warnings
WARNINGS AND PRECAUTIONS 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 topical fluorouracil 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 FLUORAC cream because the intensity of the reaction may be increased. Patients should discontinue therapy with FLUORAC if symptoms of DPD enzyme deficiency develop. 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 life-threatening systemic toxicity has been reported with the topical use of fluorouracil 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 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. There is a possibility of increased absorption through ulcerated or inflamed skin. 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 FLUORAC cream because the intensity of the reaction may be increased. If FLUORAC is applied with the fingers, the hands should be washed immediately afterward. FLUORAC should not be applied on the eyelids or directly into the eyes, nose or mouth because irritation may occur. 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. Adequate long-term studies in animals to evaluate carcinogenic potential have not been conducted with fluorouracil cream. Studies with the active ingredient of FLUORAC, 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 (ie, chromatid gaps, breaks and exchanges) in Chinese hamster fibroblasts at concentrations of 1.0 and 2.0 µg/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. Serious and potentially fatal cardiovascular (CV) thrombotic events, myocardial infarction, and stroke can occur with NSAID treatment. The lowest possible dose of FLUORAC cream should be used in patients with known CV disease or risk factors for CV disease. It is not known whether fluorouracil cream is excreted in human milk. Because there is some systemic absorption of fluorouracil after topical administration, 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. Safety and effectiveness in children have not been established. NSAIDs, including diclofenac, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation. FLUORAC cream should be prescribed with caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Elevation of one or more liver tests may occur during therapy with diclofenac. FLUORAC cream should be discontinued immediately if abnormal liver tests persist or worsen. Long-term administration of NSAIDs can result in renal papillary necrosis and other renal injury. FLUORAC cream should be used with caution in patients at greatest risk of this reaction, including the elderly, those with impaired renal function, heart failure, liver dysfunction, and those taking diuretics and ACE-inhibitors. Hypertension can occur with NSAID treatment. Blood pressure should be monitored closely during treatment with FLUORAC cream. Fluid retention and edema have been observed in some patients taking NSAIDs. FLUORAC cream should be used with caution in patients with fluid retention or heart failure. Anaphylactoid reactions may occur in patients with the aspirin triad or in patients without prior exposure to FLUORAC cream and should be discontinued immediately if an anaphylactoid reaction occurs. NSAIDs can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. FLUORAC cream should be discontinued if rash or other signs of local skin reaction occur.