AMELUZ Gel Ref.[27465] Active ingredients: Aminolevulinic acid

The pharmacodynamics of AMELUZ in the treatment of actinic keratosis are unknown.

Pharmacokinetics (PK) of aminolevulinic acid and PpIX was evaluated in a trial of 12 adult subjects with mild to moderate AK with at least 10 AK lesions on the face or forehead. A single dose of one entire tube of AMELUZ (2 grams) was applied under occlusion for 3 hours followed by PDT to a total area of 20 cm². The mean ± SD baseline plasma aminolevulinic acid and PpIX concentrations were 20.16 ± 16.53 ng/mL and 3.27 ± 2.40 ng/mL, respectively. In most subjects, an up to 2.5-fold increase of aminolevulinic acid plasma concentrations was observed during the first 3 hours after AMELUZ application. The mean ± SD area under the concentration time curve (AUC_0-t) and maximum concentration (C_max) for baseline corrected aminolevulinic acid (n=12) were 142.83 ± 75.50 ng.h/mL and 27.19 ± 20.02 ng/mL, respectively. The median T_max (time at which C_max occurred) was 3 hours.

The majority (about 55%) of the PpIX concentrations were below the limit of quantification (LOQ = 1 ng/mL) and baseline corrected values were negative in all subjects except for one. The baseline corrected AUC_0-t and C_max in the single subject was 0.07 ng.h/mL and 0.29 ng/mL, respectively. PK of aminolevulinic acid and PpIX following treatment on the scalp was not evaluated.

Long-term studies to evaluate the carcinogenic potential of AMELUZ or aminolevulinic acid have not been performed.

Aminolevulinic acid revealed no evidence of mutagenic or clastogenic potential based on the results of three in vitro genotoxicity tests (Ames assay, HPRT test in V79 cells, and Human lymphocyte chromosomal aberration assay) and one in vivo genotoxicity test (mouse micronucleus assay). These genotoxicity studies were conducted without exposure to light. There is a literature report that indicates that aminolevulinic acid may cause genotoxic effects in the presence and in the absence of activating light. These genotoxic effects are likely caused by the formation of reactive oxygen species.

Animal fertility studies have not been conducted with aminolevulinic acid because of the negligible systemic absorption of aminolevulinic acid in humans following topical administration of AMELUZ under maximal clinical use conditions.

The efficacy and safety of AMELUZ in combination with PDT using a narrow spectrum (red light lamp) source were evaluated in three randomized, multicenter trials (Trials 1, 2, and 3). Trials 2 and 3 were vehicle-controlled and double-blind. Trial 1 was double-blind with respect to vehicle and observer-blind regarding the active comparator arm. All clinical trials included a follow-up assessment after 6 and 12 months.

In these trials, 212 subjects with 4 to 8 mild to moderate AK lesions on the face/forehead and/or bald scalp were treated with AMELUZ and a narrow band spectrum lamp. Subjects ranged from 49 to 87 years of age (mean 71 years), and 92% had Fitzpatrick skin type I, II, or III. No subjects had Fitzpatrick skin type V or VI. Approximately 86% of subjects were male, and all subjects were Caucasian.

All sessions were comprised of lesion preparation to roughen the surface and remove crusts, application of AMELUZ with occlusion for 3 hours, and removal of the residual gel. Subsequently, the entire treatment area was illuminated with a narrow spectrum red light source, a lamp of either 630 nm or 633 nm and a light dose of approximately 37 J/cm ². In Trial 3, illumination was performed with BF-RhodoLED, a red light source with a narrow spectrum around 635 nm and a light dose of approximately 37 J/cm ².

In all trials, the lesions that were not completely cleared 12 weeks after the initial treatment were treated a second time with an identical regimen. In the trials, 42% (88/212) of subjects needed a second treatment.

The primary endpoint for all trials was complete clearance 12 weeks after the last PDT. The results of Trials 1, 2 and 3 are presented in Table 2.

Table 2. Complete Clearance 12 Weeks After the Last Narrow Spectrum PDT in Subjects with Actinic Keratoses:

Subjects who achieved complete clearance at 12 weeks after the last PDT entered a 12-month follow-up period. In the three trials, subjects who received AMELUZ with the narrowband PDT and achieved complete clearance 12 weeks after the last PDT had recurrence rates of 14%, 11%, and 25%, respectively (at 6 months) and 40%, 22%, and 37%, respectively (at 12 months).

Recurrence was defined as the percentage of subjects with at least one recurrent lesion during the 6-month or 12-month follow-up period in subjects with completely cleared lesions 12 weeks after the last PDT.

In a clinical trial designed to investigate the sensitization potential of aminolevulinic acid hydrochloride with 216 healthy subjects, 13 subjects (6%) developed allergic contact dermatitis after continuous exposure for 21 days with doses of aminolevulinic acid hydrochloride that were higher than doses normally used in the treatment of AK.