There is a possibility of increased absorption through
ulcerated or inflamed skin.
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 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/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 (3 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.
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
Safety and effectiveness in children have not been