Fluorouracil

Fluorouracil is an antineoplastic agent belonging to the pharmacological class of anti-metabolites.

The FDA has approved Fluorouracil for treating breast, colorectal, gastrointestinal cancers, and pancreatic cancer, often used in combination therapy.

Fluorouracil actively absorbs systemically post-administration, exhibiting variable kinetics determining peak plasma concentrations. Upon bolus intravenous injection, it is extensively distributed to various tissues. Liver metabolism produces active metabolites, and the drug is eliminated through urine and lungs.

Fluorouracil's most common side effects are an increased risk of infection, mouth ulcers, vomiting, weakness, and nausea.

Fluorouracil is available as an injectable solution and topical cream or ointment.

The molecule is available in India, the United States, Canada, the United Kingdom, Australia, Germany, France, Japan, China, Brazil and South Africa.

Fluorouracil is an antineoplastic agent belonging to the pharmacological class of anti-metabolites.

As a pyrimidine antagonist, Fluorouracil is an analogue of the pyrimidine uracil. Three different mechanisms of action are possible. First, the fluorouracil metabolite fluorodeoxyuridine monophosphate (FdUMP) competes with uracil to bind with thymidylate synthetase (TS) and the folate cofactor. Consequently, less thymidine is produced, which lowers DNA synthesis and repair and, eventually, reduces cell proliferation.

Leucovorin stabilizes the binding of FdUMP to TS, enhancing the effects of Fluorouracil (formyltetrahydrofolate, formyl-FH4).

Second, fluorodeoxyuridine triphosphate (FdUTP), a metabolite of Fluorouracil, is integrated into DNA and obstructs DNA replication. Finally, instead of uridine triphosphate (UTP), the fluorouracil metabolite fluorouridine-5-triphosphate (FUTP) is incorporated into RNA, resulting in a fraudulent RNA and disrupting protein synthesis and RNA processing. The cell cycle is specific to Fluorouracil (S-phase).

Fluorouracil's onset occurs within 2-7 days but may extend up to 12 weeks.

The duration of Fluorouracil is 24 hours.

As the physician recommends, take the medication with or without food. Dosage and frequency depend on the specific medical condition.

In treating cancers like breast, lung, colon, and rectal cancer, Fluorouracil, a chemotherapy medication, actively inhibits the growth and multiplication of cancer cells. It can be administered alone or with other medicines to target cancer cells in various body parts effectively. Fluorouracil's mechanism involves interfering with the synthesis of DNA and RNA, thereby disrupting the production of cancerous cells. By explicitly targeting rapidly dividing cells, Fluorouracil not only halts the growth of tumours but also alleviates cancer symptoms, emphasizing its crucial role in cancer treatment.

Fluorouracil treats actinic keratosis, an irregular, rough, and scaly skin growth from prolonged sun exposure. This condition, if left untreated, can progress to skin cancer and requires prompt medical attention. Fluorouracil kills or halts the growth of cancer cells and obstructs the multiplication of these cells. Its mechanism involves interfering with the synthesis of DNA and RNA in rapidly dividing cells, thereby impeding the progression of abnormal skin cells.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Fluorouracil is available as an injectable solution and topical cream or ointment.

400 mg/m² IV on Day 1 and 2400–3000 mg/m² IV continuously infused over 46 hours every two weeks in conjunction with leucovorin, either with or without oxaliplatin/irinotecan

500 or 600 mg/m² IV on Days 1 and 8 q28 Days for six cycles as part of a multidrug regimen based on cyclophosphamide

200–1000 mg/m³/day given continuously via IV over 24 hours for gastric cancer (as part of a regimen containing platinum)

Each cycle's length and frequency vary according to the dose and regimen.

400 mg/m² IV on Day 1 and 2400 mg/m² IV continuously infused over 46 hours every two weeks.

400 mg/m² IVP on Day 1 and 2400 mg/m² IV as a continuous infusion over 46 hours every two weeks are the dosages for leucovorin in combination with other drugs or as part of a multidrug chemotherapy regimen that includes leucovorin.

Apply a thin layer of 0.5% cream to the affected area once a day for up to four weeks or as long as tolerated. Use 1% cream on lesions and leave on for two to six weeks. Apply 4% cream to lesions daily for four weeks or as accepted. Apply a 5% cream or solution (2% or 5%) to lesions 1-2 times daily for 2-4 weeks.

Follow essential dietary guidelines and precautions when using Fluorouracil. Manage potential gastrointestinal issues with small, frequent meals. Maintain a balanced, nutrient-rich diet and ensure adequate water intake. Avoid smoking and alcohol consumption. Incorporate leafy vegetables, citrus fruits, fatty fish, berries, yoghurt, apples, peaches, cauliflower, cabbage, broccoli, beans, and herbs into your diet. Refrain from fast food, fried items, processed meats, refined carbs, and added sugars.

The dietary restriction should be individualized as per patient requirements.

The adverse reactions related to Fluorouracil can be categorized as

•Common Adverse Effects: Gastrointestinal issues, myelosuppression, and dermatological effects.

•Less Common Adverse Effects: Cardiotoxicity and neurotoxicity.

•Rare Adverse Effects: Hyperammonemic encephalopathy, severe mucositis, and thromboembolism.

Blood-related: pancytopenia

Gastrointestinal (GI): nausea, vomiting, and ulcers

Anaphylaxis and generalized allergic reactions are examples of allergic reactions.

Neurologic: headache and nystagmus

Dermatologic conditions include dry skin, fissuring, photosensitivity shown by erythema or increased skin pigmentation, and vein pigmentation.

Ophthalmic: alterations in vision, lacrimation, photophobia, and stenosis of the lacrimal duct

Mood disorders: euphoria

Other: thrombophilia, epistaxis, and alterations to the nails, including nail loss

The clinically relevant drug interactions of Fluorouracil are briefly summarized here.

Patients taking Fluorouracil and warfarin simultaneously have been reported to have elevated coagulation times. Although there are no pharmacokinetic data to evaluate the impact of fluorouracil administration on warfarin pharmacokinetics, warfarin concentrations rise along with the elevation of coagulation times brought on by the fluorouracil prodrug capecitabine. Therefore, the interaction might result from fluorouracil or its metabolites' inhibition of cytochrome P450 2C9.

ROUTE(S): Intra-arterial / IV / Parenteral: D; Use in cases where no safer medication is available, and life is in danger. Positive evidence of prenatal risk in humans.

ROUTE(S): Topical: X; When pregnant, avoid using. Potential benefits are outweighed by the risks. There are safer alternatives available.

Due to the lack of sufficient and carefully monitored research, Fluorouracil's mechanism of action suggests that giving the medication to a pregnant woman could harm the fetus.

Inform the patient of the possible risk to a fetus if this medication is used during pregnancy or if the patient gets pregnant while taking this medication.

Females: Because of the medication's mode of action, it may harm a fetus if it is given to a pregnant woman. Therefore, it is advised that women who are capable of becoming pregnant use effective contraception while receiving fluorouracil therapy and for up to three months after stopping it.

Men: Because Fluorouracil can harm spermatozoa, men who have female partners who are capable of having children should use effective contraception both during and for three months after therapy ends.

Women: Inform women who are fertile that fluorouracil treatment may affect their fertility, according to data from animals.

Males: Educate sexually active males that fluorouracil treatment may reduce their fertility, based on data from animals.

It is unknown if Fluorouracil or its metabolites are found in human milk. Considering the importance of the drug to the mother, a decision should be made regarding whether to stop nursing or to stop taking the drug, as many drugs are found in human milk and can cause severe adverse reactions in nursing infants.

As per the FDA, the safety and efficacy of pediatric patients have not been established.

Renal impairment: Dose reduction may be required.

Hepatic impairment: Dose reduction may be required.

The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of Fluorouracil.

Overconsumption of Fluorouracil could lead to nausea, vomiting, diarrhoea, gastrointestinal ulcers, bleeding and bone marrow depression (e.g. thrombocytopenia, leucopenia, agranulocytosis).

Supportive care and symptom-specific interventions are essential in Fluorouracil overdosage, as there is no specific antidote. Close monitoring of vital signs, blood counts, and liver function is crucial. Administer activated charcoal to reduce further absorption and consider appropriate interventions like antiemetics to alleviate nausea and vomiting, hematopoietic growth factors, or neurotoxicity-focused supportive care. Given Fluorouracil's short half-life, enhanced elimination methods such as hemodialysis may be considered, though their efficacy is uncertain. Supportive care may be necessary, including blood transfusions, antimicrobial therapy, and symptomatic treatment for gastrointestinal issues. Chronic overdosage may lead to severe myelosuppression, necessitating daily haematological evaluation and prompt transfusions at signs of bleeding. Careful observation for intercurrent infection is vital, with timely initiation of appropriate antibiotic therapy if needed.

As an anti-metabolite, Fluorouracil is antineoplastic. When purine or pyrimidine are transformed into DNA building blocks, anti-metabolites pose as them. They halt normal growth and division by preventing these chemicals from integrating into DNA during the "S" phase of the cell cycle. Cytosine nucleotide is converted into its deoxy derivative by an enzyme that Fluorouracil blocks. Furthermore, the incorporation of the thymidine nucleotide into the DNA strand is blocked by Fluorouracil, further inhibiting DNA synthesis.

Absorption: Fluorouracil undergoes systemic absorption post-administration, with variable absorption kinetics. Peak plasma concentrations depend on the formulation, typically manifesting within a specific timeframe.

Distribution: Upon bolus intravenous injection, Fluorouracil is extensively distributed throughout the body, reaching various tissues, including the intestinal mucosa, bone marrow, liver, cerebrospinal fluid, and brain tissue.

Metabolism: Metabolism occurs predominantly in the liver, facilitated by the dehydrogenase enzyme. This process forms active metabolites, namely, 5-fluoroxyuridine monophosphate (F-UMP) and 5-5-fluoro-2'-deoxyuridine-5'-O-monophosphate (F-dUMP).

Excretion: Fluorouracil is excreted via urine, with 5-20% as an unchanged drug and metabolites like urea and α-fluoro-β-alanine over 3-4 hours. Additionally, a considerable amount is eliminated through the lungs as carbon dioxide.

Elimination Half-life: The elimination half-life of Fluorouracil ranges from 8-20 minutes for bolus administration and approximately 16 minutes for intravenous infusion.