FLURACIL INJECTION 250MG/5ML

Indications

• Colorectal cancer
• Breast cancer
• Gastric cancer
• Superficial basal cell carcinoma
• Actinic keratosis

Dosage

Adults: Refer to BNF for specific dosing guidelines based

Mechanism of action

Fluorouracil exerts its effects primarily through the binding of its active form, deoxyribonucleotide (FdUMP), to thymidylate synthase (TS) in the presence of the folate cofactor N5–10-methylenetetrahydrofolate, forming a covalent complex. This action inhibits the conversion of uracil to thymidylate, ultimately blocking DNA and RNA synthesis, thus inducing cell death. Additionally, fluorouracil can be incorporated into RNA, leading to impaired RNA processing and protein synthesis.

Pharmacodynamics

Fluorouracil acts as an antimetabolite by mimicking the natural pyrimidine bases necessary for DNA synthesis. It specifically inhibits thymidylate synthase, which is crucial for the production of thymidine nucleotides, thereby halting DNA replication during the S phase of the cell cycle. This disruption results in the cessation of cell division and eventual apoptosis of cancer cells, making it effective against rapidly dividing tumors.

Pharmacokinetics

Fluorouracil is administered intravenously and undergoes rapid metabolism in the liver, primarily via dihydropyrimidine dehydrogenase (DPD). Its half-life is approximately 15-20 minutes, with its metabolites excreted mainly through urine. The pharmacokinetic profile can be influenced by the patient's DPD enzyme activity, with those deficient in DPD at risk for severe toxicity. Dose adjustment is necessary for patients with impaired renal function, particularly those with a creatinine clearance of 30-70 mL/min.

Contra-indications

• Bone marrow depression (after treatment with radiotherapy or other antineoplastic agents)
• Complete or near complete absence of dihydropyrimidine dehydrogenase activity (increased risk of severe, life-threatening, or fatal toxicity)
• Serious infections

Adverse effects

• Anaemia
• Alopecia
• Anal inflammation
• Appetite decreased
• Asthenia
• Bone marrow disorders
• Bronchospasm
• Diarrhoea
• Gastrointestinal disorders
• Haemorrhage
• Hand-foot syndrome (long term use)
• Immunosuppression
• Increased risk of infection
• Leucopenia
• Malaise
• Mucositis
• Nausea
• Neutropenia
• Skin reactions
• Stomatitis
• Thrombocytopenia
• Vomiting

Interactions

• Fluorouracil + folates: Severe (increases risk of toxicity)
• Fluorouracil + antiepileptics: Moderate (increases concentration)
• Fluorouracil + fosphenytoin: Moderate (increases concentration)
• Fluorouracil + phenytoin: Moderate (increases concentration)
• Fluorouracil + coumarins: Unknown (increases anticoagulant effect)
• Live vaccines + fluorouracil: Unknown (increases risk of generalized infection)
• Metronidazole + fluorouracil: Unknown (increases risk of toxicity)
• Cimetidine + fluorouracil: Unknown (increases exposure)

Precautions

• Monitor for signs of haemolysis
• Patients over 65 years should be monitored closely
• Test all patients for DPD deficiency before initiating treatment
• Counsel patients on the benefits and risks of their treatment
• Therapeutic drug monitoring may improve clinical outcomes

Pregnancy

Avoid (embryotoxic and teratogenic in animal studies)

Breast-feeding

Discontinue breastfeeding

Storage

Store below 25°C. Protect

Mechanism of action

The precise mechanism of action has not been fully determined, but the main mechanism of fluorouracil is thought to be the binding of the deoxyribonucleotide of the drug (FdUMP) and the folate cofactor, N5–10-methylenetetrahydrofolate, to thymidylate synthase (TS) to form a covalently bound ternary complex. This results in the inhibition of the formation of thymidylate from uracil, which leads to the inhibition of DNA and RNA synthesis and cell death. Fluorouracil can also be incorporated into RNA in place of uridine triphosphate (UTP), producing a fraudulent RNA and interfering with RNA processing and protein synthesis. 5-FU requires enzymatic conversion to the nucleotide (ribosylation and phosphorylation) in order to exert its cytotoxic activity. Several routes are available for the formation of the 5'-monophosphate nucleotide (F-UMP) in animal cells. 5-FU may be converted to fluorouridine by uridine phosphorylase and then to F-UMP by uridine kinase, or it may react directly with 5-phosphoribosyl-1-pyrophosphate (PRPP), in a reaction catalyzed by ... orotate phosphoribosyl transferase, to form F-UMP. Many metabolic pathways are available to F-UMP, including incorporation in to RNA. A reaction sequence crucial for antineoplastic activity involves reduction of the diphosphate nucleotide by the enzyme ribonucleoside diphosphate reductase to the deoxynucleotide level and the eventual formation of 5-fluoro-2'-deoxyuridine-5'-phosphate (F-dUMP). 5-FU also may be converted directly to the deoxyriboside 5-FUdR by the enzyme thymidine phosphorylase and further to F-dUMP, a potent inhibitor of thymidylate synthesis, by thymidine kinase ... The interaction between F-dUMP and the enzyme thymidylate synthase leads to depletion of TTP, a necessary constituent of DNA ... The folate cofactor, 5,10-methylenetetrahydrofolate, and F-dUMP form a covalently bound ternary complex with the enzyme. The inhibitory complex resembles the transition state formed during the normal enzymatic reaction when dUMP is converted to thymidylate. Although the physiological complex progresses to the synthesis of thymidylate by transfer of the methylene group and 2 hydrogen atoms from folate to dUMP, this reaction is blocked in the inhibitory complex by the stability of the fluorine carbon bond on F-dUMP; sustained inhibition of the enzyme results ... Although the precise mechanisms of action of fluorouracil have not been fully elucidated, the main mechanism is thought to be the binding of the deoxyribonucleotide of the drug (FdUMP) and the folate cofactor, N5-10-methylenetetrahydrofolate, to thymidylate synthase (TS) to form a covalently bound ternary complex, which inhibits the formation of thymidylate from uracil, thereby interfering with DNA synthesis. In addition, FUTP can be incorporated into RNA in place of uridine triphosphate (UTP), producing a fraudulent RNA and interfering with RNA processing and protein synthesis. Fluorouracil is an antimetabolite of the pyrimidine analog type. Fluorouracil is considered to be cell cycle-specific for the S phase of cell division. Activity results from its conversion to an active metabolite in the tissues, and includes inhibition of DNA and RNA synthesis. There is evidence that the metabolism of fluorouracil in the anabolic pathway blocks the methylation reaction of deoxyuridylic acid to thymidylic acid. In this manner fluorouracil interferes with the synthesis of deoxyribonucleic acid (DNA) and to a lesser extent inhibits the formation of ribonucleic acid (RNA). Since DNA and RNA are essential for cell division and growth, the effect of fluorouracil may be to create a thymine deficiency which provokes unbalanced growth and death of the cell. The effects of DNA and RNA deprivation are most marked on those cells which grow more rapidly and take up fluorouracil at a more rapid rate. The catabolic metabolism of fluorouracil results in degradation products (eg, CO2 , urea, (alpha)-fluoro-(beta)-alanine) which are inactive.

Pharmacodynamics

Fluorouracil is an antineoplastic anti-metabolite. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances from becoming incorporated into DNA during the "S" phase (of the cell cycle), stopping normal development and division. Fluorouracil blocks an enzyme which converts the cytosine nucleotide into the deoxy derivative. In addition, DNA synthesis is further inhibited because Fluorouracil blocks the incorporation of the thymidine nucleotide into the DNA strand.