Fluorouracil (Topical)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Cream, External:

Carac: 0.5% (30 g) [contains methylparaben, polysorbate 80, propylene glycol, propylparaben, trolamine (triethanolamine)]

Efudex: 5% (40 g)

Fluoroplex: 1% (30 g) [contains benzyl alcohol]

Tolak: 4% (40 g) [contains cetyl alcohol, methylparaben, peanut oil, propylparaben]

Generic: 0.5% (30 g); 5% (40 g)

Solution, External:

Generic: 2% (10 mL); 5% (10 mL)

Pharmacology

Mechanism of Action

A pyrimidine antimetabolite that interferes with DNA synthesis by blocking the methylation of deoxyuridylic acid to thymidylic acid; blocks DNA synthesis to prevent cell proliferation of fast growing cells and cause cell death.

Pharmacokinetics/Pharmacodynamics

Absorption

~6% of a topical dose is absorbed systemically (5% cream)

Time to Peak

~1 hour following application (4% cream)

Use: Labeled Indications

Actinic or solar keratosis: Management of multiple actinic or solar keratoses

Basal cell carcinoma (5%): Treatment of superficial basal cell carcinomas when conventional methods are impractical (eg, due to multiple lesions or difficult treatment sites)

Limitations of use: Establish diagnosis of superficial basal cell carcinoma prior to treatment (use has not been proven effective in other types of basal cell carcinomas); surgery is preferred with isolated, easily accessible basal cell carcinomas because success with such lesions is almost 100% and the success rate with fluorouracil cream and solution is ~93%.

Contraindications

Hypersensitivity to fluorouracil or any component of the formulation; dihydropyrimidine dehydrogenase (DPD) enzyme deficiency; women who are or may become pregnant

Dosage and Administration

Dosing: Adult

Actinic or solar keratosis: Topical:

Cream (0.5%): Apply thin film to lesions once daily for up to 4 weeks, as tolerated

Cream (1%): Apply to lesions twice daily for 2 to 6 weeks

Cream (4%): Apply to lesions once daily for 4 weeks as tolerated

Cream (5%) or solution (2% and 5%): Apply to lesions twice daily for 2 to 4 weeks; complete healing may not be evident for 1 to 2 months following treatment

Superficial basal cell carcinoma: Topical: Cream (5%) or solution (5%): Apply to affected lesions twice daily for 3 to 6 weeks; treatment may be continued for up to 10 to 12 weeks

Dosing: Geriatric

Refer to adult dosing.

Administration

Topical: Apply 10 minutes after washing, rinsing, and drying the affected area. Apply a sufficient amount to cover lesions, preferably using a nonmetal applicator or suitable glove.

Cream (4%): Apply after washing, rinsing, and drying the affected area. Apply a sufficient amount to cover lesions of the face, ears, and/or scalp with a thin film, using fingertips to gently massage uniformly into skin.

If applied with fingertip, wash hands immediately after application. Do not cover area with an occlusive dressing. Topical preparations are for external use only; not for ophthalmic, oral, mucous membrane, or intravaginal use.

Storage

Store at controlled room temperature of 15°C to 30°C (59°F to 86°F). Do not freeze.

Drug Interactions

Fosphenytoin: Fluorouracil (Topical) may increase the serum concentration of Fosphenytoin. Monitor therapy

Gemcitabine: May increase the serum concentration of Fluorouracil (Topical). Monitor therapy

Leucovorin Calcium-Levoleucovorin: May enhance the adverse/toxic effect of Fluorouracil (Topical). Monitor therapy

Phenytoin: Fluorouracil (Topical) may increase the serum concentration of Phenytoin. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Fluorouracil (Topical) may increase the serum concentration of Vitamin K Antagonists. Monitor therapy

Adverse Reactions

>10%:

Dermatologic: Application site scaling (≤95%), application site dryness (70% to ≤95%), stinging of the skin (application site: ≤87%), skin erosion (application site: 25% to 68%)

Local: Application site erythema (90% to 99%), application site reaction (92% to 97%; crusting: 87%), application site burning (60% to ≤87%), application site pruritus (85%), application site edema (14% to 69%), application site pain (31% to 61%)

1% to 10%:

Central nervous system: Headache (4%)

Dermatologic: Skin irritation (1% to 2%)

Infection: Common cold (5%)

Ophthalmic: Eye irritation (3% to 7%; burning, watering, sensitivity, stinging, itching)

Respiratory: Sinusitis (5%)

<1%, postmarketing, and/or case reports: Allergic contact dermatitis, alopecia, anxiety, bullous pemphigoid, burning sensation of skin, conjunctival irritation, conjunctivitis, corneal disease, eosinophilia, eye irritation, herpes simplex infection, hyperpigmentation, ichthyosis, inflammation, insomnia, irritability, lacrimation, leukocytosis, lymphocytic leukemia, medicine-like taste, muscle tenderness, nasal discomfort, pain, pancytopenia, pruritus, scarring, skin blister, skin irritation, skin neoplasm (nonmelanoma), skin photosensitivity, skin rash, skin tenderness, stomatitis, suppuration, swelling, swelling of eye, telangiectasia, thrombocytopenia, toxic granulations, ulcer, urticaria

Warnings/Precautions

Concerns related to adverse effects:

• Hypersensitivity: May be associated with delayed-type hypersensitivity reactions, including allergic contact dermatitis. Severe pruritus or eczema (at the application site or at a distant site) may be indicative of hypersensitivity. Patch testing may not be useful in the evaluation of these reactions. Discontinue immediately for signs of hypersensitivity.
• Local skin reactions: When applied to a lesion, erythema followed by vesiculation, desquamation, erosion and reepithelialization occurs. Local reactions and alterations in skin appearance may persist for several weeks after discontinuation. Bruising, burning, crusting, dryness, edema, irritation, pain, pruritus, scaling, scarring, soreness, stinging, and ulceration may commonly result from topical therapy. Increased absorption through ulcerated or inflamed skin is possible.
• Photosensitivity: Topical fluorouracil is associated with photosensitivity, including severe sunburn. Avoid prolonged exposure to sunlight or UV irradiation during treatment; reaction intensity may be increased.

Disease-related concerns:

• Dihydropyrimidine dehydrogenase enzyme deficiency: Individuals lacking dihydropyrimidine dehydrogenase (DPD) enzyme activity may exhibit severe toxicity with topical fluorouracil. Life-threatening systemic toxicity has been reported with the topical use of fluorouracil in a patient with DPD enzyme deficiency; signs/symptoms included bloody diarrhea, stomatitis, esophagus, stomach, and small bowel inflammation, severe abdominal pain, vomiting, chills, fever, erythematous skin rash, neutropenia, and thrombocytopenia. It is unknown if patients with profound DPD enzyme deficiency would develop systemic toxicity with lower concentrations of topical fluorouracil. Discontinue if signs of DPD deficiency develop.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension and cardiovascular collapse (AAP ["Inactive"[, 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors, 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer’s labeling.
• Peanut oil: Some dosage forms contain peanut oil.

Other warnings/precautions:

• Appropriate use: Avoid topical application to mucous membranes due to potential for local inflammation and ulceration; cases of miscarriage and a birth defect (ventricular septal defect) have been reported when fluorouracil was applied to mucous membrane areas during pregnancy. The use of occlusive dressings with topical preparations may increase the severity of inflammation in nearby skin areas (a porous gauze dressing may be applied for cosmetic reasons without increase in reaction). Avoid eyelids, eyes, and periocular area when applying (corneal and conjunctival disorders have occurred with topical fluorouracil). Wash hands well following application; if ocular exposure occurs, flush with large amounts of water.

Pregnancy

Pregnancy Considerations

Use is contraindicated in women who are or who may become pregnant. Adverse effects, including ventricular septal defect and miscarriage, have been reported following topical application of fluorouracil products to mucous membranes in pregnant women.

Women of reproductive potential should use effective contraception during and for 1 month after the final application of topical fluorouracil.

Patient Education

What is this drug used for?

• It is used to treat a precancerous skin problem called actinic keratosis.

Frequently reported side effects of this drug

• Burning
• Dry skin
• Redness

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Severe abdominal pain
• Bloody diarrhea
• Vomiting
• Severe skin irritation
• Severe diarrhea
• Vision changes
• Eye pain
• Severe eye irritation
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.