AHFS Class:

• Antiproliferants 84:18

Generic Name(s):

• Fluorouracil

Fluorouracil, a fluorinated pyrimidine antagonist, acts as an antimetabolite interfering with DNA synthesis.

Fluorouracil is used topically for the treatment of multiple actinic (solar) keratoses; curettage or cryotherapy is preferred for the treatment of isolated lesions.

Fluorouracil is also used topically for the treatment of superficial basal cell carcinoma when conventional methods are impractical (e.g., in patients with multiple lesions or difficult treatment sites). Since topical fluorouracil has not been shown to be more effective than other therapies in the treatment of other basal cell carcinomas, the diagnosis should be established before treatment is begun. When lesions are isolated and easily accessible, conventional techniques (e.g., surgery, curettage and dessication, cryotherapy) are preferred because they have a higher response rate (almost 100% vs approximately 93% with topical fluorouracil).

For systemic uses of fluorouracil, see 10:00.

Administration

Fluorouracil cream or solution is applied topically with a nonmetallic applicator, clean fingertips, or gloved fingers in an amount sufficient to cover the lesions. If the fingers are used to apply the drug, the hands should be washed immediately afterward.

Dosage

At equivalent concentrations, the solutions are considered more effective than the creams.

Multiple Actinic (Solar) Keratoses

For the treatment of multiple actinic keratoses, preparations containing 1 or 2% fluorouracil are applied topically twice daily to lesions on the head and neck and the cream containing 0.5% fluorouracil is applied topically once daily to the face and anterior scalp; the 5% fluorouracil preparations are used on lesions in other areas.

A typical response following topical application of fluorouracil is manifested by erythema, followed by scaling, tenderness, vesiculation, erosion, ulceration, necrosis, and reepithelialization. Topical fluorouracil therapy is continued until the erosion, necrosis, and ulceration stage is reached, usually 2-6 weeks after initiation of treatment. Increased frequency of application, longer duration of treatment, or temporary, initial combination therapy with topical tretinoin may be necessary on areas other than the head and neck (e.g., hands, arms). Responses in areas which appear clinically normal may indicate sites of subclinical actinic keratoses. Complete healing may not occur until 1-2 months after cessation of topical fluorouracil therapy. Healing may be hastened after fluorouracil therapy is discontinued by application of a topical corticosteroid.

Superficial Basal Cell Carcinoma

For the treatment of superficial basal cell carcinoma, 5% fluorouracil preparations only are used. Topical fluorouracil therapy is administered twice daily for at least 3-6 weeks; treatment may be required for up to 10-12 weeks before the lesions are obliterated. Patients should be evaluated for a reasonable period of time to determine if a cure has been obtained.

Adverse Effects

Adverse effects reported following topical application of fluorouracil have been minimal and were generally limited to local inflammatory reactions involving particularly the creases and folds of the skin; dermatitis; stomatitis; and photosensitivity. Local adverse effects have occurred more frequently when propylene glycol solutions of the drug were used than when the cream was applied, probably because of the greater tendency for the liquid to collect in creases and folds of the skin such as the circumoral and nasolabial areas and the chin. Other adverse effects associated with fluorouracil topical therapy include insomnia, irritability, medicinal taste, telangiectasia, and lacrimation.

The major adverse effects of fluorouracil topical therapy are local inflammatory reactions at the site of the actinic lesions which are necessary for the therapeutic response. These reactions include swelling, scaling, pain, pruritus, burning, soreness, tenderness, suppuration, scarring, and hyperpigmentation. Inflammatory responses may occur in sites of normal appearing subclinical actinic keratoses. Increased incidence of inflammatory reactions may occur in the normal skin near a lesion if an occlusive dressing is used; a porous gauze dressing may be used for cosmetic reasons without increasing inflammatory reactions.

Although reports of systemic toxicity related to topical application of fluorouracil have not appeared in the published literature, one manufacturer reports that leukocytosis, thrombocytopenia, toxic granulation, and eosinophilia have occurred. In one study, 5% fluorouracil in hydrophilic petrolatum and up to 5% fluorouracil in propylene glycol were concurrently applied to the face, neck, chest, arms, and legs in patients with multiple solar keratoses and no systemic toxicity such as bone marrow depression was reported. Systemic absorption of fluorouracil following accidental ingestion of fluorouracil topical preparations may be manifested by leukopenia, thrombocytopenia, stomatitis, diarrhea, GI ulceration and bleeding, and hemorrhage from any site. If leukocytosis and granulocytopenia occur, the patient should be isolated and given prophylaxis against infection.

Precautions and Contraindications

Fluorouracil topical solution or cream should be applied with caution near the eyes, nose, and mouth. The possibility of systemic toxicity should be considered when fluorouracil is applied topically on large ulcerated areas.

Because exposure to ultraviolet light increases the intensity of the inflammatory reaction, patients receiving fluorouracil topical therapy should avoid prolonged exposure to sunlight or other ultraviolet rays. Patients with actinic keratoses should be warned that the reaction in the treated areas may be unsightly during therapy and, in some cases, for several weeks after therapy is discontinued.

If an area does not respond to fluorouracil treatment or the keratotic lesion recurs following therapy, a biopsy should be taken to confirm the diagnosis. Follow-up biopsies should be performed as necessary in the treatment of superficial basal cell carcinoma.

Fluorouracil topical cream and solution are contraindicated in patients with a known hypersensitivity to the drug or any of the ingredients in the various formulations.

Pregnancy

Pregnancy

Safe use of fluorouracil topical solution or cream during pregnancy has not been established.

Pharmacology

Fluorouracil acts as an antimetabolite interfering with DNA synthesis by inhibiting thymidylate synthetase activity. Thymidylate synthetase catalyzes the methylation of deoxyuridylic acid to thymidylic acid, a DNA precursor. Since topically applied fluorouracil shows a specificity for actinic keratoses, it has been suggested that absorption of the drug into cells is selectively greater in diseased skin than in normal skin.

Pharmacokinetics

Systemic absorption of fluorouracil following topical application appears to be insignificant (less than 5-10%). One manufacturer states that studies with radiolabeled drug indicate that following topical application, negligible amounts of the drug are absorbed systemically as determined by the radioactivity measured in plasma, urine, and expired carbon dioxide. In another study, 1 g of 5% fluorouracil in hydrophilic petrolatum was applied to diseased skin on the entire face (except the eyelids) and the neck. Approximately 6% of the drug was absorbed systemically.

To date, there is no published information regarding the metabolic fate of topically applied fluorouracil.

Chemistry and Stability

Chemistry

Fluorouracil is a fluorinated pyrimidine antagonist. The drug occurs as a white to practically white, practically odorless, crystalline powder and is sparingly soluble in water and slightly soluble in alcohol. One gram of fluorouracil is soluble in 100 mL of propylene glycol; however, solubility of the drug in propylene glycol increases with increases in pH.

For topical use, fluorouracil is commercially available as a solution (Efudex^®) containing 2 or 5% fluorouracil with propylene glycol, tromethamine, hydroxypropyl cellulose, methylparaben and propylparaben, and disodium edetate; a cream containing 0.5% fluorouracil (with 0.35% being incorporated into porous microspheres composed of methyl methacrylate/glycol dimethacrylate crosspolymer and dimethicone) and other excipients; a cream (Fluoroplex^®) containing 1% fluorouracil with emulsifying wax, mineral oil, isopropyl myristate, sodium hydroxide, and benzyl alcohol; and a cream (Efudex^®) containing 5% fluorouracil with white petrolatum, stearyl alcohol, propylene glycol, polysorbate 60, and methylparaben and propylparaben.

Stability

Fluorouracil creams and solutions should be stored at 15-30°C; freezing should be avoided.