Usage
Fluorouracil is an antineoplastic antimetabolite used to treat various types of cancers, including adenocarcinoma of the colon, rectum, breast, stomach, and pancreas. It is also used topically to treat actinic keratosis, superficial basal cell carcinoma, and other skin cancers.
Pharmacological Classification: Antineoplastic antimetabolite.
Mechanism of Action: Fluorouracil disrupts DNA and RNA synthesis by inhibiting thymidylate synthase, ultimately leading to cell death.
Alternate Names
5-FU, 5-fluorouracil
Brand Names: Adrucil, Carac, Efudex, Fluoroplex, Tolak
How It Works
Pharmacodynamics: Fluorouracil is metabolized intracellularly to its active forms, which interfere with DNA and RNA synthesis by inhibiting thymidylate synthase. This leads to an imbalance of intracellular nucleotides and inhibition of cell growth and division.
Pharmacokinetics:
- Absorption: Topical application has minimal systemic absorption. Intravenous administration results in rapid and complete systemic availability.
- Metabolism: Primarily metabolized in the liver by dihydropyrimidine dehydrogenase (DPD).
- Elimination: Primarily eliminated renally.
Mode of Action: Fluorouracil acts as a “suicide inhibitor” of thymidylate synthase, blocking the formation of thymidine, a crucial nucleotide for DNA synthesis. This inhibition disrupts DNA replication and repair, leading to cell cycle arrest and apoptosis.
Receptor Binding, Enzyme Inhibition: Thymidylate synthase inhibition.
Elimination Pathways: Primarily renal excretion.
Dosage
Standard Dosage
Adults:
- Intravenous: Dosing varies widely based on cancer type and regimen, typically ranging from 200-600 mg/m² per dose, administered as bolus or infusion.
- Topical (Actinic keratosis): Apply a thin film to the affected area once or twice daily for 2-4 weeks (depending on concentration and brand).
- Topical (Superficial basal cell carcinoma): Apply twice daily for 3-6 weeks, sometimes up to 10-12 weeks.
Children: Safety and effectiveness in children have not been established. Limited use exists, but dosing must be determined by a doctor.
Special Cases:
- Elderly Patients: Increased risk of toxicity; dose adjustment may be required.
- Patients with Renal Impairment: No dose adjustment generally required, but caution is advised with severe insufficiency.
- Patients with Hepatic Dysfunction: Dose reduction needed for moderate to severe impairment.
- Patients with Comorbid Conditions: Close monitoring is essential, particularly for those with cardiovascular disease or DPD deficiency.
Clinical Use Cases
Dosing is highly individualized based on cancer type and specific regimen. Institutional protocols should be consulted. Examples:
- Colon/Rectum Cancer: 400 mg/m² IV bolus on Day 1, followed by 2400-3000 mg/m² continuous infusion over 46 hours every two weeks in combination with leucovorin, with or without oxaliplatin/irinotecan.
- Breast Cancer: 500-600 mg/m² IV on Days 1 and 8 every 28 days for 6 cycles as part of a multidrug regimen.
- Gastric Cancer: 200-1000 mg/m²/day continuous IV infusion over 24 hours (as part of a platinum-containing regimen).
Fluorouracil is not typically used in clinical scenarios such as intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations outside its role in cancer treatment.
Dosage Adjustments
Dosage must be adjusted based on patient response, toxicity, renal/hepatic function, DPD activity, and other factors. Dose reductions are common in cases of myelosuppression, mucositis, diarrhea, hand-foot syndrome, and organ toxicity.
Side Effects
Common Side Effects
Nausea, vomiting, diarrhea, stomatitis, mucositis, anorexia, alopecia, hand-foot syndrome, skin reactions (topical use), myelosuppression.
Rare but Serious Side Effects
Cardiotoxicity, severe myelosuppression, severe diarrhea, neurotoxicity, hyperammonemic encephalopathy, allergic reactions.
Long-Term Effects
Secondary malignancies, infertility, chronic skin changes (topical use).
Adverse Drug Reactions (ADR)
Severe myelosuppression, cardiotoxicity, neurotoxicity, allergic reactions.
Contraindications
Pregnancy, DPD deficiency, severe bone marrow suppression, serious infection, hypersensitivity to fluorouracil.
Drug Interactions
Numerous drug interactions exist; consult a comprehensive drug interaction database before co-administration. Some examples include:
- CYP450 Interactions: Minimal direct CYP450 interaction.
- Other Interactions: Leucovorin (synergistic), other myelosuppressive drugs (additive toxicity), live vaccines (contraindicated).
- Food/Lifestyle: Grapefruit may increase fluorouracil levels.
Pregnancy and Breastfeeding
Pregnancy Safety Category: D/X (contraindicated)
Fetal Risks: Highly teratogenic; can cause fetal malformations and death.
Breastfeeding: Contraindicated.
Drug Profile Summary
- Mechanism of Action: Inhibits thymidylate synthase, disrupting DNA and RNA synthesis.
- Side Effects: Myelosuppression, mucositis, diarrhea, nausea, vomiting, alopecia, hand-foot syndrome.
- Contraindications: Pregnancy, DPD deficiency, severe myelosuppression, active infection.
- Drug Interactions: Consult a comprehensive drug interaction database.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: Highly variable; see detailed dosage guidelines above.
- Monitoring Parameters: Complete blood count, liver function tests, renal function tests, cardiac function.
Popular Combinations
Leucovorin (enhances efficacy), oxaliplatin, irinotecan.
Precautions
- General Precautions: Assess bone marrow function, liver and renal function, nutritional status, and DPD activity before and during treatment.
- Specific Populations: Contraindicated in pregnancy and breastfeeding. Use with caution in elderly patients and those with hepatic or renal impairment.
- Lifestyle Considerations: Avoid alcohol, monitor for sun sensitivity (topical use).
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Fluorouracil?
A: Dosing is highly variable depending on indication, administration route (topical vs. IV), patient characteristics, and specific treatment regimen. See detailed dosage guidelines above.
Q2: What are the most common side effects of Fluorouracil?
A: Myelosuppression, mucositis, nausea, vomiting, diarrhea, alopecia, hand-foot syndrome.
Q3: What are the contraindications to using Fluorouracil?
A: Pregnancy, DPD deficiency, severe myelosuppression, active serious infections, hypersensitivity to fluorouracil.
Q4: How does Fluorouracil interact with other medications?
A: Numerous drug interactions are possible. Consult a drug interaction database before prescribing.
Q5: Can Fluorouracil be used during pregnancy or breastfeeding?
A: No, it is contraindicated in both pregnancy and breastfeeding due to its teratogenic effects and excretion into breast milk.
Q6: How should Fluorouracil be administered?
A: Intravenous administration: by bolus, intermittent infusion, or continuous infusion, depending on the specific regimen. Topical administration: Apply a thin layer to affected skin area.
A: Patients with DPD deficiency cannot metabolize fluorouracil effectively, leading to increased drug levels and a significantly higher risk of severe, even fatal, toxicity. Testing for DPD deficiency is recommended before initiating treatment.
Q8: What monitoring parameters are essential during Fluorouracil treatment?
A: Regular monitoring of complete blood counts, liver function tests, and renal function tests are crucial. Cardiac monitoring may also be indicated.
Q9: What are the long-term side effects of Fluorouracil?
A: Potential long-term side effects include secondary malignancies and infertility.
Q10: What precautions should be taken when administering topical Fluorouracil?
A: Avoid contact with mucous membranes and eyes. Advise patients to avoid sun exposure and use sunscreen during treatment due to increased photosensitivity. The treated area should not be covered with occlusive dressings unless specifically directed by a physician.
