TOLAK Cream Ref.[27448] Active ingredients: Fluorouracil

A systemic absorption study of topically applied Tolak Cream was performed in 21 patients with at least 3 actinic keratosis lesions (4 mm or greater in diameter). The steady state concentration of 5-fluorouracil in plasma was examined at 1, 2, 4, 6, 8, 10, 12, 16, and 24 hours after the last dose of a 4-week regimen in subjects with actinic keratosis after “area application” to area(s) in which actinic keratosis lesions were identified at baseline. Areas were defined as the whole region of the left cheek, right cheek, chin and forehead, bald scalp, and right and left ears, where actinic keratosis was identified at baseline. Thus, for example, if an actinic keratosis lesion was identified on the left cheek, Tolak Cream was to be applied as a thin film to the whole area of the left cheek.

Eight patients had undetectable levels of plasma 5-fluorouracil (the lower limit of quantification was 1.00 ng/ml) in all plasma samples following treatment with Tolak Cream. Among patients with detectable plasma 5-fluorouracil levels, the highest level of plasma 5-fluorouracil was generally observed at 1 hour post-dose. The mean observed maximum concentration (± standard deviation) of plasma 5-fluorouracil was 3.66 (±1.58) ng/mL with the range between 1.11–7.35 ng/mL.

The catabolism of 5-fluorouracil results in inactive degradation products (such as CO₂, urea, α-fluoro-β-alanine).

Adequate long-term studies in animals to evaluate carcinogenic potential of fluorouracil have not been conducted. Studies with the active ingredient of Tolak, fluorouracil, have shown mutagenic effects in in vitro and in vivo tests and impairment of fertility in in vivo animal studies.

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.

Although no evidence for mutagenic activity of fluorouracil was observed in 3 studies utilizing the Ames test, mutagenic activity was observed 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 demonstrated positive results in the micronucleus test using bone marrow cells of male mice.

Fluorouracil demonstrated clastogenic activity in vitro in Chinese hamster fibroblasts at concentrations of 1.0 and 2.0 µg/mL and was associated with chromatid gaps, breaks, and exchanges. In human lymphocytes, fluorouracil increased sister chromatid exchange in vitro. Additionally, an increase in numerical and structural chromosome aberrations have been observed in peripheral lymphocytes of patients treated with 5-fluorouracil.

In rats, chromosomal abnormalities and changes in chromosome organization in spermatogonia have been observed after intraperitoneal administration of 125 to 250 mg/kg of fluorouracil. Spermatogonial differentiation was also inhibited and resulted in transient infertility. Fluorouracil was inactive, however, at oral doses of 5 to 80 mg/kg/day 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. In female rats, fluorouracil administered intraperitoneally at doses of 25 and 50 mg/kg during the preovulatory phase of oogenesis resulted in a significant reduction in the incidence of fertile matings, a delay in the development of preimplantation and postimplantation embryos, an increased incidence of preimplantation lethality, and an induction of chromosomal anomalies in these embryos. In mice, single intravenous or intraperitoneal injections of fluorouracil were toxic to differentiated spermatogonia and spermatocytes (at 500 mg/kg) and produced abnormalities in spermatids (at 50 mg/kg).

The efficacy and safety of Tolak Cream was evaluated in two double-blind multi-center trials (Trial 1 and Trial 2) in subjects with at least 5 visible actinic keratosis lesions on the face, scalp, and/or ears. Subjects applied the assigned medication (Tolak Cream or vehicle placebo) to the face, and/or ears and/or scalp once or twice daily for four weeks as directed. Application of the medication involved field treatment of the whole area of the face and/or ears and/or scalp where actinic keratosis lesions were identified at baseline. Subjects receiving confounding treatments or medications were excluded. The effect of treatment was assessed at 4 weeks post-treatment. Subjects were almost all Caucasian, the mean age was approximately 68 years (range was from 33 to 89 years), and the mean number of actinic keratosis lesions was 14.4 in the Tolak group and 16.2 in the vehicle group in Trial 1, and 19.2 in the Tolak group and 23.2 in the vehicle group in Trial 2.

The number and percentage of subjects with 100% clearing of their actinic keratosis lesions and with at least 75% clearing of their actinic keratosis lesions are shown in Table 2.

Table 2. Subjects with 100% and at least 75% Clearing of Actinic Keratosis Lesions at 4 Weeks Post-Treatment:

Examination of age (<68 years versus ≥68 years) and gender subgroups did not identify differences in response to Tolak Cream among these subgroups. There were too few non-Caucasian subjects to adequately assess differences in effects among racial subgroups.

After completing Trials 1 and 2, subjects who achieved 100% clearing of actinic keratosis lesions with Tolak Cream treatment were followed for 12 months for lesion recurrence. Table 3 presents the long term outcomes of these 204 subjects.

Table 3. Recurrence of Actinic Keratosis Lesions within 12 Months After Completing Trial 1 or 2:

^* Subjects who applied other treatments for actinic keratosis were counted as having recurrence.