Fluorouracil (Page 2 of 2)

Laboratory Tests

Solar keratoses which do not respond should be biopsied to confirm the diagnosis. Follow-up biopsies should be performed as indicated in the management of superficial basal cell carcinoma.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Adequate long-term studies in animals to evaluate carcinogenic potential have not been conducted with fluorouracil. Studies with the active ingredient of Fluorouracil 5% Topical Cream, 5-fluorouracil, have shown positive effects in in vitro tests for mutagenicity and on impairment of fertility.

5-Fluorouracil was positive in three in vitro cell neoplastic transformation assays. In the C3H/10T½ clone 8 mouse embryo cell system, the resulting morphologically transformed cells formed tumors when inoculated into immunosuppressed syngeneic mice.

While no evidence for mutagenic activity was observed in the Ames test (three studies), fluorouracil has been shown to be mutagenic in the survival count rec-assay with Bacillus subtilis and in the Drosophila wing-hair spot test. Fluorouracil produced petite mutations in Saccharomyces cerevisiae and was positive in the micronucleus test (bone marrow cells of male mice).

Fluorouracil was clastogenic in vitro (i.e., chromatid gaps, breaks, and exchanges) in Chinese hamster fibroblasts at concentrations of 1.0 and 2.0 mcg/mL and has been shown to increase sister chromatid exchange in vitro in human lymphocytes. In addition, 5-fluorouracil has been reported to produce an increase in numerical and structural chromosome aberrations in peripheral lymphocytes of patients treated with this product.

Doses of 125 to 250 mg/kg, administered intraperitoneally, have been shown to induce chromosomal aberrations and changes in chromosome organization of spermatogonia in rats. Spermatogonial differentiation was also inhibited by fluorouracil, resulting in transient infertility. However, in studies with a strain of mouse which is sensitive to the induction of sperm head abnormalities after exposure to a range of chemical mutagens and carcinogens, fluorouracil was inactive at oral doses of 5 to 80 mg/kg/day. In female rats, fluorouracil administered intraperitoneally at doses of 25 and 50 mg/kg during the preovulatory phase of oogenesis significantly reduced the incidence of fertile matings, delayed the development of preimplantation and postimplantation embryos, increased the incidence of preimplantation lethality and induced chromosomal anomalies in these embryos. Single-dose intravenous and intraperitoneal injections of 5-fluorouracil have been reported to kill differentiated spermatogonia and spermatocytes (at 500 mg/kg) and to produce abnormalities in spermatids (at 50 mg/kg) in mice.

Pregnancy

See CONTRAINDICATIONS.

Nursing Mothers

It is not known whether Fluorouracil 5% Topical Cream is excreted in human milk. Because there is some systemic absorption of fluorouracil after topical administration (see CLINICAL PHARMACOLOGY), because many drugs are excreted in human milk, and 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 the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in children have not been established.

ADVERSE REACTIONS

The most frequent adverse reactions to Fluorouracil 5% Topical Cream occur locally and are often related to an extension of the pharmacological activity of the drug. These include burning, crusting, allergic contact dermatitis, pruritus, scarring, rash, soreness, and ulceration. Ulcerations, other local reactions, cases of miscarriage, and a birth defect (ventricular septal defect) have been reported when Fluorouracil 5% Topical Cream was applied to mucous membrane areas. Leukocytosis is the most frequent hematological side effect.

Although a causal relationship is remote, other adverse reactions which have been reported infrequently are:

Central Nervous System: Emotional upset, insomnia, irritability.

Gastrointestinal: Medicinal taste, stomatitis.

Hematological: Eosinophilia, thrombocytopenia, toxic granulation.

Integumentary: Alopecia, blistering, bullous pemphigoid, discomfort, ichthyosis, scaling, suppuration, swelling, telangiectasia, tenderness, urticaria, skin rash.

Special Senses: Conjunctival reaction, corneal reaction, lacrimation, nasal irritation.

Miscellaneous: Herpes simplex.

To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

OVERDOSAGE

There have been no reports of overdosage with Fluorouracil 5% Topical Cream.

The oral LD50 for the 5% topical cream was 234 mg/kg in rats and 39 mg/kg in dogs. These doses represented 11.7 and 1.95 mg/kg of fluorouracil, respectively. Studies with a 5% topical solution yielded an oral LD50 of 214 mg/kg in rats and 28.5 mg/kg in dogs, corresponding to 10.7 and 1.43 mg/kg of fluorouracil, respectively. The topical application of the 5% cream to rats yielded an LD50 of greater than 500 mg/kg.

DOSAGE AND ADMINISTRATION

When Fluorouracil 5% Topical Cream is applied to a lesion, a response occurs with the following sequence: erythema, usually followed by vesiculation, desquamation, erosion, and re-epithelialization.

Fluorouracil 5% Topical Cream should be applied preferably with a nonmetal applicator or suitable glove. If Fluorouracil 5% Topical Cream is applied with the fingers, the hands should be washed immediately afterward.

Actinic or Solar Keratosis

Apply cream or solution twice daily in an amount sufficient to cover the lesions. Medication should be continued until the inflammatory response reaches the erosion stage, at which time use of the drug should be terminated. The usual duration of therapy is from 2 to 4 weeks. Complete healing of the lesions may not be evident for 1 to 2 months following cessation of Fluorouracil 5% Topical Cream therapy.

Superficial Basal Cell Carcinomas

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

HOW SUPPLIED

Fluorouracil 5% Topical Cream is available in 40 g tubes containing 5% fluorouracil (NDC 0378-4791-06) in a vanishing cream base consisting of methylparaben, polysorbate 60, propylene glycol, propylparaben, purified water, stearyl alcohol, and white petrolatum.

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).

Manufactured for:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

1337.3

Revised: 6/2021
FLUOR:R3

PRINCIPAL DISPLAY PANEL – 5%

NDC 0378-4791-06 Rx only

Fluorouracil Topical Cream 5%

FOR TOPICAL USE ONLY — NOT FOR OPHTHALMIC, ORAL, OR INTRAVAGINAL USE

40 g

Each gram contains: 5% fluorouracil in a vanishing cream base consisting of methylparaben, polysorbate 60, propylene glycol, propylparaben, purified water, stearyl alcohol, and white petrolatum.

Apply preferably with a nonmetal applicator or suitable glove.

Manufactured for:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Product of Mexico

Usual Dosage: For dosage recommendations and other important prescribing information, see accompanying insert.

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).

FOR TOPICAL USE ONLY

Keep out of reach of children.
May be fatal if your pet licks or ingests.
Avoid allowing pets to contact this tube or your skin where Fluorouracil 5%
Topical Cream has been applied. Store and dispose out of the reach of pets.

M:4791:06:1C:R6
1231.6

Fluorouracil Topical Cream 5% Carton Label
(click image for full-size original)
FLUOROURACIL
fluorouracil cream
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0378-4791
Route of Administration TOPICAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
FLUOROURACIL (FLUOROURACIL) FLUOROURACIL 5 mg in 1 g
Inactive Ingredients
Ingredient Name Strength
PETROLATUM
STEARYL ALCOHOL
PROPYLENE GLYCOL
POLYSORBATE 60
METHYLPARABEN
PROPYLPARABEN
WATER
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:0378-4791-06 1 TUBE in 1 CARTON contains a TUBE
1 40 g in 1 TUBE This package is contained within the CARTON (0378-4791-06)
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA authorized generic NDA016831 09/19/2013
Labeler — Mylan Pharmaceuticals Inc. (059295980)

Revised: 06/2021 Mylan Pharmaceuticals Inc.

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