Fluorouracil (5-FU)

Overview

Fluorouracil (5-FU) is an antimetabolite chemotherapeutic agent used in veterinary medicine primarily for the treatment of certain neoplastic conditions in dogs. It is available as a 50 mg/mL injectable solution for systemic chemotherapy in dogs; the topical creams and solutions are human products for skin cancer and solar keratoses in people and are a documented source of accidental, potentially fatal poisoning in pets.

Fluorouracil works by interfering with pyrimidine synthesis, leading to inhibition of DNA synthesis and cellular replication, particularly in rapidly dividing tumor cells. It is a cytotoxic drug that the National Institute for Occupational Safety and Health classifies as hazardous.

In small animal practice, fluorouracil is used infrequently and typically reserved for specific oncologic indications under specialist guidance. Its use requires strict adherence to chemotherapy safety protocols.

Important species limitation: Fluorouracil is contraindicated in cats in all forms — including topical creams and compounded eye drops — because it causes severe, potentially fatal neurotoxicity by any route of exposure.

Mechanism of Action (MOA): Fluorouracil is converted intracellularly to active metabolites that interfere with DNA and RNA synthesis, inhibit cell growth and promote cell death; this mechanism targets rapidly growing cells such as bone marrow and intestinal crypts.

Indications

Fluorouracil is used in dogs for selected neoplastic conditions, given intravenously as part of a chemotherapy protocol or injected into the site of a resected tumour. Its use is generally limited and should be guided by oncology-specific protocols.

• Cutaneous neoplasia (topical use): Sun-induced (dermal) squamous cell carcinoma is treated in dogs with the intravenous regimen. The topical creams and solutions are human preparations for skin cancer and solar keratoses in people, and no canine topical protocol is published.
• Systemic chemotherapy (dogs): Documented canine uses include soft tissue sarcoma, which have their own rows in the dog dose table, along with mammary carcinoma, dermal squamous cell carcinoma, and gastrointestinal, anal-sac and nasal adenocarcinoma. Other veterinary protocols have included osteosarcoma, haemangiosarcoma, transmissible venereal tumour and mast cell tumours.
• Adjunct in oncology protocols: It is given as part of a combination protocol, with cyclophosphamide and/or doxorubicin for mammary carcinoma, or with carboplatin for various carcinomas, at the doses shown in the dog dose table.
• Ocular surface neoplasia and glaucoma surgery: A compounded 1% ophthalmic solution is used for ocular surface neoplasia, including squamous cell carcinoma, and as an antifibrotic adjunct during glaucoma drainage-implant surgery to limit scarring; the surgical protocols are the province of a veterinary ophthalmologist. The dose for ocular surface neoplasia is shown in the dog dose table.

Dosage (Reference)

Dog

For systemic chemotherapy in dogs, fluorouracil may be dosed by body surface area (mg/m²) or by body weight (mg/kg); separate incisional and ophthalmic regimens are listed below. Treatment should only be performed under appropriate oncologic supervision with strict safety precautions.

Warnings & Precautions

Fluorouracil is a cytotoxic chemotherapeutic agent that requires careful handling, appropriate patient selection, and close monitoring during use.

• Contraindicated in cats: Do not use in cats in any form (including topical), as it can cause severe and potentially fatal neurotoxicity.
• Cytotoxic drug handling: Wear personal protective equipment whenever this drug or its byproducts are handled, including gloves and a mask when it is applied; pregnant women and anyone who is ill or immunocompromised should avoid contact altogether.
• Bone marrow suppression: Myelosuppression is dose-dependent and affects all cell lines; monitor haematology closely, and do not give fluorouracil at all to an animal that is already myelosuppressed.
• Organ dysfunction: Fluorouracil is contraindicated in animals with known hypersensitivity, poor nutritional status, bone marrow suppression or concurrent serious infection, and should be used with caution in severe renal or hepatic impairment.
• Neurologic toxicity: Neurotoxicity, including seizures, may occur; ataxia has been reported with toxic exposure.
• Specialist use: Should be used under veterinary oncologist guidance with established chemotherapy protocols; there is no veterinary-licensed fluorouracil product, so every canine dose is extra-label.
• Pregnancy: Fluorouracil is a known teratogen: it has caused fetal malformations including cleft palate and skeletal defects, and embryo death, in laboratory animals. Weigh systemic use against the risk to the offspring, and do not use the ophthalmic preparation in a pregnant animal.
• Nursing: It is not known whether fluorouracil passes into milk; because it blocks DNA, RNA and protein synthesis, consider milk replacer for the litter if the dam must receive it.
• High-alert medication: Fluorouracil is a high-alert medication: check the dose and the volume twice, use a distinguishing label, and take care not to confuse it with flucytosine, a different drug with a similar name.
• Accidental exposure: Any suspected exposure — including a pet licking an owner’s treated skin or chewing a tube of cream — needs immediate veterinary assessment. Very small amounts can kill a cat, and blindness has been reported in cats as well as fatal neurotoxicity.
• Signs owners must report: Tell the owner to report at once any abnormal bleeding or bruising, depression, sign of infection, shortness of breath, or change in urination.

Drug Interactions

Fluorouracil has a number of drug interactions that are reported or considered theoretical in humans or animals; none has been reported in animals themselves, where veterinary use is limited. These interactions may alter drug metabolism or enhance cytotoxic effects; unless otherwise noted, concurrent use is not necessarily a contraindication, but weigh the risks and monitor additionally when appropriate.

• Cimetidine: Inhibits the metabolism of fluorouracil, potentially increasing drug exposure and toxicity.
• Carboplatin: Fluorouracil has been used with carboplatin for various canine carcinomas; one study reported an overall response rate of 43%, and small studies found the combination tolerable, but its efficacy is not yet established.
• Methotrexate: Sequencing effects with fluorouracil have not been reported in dogs. There is, however, a physical incompatibility: the two must not be mixed as an intravenous additive, although they are compatible in syringes and in Y-lines.
• Folic acid and leucovorin: Folic acid or leucovorin may increase the toxicity of fluorouracil, and leucovorin may increase its antitumour effect as well. Do not mix leucovorin calcium into a solution containing fluorouracil.
• Nitroimidazole antimicrobials: Metronidazole, tinidazole and ronidazole may increase fluorouracil concentrations and the risk of toxicity.
• Amphotericin B: May increase the toxic effects of fluorouracil.
• Other myelosuppressive drugs: Antineoplastics, immunosuppressants and iron chelators add to fluorouracil’s bone marrow suppression; leflunomide in particular should not be given concurrently or in sequence without a washout period, which may increase the risk of myelosuppression and infection.
• CYP2C9 substrates: Fluorouracil may decrease the metabolism of CYP2C9 substrates such as diclofenac.
• Vaccines: Fluorouracil may diminish the efficacy of live and inactivated vaccines and enhance their adverse effects.

Side Effects & Overdose

Side Effects

Adverse effects of fluorouracil follow from its cytotoxic activity and may involve the gastrointestinal tract, the bone marrow, the nervous system, the heart and the lungs.

• Gastrointestinal effects: Salivation, vomiting that may become bloody, diarrhoea and bloody stool, abdominal pain, stomatitis, and ulceration or sloughing of the gastrointestinal lining.
• Hematologic toxicity: Leukopenia, thrombocytopenia and anaemia may occur; in people the blood-count nadir falls between days 9 and 14 with recovery by about day 30.
• Dermatologic effects: With ophthalmic administration, local effects may include burning, crusting, contact dermatitis, erosions, erythema, hyperpigmentation, irritation, pain, periorbital alopecia, photosensitivity, pruritus, scarring, rash, soreness and ulceration.
• Neurologic effects: Behavioural change, other neurologic signs and seizures have occurred in dogs; after a toxic exposure, lethargy, ataxia, depression, disorientation and tremors are also seen, and the seizures are often refractory to treatment.
• Cardiac and respiratory effects: Cardiac abnormalities and respiratory distress have occurred in dogs; after a toxic exposure, hypotension, myocardial ischaemia, arrhythmias and non-cardiogenic pulmonary oedema with dyspnoea and cyanosis have been reported.

Overdose

Overdose is well described in dogs: toxic effects have been reported from as little as 5 mg/kg, seizures and death from 10.3 mg/kg, doses of 40 mg/kg or more are reported to be uniformly fatal, and the intravenous LD50 in dogs is 31.5 mg/kg. Signs may appear within 30 minutes to 6 hours of ingestion and death has been reported as early as 7 hours; the reported fatality rate in dogs is 65%, and an animal that survives the acute phase may still succumb to bone marrow suppression later.

• Hematologic toxicity: Severe myelosuppression affecting all cell lines raises the risk of infection and bleeding; check a complete blood count every 3 to 4 days for at least 18 days, since all cell lines may take up to 3 weeks to recover, and continue intensive haematologic monitoring for at least 4 weeks after an accidental parenteral overdose.
• Gastrointestinal signs: Severe vomiting, haemorrhagic diarrhoea, abdominal pain and sloughing of the gastrointestinal lining.
• Neurologic toxicity: Ataxia and severe, non-responsive seizures.
• Management: Treatment is supportive and intensive: in an animal that is still free of clinical signs and seen within about an hour, consider emesis and activated charcoal, since seizures develop quickly thereafter; give antiemetics, gastrointestinal protectants, intravenous fluids, pain relief and temperature control, broad-spectrum antibiotics if the white cell count falls, transfusion if the packed cell volume drops below 20%, and colony-stimulating factors if the marrow is suppressed. Avoid non-steroidal anti-inflammatory drugs and central nervous system depressants. A benzodiazepine may be used initially for seizures but is usually ineffective in severe exposure; levetiracetam is the more reliable choice, and phenobarbital, propofol or general anaesthesia may be needed if it fails.
• Antidote: There is no practical antidote. Uridine triacetate works in people but is not used in veterinary medicine on grounds of cost and administration, and would have to be started before nervous signs appear; fluorouracil is dialysable, but toxicity comes on too fast for dialysis to help.
• Poison control: For a known or suspected overdose, contact a 24-hour poison control service that provides veterinary-specific advice.
• Other findings and measures: Severe metabolic acidosis and signs of multi-organ failure may also develop. After a recent exposure, gastric lavage may be considered with the airway protected, and blood pressure should be monitored every 4 to 6 hours.

Key Notes

Practical clinical points that support the safe and effective use of fluorouracil in dogs:

• Specialist-guided therapy: Use is typically limited to oncology protocols and should be planned with appropriate reference guidelines.
• Body surface area dosing: Chemotherapy dosing may be calculated by body surface area (mg/m²) or by body weight (mg/kg); check which the protocol uses and convert carefully, and do not confuse the two.
• Topical vs systemic use: The 50 mg/mL injectable solution is the form used for systemic chemotherapy in dogs. The topical creams and solutions are human preparations for skin cancer and solar keratoses in people, supplied as 0.5%, 1%, 4% and 5% creams and 0.5%, 1%, 2% and 5% solutions. For ophthalmic use a 1% solution is compounded from the injection; a 1% ophthalmic ointment has also been described.
• Protocol variability: Dosing intervals and combinations may vary depending on the specific chemotherapy protocol used.
• Monitoring importance: Regular evaluation of clinical response and haematology is essential during treatment, and results must be read knowing that fluorouracil itself can raise alkaline phosphatase, serum transaminases, bilirubin, lactate dehydrogenase and total thyroxine — the last of which makes a thyroid-stimulating hormone stimulation test hard to interpret.
• Limited routine use: Fluorouracil is not commonly used in general small animal practice and is typically reserved for selected cases.
• Pharmacokinetics: Human data give a plasma half-life of about 15 minutes after intravenous injection. Fluorouracil distributes principally into tumour cells, intestinal lining, liver and bone marrow, is metabolised mainly by the liver, and is cleared through the lungs and urine, with about 15% of the dose excreted unchanged in urine.
• Storage and stability: Store the injection at 20–25°C, protected from light, and do not freeze. A precipitate that forms on storage can be redissolved by gentle warming and cooling to body temperature before use; discard the vial if it will not redissolve. The manufacturer advises using an entered vial within 4 hours and giving infusions immediately.
• Giving the eye preparation: Leave 5 to 10 minutes between fluorouracil and any other eye medicine, and do not mix it directly with another ophthalmic preparation. Discard the solution if it changes colour, turns cloudy or contains particles.
• Monitoring ophthalmic treatment: During ophthalmic treatment, monitor the clinical response, the patency of a glaucoma implant and the intraocular pressure it controls, and sample cells or tissue where needed to confirm that a surface tumour has gone into remission.