Fluorouracil Cream

FLUOROURACIL CREAM- fluorouracil cream
Mylan Pharmaceuticals Inc.


Fluorouracil cream, 0.5%, contains fluorouracil for topical dermatologic use. Chemically, fluorouracil is 5-fluoro-2,4(1H, 3H)-pyrimidinedione. The molecular formula is C4 H3 FN2 O2 . Fluorouracil has a molecular weight of 130.08.

Fluorouracil Structural Formula

Fluorouracil cream contains 0.5% fluorouracil, with 0.35% being incorporated into a patented porous microsphere (Microsponge®) composed of methyl methacrylate / glycol dimethacrylate crosspolymer and dimethicone. The cream formulation contains the following other inactive ingredients: Carbomer Homopolymer Type C, glycerin, methyl gluceth-20, methylparaben, octyl hydroxy stearate, polyethylene glycol 400, polysorbate 80, propylene glycol, propylparaben, purified water, sorbitan monooleate, stearic acid, and trolamine.


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 that provokes unbalanced growth and death of the cell. The effects of DNA and RNA deprivation are most marked on those cells that grow more rapidly and take up fluorouracil at a more rapid rate. The contribution to efficacy or safety of individual components of the vehicle has not been established.


A multiple-dose, randomized, open-label, parallel study was performed in 21 patients with actinic keratoses. Twenty patients had pharmacokinetic samples collected: 10 patients treated with fluorouracil cream, 0.5% and 10 treated with Efudex® 5% Cream. Patients were treated for a maximum of 28 days with fluorouracil cream, 0.5%, 1 g once daily in the morning; or Efudex® 5% Cream, 1 g twice daily, in the morning and evening. Steady-state plasma concentrations and the amounts of fluorouracil in urine resulting from the topical application of either product were measured. Three patients who received fluorouracil cream, 0.5% and nine patients who received Efudex® 5% Cream had measurable plasma fluorouracil levels; however, only one patient receiving fluorouracil cream, 0.5% and six patients receiving Efudex® 5% Cream had a sufficient number of data points to calculate mean pharmacokinetic parameters.

Plasma Pharmacokinetic Summary

PK Parameter

Fluorouracil Cream, 0.5% n=1

Efudex® (Mean ± SD) n=6


0.77 ng/mL

11.49 ± 8.24 ng/mL


1.00 hr

1.03 ± 0.028 hr

AUC (0–24)

2.80 ng∙hr/mL

22.39 ± 7.89 ng∙hr/mL

Five of 10 patients receiving fluorouracil cream, 0.5% and nine of 10 patients receiving Efudex® 5% Cream had measurable urine fluorouracil levels.

Urine Pharmacokinetic Summary
Cumulative urinary excretion

PK Parameter

Fluorouracil Cream, 0.5% (Mean ± SD) (Range) n=10

Efudex® (Mean ± SD) (Range) n=10

Cum Ae *

2.74 ± 5.22 mcg

119.83 ± 94.80 mcg




Max excretion rate

0.19 ± 0.52 mcg/hr

40.27 ± 47.14 mcg/hr




Both fluorouracil cream, 0.5% and Efudex® 5% Cream demonstrated low measurable plasma concentrations for fluorouracil when administered under steady-state conditions. Cumulative urinary excretion of fluorouracil was low for fluorouracil cream, 0.5% and for Efudex® , corresponding to 0.055% and 0.24% of the applied doses, respectively.

Clinical Trials

Under the experimental conditions of the topical safety studies, fluorouracil cream 0.5% was not observed to cause contact sensitization. However, approximately 95% of subjects in the active arms of the Phase 3 clinical studies experienced facial irritation. Irritation is likely and sensitization is unlikely based on the results of the topical safety and Phase 3 studies.

Two Phase 3 identically designed, multicenter, vehicle-controlled, double-blind studies were conducted to evaluate the clinical safety and efficacy of fluorouracil cream, 0.5%. Patients with five or more actinic keratoses (AKs) on the face or anterior bald scalp were randomly allocated to active or vehicle treatment in a 2:1 ratio. Patients were randomly allocated to treatment durations of 1, 2, or 4 weeks in a 1:1:1 ratio. They applied the study cream once daily to the entire face/anterior bald scalp. Each patient’s clinical response was evaluated 4 weeks after the patient’s last scheduled application of study cream. No additional post-treatment follow-up efficacy or safety assessments were performed beyond 4 weeks after the last scheduled application. The following graphs show the percentage of patients in whom 100% of treated lesions cleared, and the percentage of patients in whom 75% or more of treated lesions cleared. Treatment with fluorouracil cream, 0.5% for 1, 2, or 4 weeks is compared to treatment with vehicle cream. Outcomes from 1, 2, and 4 weeks of treatment with vehicle cream are pooled because duration of treatment with vehicle had no substantive effect on clearance. Results from the two Phase 3 studies are shown separately. Although all treatment regimens of fluorouracil cream, 0.5% studied demonstrated efficacy over vehicle for the treatment of actinic keratosis, continuing treatment up to 4 weeks as tolerated results in further lesion reduction and clearing.

Percentage of Subjects with 100% Clearance
(click image for full-size original)
Percentage of Subjects with 75% Clearance
(click image for full-size original)

Clinical efficacy and safety in the treatment of AKs on the ears and other sun-exposed areas were not evaluated in the studies.

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