Efudex prescribing info

DESCRIPTION: Efudex Solutions and Cream are topical preparations
containing the fluorinated pyrimidine 5-fluorouracil, an antineoplastic
antimetabolite.
Efudex Solution consists of 2% or 5% fluorouracil on a weight/weight
basis, compounded with propylene glycol, tris (hydroxymethyl) aminomethane,
hydroxypropyl cellulose, parabens (methyl and propyl) and
disodium edetate.
Efudex Cream contains 5% fluorouracil in a vanishing cream base consisting
of white petrolatum, stearyl alcohol, propylene glycol, polysorbate 60
and parabens (methyl and propyl).
Chemically, fluorouracil is 5-fluoro-2,4(1H,3H)-pyrimidinedione. It is a
white to practically white, crystalline powder which is sparingly soluble in
water and slightly soluble in alcohol. One gram of fluorouracil is soluble in
100 mL of propylene glycol. The molecular weight of 5-fluorouracil is
130.08 and the structural formula is:
CLINICAL PHARMACOLOGY: There is evidence that the metabolism of
fluorouracil in the anabolic pathway blocks the methylation reaction of
deoxyuridylic acid to thymidylic acid. In this manner fluorouracil interferes
with the synthesis of deoxyribonucleic acid (DNA) and to a lesser extent
inhibits the formation of ribonucleic acid (RNA). 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. The effects of DNA and RNA deprivation are most marked on
those cells which grow more rapidly and take up fluorouracil at a more
rapid rate. The catabolic metabolism of fluorouracil results in degradation
products (eg, CO2, urea, a-fluoro-b-alanine) which are inactive.
Systemic absorption studies of topically applied fluorouracil have been
performed on patients with actinic keratoses using tracer amounts of 14Clabeled
fluorouracil added to a 5% preparation. 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. One gram of labeled preparation was
applied to the entire face and neck and left in place for 12 hours. Urine
samples were collected. At the end of 3 days, 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. 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. In an
additional study, negligible amounts of labeled material were found in plasma,
urine and expired CO2 after 3 days of treatment with topically applied
14C-labeled fluorouracil.
INDICATIONS AND USAGE: Efudex is recommended for the topical treatment
of multiple actinic or solar keratoses. In the 5% strength it is also
useful in the treatment of superficial basal cell carcinomas when conventional
methods are impractical, such as with multiple lesions or difficult
treatment sites. Safety and efficacy in other indications have not been
established.
The diagnosis should be established prior to treatment, since this method
has not been proven effective in other types of basal cell carcinomas. With
isolated, easily accessible basal cell carcinomas, surgery is preferred
since success with such lesions is almost 100%. The success rate with
Efudex Cream and Solution is approximately 93%, based on 113 lesions in
54 patients. Twenty-five lesions treated with the solution produced 1 failure
and 88 lesions treated with the cream produced 7 failures.
CONTRAINDICATIONS: Efudex may cause fetal harm when administered
to a pregnant woman.
There are no adequate and well-controlled studies in pregnant women
with either the topical or the parenteral forms of fluorouracil. One birth
defect (cleft lip and palate) has been reported in the newborn of a patient
using Efudex as recommended. One birth defect (ventricular septal defect)
and cases of miscarriage have been reported when Efudex was applied to
mucous membrane areas. Multiple birth defects have been reported in a
fetus of a patient treated with intravenous fluorouracil.
Animal reproduction studies have not been conducted with Efudex.
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; however, the amount of fluorouracil absorbed
systemically after topical administration to actinic keratoses is minimal
(see CLINICAL PHARMACOLOGY). Fluorouracil exhibited maximum teratogenicity
when given to mice as single intraperitoneal injections of 10 to
40 mg/kg on Day 10 or 12 of gestation. Similarly, intraperitoneal doses of
12 to 37 mg/kg given to rats between Days 9 and 12 of gestation and intramuscular
doses of 3 to 9 mg/kg given to hamsters between Days 8 and 11
of gestation were teratogenic and/or embryotoxic (ie, resulted in increased
resorptions or embryolethality). In monkeys, divided doses of 40 mg/kg
given between Days 20 and 24 of gestation were not teratogenic. Doses
higher than 40 mg/kg resulted in abortion.
Efudex should not be used in patients with dihydropyrimidine dehydrogenase
(DPD) enzyme deficiency. A large percentage of fluorouracil is
catabolized by the DPD enzyme. DPD enzyme deficiency can result in
shunting of fluorouracil to the anabolic pathway, leading to cytotoxic activity
and potential toxicities.
Efudex is contraindicated in women who are or may become pregnant
during therapy. If this drug is used during pregnancy, or if the
patient becomes pregnant while using this drug, the patient should
be apprised of the potential hazard to the fetus.
Efudex is also contraindicated in patients with known hypersensitivity
to any of its components.
WARNINGS: Application to mucous membranes should be avoided
due to the possibility of local inflammation and ulceration.
Additionally, cases of miscarriage and a birth defect (ventricular septal
defect) have been reported when Efudex was applied to mucous
membrane areas during pregnancy.
Occlusion of the skin with resultant hydration has been shown to increase
percutaneous penetration of several topical preparations. 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. A porous gauze dressing may be applied for cosmetic reasons without
increase in reaction.
Exposure to ultraviolet rays should be minimized during and immediately
following treatment with Efudex because the intensity of the reaction may
be increased.
Patients should discontinue therapy with Efudex if symptoms of DPD
enzyme deficiency develop (see CONTRAINDICATIONS section).
Rarely, life-threatening toxicities such as stomatitis, diarrhea, neutropenia,
and neurotoxicity have been reported with intravenous administration of
fluorouracil in patients with DPD enzyme deficiency. One case of lifethreatening
systemic toxicity has been reported with the topical use of
Efudex in a patient with DPD enzyme deficiency. Symptoms included
severe abdominal pain, bloody diarrhea, vomiting, fever, and chills.
Physical examination revealed stomatitis, erythematous skin rash, neutropenia,
thrombocytopenia, inflammation of the esophagus, stomach, and
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small bowel. Although this case was observed with 5% fluorouracil
cream, it is unknown whether patients with profound DPD enzyme deficiency
would develop systemic toxicity with lower concentrations of topically
applied fluorouracil.
PRECAUTIONS: General: There is a possibility of increased absorption
through ulcerated or inflamed skin.
Information for Patients: Patients should be forewarned that the reaction
in the treated areas may be unsightly during therapy and, usually, for several
weeks following cessation of therapy. Patients should be instructed to
avoid exposure to ultraviolet rays during and immediately following treatment
with Efudex because the intensity of the reaction may be increased.
If Efudex is applied with the fingers, the hands should be washed immediately
afterward. Efudex should not be applied on the eyelids or directly into
the eyes, nose or mouth because irritation may occur.
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 longterm
studies in animals to evaluate carcinogenic potential have not been
conducted with fluorouracil. Studies with the active ingredient of Efudex, 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/10T1⁄ 2 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 (3
studies), fluorouracil has been shown to be mutagenic in the survival count
rec-assay with Bacillus subtilis and in the Drosophilia 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 (ie, chromatid gaps, breaks and
exchanges) in Chinese hamster fibroblasts at concentrations of 1.0 and
2.0 mg/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: Teratogenic Effects: Pregnancy Category X: See CONTRAINDICATIONS
section.
Nursing Mothers: It is not known whether Efudex 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 Efudex
occur locally and are often related to an extension of the pharmacological
activity of the drug. These include burning, crusting, allergic contact dermatitis,
erosions, erythema, hyperpigmentation, irritation, pain, photosensitivity,
pruritus, scarring, rash, soreness and ulceration. Ulcerations, other
local reactions, cases of miscarriage and a birth defect (ventricular septal
defect) have been reported when Efudex 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.
OVERDOSAGE: There have been no reports of overdosage with Efudex.
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 Efudex is applied to a lesion, a
response occurs with the following sequence: erythema, usually followed
by vesiculation, desquamation, erosion and reepithelialization.
Efudex should be applied preferably with a nonmetal applicator or suitable
glove. If Efudex 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 Efudex 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: Efudex Solution is available in 10-mL drop dispensers
containing either 2% (NDC 0187-3202-10) or 5% (NDC 0187-3203-10) fluorouracil
and 25-mL drop dispensers containing either 2% (NDC 0187-3202-
02) or 5% (NDC 0187-3203-02) fluorouracil on a weight/weight basis
compounded with propylene glycol, tris (hydroxymethyl) aminomethane,
hydroxypropyl cellulose, parabens (methyl and propyl) and disodium edetate.
Efudex Cream is available in 40-gm tubes (NDC 0187-3204-47) containing
5% fluorouracil in a vanishing cream base consisting of white petrolatum,
stearyl alcohol, propylene glycol, polysorbate 60 and parabens (methyl
and propyl).
Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F).
EFUDEX® (fluorouracil) EFUDEX® (fluorouracil)