SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Epiduo 0.1% / 2.5% gel

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

1 g of gel contains:

Adapalene 1 mg (0.1%)

Benzoyl Peroxide 25 mg (2.5%)

Excipient with known effect: Propylene glycol.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Gel.

A white to very pale yellow opaque gel.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Cutaneous treatment of Acne vulgaris when comedones, papules and pustules are present (See section 5.1).

4.2    Posology and method of administration

Epiduo 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 (see section 4.4).

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 have not been studied in children below 9 years of age.

4.3    Contraindications

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

4.4    Special warnings and precautions for use

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

Epiduo 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 should be discontinued.

Excessive exposure to sunlight or UV radiation should be avoided.

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

4.5    Interaction with other medicinal products and other forms of

interaction

No interaction studies have been conducted with Epiduo.

From previous experience with adapalene and benzoyl peroxide, there are no known interactions with other medicinal products which might be used cutaneously and concurrently with Epiduo. However, other retinoids or benzoyl peroxide or drugs with a similar mode of action should not be used concurrently. Caution should be exercised if cosmetics with desquamative, irritant or drying effects are used, as they may produce additive irritant effects with Epiduo.

Absorption of adapalene through human skin is low (see section 5.2), and therefore interaction with systemic medicinal products is unlikely.

The percutaneous penetration of benzoyl peroxide in the skin is low and the drug substance is completely metabolised into benzoic acid which is rapidly eliminated. Therefore, the potential interaction of benzoic acid with systemic medicinal products is unlikely to occur.

4.6    Fertility, pregnancy and lactation Pregnancy:

Animal studies by the oral route have shown reproductive toxicity at high systemic exposure (see section 5.3).

Clinical experience with locally applied adapalene and benzoyl peroxide in pregnancy is limited but the few available data do not indicate harmful effects in patients exposed in early pregnancy.

Due to the limited available data and because a very weak cutaneous passage of adapalene is possible, Epiduo should not be used during pregnancy.

In case of unexpected pregnancy, treatment should be discontinued.

Breastfeeding:

No study on animal or human milk transfer was conducted after cutaneous application of Epiduo (adapalene / benzoyl peroxide) Gel.

No effects on the suckling child are anticipated since the systemic exposure of the breast-feeding woman to Epiduo is negligible. Epiduo can be used during breastfeeding.

To avoid contact exposure of the infant, application of Epiduo to the chest should be avoided when used during breast-feeding.

4.7    Effects on ability to drive and use machines

Not relevant.

4.8 Undesirable effects

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

Body System (MedDRA)	Frequency	Adverse Drug Reaction
Eye disorders	Not known*	Eyelid oedema
Respiratory, thoracic and	Not known*	Throat tightness

*Post marketing surveillance data

If skin irritation appears after application of Epiduo, 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 reaction 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

4.9    Overdose

Epiduo is for once-daily cutaneous use only.

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

5 PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: D10A Anti-Acne Preparations for Topical Use

Mechanism of action and Pharmacodynamic effects:

Epiduo 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 in patients aged 12 years and older:

The safety and efficacy of Epiduo applied once daily for the treatment of acne vulgaris were assessed in two 12-week, multicenter, controlled clinical studies of similar design, comparing Epiduo 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 noninflammatory 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 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 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 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 forth week of treatment. The benefit on nodules in acne has not been established.

Study 1
Study 1 Week 12 LOCF; ITT	Adapalene+BPO N=149	Adapalene N=148	BPO N=149	Vehicle N=71
Success (Clear, Almost Clear)	41 (27.5%)	23 (15.5%) p=0.008	23 (15.4%) p=0.003	7 (9.9%) p=0.002
Median Reduction (% Reduction) in
Inflammatory Lesion Count	17 (62.8 %)	13 (45.7 %) p<0.001	13 (43.6 %) p<0.001	11 (37.8 %) p<0.001
Noninflammatory Lesion Count	22 (51.2 %)	17 (33.3 %) p<0.001	16 (36.4 %) p<0.001	14 (37.5 %) p<0.001
Total lesion Count	40 (51.0 %)	29 (35.4 %) p<0.001	27 (35.6 % p<0.001	26 (31.0 %) p<0.001
Study 2
Study 2 Week 12 LOCF; ITT	Adapalene+BPO N=415	Adapalene N=420	BPO N=415	Vehicle N=418
Success (Clear, Almost Clear)	125 (30.1%)	83 (19.8%) p<0.001	92 (22.2%) p=0.006	47 (11.3%) p<0.001
Median Reduction (% Reduction) in
Inflammatory Lesion Count	16 (62.1 %)	14 (50.0 %) p<0.001	16 (55.6 %) p=0.068	10 (34.3 %) p<0.001
Noninflammatory Lesion Count	24 (53.8 %)	22 (49.1 %) p=0.048	20 (44.1 %) p<0.001	14 (29.5 %) p<0.001
Total Lesion Count	45 (56.3 %)	39 (46.9 %) p=0.002	38 (48.1 %) p<0.001	24 (28.0 %) p<0.001

Table 2    Clinical efficacy in combined comparative trials

	Adapalene+BPO N=564	Adapalene N=568	BPO N=564	Gel Vehicle N=489
Success (Clear, Almost Clear)	166 (29.4%)	106 (18.7%)	115 (20.4%)	54 (11.1%)
Median Reduction (% Reduction) in
Inflammatory Lesion Count	16.0 (62.1)	14.0 (50.0)	15.0(54.0)	10.0 (35.0)
Noninflammatory Lesion Count	23.5 (52.8)	21.0 (45.0)	19.0 (42.5)	14.0 (30.7)
Total Lesion Count	41.0 (54.8)	34.0 (44.0)	33.0 (44.9)	23.0 (29.1)

Clinical efficacy of Epiduo 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 (Noninflammatory and/or Inflammatory) on the face (including the nose) at baseline were treated with Epiduo Gel once daily for 12 weeks.

The study concludes that the efficacy and safety profiles of Epiduo Gel 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 Gel compared to Gel Vehicle was consistently observed for all Lesions (Inflammatory, Non-Inflammatory, and Total) at Week 1 and continuing to Week 12.

Study 3
Week 12 LOCF; ITT	Adapalene + BPO N=142	Vehicle Gel N=143
Success (Clear, Almost Clear)	67 (47.2%)	22 (15.4%)
Median Reduction (% Reduction) in
Inflammatory Lesion Count	6 (62.5%)	1 (11.5%)
Noninflammatory Lesion Count	19 (67.6%)	5 (13.2%)
Total Lesion Count	26 (66.9%)	8 (18.4%)

5.2    Pharmacokinetic properties

The pharmacokinetic (PK) properties of Epiduo 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 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.

5.3    Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, phototoxicity or carcinogenicity.

Reproductive toxicology studies with adapalene have been performed by the oral and dermal routes of administration in the rat and rabbit. A teratogenic effect has been demonstrated at high systemic exposures (oral doses from 25 mg/kg/day). At lower exposures (dermal dose of 6 mg/kg/day), changes in the numbers of ribs or vertebrae were seen.

Animal studies performed with Epiduo include local tolerance studies and dermal repeat-dose toxicity studies in rat, dog and minipig up to 13 weeks and demonstrated local irritation and a potential for sensitisation, as expected for a combination containing benzoyl peroxide. Systemic exposure to adapalene following repeat dermal application of the fixed combination in animals is very low, consistent with clinical pharmacokinetic data. Benzoyl peroxide is rapidly and completely converted to benzoic acid in the skin and after absorption is eliminated in the urine, with limited systemic exposure.

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Disodium edetate Docusate sodium Glycerin Poloxamer

Propylene glycol (E1520)

Simulgel 600PHA (copolymer of acrylamide and sodium acryloyldimethyltaurate, isohexadecane, polysorbate 80, sorbitan oleate) Purified water

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

2 years.

Epiduo in-use stability is at least 6 months after first opening.

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

Epiduo is stored in two types of container:

Tube:

5 g , 15 g, 30 g, 45 g, 60 g and 90 g white plastic tubes having a high density polyethylene body structure with a high density polyethylene head, closed with a white polypropylene screw-cap.

Multidose container with airless pump:

15g, 30g, 45g and 60g white multidose container with airless pump and snap on cap, made of polypropylene, low density polyethylene and high density polyethylene.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

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

7 MARKETING AUTHORISATION HOLDER

Galderma (UK) Ltd Meridien House 69-71 Clarendon Road Watford Herts

WD17 1DS UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 10590/0057

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

28/11/2012

10    DATE OF REVISION OF THE TEXT

05/06/2015