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 Carac and 10 treated with Efudex®Efudex is a registered trademark of ICN Pharmaceuticals, Inc. 5% Cream. Patients were treated for a maximum of 28 days with Carac, 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 Carac and nine patients who received Efudex® 5% Cream had measurable plasma fluorouracil levels; however, only one patient receiving Carac and six patients receiving Efudex® 5% Cream had a sufficient number of data points to calculate mean pharmacokinetic parameters.
Plasma Pharmacokinetic Summary
|Efudex (Mean ± SD)|
| Cmax ||0.77 ng/mL||11.49 ± 8.24 ng/mL|
| Tmax ||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 Carac and nine of 10 patients receiving Efudex® 5% Cream had measurable urine fluorouracil levels.
Urine Pharmacokinetic Summary
|PK Parameter||Carac (Mean ± SD)|
|Efudex (Mean ± SD)|
| Cum AeCumulative urinary excretion ||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 Carac 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 Carac and for Efudex®, corresponding to 0.055% and 0.24% of the applied doses, respectively.
Under the experimental conditions of the topical safety studies, Carac 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, multi-center, vehicle-controlled, double-blind studies were conducted to evaluate the clinical safety and efficacy of Carac. Patients with 5 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 Carac cream 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 Carac 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
Percentage of Subjects with at Least 75% Clearance
Clinical efficacy and safety in the treatment of AKs on the ears and other sun-exposed areas were not evaluated in the studies.