Fluorouracil Cream

The following were adverse events considered to be drug-related and occurring with a frequency of ≥ 1% with Fluorouracil Cream USP, 0.5% (Microsphere): application site reaction (94.6%), and eye irritation (5.4%). The signs and symptoms of facial irritation (application site reaction) are presented below.

Summary of Facial Irritation Signs and Symptoms - Pooled Phase 3 Studies

During clinical trials, irritation generally began on day 4 and persisted for the remainder of treatment. Severity of facial irritation at the last treatment visit was slightly below baseline for the vehicle group, mild to moderate for the 1 week active treatment group, and moderate for the 2 and 4 week active treatment groups. Mean severity declined rapidly for each active group after completion of treatment and was below baseline for each group at the week 2 post-treatment follow-up visit.

Thirty-one patients (12% of those treated with Fluorouracil Cream USP, 0.5% (Microsphere) in the Phase 3 clinical studies) discontinued study treatment early due to facial irritation. Except for three patients, discontinuation of treatment occurred on or after day 11 of treatment.

Eye irritation adverse events, described as mild to moderate in intensity, were characterized as burning, watering, sensitivity, stinging and itching. These adverse events occurred across all treatment arms in one of the two Phase 3 studies.

Summary of All Adverse Events Reported in ≥ 1% of Patients in the Combined Active Treatment and Vehicle Groups - Pooled Phase 3 Studies
9721 and 9722 Combined

Adverse Experiences Reported By Body System

In the Phase 3 studies, no serious adverse event was considered related to study drug. A total of five patients, three in the active treatment groups and two in the vehicle group, experienced at least one serious adverse event. Three patients died as a result of adverse event(s) considered unrelated to study drug (stomach cancer, myocardial infarction and cardiac failure).

Post-treatment clinical laboratory tests other than pregnancy tests were not performed during the Phase 3 clinical studies. Clinical laboratory tests were performed during conduct of a Phase 2 study of 104 patients and 21 patients in a Phase 1 study. No abnormal serum chemistry, hematology, or urinalysis results in these studies were considered clinically significant.

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© Fluorouracil Cream Patient Information is supplied by Cerner Multum, Inc. and Fluorouracil Cream Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

Fluorouracil Cream USP, 0.5% (Microsphere), contains fluorouracil for topical dermatologic use. Chemically, fluorouracil is 5-fluoro-2,4(1H, 3H)-pyrimidinedione. The molecular formula is C4H3FN2O2. Fluorouracil has a molecular weight of 130.08.

*Fluorouracil Cream USP, 0.5% (Microsphere) contains 0.5% fluorouracil, with 0.425% being incorporated into a porous microsphere composed of methyl methacrylate/glycol dimethacrylate crosspolymer and dimethicone. The cream formulation contains the following other inactive ingredients: carbomer 980, dimethicone, glycerin, methyl gluceth-20, methyl methacrylate/glycol dimethacrylate crosspolymer, methylparaben, octyl hydroxy stearate, polyethylene glycol 400, polysorbate 80, propylene glycol, propylparaben, purified water, sorbitan monooleate, stearic acid, and trolamine.

Fluorouracil may cause fetal harm when administered to a pregnant woman. Fluorouracil is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

No adequate and well-controlled studies have been conducted in pregnant women with either topical or parenteral forms of fluorouracil. One birth defect (ventricular septal defect) and cases of miscarriage have been reported when fluorouracil was applied to mucous membrane areas. Multiple birth defects have been reported in the fetus of a patient treated with intravenous fluorouracil.

Animal reproduction studies have not been conducted with Fluorouracil Cream USP, 0.5% (Microsphere). Fluorouracil, the active ingredient, has been shown to be teratogenic in mice, rats, and hamsters when administered parenterally at doses greater than or equal to 10, 15 and 33 mg/kg/day, respectively, [4X, 11X and 20X, respectively, the Maximum Recommended Human Dose (MRHD) based on body surface area (BSA)]. Fluorouracil was administered during the period of organogenesis for each species. Embryolethal effects occurred in monkeys at parenteral doses greater than 40 mg/kg/day (65X the MRHD based on BSA) administered during the period of organogenesis.

Fluorouracil Cream USP, 0.5% (Microsphere) should not be used in patients with dihydropyrimidine dehydrogenase (DPD) enzyme deficiency. A large percentage of fluorouracil is catabolized by the enzyme dihydropyrimidine dehydrogenase (DPD). DPD enzyme deficiency can result in shunting of fluorouracil to the anabolic pathway, leading to cytotoxic activity and potential toxicities.

Fluorouracil Cream USP, 0.5% (Microsphere) is contraindicated in patients with known hypersensitivity to any of its components.

General

There is a possibility of increased absorption through ulcerated or inflamed skin.

Information for the Patient

Patients using Fluorouracil Cream USP, 0.5% (Microsphere) should receive the following information and instructions:

1. This medication is to be used as directed.
2. This medication should not be used for any disorder other than that for which it was prescribed.
3. It is for external use only.
4. Avoid contact with the eyes, eyelids, nostrils, and mouth.
5. Cleanse affected area and wait 10 minutes before applying Fluorouracil Cream USP, 0.5% (Microsphere).
6. Wash hands immediately after applying Fluorouracil Cream USP, 0.5% (Microsphere).
7. Avoid prolonged exposure to sunlight or other forms of ultraviolet irradiation during treatment, as the intensity of the reaction may be increased.
8. Most patients using Fluorouracil Cream USP, 0.5% (Microsphere) get skin reactions where the medicine is used. These reactions include redness, dryness, burning, pain, erosion (loss of the upper layer of skin), and swelling. Irritation at the application site may persist for two or more weeks after therapy is discontinued. Treated areas may be unsightly during and after therapy.
9. If you develop abdominal pain, bloody diarrhea, vomiting, fever, or chills while on Fluorouracil Cream USP, 0.5% (Microsphere) therapy, stop the medication and contact your physician and/or pharmacist.
10. Report any side effects to the physician and/or pharmacist.

Laboratory Tests

To rule out the presence of a frank neoplasm, a biopsy may be considered for those areas failing to respond to treatment or recurring after treatment.

Carcinogenesis, Mutagenesis and 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 Cream USP, 0.5% (Microsphere), fluorouracil, have shown positive effects in in vitro and in vivo tests for mutagenicity and on impairment of fertility in in vivo animal studies.

Fluorouracil produced morphological transformation of cells in in vitro cell transformation assays. Morphological transformation was also produced in an in vitro assay by a metabolite of fluorouracil, and the transformed cells produced malignant tumors when injected into immunosuppressed syngeneic mice. Fluorouracil has been shown to exert mutagenic activity in yeast cells, Bacillus subtilis, and Drosophila assays. In addition, fluorouracil has produced chromosome damage at concentrations of 1.0 and 2.0 mcg/mL in an in vitro hamster fibroblast assay, was positive in a microwell mouse lymphoma assay, and was positive in in vivo micronucleus assays in rats and mice following intraperitoneal administration. Some patients receiving cumulative doses of 0.24 to 1.0 g of fluorouracil parenterally have shown an increase in numerical and structural chromosome aberrations in peripheral blood lymphocytes.

Fluorouracil has been shown to impair fertility after parenteral administration in rats. Fluorouracil administered at intraperitoneal doses of 125 and 250 mg/kg has been shown to induce chromosomal aberrations and changes in chromosome organization of spermatogonia in rats. In mice, single-dose intravenous and intraperitoneal injections of fluorouracil have been reported to kill differentiated spermatogonia and spermatocytes at a dose of 500 mg/kg and produce abnormalities in spermatids at 50 mg/kg.

Pediatric Use

Actinic keratosis is not a condition seen within the pediatric population, except in association with rare genetic diseases. Fluorouracil Cream USP, 0.5% (Microsphere) should not be used in children. The safety and effectiveness of Fluorouracil Cream USP, 0.5% (Microsphere) have not been established in patients less than 18 years old.

Geriatric Use

No significant differences in safety and efficacy measures were demonstrated in patients age 65 and older compared to all other patients.

Teratogenic Effects: Pregnancy Category X: See CONTRAINDICATIONS.

It is not known whether fluorouracil is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from fluorouracil, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

The following were adverse events considered to be drug-related and occurring with a frequency of ≥1% with Fluorouracil Cream USP, 0.5% (Microsphere): application site reaction (94.6%), and eye irritation (5.4%). The signs and symptoms of facial irritation (application site reaction) are presented below.

During clinical trials, irritation generally began on day 4 and persisted for the remainder of treatment. Severity of facial irritation at the last treatment visit was slightly below baseline for the vehicle group, mild to moderate for the 1 week active treatment group, and moderate for the 2 and 4 week active treatment groups. Mean severity declined rapidly for each active group after completion of treatment and was below baseline for each group at the week 2 post-treatment follow-up visit.

Thirty-one patients (12% of those treated with Fluorouracil Cream USP, 0.5% (Microsphere) in the Phase 3 clinical studies) discontinued study treatment early due to facial irritation. Except for three patients, discontinuation of treatment occurred on or after day 11 of treatment.

Eye irritation adverse events, described as mild to moderate in intensity, were characterized as burning, watering, sensitivity, stinging and itching. These adverse events occurred across all treatment arms in one of the two Phase 3 studies.

Summary of All Adverse Events Reported in ≥1% of Patients in the Combined Active Treatment and Vehicle Groups - Pooled Phase 3 Studies

9721 and 9722 Combined

Adverse Experiences Reported by Body System:

In the Phase 3 studies, no serious adverse event was considered related to study drug. A total of five patients, three in the active treatment groups and two in the vehicle group, experienced at least one serious adverse event. Three patients died as a result of adverse event(s) considered unrelated to study drug (stomach cancer, myocardial infarction and cardiac failure).

Post-treatment clinical laboratory tests other than pregnancy tests were not performed during the Phase 3 clinical studies. Clinical laboratory tests were performed during conduct of a Phase 2 study of 104 patients and 21 patients in a Phase 1 study. No abnormal serum chemistry, hematology, or urinalysis results in these studies were considered clinically significant.