Fluorouracil

Fluorouracil (5-FU) is a fluorinated pyrimidine and a cytostatic antimetabolite. Its structure resembles uracil and thymine, bases found in nucleic acids, so cells handle it through the same pathways as the natural bases. Given by injection or infusion, it acts on rapidly dividing cells throughout the body. Applied as a cream, it acts on abnormal skin cells in the treated area, including lesions too small to see, with a lesser effect on normal cells.

Mechanism of Action

• Thymidylate synthase: the main mechanism is thought to be the binding of the drug’s deoxyribonucleotide metabolite (FdUMP), together with the folate cofactor N5,10-methylenetetrahydrofolate, to thymidylate synthase. The covalently bound ternary complex that forms stops uracil being converted to thymidylate, so DNA and RNA synthesis are inhibited and the cell dies.
• RNA incorporation: fluorouracil can also be built into RNA in place of uridine triphosphate, producing faulty RNA that disturbs RNA processing and protein synthesis.
• Antimetabolite action: because it resembles thymine, fluorouracil prevents the formation and use of nucleic acids, which inhibits DNA and RNA synthesis and halts growth. It acts mainly in the S phase of the cell cycle.
• Topical effect: on the skin, the response to the cream (redness, scaling, crusting and erosion, then healing) reflects the drug’s action on dysplastic cells in actinic keratosis lesions.

Pharmacokinetics

Solution for injection or infusion

• Distribution: plasma protein binding is low, about 8–12%.
• Metabolism: mainly in the liver. The rate-limiting step is conversion to 5,6-dihydrofluorouracil by DPD, and the breakdown products (carbon dioxide, urea and α-fluoro-β-alanine) are inactive.
• Elimination: the half-life is very short, about 10–20 minutes. About 7–20% of the dose is excreted unchanged in the urine within 6 hours, more than 90% of that in the first hour; the rest is metabolised.
• Special populations: people with low DPD activity eliminate the drug more slowly and are at risk of severe toxicity (see Special Instructions).

Cream (Tolak 40 mg/g)

• Absorption: low through the skin. In a systemic-absorption study in 21 patients, 8 had undetectable levels (below 1 ng/mL). In the others, the highest levels were generally seen 1 hour after application, with peak concentrations of 1.1–7.4 ng/mL.
• Metabolism: fluorouracil can be handled through catabolic and anabolic pathways similar to those of natural uracil. The rate-limiting step is again its conversion by DPD.

Fluorouracil is authorised in two forms with different uses. Their indications are listed separately and are not interchangeable.

Solution for injection or infusion (50 mg/mL), adults

• Colorectal cancer: treatment of metastatic colorectal cancer, and adjuvant treatment of colon and rectal cancer.
• Gastric cancer: treatment of advanced gastric cancer.
• Pancreatic cancer: treatment of advanced pancreatic cancer.
• Oesophageal cancer: treatment of advanced oesophageal cancer.
• Breast cancer: treatment of advanced or metastatic breast cancer, and adjuvant treatment of operable primary invasive breast cancer.
• Head and neck cancer: treatment of locally advanced, inoperable squamous cell carcinoma of the head and neck in previously untreated patients, and of locally recurrent or metastatic squamous cell carcinoma of the head and neck.

Cream (Tolak 40 mg/g), adults

• Actinic keratosis: topical treatment of non-hyperkeratotic, non-hypertrophic actinic keratosis (Olsen grade I and II) of the face, ears and/or scalp.

Other topical fluorouracil medicines (for example Efudix) are authorised nationally with their own indications, strengths and regimens, which this page does not describe.

Cream (Tolak)

• Hypersensitivity to fluorouracil or to any of the excipients.
• Allergy to peanuts or soya (the cream contains refined peanut oil).
• Pregnancy.
• Breastfeeding.
• Combination with brivudine, sorivudine or similar substances, which are potent DPD inhibitors and can substantially raise fluorouracil blood levels and its toxicity.

Solution for injection or infusion

• Known hypersensitivity to fluorouracil or to any of the excipients.
• Potentially serious infections, for example herpes zoster or chickenpox.
• Severe debilitation.
• Bone marrow depression after radiotherapy or other anti-cancer treatment.
• Treatment of non-malignant disease.
• Severe hepatic impairment.
• Treatment with brivudine, sorivudine or chemically related analogues, which are potent inhibitors of DPD: fluorouracil must not be used within 4 weeks after them.
• Known complete DPD deficiency, including patients homozygous for DPD deficiency.
• Breastfeeding.

The two forms have different safety profiles and are described separately. The cream mainly causes local reactions in the treated skin; the injection or infusion is a cytotoxic medicine with effects throughout the body.

Cream (Tolak 40 mg/g). The most common reactions are local reactions in the treated area that reflect the drug’s action on abnormal cells: redness, scaling or dryness, swelling, crusting, erosions, stinging or burning, and itching. They occurred in 62% to 99% of patients in the pivotal studies, depending on the symptom, and were mild in 17% to 37%, moderate in 22% to 44% and severe in 6% to 38%. They were transient, peaked at 4 weeks of treatment and resolved within 2 to 4 weeks after treatment ended.

Very common (≥1/10): local skin reactions in the treated area (redness, scaling or dryness, swelling, crusting, erosion, stinging or burning, itching).

Common (≥1/100 to <1/10): eye irritation; application site irritation, pain, reaction, redness, itching, inflammation and swelling.

Uncommon (≥1/1,000 to <1/100): impetigo, pharyngitis; insomnia; eye swelling, swelling around the eyes (periorbital oedema), increased tear production; nasal discomfort; lip blister (cold sore), nausea; rash; application site bleeding, erosion, dermatitis, discomfort, dryness, tingling or numbness (paraesthesia) and photosensitivity reaction.

Not known: hypersensitivity reaction. Allergic contact dermatitis, a delayed-type reaction, has been reported with topical fluorouracil medicines and with Tolak since it was first authorised.

Topical fluorouracil is associated with photosensitivity reactions, including severe sunburn. In the pivotal studies one patient on Tolak (0.3%) reported one, as did one patient given the vehicle.

Solution for injection or infusion. Systemic fluorouracil is a cytotoxic medicine, and its main toxic effects fall on rapidly dividing tissues. The SmPC requires blood counts and checks for gastrointestinal and neurological toxicity before each dose, which reflects these effects:

• Bone marrow: falls in white blood cells and platelets, which may require treatment to be interrupted.
• Digestive tract: inflammation of the mouth (stomatitis), diarrhoea and gastrointestinal bleeding.
• Nervous system: neurological toxicity.
• Other recognised effects of systemic fluorouracil: nausea and vomiting, hand-foot syndrome (palmar-plantar erythrodysaesthesia) and heart problems such as chest pain and rhythm disturbances.
• DPD deficiency: people with reduced DPD activity can develop severe toxicity.

How often these occur depends on the regimen and the other medicines combined with fluorouracil. The frequencies are given in the SmPC of the product used.

• Brivudine, sorivudine and related analogues: these antiviral nucleoside analogues are potent inhibitors of DPD, the enzyme that breaks down fluorouracil. Taken with fluorouracil, they can substantially raise its blood levels and its toxicity. The combination is contraindicated with both forms. For the injection or infusion, fluorouracil must not be used within 4 weeks after brivudine, sorivudine or related drugs. For the cream, treatment with the antiviral and topical application of Tolak must be separated by at least 4 weeks.
• Other medicines (injection or infusion): the SmPCs of systemic fluorouracil products describe further interactions, for example with warfarin and other coumarin anticoagulants, with phenytoin, and with folinic acid (which strengthens both the effect and the toxicity of fluorouracil). Other medicines that suppress the bone marrow, and radiotherapy, add to its effect on blood counts. Check the SmPC of the product used.
• Cream: the Tolak SmPC names no other interactions.

The two forms are used in completely different ways, and their doses must never be confused. The cream is applied to the skin by the patient once daily for a short course; the injection or infusion is a cytotoxic medicine given by a specialist, in hospital at first, on a regimen chosen for the cancer being treated. Other topical fluorouracil medicines (for example Efudix) have their own strengths and regimens in their own SmPCs, and the cream directions below apply to Tolak 40 mg/g only.

Cream (Tolak 40 mg/g): Actinic Keratosis

• Application: once daily, in enough quantity to cover the affected actinic skin area of the face and/or ears and/or scalp with a thin layer, including the places where actinic keratosis lesions have been identified. The cream is spread evenly with a gentle massage using the fingertips.
• Before and after: wash, rinse and dry the area before application, and wash the hands thoroughly afterwards.
• Duration: 4 weeks, if tolerated. If discomfort is severe or the skin reactions last longer than 4 weeks, symptomatic treatment such as emollients or topical corticosteroids is offered.
• Assessment: the therapeutic effect is assessed about 4 weeks after treatment ends.
• Repeat treatment: repeat courses have not been formally evaluated. In clinical studies, retreatment came 7 to 13 months (mean 9.4 months) after the first course. The doctor decides how many retreatments to give.
• Elderly: no dose adjustment from 65 years of age.
• Renal or hepatic impairment: no dose adjustment.
• Children: there is no specific use, because children do not develop actinic keratosis, and no data exist.

Solution for Injection or Infusion (50 mg/mL): Cancer

• Who gives it: only under the supervision of a physician with extensive experience of cytotoxic treatment. Patients are monitored closely and frequently, and the risks and benefits for each patient are weighed before each treatment. The first treatment is given in hospital.
• How it is given: intravenously, as a bolus injection, an infusion or a continuous infusion lasting up to several days. These are general recommendations, and local and international guidelines give more up-to-date ones. Dilution before administration is covered in section 6.6 of the SmPC.
• Dose: there is no single dose. The dose and schedule depend on the regimen chosen, the indication, the patient’s condition and previous treatment. Regimens differ in the other cytotoxic medicines combined with fluorouracil and in the dose of folinic acid used with it. The treating physician decides the number of cycles from the treatment protocols and local guidelines, taking account of the success of treatment and tolerance in the individual patient.
• Dose reduction: recommended in patients with cachexia, major surgery in the previous 30 days, reduced bone marrow function, or hepatic or renal impairment.
• Monitoring: adult and elderly patients are monitored before each dose for haematological toxicity (platelet, leukocyte and granulocyte counts), gastrointestinal toxicity (stomatitis, diarrhoea, gastrointestinal bleeding) and neurological toxicity, and the dose is reduced or withheld if necessary. A fall in leukocytes to 3,500/mm³ or below and/or in platelets to 100,000/mm³ or below may require treatment to be interrupted, and the physician decides whether to resume according to the patient’s clinical state.

DPD Deficiency

DPD is the key enzyme in the breakdown and elimination of fluorouracil. People with reduced DPD activity can develop serious toxicity, and the injection or infusion is contraindicated in patients known to have complete DPD deficiency, including those homozygous for it. Testing for DPD deficiency before systemic treatment is recommended in the EU, and the SmPC of the product used gives the details.

For the cream, significant systemic toxicity through the skin is unlikely when it is used as authorised. The likelihood rises when it is applied to skin with a damaged barrier (for example, cuts), under an occlusive dressing, or in people with DPD deficiency. Increased toxicity has been reported in patients with reduced DPD activity. If systemic toxicity is suspected, Tolak is stopped and DPD activity can be measured. Patients with known DPD deficiency must be closely monitored for signs of systemic toxicity during treatment with topical fluorouracil.

Cream: Eyes, Mucous Membranes and Broken Skin

Tolak must not be applied directly to the eyes, nose, mouth or other mucous membranes, because it can cause irritation, local inflammation and ulceration. If contact occurs, the cream is washed off with plenty of water. It must not be applied to open wounds or to damaged skin with an impaired barrier. Corneal and conjunctival disorders have been reported with topical fluorouracil, so the area around the eyes is avoided. The hands are washed thoroughly after each application to prevent transfer of the drug to the eyes, contact lenses and eye area, and accidental eye exposure is treated by rinsing with plenty of water.

Cream: Expected Skin Reaction

Inflammation of the treated skin is part of how the cream works. The normal pattern is an early inflammatory phase (redness that can become intense and blotchy), an apoptotic phase (skin erosion) and finally healing with new skin growth. It usually shows in the second week of treatment and can occasionally be more intense than expected. Severe discomfort, or reactions lasting more than 4 weeks, should be treated with emollients or topical corticosteroids. An occlusive dressing can increase the skin inflammation.

Cream: Sunlight

Topical fluorouracil is associated with photosensitivity reactions. Exposure to ultraviolet radiation, including sunlight, sunlamps and tanning booths, must be avoided during treatment with Tolak.

Cream: Allergic Contact Dermatitis

Allergic contact dermatitis (a delayed-type hypersensitivity reaction) has been seen with topical medicines containing fluorouracil. It should be suspected if severe itching or eczema appears at the application site or at a distant site. Patch testing to confirm it can be inconclusive.

Injection or Infusion: Handling and Specialist Use

Fluorouracil solution for injection or infusion is a cytotoxic medicine. Precautions for handling and instructions for dilution are given in section 6.6 of the SmPC. Treatment, monitoring and dose adjustment are described under Administration and Dosage.

Pregnancy, Breastfeeding and Fertility

• Cream, pregnancy: there are no data in pregnant women, and animal studies show that fluorouracil is teratogenic. Tolak must not be used in pregnancy. If pregnancy occurs during treatment, treatment is stopped, the patient is told of the risk of treatment-related harm to the child, and genetic counselling is recommended.
• Cream, contraception: because of the drug’s genotoxic potential, women who could become pregnant must not become pregnant during treatment and must use effective contraception during it and for 6 months afterwards. Men must use effective contraception and avoid fathering a child during treatment and for 3 months afterwards.
• Cream, breastfeeding: there is no information on excretion in breast milk, and a risk to the infant cannot be excluded, so Tolak must not be used by breastfeeding mothers. If use is absolutely necessary, breastfeeding must be stopped.
• Cream, fertility: there are no human data. Animal experiments show that fluorouracil affects fertility and reproductive performance, so topical use could affect male and female fertility.
• Injection or infusion: use is contraindicated during breastfeeding. Fluorouracil is genotoxic and teratogenic in animals, and the SmPC of the product used gives the advice on pregnancy, contraception and fertility.

Excipients with Known Effect (Cream)

• Peanut oil: Tolak contains refined arachis (peanut) oil (100 mg/g) and must not be used by people allergic to peanuts or soya.
• Butylhydroxytoluene (E321) (2.0 mg/g): can cause local skin reactions such as contact dermatitis, or irritation of the eyes and mucous membranes.
• Cetyl alcohol (20.0 mg/g) and stearyl alcohol (20.0 mg/g): can cause local skin reactions such as contact dermatitis.
• Methyl parahydroxybenzoate (E218) (1.8 mg/g) and propyl parahydroxybenzoate (0.2 mg/g): can cause allergic reactions, possibly delayed.

Effect on Driving

The cream is unlikely to affect the ability to drive and use machines when used as directed.

Cream (Tolak): do not store above 25 °C. Once opened, use within 4 weeks. The cream is supplied in an aluminium tube with an epoxy-phenolic lacquer lining and a perforating polypropylene screw cap, in packs of 20 g and 40 g (not all sizes may be marketed). It needs no cold chain.

Solution for injection or infusion: store below 25 °C. Do not refrigerate or freeze. Keep the container in the outer carton to protect it from light. The pH of the solution is 8.9, and the medicine is most stable between pH 8.6 and 9.4. If a precipitate forms after exposure to low temperatures, warm the product to 60 °C and shake it vigorously to redissolve it, then let it cool to room temperature before use. Discard the medicine if the solution turns yellow or brown. Storage of the diluted medicine is covered in section 6.3 of the SmPC.

Cream (Tolak): 2 years unopened, and 4 weeks after the tube is first opened.

Solution for injection or infusion: the shelf life depends on the manufacturer and presentation and is stated on the pack and in the SmPC.

Prescription only (Rx). The solution for injection or infusion is a cytotoxic medicine prescribed and supervised by a physician experienced in cytotoxic treatment, and the first treatment is given in hospital, so it is supplied to the hospital or clinic that administers it. The cream is prescribed by a doctor and applied by the patient at home, so it is supplied to the patient or to the treating clinic on prescription. Neither form needs refrigeration.