Epiduo Forte

Cutaneous treatment of Acne vulgaris when comedones, papules and pustules are present

Epiduo Forte is indicated in adults and adolescents aged 9 years and over.

Epiduo Forte should be applied to the entire acne affected areas once a day in the evening on a clean and dry skin. A thin film of gel should be applied, with the fingertips, avoiding the eyes and lips.

If irritation occurs, the patient should be directed to apply non-comedogenic moisturizers, to use the medication less frequently (e.g. every other day), to suspend use temporarily, or to discontinue use altogether.

The duration of treatment should be determined by the Doctor on the basis of the clinical condition. Early signs of clinical improvement usually appear after 1 to 4 weeks of treatment.

The safety and effectiveness of Epiduo Forte have not been studied in children below 9 years of age.

Epiduo Forte Gel should not be applied to damaged skin, either broken (cuts or abrasions), eczematous or sunburned.

Epiduo Forte should not come into contact with the eyes, mouth, nostrils or mucous membranes. If product enters the eye, wash immediately with warm water.

This product contains propylene glycol (E1520) that may cause skin irritation.

If a reaction suggesting sensitivity to any component of the formula occurs, the use of Epiduo Forte should be discontinued.

Excessive exposure to sunlight or UV radiation should be avoided.

Epiduo Forte should not come into contact with any coloured material including hair and dyed fabrics as this may result in bleaching and discoloration.

Not relevant.

Epiduo Forte may cause the following adverse reactions at the site of application:

*Post marketing surveillance data

If skin irritation appears after application of Epiduo Forte, the intensity is generally mild or moderate, with local tolerability signs and symptoms (erythema, dryness, scaling, burning and pain of skin (stinging pain) peaking during the first week and then subsiding spontaneously.

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. Website: www.mhra.gov.uk/yellowcard

Epiduo Forte is for once-daily cutaneous use only.

In case of accidental ingestion, appropriate symptomatic measures should be taken.

Pharmacotherapeutic group: Anti-Acne Preparations for Topical Use, D10AD Retinoids for topical use in acne;

ATC code: D10AD53

Mechanism of action and Pharmacodynamic effects:

Epiduo Forte combines two active substances, which act through different, but complementary, mechanisms of action.

- Adapalene: Adapalene is a chemically stable, naphthoic acid derivative with retinoid-like activity. Biochemical and pharmacological profile studies have demonstrated that adapalene acts in the pathology of Acne vulgaris: it is a potent modulator of cellular differentiation and keratinisation and it has anti-inflammatory properties. Mechanistically, adapalene binds to specific retinoic acid nuclear receptors. Current evidence suggests that topical adapalene normalizes the differentiation of follicular epithelial cells resulting in decreased microcomedone formation. Adapalene inhibits the chemotactic (directional) and chemokinetic (random) responses of human polymorphonuclear leucocytes in in vitro assay models; it also inhibits the metabolism of arachidonic acid to inflammatory mediators. In vitro studies have shown inhibition of the AP-1 factors and the inhibition of the expression of toll like receptors 2. This profile suggests that the cell mediated inflammatory component of acne is reduced by adapalene.

- Benzoyl peroxide: Benzoyl peroxide has been shown to have antimicrobial activity; particularly against P. acnes, which is abnormally present in the acne-affected pilosebaceous unit. Additionally benzoyl peroxide has demonstrated exfoliative and keratolytic activities. Benzoyl peroxide is also sebostatic, counteracting the excessive sebum production associated with acne.

Clinical efficacy of Epiduo Forte in patients aged 12 years and older:

The safety and efficacy of Epiduo Forte applied once daily for the treatment of acne vulgaris were assessed in two 12-week, multicenter, controlled clinical studies of similar design, comparing Epiduo Forte to its individual active components, adapalene and benzoyl peroxide, and to the gel vehicle in acne patients. A total of 2185 patients were enrolled in Study 1 and Study 2. The distribution of patients in the two studies was approximately 49% male and 51% female, 12 years of age or older (mean age: 18.3 years; range 12 - 50), presenting 20 to 50 inflammatory lesions and 30 to 100 non-inflammatory lesions at baseline. The patients treated the face and other acne affected areas as needed once daily in the evening.

The efficacy criteria were:

(1) Success rate, percentage of patients rated 'Clear' and 'Almost Clear' at Week 12 based on the Investigator's Global Assessment (IGA);

(2) Change and Percent Change from baseline at Week 12 in

- Inflammatory lesion counts

- Non-inflammatory lesion counts

- Total lesion count

The efficacy results are presented for each study in Table 1 and combined results in Table 2. Epiduo Forte was shown to be more effective compared to its monads and gel vehicle in both studies. Overall, the net beneficial effect (active minus vehicle) obtained from Epiduo Forte was greater than the sum of the net benefits obtained from the individual components, thus indicating a potentiation of the therapeutic activities of these substances when used in a fixed-dose combination. An early treatment effect of Epiduo Forte was consistently observed in Study 1 and Study 2 for Inflammatory Lesions at Week 1 of treatment. Noninflammatory lesions (open and closed comedones) noticeably responded between the first and fourth week of treatment. The benefit on nodules in acne has not been established.

Table 1 Clinical efficacy in two comparative trials

Table 2 Clinical efficacy in combined comparative trials

Clinical efficacy of Epiduo Forte in children 9 to 11 years old

During a paediatric clinical trial, 285 children with acne vulgaris, aged 9 - 11 years (53% of the subjects were 11 years old, 33% were 10 years old and 14% were 9 years old) with a score of 3 (moderate) on the IGA scale and a minimum of 20 but not more than 100 total lesions (Non-inflammatory and/or Inflammatory) on the face (including the nose) at baseline were treated with Epiduo Forte Gel once daily for 12 weeks.

The study concludes that the efficacy and safety profiles of Epiduo Forte Gel in the treatment of facial acne in this specific younger age group are consistent with results of other pivotal studies in subjects with acne vulgaris aged 12 years and older showing significant efficacy with an acceptable tolerability. A sustained early treatment effect of Epiduo Forte Gel compared to Gel Vehicle was consistently observed for all Lesions (Inflammatory, Non-Inflammatory, and Total) at Week 1 and continuing to Week 12.

The pharmacokinetic (PK) properties of Epiduo Forte are similar to the PK profile of Adapalene 0.1% gel alone.

In a 30-day clinical PK study, conducted in patients with acne who were tested with either the fixed-combination gel or with an adapalene 0.1% matched formula under maximised conditions (with application of 2 g gel per day), adapalene was not quantifiable in the majority of plasma samples (limit of quantification 0.1 ng/ml). Low levels of adapalene (C_max between 0.1 and 0.2 ng/ml) were measured in two blood samples taken from the subjects treated with Epiduo Forte and in three samples from the subjects treated with Adapalene 0.1% Gel. The highest adapalene AUC _0-24h determined in the fixed-combination group was 1.99 ng.h/ml.

These results are comparable to those obtained in previous clinical PK studies on various Adapalene 0.1% formulations, where systemic exposure to adapalene was consistently low.

The percutaneous penetration of benzoyl peroxide is low; when applied on the skin, it is completely converted into benzoic acid which is rapidly eliminated.

Not applicable.

No special requirements.

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