Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Almirall Hermal GmbH, Scholtzstrasse 3, 21465 Reinbek, Germany
Pharmacotherapeutic group: Antineoplastic agents; Antimetabolites; Pyrimidine analogues
ATC code: L01BC52
The active substance fluorouracil (FU) is a cytostatic agent that has an antimetabolite effect. Due to its structural similarity with the thymine (5-methyluracil) occurring in nucleic acids, FU prevents its formation and utilisation and in this way inhibits both DNA and RNA synthesis which results in growth inhibition.
Topical salicylic acid (SA) has a keratolytic effect and reduces the hyperkeratosis associated with actinic keratosis. Its mechanism of action as a keratolytic and corneolytic agent is thought to be related to its interference with corneocyte adhesion, its solubilising effect on intercellular cement, and its loosening and detachment of corneocytes.
In a pivotal randomized, placebo-controlled, double-blind, three-armed, parallel group, multi-center Phase III trial 470 patients with actinic keratosis (AK) grade I to II (see below) were treated with Actikerall or placebo or a diclofenac gel (30 mg/g) (DG). 187 patients were exposed to the fixed combination Actikerall for up to 12 weeks. The primary endpoint was the histological clearance of a lesion 8 weeks post end of treatment. Topical treatment with Actikerall showed superiority to placebo treatment and to DG treatment. Secondary efficacy endpoints, such as total lesion count, total AK lesion size, lesion response, physician’s global assessment and subject’s overall assessment of efficacy, confirmed the results of the primary endpoint. In 72.0% of the subjects in the Actikerall group actinic keratosis could no longer be detected in the biopsy taken, whereas clearance rates in the DG and placebo groups were 59.1% and 44.8% respectively (per protocol analysis). The number of subjects with complete response (all lesions clinically cleared) was also highest in the Actikerall group 55.4% compared to 32.0% in the DG group and 15.1% in the placebo group. The most frequent adverse reactions to Actikerall were application and site irritation (including burning) (86.1%) and application site inflammation (73.3%). Also, application site pruritus (44.9%) and application site pain (25.1%) occurred at a high frequency. Other adverse reactions were application site erythema and erosion. Discontinuation due to skin and application site reactions was low (0.5%).
In a randomized, placebo-controlled, double-blind, two-armed, parallel group, multi-centre Phase III trial, 166 patients with actinic keratosis (AK) grade I to II were treated with Actikerall or vehicle (2:1 ratio). Patients were exposed to treatment for up to 12 weeks by applying Actikerall or its vehicle on an affected area of 25 cm2 with 4 to 10 actinic keratosis clinical lesions and, in a subgroup of 30 patients, with at least 3 subclinical lesions identified by reflectance confocal microscopy (RCM). The primary endpoint was complete clinical clearance (CCC) of AK lesions in the treatment field 8 weeks after the end of treatment. In 49.5% (intention-to-treat analysis) or 55.1% (per protocol analysis) of the Actikerall group, CCC was observed compared to 18.2% or 19.6% of the vehicle group, respectively. Topical treatment with Actikerall showed superiority to vehicle treatment. Secondary efficacy endpoints, such as partial clearance, total lesion count, severity of lesion grade, physician’s global assessment and subject’s overall assessment of efficacy, confirmed the results of the primary endpoint.
From the RCM subgroup analysis on complete clearance of a single clinical AK lesion and lesion count of selected subclinical lesions, Actikerall was shown to be significantly more effective than vehicle (87.5% vs. 44.4%, p=0.0352 and 89.6% vs. 47.1%, p=0.0051 respectively).
The majority of adverse reactions to Actikerall were application-site reactions, most were of mild intensity. There were 30 application site bleeding events reported in 27 patients (24.1%) treated with Actikerall: 26 of mild, 3 of moderate, and 1 of severe intensity. Four application site ulcer events were reported in 3 patients (2.8%) treated with Actikerall: 3 of mild and 1 of moderate intensity. Discontinuation due to drug-related skin and application-site reactions in the treatment group was low (n=1, 0.9%).
Clinical efficacy is further supported by a Phase II, randomised, parallel-group, multi-centre study with cryotherapy as comparator. Actikerall showed a higher histological clearance rate at 8 weeks after a 6-week treatment (n = 33) than cryotherapy at 14 weeks after the first treatment on Day 1 and on Day 21, if necessary (n = 33) (62.1% vs 41.9%). In addition, a lower AK recurrence rate was found in the Actikerall group at 6-month follow-up (27.3% vs 67.7%).
Efficacy of Actikerall in terms of treatment duration (from ≤4 to >12 weeks) was demonstrated in a multi-centre non-interventional study in AK grade I to III patients (n = 1,051). At approximately 8 weeks after treatment, the average reduction in lesion number and size was 69.7% and 82.1%, respectively, which was achieved in about 50% of the patients within less than 6 weeks on treatment. All treatment durations (≤4 weeks; >4 to ≤6 weeks; >6 to ≤9 weeks; >9 to ≤12 weeks; and >12 weeks) showed an average reduction in lesion number of 65-70%.
In both the Phase II and the non-interventional studies, the safety profile of Actikerall was found to be consistent with the adverse reactions of the drug product (see section 4.8).
When deciding on treatment of other parts of the body than the face, forehead and bald scalp the epidermal thickness in different areas may be taken into consideration. The mean epidermal thickness of different body parts has been published as: face 49.4 µm, forehead 50.3 µm, upper trunk front (décolleté) 42.2 µm, and arms/legs 60.1 µm (Koehler 2010, Skin Res Technol 2010, 16:259-264; Sandby-Moller 2003, Acta Derm Venereol 2003; 83(6):410-3; Whitton et Everall 1973 Br J Dermatol 1973; 89(5):467-76).
Actinic keratosis lesion intensity was graded according to the 4-point scale based on Olsen et al.,1991 (J Am Acad Dermatol 1991; 24: 738-743):
| Grade | Clinical description of intensity grading | |
| 0 | none | no AK lesion present, neither visible nor palpable |
| I | mild | flat, pink maculae without signs of hyperkeratosis and erythema, slight palpability, with AK felt better than seen |
| II | moderate | pink to reddish papules and erythematous plaques with hyperkeratotic surface, moderately thick AK that are easily seen and felt |
| III | severe | very thick and/or obvious AK |
The European Medicines Agency has waived the obligation to submit the results of studies with Actikerall in all subsets of the paediatric population based on a class waiver for the treatment of actinic keratosis (see section 4.2 for information on paediatric use).
In an absorption study carried out on pigs no fluorouracil was detected in the serum after the cutaneous application – even in large quantities – i.e. the active substance was not absorbed in quantities which could be detected with standard analytical methods (HPLC).
No fluorouracil concentration above 0.05 µg/ml could be identified in actinic keratosis patients (n=12).
According to a pharmacokinetic study analysing the absorption rate of fluorouracil in humans after the application in warts with the same formulation, this is markedly below 0.1 %.
After application on the skin Actikerall forms a solid film which appears white after the solvent has evaporated. This produces an occlusive effect which promotes penetration of the active substances into the epidermis, where actinic keratoses are located.
Salicylic acid has been added due to its keratolytic properties in order to improve penetration of the active substance, which is particularly difficult in the case of hyperkeratotic actinic keratoses. The same effect is achieved by the excipient dimethyl sulfoxide, which acts as a solubiliser for the active ingredient fluorouracil.
The keratolytic effect of salicylic acid is based on its direct action on the intracellular cement substances or desmosomes, which promote the cornification process.
Experiments on animals and human pharmacokinetic trials have shown that salicylic acid penetrates the surface rapidly, depending on the substrate and other factors influencing penetration, such as the condition of the skin.
Salicylic acid is metabolised by conjugation with glycine to form salicyluric acid, with glucuronic acid on the phenolic OH group to form ether glucuronide and on the COOH group to form ester glucuronide, or by hydroxylation to gentisic acid and dihydroxybenzoic acid. In the normal dose range the half-life of systemically absorbed salicylic acid is between 2 and 3 hours, but may increase to 15 to 30 hours in the case of high dosages as a result of the limited capacity of the liver to conjugate salicylic acid.
No toxic side effects are generally to be expected from the topical application of salicylic acid (but see the contraindications), as serum levels above 5 mg/dl are hardly ever reached. Early symptoms of salicylate intoxication are only to be expected at serum values of more than 30 mg/dl.
No experimental data on the acute and sub-chronic toxicity of fluorouracil (FU) after topical application are available. In rats dose-dependent systemic bioavailability of FU occurs and results in severe local reactions and fatal systemic effects due to the antimetabolite actions of FU at such high (up to 10,000 fold above the human) doses that are not reached with Actikerall when used as recommended.
FU was in vitro mutagenic in some test strains. A number of studies investigated carcinogenicity for FU in rodents and showed no effect. However, in a single study there is evidence of carcinogenicity of FU in mice following intraperitoneal administration. Several studies following systemic administration of FU indicate potential high dose teratogenic or embryotoxic effects but less or no effects on fertility or general reproductive performance. Fertility studies with systemic FU resulted in transient male infertility and in reduction of pregnancy rates in female rodents. However, because of the very limited absorption after cutaneous administration, any such effect is very unlikely to be of relevance in man.
Salicylic acid has a low acute toxicity but may induce skin reactions after topical application at higher concentrations. Salicylic acid is not known to have any mutagenic, genotoxic, carcinogenic or teratogenic effects.
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