resolves within 3 weeks. At the recommended dose and schedule it is rather uncommon for hematological toxicity to be severe. Any ontribute to severe effects from 5-fluorouracil on the blood-forming cells. Thus extensive prior irradiation or the concomitant use of cytotoxic drugs tend to exacerbate the severity of the hematological side effects of 5-fluorouracil.

Neurological effects: Effects on the central nervous system have been occasionally reported and cerebral ataxia is dose-dependent with an incidence of between 3.1 and 7%. Acute cerebellar syndromes and myelopathy have been described following intrathecal 5-fluorouracil. Neurological syndromes may occur rarely after carotid artery perfusion in head and neck cancer. Other effects Allergic reaction (including difficulty in breathing, closing of the throat, swelling of the lips, tongue, or face, or hives), decreased bone marrow function and blood problems (extreme fatigue, easy bruising or bleeding, black, bloody or tarry stools, or fever, chills, or signs of infection), hand-foot syndrome (tingling, pain, redness, swelling or tenderness of the hands and feet), severe vomiting, diarrhoea, frequent bowel movements or watery stools, or sores in the mouth or throat, or stomach pain or heartburn or black, bloody or tarry stools. Other less serious side effects may include mild to moderate nausea, vomiting or loss of appetite, balance problems, confusion, rash and itching, or temporary hair loss. Conjunctivitis, both acute and chronic can proceed to tear duct stenosis and ectropion following prolonged administration. Very chronic administration, extending beyond 3 months, of low dosage has been associated with low systemic toxicity but includes the possibility of painful and tender hands and feet associated with erythema of the extremities.

Fluorouracil is contraindicated throughout pregnancy. The literature pertaining to pregnancy and cytotoxic drugs is necessarily limited but it appears in general that risk of teratogenesis diminishes with the advancement of pregnancy. Therefore most cytotoxic drugs are absolutely contraindicated in the first trimester and 5-fluorouracil, used in the first trimester has been reported to cause multiple congenital abnormalities. There are many case reports, however, of pregnancy being conducted successfully with combination chemotherapy being given to the mother during the second and third trimesters. Because of the age of the population and the natural history of the tumors treated, most of the data on long-term follow-up pertain to therapy for leukemias. More data need to be accrued on the subsequent development of neonates before it is certain that any of these compounds are free of late effects.

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.

5-fluorouracil is highly toxic drug with a narrow margin of safety. Therefore patients should be carefully supervised, since therapeutic response is unlikely to occur without some evidence of toxicity. Daily dose should not exceed 1 gram. Treatment should be discontinued promptly when one of the following signs of toxicity appears: Leucopenia (WBC under 3500/mm3). Thrombocytopenia (platelet under 100000/mm3). Stomatitis ( the first small ulceration at the inner margin of the lips is a signal for stopping treatment). Severe diarrhoea (frequent bowel movements and watery stools). Gastro-intestinal ulceration and bleeding.

Neonates: No dosage recommendations are made for neonates.

Children: Safety and effectiveness in children have not been established.

The elderly: No special precautions are required, doses being adjusted for the patient’s weight and height.

Cases of deliberate overdose are unknown but excessive toxicity because of the hematological effects as described above. There is no specific antidote to 5-fluorouracil toxicity; treatment consists in supportive care. In addition to the hematological toxicity other toxicities will occur with overdose. Sign and symptoms are qualitatively similar to the side effects. Treatment should be performed promptly and appropriate drugs are given to control symptoms of overdose.

Store the vial in original carton not exceeding 25℃. Do not refrigerate. Protect from light.