This information is intended for use by health professionals

1. Name of the medicinal product

Actikerall 5 mg/g + 100 mg/g Cutaneous Solution

2. Qualitative and quantitative composition

1 g (= 1.05 ml) cutaneous solution contains 5 mg of fluorouracil and 100 mg of salicylic acid.

Excipient with known effect:

80 mg of dimethyl sulfoxide/g of solution.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Cutaneous solution.

Actikerall is a clear, colourless to slightly orange-white solution.

4. Clinical particulars
4.1 Therapeutic indications

Actikerall is indicated for the topical treatment of slightly palpable and/or moderately thick hyperkeratotic actinic keratosis (grade I/II) in immunocompetent adult patients.

Grade I/II intensity is based on the 4-point scale of Olsen et al. (1991), see section 5.1.

4.2 Posology and method of administration

Posology

Adults

Actikerall should be applied once daily to the affected area (up to 25 cm²) until the lesions have completely cleared or for up to a maximum of 12 weeks. If severe side effects occur, reduce the frequency of drug application to three times per week until the side effects improve. If areas of skin with a thin epidermis are treated, the solution should be applied less frequently and the course of the therapy monitored more often.

Response can be seen as early as in four weeks (see section 5.1). Response increases over time and data are available for treatment up to 12 weeks. Complete healing of the lesion(s) or optimal therapeutic effect may not be evident for up to eight weeks after treatment cessation. Treatment should be continued, although response is not apparent after the first four weeks.

When assessing options to treat recurrent lesions, the physician should consider that the efficacy of retreatment with Actikerall has not been formally measured in clinical trials.

Paediatric population

There is no relevant use of Actikerall in the paediatric population for the indication of actinic keratosis.

Elderly population

No dose adjustment is necessary.

Method of administration

Actikerall is intended for cutaneous use only. There is experience in treating up to ten single lesions at the same time. Multiple actinic keratoses and surrounding skin can be treated simultaneously, when field treatment is preferred. The total area of skin being treated with Actikerall at any one time should not exceed 25 cm2 (5 cm x 5 cm).

Actikerall is applied by use of the brush applicator connected to the closure cap. To avoid overloading the brush with solution, the brush should be wiped off in the neck of the bottle before application, although allowing enough product for film formation upon drying.

The treated area should not be covered after application and the solution should be left to dry to form a film over the applied area. Each time Actikerall is reapplied the existing film should be removed beforehand by gently peeling it off. Warm water may help to remove the film. Actikerall should not be applied to hairy skin. Use on hairy skin can lead to conglutination of hair in the affected area. When applied to hairy skin a shave or other suitable methods of hair removal should be considered prior to any application of Actikerall.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Actikerall is contraindicated in pregnancy and lactation (see section 4.6).

Actikerall must not be used to treat patients with renal insufficiency.

Actikerall must not be used in conjunction with brivudine, sorivudine and analogues. Brivudine, sorivudine and analogues are potent inhibitors of the fluorouracil-degrading enzyme dihydropyrimidine dehydrogenase (DPD) (see also sections 4.4 and 4.5).

Actikerall must not be allowed to come into contact with the eyes or mucous membranes.

4.4 Special warnings and precautions for use

DPD enzyme

The enzyme dihydropyrimidine dehydrogenase (DPD) plays an important role in the breakdown of fluorouracil. Inhibition, deficiency or decreased activity of this enzyme can result in accumulation of fluorouracil.

If applicable, the determination of DPD enzyme activity is indicated before starting treatment with fluorouracil or other fluoropyrimidines.

In patients with DPD deficiency, testing for elevated plasma levels of phenytoin should be considered, if phenytoin is taken concomitantly with Actikerall (see section 4.5).

Sensory disturbances

In patients with sensory disturbances (e.g. those with diabetes mellitus) close medical monitoring of the treatment area is required.

Sun exposure

Actinic keratosis is due to chronic UV damage. Any local irritation where Actikerall has been applied may worsen with sun exposure. Patients should be counselled to protect the skin against further excessive or cumulative exposure, especially in the area being actively treated.

Other skin conditions

There is no experience in treating actinic keratoses in an area that is also affected by another skin disease and the clinician should take into account that the outcome of treatment may differ.

No experience exists for the treatment of basal cell carcinoma (BCC) and Bowen's disease, which should therefore not be treated with the product.

General

Actikerall contains the cytostatic agent fluorouracil.

Actikerall should not be used on bleeding lesions.

The bottle should be closed tightly after use or the solution will dry up quickly and can no longer be used correctly.

The solution should not be used if crystals occur.

Actikerall solution should not come into contact with textiles or acrylics (e.g. acrylic bathtubs) as the solution may cause permanent stains.

Caution flammable: keep away from fire or flames.

This medicinal product contains dimethyl sulfoxide which may be irritant to the skin.

4.5 Interaction with other medicinal products and other forms of interaction

The enzyme dihydropyrimidine dehydrogenase (DPD) plays an important role in the breakdown of fluorouracil. Antiviral nucleoside analogues such as brivudine and sorivudine may lead to a drastic increase in plasma concentrations of fluorouracil or other fluoropyrimidines and thus an associated increase in toxicity. For this reason, an interval of at least 4 weeks between the use of fluorouracil and brivudine, sorivudine and analogues should be observed.

In case of accidental administration of nucleoside analogues such as brivudine and sorivudine to patients who are being treated with fluorouracil, effective measures for reducing fluorouracil toxicity should be taken. Admission to a hospital may be indicated. All necessary measures for protection from systemic infections and dehydration should be introduced.

Elevated plasma levels of phenytoin leading to symptoms of phenytoin intoxication have been reported with the concomitant administration of systemic fluorouracil and phenytoin (see section 4.4).

There is no evidence for relevant systemic absorption of salicylic acid, however absorbed salicylic acid may interact with methotrexate and sulphonylureas.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of topical fluorouracil in pregnant women. A teratogenic effect of systemically administered fluorouracil has been observed in animals (see section 5.3). Salicylic acid can adversely influence the outcome of pregnancy in rodents.

Actikerall is contraindicated during pregnancy (see section 4.3).

Breastfeeding

It is unknown whether fluorouracil or its metabolites are excreted in human milk after topical application. A risk to the suckling child cannot be excluded.

Actikerall is contraindicated during lactation (see section 4.3).

Fertility

Fertility studies with systemic fluorouracil resulted in transient male infertility and in reduction of pregnancy rates in female rodents. However, this is unlikely to be of relevance to human, due to the very limited absorption of active compounds after cutaneous administration of Actikerall.

4.7 Effects on ability to drive and use machines

Actikerall has no influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

Mild to moderate irritation and inflammation at the application site occurred in the majority of patients treated with the solution for actinic keratosis. In case of severe reactions frequency of treatment may be reduced.

As the medicinal product has a very strong softening effect on the stratum corneum, whitish discolorations and scaling of the skin may occur, particularly in the area surrounding the actinic keratosis.

Due to its salicylic acid content, use of this medicinal product may cause slight signs of irritation, such as dermatitis and contact allergic reactions, in predisposed patients. Such contact allergy reactions may be manifested in the form of itching, reddening and small blisters even outside the area of application.

Tabulated list of adverse reactions

Adverse reactions according to MedDRA system organ class and in decreasing frequency are listed below. Frequencies are defined as very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from the available data).

System organ class

Frequency

Adverse reaction

General disorders and administration site conditions

Very common

At application site: erythema, inflammation, irritation (including burning), pain, pruritus.

Common

At application site: bleeding, erosion, scab

Uncommon

At application site: oedema, ulcer, dermatitis

Skin and subcutaneous tissue disorders

Common

Skin exfoliation

Nervous system disorders

Common

Headache

Eye disorders

Uncommon

Dry eye, eye pruritus, increased lacrimation.

Description of selected adverse reactions

Application site reactions are frequently reported with Actikerall treatment and are expected to occur, because these are related to the pharmacological activity of the active substances fluorouracil and salicylic acid on the skin. Severe application site reactions can be managed by dose reduction (see section 4.2). In case of bleeding stop treatment until adverse reaction improves (see section 4.4). When surface of contiguous application increases (field up to 25cm2), administration site adverse reactions frequency may increase. In particular frequency of dermatitis, scab, erosion, bleeding, oedema may be Very common, while frequency of ulcer may be Common.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

When applied on the skin as recommended, systemic intoxication with either active is unlikely. Significantly more applications than recommended result in an increase of frequency of reactions at the application site and their severity.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents; Antimetabolites; Pyrimidine analogues, ATC code: L01BC52

Mechanism of action of fluorouracil

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.

Mechanism of action of salicylic acid

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.

Clinical efficacy and safety

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).

5.2 Pharmacokinetic properties

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.

5.3 Preclinical safety data

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.

6. Pharmaceutical particulars
6.1 List of excipients

Dimethyl sulfoxide

Ethanol, anhydrous

Ethyl acetate

Pyroxyline

Poly(butyl methacrylate, methyl methacrylate)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

Shelf life after opening: 3 months

6.4 Special precautions for storage

Do not store above 25 °C.

Do not refrigerate or freeze.

Keep the bottle tightly closed to prevent drying up.

6.5 Nature and contents of container

This medicinal product is packed in a brown glass bottle with a child resistant closure of white polypropylene in a cardboard carton. The closure of the bottle is connected to a brush to apply the solution. The brush applicator (CE mark) consists of polyethylene (HDPE and LDPE 1:1) with brush hairs of nylon secured in shaft with stainless steel (V2A).

Pack size: 25 ml cutaneous solution.

6.6 Special precautions for disposal and other handling

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Almirall Hermal GmbH

Scholtzstrasse 3

21465 Reinbek

Germany

8. Marketing authorisation number(s)

PL 33016/0015

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 03 June 2011

Date of latest renewal: 04 May 2016

10. Date of revision of the text

30 December 2016