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Fluorouracil (Topical)


VA CLASSIFICATION
Primary: DE600

Commonly used brand name(s): Efudex; Fluoroplex.

Another commonly used name is
5-FU .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antineoplastic, topical—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Actinic keratoses, multiple (treatment)
[Actinic cheilitis (treatment)]1
[Leukoplakia, mucosal (treatment)]1
[Radiodermatitis (treatment)]1
[Bowen's disease (treatment)]1or
[Erythroplasia of Queyrat (treatment)]1—Topical fluorouracil is indicated for treatment of precancerous skin conditions including multiple actinic (solar) keratoses, actinic cheilitis, mucosal leukoplakia, radiodermatitis, Bowen's disease, and erythroplasia of Queyrat.

Carcinoma, skin (treatment)—Topical fluorouracil is indicated for treatment of superficial basal cell carcinomas (multiple lesions or difficult access sites), although conventional treatment is preferred whenever possible.

Note: The diagnosis should be established prior to treatment, since topical fluorouacil has not been proven effective in other types of basal cell carcinomas {02}. Surgery is preferred with isolated, easily accessible basal cell carcinomas, since success with such lesions is almost 100% {02}. The success rate with fluorouracil cream and solution is approximately 93% {02}.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    130.08

pKa—
    8 and 13

Mechanism of action/Effect:

There is evidence that the metabolism of fluorouracil via the anabolic pathway blocks the methylation reaction of deoxyuridylic acid to thymidylic acid {02}. In this manner fluorouracil interferes with the synthesis of DNA and, to a lesser extent, inhibits the formation of RNA {02}. Since DNA and RNA are essential for cell division and growth, the effect of fluorouracil may be to create a thymine deficiency, which provokes unbalanced growth and death of the cell {02}. The effects of DNA and RNA deprivation are most marked on cells that grow more rapidly and take up fluorouracil at a more rapid rate {02}.

Absorption:

Systemic absorption studies of topically applied fluorouracil have been performed on patients with actinic keratoses using tracer amounts of carbon-labeled fluorouracil added to a 5% preparation {02}. All patients had been receiving nonlabeled fluorouracil until the peak of the inflammatory reaction occurred (2 to 3 weeks), ensuring that the time of maximum absorption was used for measurement {02}. One gram of labeled preparation was applied to the entire face and neck and left in place for 12 hours {02}. At the end of 3 days, urine samples were collected {02}. The total recovery ranged between 0.48% and 0.94% with an average of 0.76%, indicating that approximately 5.98% of the topical dose was absorbed systemically {02}. If applied twice daily, this would indicate systemic absorption of topical fluorouracil to be in the range of 5 to 6 mg per daily dose of 100 mg {02}.

Distribution:

In one clinical study, negligible amounts of labeled material were found in the plasma after 3 days of treatment with topically applied carbon-labeled fluorouracil {02}.

Onset of action:

2 to 3 days. A treatment period of 2 to 6 weeks is usually required to reach the erosion and necrosis stage, or up to 12 weeks in some patients with superficial basal cell carcinomas. Complete healing may not occur until 1 to 2 months after therapy is stopped.


Precautions to Consider

Carcinogenicity

Studies have not been done {04}. However, morphological transformation of cells was produced by fluorouracil in three in vitro cell transformation assays {04}. In one of these assays, a metabolite of fluorouracil produced morphological transformation, and injection of the transformed cells into immunosuppressed syngeneic mice produced malignant tumors {04}.

Mutagenicity

Parenteral administration of fluorouracil in humans at cumulative doses of 240 mg to 1 gram has produced an increase in numerical and structural chromosome aberrations in peripheral blood lymphocytes {04}. Fluorouracil is mutagenic in yeast cells, Bacillus subtilis , and Drosophila assays {04}. It produced chromosome damage in an in vitro hamster fibroblast assay at concentrations of 1 and 2 mcg per liter and increased micronuclei formation in the bone marrow of mice at intraperitoneal doses within the human therapeutic dose range of 12 to 15 mg per kg of body weight (mg/kg) per day {04}. Results of the dominant lethal mutation assay performed in mice were negative {04}.

Pregnancy/Reproduction
Fertility—
Parenteral fluorouracil impairs fertility in rats {04}. In mice, single-dose intravenous and intraperitoneal injections of fluorouracil killed differentiated spermatogonia and spermatocytes at a dose of 500 mg/kg and produced abnormalities in spermatids at a dose of 50 mg/kg {04}.

Pregnancy—
Adequate and well-controlled studies with either the topical or the parenteral forms of fluorouracil have not been done in humans {02}. However, topical fluorouracil may cause fetal harm when administered to a pregnant woman {02}. One case of birth defect, cleft lip and palate, has been reported in the newborn of a patient using topical fluorouracil as recommended. One case of birth defect, ventricular septal defect, and some cases of miscarriage have been reported when topical fluorouracil was applied to mucous membrane areas {02}. Multiple birth defects were reported in the fetus of a patient treated with intravenous fluorouracil {02}.

Studies with topical fluorouracil have not been done in animals {02}. Fluorouracil administered parenterally has been shown to be teratogenic in mice, rats, and hamsters when given at doses equivalent to the usual human intravenous dose {02}. However, the amount of fluorouracil absorbed systemically after topical administration to actinic keratoses is minimal {02}.

FDA Pregnancy Category X {03}.

Breast-feeding

It is not known whether topical fluorouracil is distributed into breast milk {02}. However, there is some systemic absorption of fluorouracil after topical administration {02}. Therefore, because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue use of topical fluorouracil, taking into account the importance of topical fluorouracil treatment to the mother {02}.

Pediatrics

Appropriate studies on the relationship of age to the effects of topical fluorouracil have not been performed in the pediatric population. Safety and efficacy have not been established {02}.


Geriatrics


Appropriate studies on the relationship of age to the effects of topical fluorouracil have not been performed in the geriatric population. However, geriatrics-specific problems that would limit the usefulness of this medication in elderly patients are not expected.


Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Eosinophilia and
Leukocytosis and
Thrombocytopenia and
Toxic granulation    (may occur)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Hemorrhagic ulcerated tissues    (significant systemic absorption and toxicity may occur)


Pre-existing dermatoses, especially chloasma and rosacea    (may be accentuated by the inflammatory response to fluorouracil)


» Sensitivity to fluorouracil{03}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Biopsy    (recommended to confirm diagnosis if actinic (solar) keratoses do not respond or if they recur after treatment, and to confirm cure of superficial basal cell carcinomas)




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Inflammatory response or allergic reaction (redness and swelling of normal skin)

Note: A delayed hypersensitivity reaction may occur {04}. Patch testing for hypersensitivity may be inconclusive {04}.




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Burning feeling at site of application
    
contact dermatitis (skin rash)
    
increased sensitivity of skin to sunlight
    
itching
    
oozing
    
soreness or tenderness of skin

Incidence less frequent or rare
    
Darkening of skin
    
scaling
    
watery eyes





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Fluorouracil (Topical).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to fluorouracil

Pregnancy—Use not recommended because of teratogenic potential; some systemic absorption occurs





Breast-feeding—Not recommended because of risk of serious side effects; some systemic systemic absorption occurs

Proper use of this medication
» Compliance with therapy; applying enough medication to cover affected areas

Washing area to be treated with soap and water and drying thoroughly; using cotton-tipped applicator or fingertips to apply

» Washing hands immediately after application if fingertips are used {01}

Possible unsightly and uncomfortable reaction during therapy and for several weeks after therapy is completed; possible temporary pink, smooth spot left during healing; checking with physician before discontinuing medication

» Proper dosing
Missed dose: Applying as soon as remembered; not applying if not remembered within a few hours; checking with physician if more than one dose is missed

» Proper storage

Precautions while using this medication
» Importance of close monitoring by physician

» Caution in applying medication; avoiding eyes, nose, and mouth

» Possible photosensitivity reactions during therapy and for 1 or 2 months after therapy is completed; avoiding sun; using protective clothing and sun block product; avoiding use of sunlamp, tanning bed, or tanning booth


Side/adverse effects
Signs of potential side effects, especially inflammatory response or allergic reaction


General Dosing Information
Patients using topical fluorouracil should be under supervision of a physician experienced in use of the medication.

Patients should be forewarned that the reaction in the treated areas may be unsightly during therapy and, usually, following cessation of therapy {02}. Patients should be instructed to avoid exposure to ultraviolet rays during and immediately following treatment with topical fluorouracil because the intensity of the reaction may be increased {02}. If topical fluorouracil is applied with the fingers, the hands should be washed immediately afterward {02}. Topical fluorouracil should not be applied on the eyelids or directly into the eyes, nose, or mouth, because irritation may occur {02}.

When topical fluorouracil is applied to a lesion, a response occurs in the following sequence: erythema, usually followed by vesiculation, desquamation, erosion, and epithelialization {02}.

Fluorouracil cream or solution should be applied twice daily on actinic or solar keratoses in an amount sufficient to cover the lesions {02}. Medication should be continued until the inflammatory response reaches the erosion stage, at which time use of topical fluorouracil should be terminated {02}. The usual duration of therapy is from 2 to 4 weeks {02}. Complete healing of the lesions may not be evident for 1 to 2 months following cessation of topical fluorouracil therapy {02}.

In superficial basal cell carcinomas, only the 5% strength is recommended {02}. Fluorouracil cream or solution should be applied twice daily in an amount sufficient to cover the lesions {02}. Treatment should be continued for at least 3 to 6 weeks {02}. Therapy may be required for as long as 10 to 12 weeks before the lesions are obliterated {02}. As in any neoplastic condition, the patient should be followed for a reasonable period of time to determine if a cure has been obtained {02}.

Occlusion of the skin with consequent hydration has been shown to increase percutaneous penetration of several topical preparations {02}. Therefore, if any occlusive dressing is used in treatment of basal cell carcinoma, there may be an increase in the severity of inflammatory reactions in the adjacent normal skin {02}. A porous gauze dressing may be applied for cosmetic reasons without an increase in reaction {02}.

It is recommended that treatment with fluorouracil be discontinued if an excessive inflammatory response occurs on normal skin.


Topical Dosage Forms

FLUOROURACIL CREAM USP

Usual adult dose
Actinic (solar keratoses)
Topical, to the skin, as a 1% cream once or twice a day in a sufficient amount to cover the lesions. Usually the 1% strength is effective on the head, neck, and chest; 2 to 5% may be needed on the hands.

Superficial basal cell carcinomas
Topical, to the skin, as a 5% cream twice a day in a sufficient amount to cover the lesions, for at least three to six weeks, and possibly up to twelve weeks.


Usual pediatric dose
Safety and efficacy have not been established {04}.

Strength(s) usually available
U.S.—


1% (Rx) [Fluoroplex (benzyl alcohol)]{03}


5% (Rx) [Efudex (methylparaben) (propylparaben)]{01}

Canada—


1% (Rx) [Fluoroplex (benzyl alcohol)]


5% (Rx) [Efudex]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by the manufacturer. Store in a tight container.

Auxiliary labeling:
   • For the skin.
   • Continue medicine for full course of treatment.
   • Avoid overexposure to sun.


FLUOROURACIL TOPICAL SOLUTION USP

Usual adult dose
Actinic (solar keratoses)
Topical, to the skin, as a 1 or 2% solution once or twice a day in a sufficient amount to cover the lesions. Usually the 1% strength is effective on the head, neck, and chest; 2 to 5% may be needed on the hands.

Superficial basal cell carcinomas
Topical, to the skin, as a 5% solution twice a day in a sufficient amount to cover the lesions, for at least three to six weeks, and possibly up to twelve weeks.


Usual pediatric dose
Safety and efficacy have not been established {04}.

Strength(s) usually available
U.S.—


1% (Rx) [Fluoroplex]


2% (Rx) [Efudex (methylparaben) (propylparaben)]{01}


5% (Rx) [Efudex (methylparaben) (propylparaben)]{01}

Canada—


1% (Rx) [Fluoroplex]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container. Protect from freezing.

Auxiliary labeling:
   • For the skin.
   • Continue medicine for full course of treatment.
   • Avoid overexposure to sun.



Revised: 09/30/1997



References

Note: References used in the development and subsequent revisions of this monograph have not been incorporated into the database and therefore are not listed below.

  1. Efudex package insert (Roche—US), Rev 12/85.
  1. Efudex package insert (Roche—US), Rev 5/95, Rec 7/97.
  1. Fluoroplex package insert (Herbert—US), Rev 2/87.
  1. Fluoroplex product information (Herbert—US), 1992 PDR.
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