Epiduo 0.3% / 2.5% Gel
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Epiduo 0.3% / 2.5% gel
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
One gram of gel contains: adapalene 3 mg (0.3%) benzoyl peroxide 25 mg (2.5%)
Excipient with known effect: propylene glycol (E1520) 40 mg (4.0%)
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Gel.
White to very pale yellow opaque gel.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Epiduo 0.3% / 2.5% gel is indicated for the cutaneous treatment of Acne vulgaris, when comedones, numerous papules and pustules are present (see sections 4.2 and 5.1).
4.2 Posology and method of administration
Posology
Epiduo 0.3% / 2.5% gel should be applied once a day in the evening to the entire acne affected areas of the face and the trunk on a clean and dry skin.
The duration of treatment should be determined by the doctor based on the overall clinical condition and on the therapeutic response to the treatment. Early signs of clinical improvement usually appear after 1 to 4 weeks of treatment. If no improvement is observed after 4-8 weeks treatment, the benefit of continued treatment should be reconsidered.
A lower strength of Epiduo is available (Epiduo 0.1% / 2.5% gel) and this concentration should be considered in patients with moderate acne vulgaris (see section 5.1).
When the entire face is involved with numerous papulopustules, an increased clinical benefit was observed in the subjects treated with Epiduo 0.3% / 2.5% gel compared with the reference therapy (Epiduo 0.1% / 2.5% gel). Doctors may choose between the two concentrations based on the presenting patient’s clinical condition and severity.
Special populations Elderly
The safety and efficacy of Epiduo 0.3% / 2.5% gel in geriatric patients aged 65 years and above have not been established.
Renal and hepatic impairment
Epiduo 0.3% / 2.5% gel has not been studied in patients with renal and hepatic impairment.
Paediatric population
The safety and efficacy of Epiduo 0.3% / 2.5% gel have not been studied in children below 12 years of age.
Method of administration Cutaneous use only.
Apply a thin layer of Epiduo 0.3% / 2.5% gel to affected areas of the face and/or trunk once daily after washing. Use a pea-sized amount for each area of the face (e.g. forehead, chin, each cheek), avoiding the eyes and lips (see section 4.4).
Patients should be instructed to wash their hands after applying the medicinal product.
Cosmetics may be applied after the medicinal product has dried.
If irritation occurs, the patient should be directed to apply non-comedogenic moisturisers as needed, to use the medication less frequently (e.g. every other day), to suspend use temporarily, or to discontinue use altogether.
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 0.3% / 2.5% gel should not be applied to damaged skin, either broken (cuts or abrasions), sunburn or eczematous skin.
The medicinal product should not come into contact with the eyes, lips, mouth, nostrils or mucous membranes. If product enters the eye, wash immediately with warm water.
If a reaction suggesting sensitivity to any component of the formula occurs, the use of Epiduo 0.3% / 2.5% gel should be discontinued.
Excessive exposure to sunlight or UV radiation should be avoided.
Epiduo 0.3% / 2.5% gel should not come into contact with any coloured material including hair and dyed fabrics as this may result in bleaching and discoloration.
This product contains propylene glycol (E1520) that may cause skin irritation.
Epiduo 0.3%/2.5% gel should not be used during pregnancy or in women of childbearing potential not using adequate contraception (see section 4.6).
The efficacy and safety of Epiduo 0.3% / 2.5% gel in patients with severe nodular or deep nodulocystic acne have not been studied. As patients with severe nodular / nodulocystic acne are at increased risk of permanent scarring secondary to acne lesions, the use of Epiduo 0.3% / 2.5% gel in these patients is not recommended due to the risk of insufficient therapeutic response.
4.5 Interaction with other medicinal products and other forms of interaction
No interaction studies have been conducted with Epiduo 0.3% / 2.5% gel.
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 0.3% / 2.5% gel. 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 the medicinal product.
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
Epiduo 0.3% / 2.5% gel should be given to women of childbearing potential only if highly effective contraception is used during treatment and for 1 month after discontinuation of treatment.
Pregnancy
There are no or limited amount of data from the use of adapalene in pregnant women.
Studies in animals 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 weak cutaneous passage of adapalene is possible, Epiduo 0.3% / 2.5% gel should not be used during pregnancy or in women of childbearing potential not using a birth-control method.
In case of unexpected pregnancy, treatment should be discontinued.
Breast-feeding
No study on animal or human milk transfer was conducted after cutaneous application of Epiduo 0.3% / 2.5% gel. Available pharmacokinetic data in rats have shown excretion of adapalene in milk after oral or intravenous administration of adapalene.
A risk to the suckling child cannot be excluded.
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Epiduo 0.3% / 2.5% Gel therapy weighting the benefit of breast-feeding for the child and the benefit of therapy for the woman.
To avoid contact exposure of the infant, application of Epiduo 0.3% / 2.5% gel to the chest should be avoided when used during breast-feeding.
Fertility
No human fertility studies were conducted with Epiduo 0.3% / 2.5% gel.
However, no effects of adapalene or benzoyl peroxide on fertility were found in rats in reproductive studies
4.7 Effects on ability to drive and use machines
Epiduo 0.3% / 2.5% gel has no or negligible effects on the ability to drive and use machines.
4.8 Undesirable effects
Summary of safety profile
Approximately 10% of patients can be expected to experience adverse skin reactions. Treatment-related adverse reactions typically associated with use of Epiduo 0.3% / 2.5% gel include mild to moderate application site reactions, such as skin irritation mainly characterized by scaling, dryness, erythema, and burning/stinging. Recommendation is to use moisturiser, temporarily reduce the application frequency to every other day, or temporarily discontinue its use until once daily schedule can be resumed.
These reactions usually occur early in the treatment, and tend to gradually lessen over time.
Tabulated summary of adverse reactions
The adverse reactions are classified by System Organ Class and frequency, using the following convention: 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), not known (cannot be estimated from the available data) and were reported with Epiduo 0.3% / 2.5% gel in vehicle-controlled Phase 3 clinical study (see Table 1).
Table 1: Adverse reactions
|
System Organ Class |
Frequency |
Adverse reactions |
|
Eye disorders |
Uncommon |
Erythema of eyelid |
|
Not known* |
Eyelid oedema | |
|
Nervous system disorders |
Uncommon |
Paresthesia (tingling at application site) |
|
Respiratory, thoracic and mediastinal disorders |
Not known* |
Throat tightness |
|
Skin and subcutaneous tissue disorders |
Common |
Atopic dermatitis, eczema, skin burning sensation, skin irritation |
|
Uncommon |
Dry skin, pruritus, rash | |
|
Not known* |
Allergic contact dermatitis, swelling face, pain of skin (stinging pain) and blisters (vesicles) |
*Post-marketing surveillance data reported since the global launch of Epiduo 0.1%/2.5% gel, from a population of unknown size
Skin-related adverse events were more frequent with Epiduo 0.3% / 2.5% gel than Epiduo gel (Adapalene 0.1% / Benzoyl peroxide 2.5%) as compared to vehicle. In the pivotal study (see section 5.1), 9.2% of subjects in the combined population treated
with Epiduo 0.3% / 2.5% gel had skin-related adverse events and 3.7% in the population treated with Epiduo gel compared to Vehicle Gel group (2.9%).
In addition to some of the above, other adverse drug reactions were reported with Epiduo gel (Adapalene 0.1% / Benzoyl peroxide 2.5%), the previously approved fixed combination of adapalene and benzoyl peroxide:
- Clinical trials:
Other adverse drug reactions reported in clinical trials with Epiduo gel are irritative contact dermatitis (common) and sunburn (uncommon).
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
Epiduo 0.3% / 2.5% gel is for once-daily cutaneous use only. Excessive application of Epiduo 0.3% / 2.5% gel may result in severe irritation. In this event, discontinue use and wait until the skin has recovered.
In case of accidental ingestion, appropriate symptomatic measures should be taken.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anti-acne preparations for topical use, ATC code: D10AD53
Mechanism of action and pharmacodynamic effects
Epiduo 0.3% / 2.5% gel 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 Propionibacterium acnes, which is abnormally present in the acne-affected pilosebaceous unit. The mechanism of action of Benzoyl peroxide has been explained by its highly lipophilic activity, enabling its penetration through the epidermis into bacterial and keratinocyte cell membranes of the pilosebaceous unit. Benzoyl peroxide is recognized as a very effective broad-spectrum antibacterial agent in the treatment of acne vulgaris. It has been demonstrated to exert bactericidal effect by generating free radicals that oxidize proteins and other essential cellular components in the bacterium wall. The minimum inhibitory concentration of benzoyl peroxide is bactericidal and has demonstrated effectiveness on antibiotic-sensitive and antibiotic-resistant P. acnes strains. Additionally benzoyl peroxide has demonstrated exfoliative and keratolytic activities.
Clinical efficacy and safety
The safety and efficacy of Epiduo 0.3% / 2.5% gel applied once daily for the treatment of acne vulgaris were assessed in a 12 week, multicenter, randomised, double-blind, controlled clinical study, comparing Epiduo 0.3% / 2.5% gel to the gel vehicle in 503 acne patients. In this study, 217 patients were treated with Epiduo 0.3% / 2.5% gel, 217 patients with adapalene 0.1% / benzoyl peroxide 2.5% gel and 69 patients with the Vehicle gel.
The efficacy criteria were:
- Success rate, defined as the percent of subjects who were rated ‘Clear’ or ‘Almost Clear’ at Week 12 with at least a two-grade improvement based on the Investigator’s Global Assessment (IGA). An IGA score of ‘Clear’ corresponded to clear skin with no inflammatory or non-inflammatory lesions. An IGA score of ‘Almost Clear’ corresponded to a few scattered comedones and a few small papules.
Mean absolute change from baseline at Week 12 in both inflammatory and non-inflammatory lesion counts.
At Baseline, 50% of enrolled patients had acne severity assessed as “moderate” (IGA=3) and 50% had scores of “severe” (IGA=4). In the overall study population, up to two nodules were allowed. For lesion counts, subjects had an average of 98 total lesions (range: 51-226), of which the mean number of inflammatory lesions was 38 (range: 20-99) and the mean number of non-inflammatory lesions was 60 (range: 30149). The age of the patients ranged from 12 to 57 years (mean age: 19.6 years), with 273 (54.3%) patients 12 to 17 years of age. A similar number of males (47.7%) and females (52.3%) were enrolled.
In this pivotal study, 55.2% of patients in the severe stratum had truncal acne. The patients treated the face and other acne affected areas on the trunk as needed once daily in the evening.
Statistical analyses were performed to compare and interpret study results in a stepwise manner:
- Epiduo 0.3% / 2.5% gel versus Vehicle gel in the overall population of patients with moderate and severe acne (IGA=3 and IGA=4).
- Epiduo 0.3% / 2.5% gel versus Vehicle gel in the subgroup of patients with severe acne (IGA=4).
The efficacy results are shown in Table 2 for the combined moderate and severe acne populations.
Table 2: Clinical efficacy in the overall population: patients with moderate and severe acne vulgaris at Week 12 (combined IGA = 3 and 4, MI, ITT population)
|
Efficacy Parameters |
Epiduo 0.3% / 2.5% Gel (N=217) |
Adapalene 0.1% / benzoyl peroxide 2.5% Gel (N = 217) a |
Vehicle Gel (N=69) |
|
Success Rate (minimum 2-grade improvement and IGA “clear” or “almost clear”) |
33.7%b |
27.3% |
11.0% |
|
Change in Inflammatory Lesions, Mean absolute (percent) reduction |
27.8 b (68.7%) |
26.5 (69.3%) |
13.2 (39.2%) |
|
Change in Non-inflammatory Lesions, Mean absolute (percent) reduction |
40.5 b (68.3%) |
40.0 (68.0%) |
19.7 (37.4%) |
MI= Multiple Imputation; ITT= Intent-to-treat
a) This study was not designed or powered to compare formally the efficacy of Epiduo 0.3% / 2.5% to the lower strength Adapalene 0.1% / Benzoyl peroxide 2.5% , nor to compare the lower strength Adapalene 0.1% / Benzoyl peroxide 2.5% to the Vehicle gel
b) p<0.001 vs Vehicle
Results of primary efficacy analyses in the severe acne population are shown in Table 3.
Table 3: Clinical efficacy in patients with severe acne vulgaris (IGA = 4, MI, ITT population)
|
Efficacy Parameters |
Epiduo 0.3% / 2.5% Gel (N=106) |
Adapalene 0.1% / benzoyl peroxide 2.5% Gel (N = 112) |
Vehicle Gel (N=34) |
|
Success Rate (minimum 2-grade improvement and IGA “clear” or “almost clear”) |
31.9%a |
20.5% |
11.8% |
|
Change in Inflammatory Lesions, Mean absolute (percent) reduction |
37.3 b (74.4%) |
30.2 (68%) |
14.3 (33.0%) |
|
Change in Non-inflammatory Lesions, Mean absolute (percent) reduction |
46.3 b (72.1%) |
43.9 (68.4%) |
17.8 (30.8%) |
MI= Multiple Imputation; ITT= Intent-to-treat
a) p=0.029 vs Vehicle
b) p<0.001 vs Vehicle
Adapalene 0.1% / benzoyl peroxide 2.5% gel was included in this trial as a reference therapy. In subjects graded as “moderate” (IGA Grade 3), Epiduo 0.3% / 2.5% gel showed no efficacy advantage compared with the reference therapy. In the analysis in subjects graded as “severe” (IGA Grade 4), Epiduo 0.3% / 2.5% gel achieved a greater efficacy over vehicle with a treatment difference of 20.1% (31.9% vs 11.8%; 95% CI: [6.0%, 34.2%)], p=0.029), whereas the reference therapy did not (treatment difference vs vehicle of 8.8%).
5.2 Pharmacokinetic properties
Absorption
A pharmacokinetic study was conducted with Epiduo 0.3% / 2.5% gel in 26 adult and adolescent subjects (12 to 33 years of age) with severe acne vulgaris. The subjects were treated with once-daily applications on all potentially affected areas during a 4 week period with, on average, 2.3 grams/day (range: 1.6-3.1 grams/day) of Epiduo 0.3% / 2.5% gel applied as a thin layer to the face, shoulders, upper chest and upper back. After 4 weeks of treatment, 16 subjects (62%) had quantifiable adapalene plasma concentrations above the limit of quantification (LOQ of 0.1 ng/mL), with a mean Cmax of 0.16 ± 0.08 ng/mL and a mean AUC0-24h of 2.49 ± 1.21 ng.h/mL. The most exposed subject had adapalene Cmax and AUC0-24h values of 0.35 ng/mL and 6.41 ng.h/mL, respectively.
Pharmacokinetics studies conducted with both Epiduo and Epiduo 0.3% / 2.5% Gels have evidenced that the transdermal absorption of adapalene is not affected benzoyl peroxide.
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 or with Epiduo 0.3% / 2.5% gel include local tolerance studies and dermal repeat-dose toxicity studies in rat, dog and/or 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 Glycerol
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.
After first opening: 3 months.
6.4 Special precautions for storage
Do not store above 25°C.
6.5 Nature and contents of container
Epiduo 0.3% / 2.5% gel is supplied in two types of containers:
Tube:
2 g and 5 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:
15 g, 30 g, 45 g and 60 g white multidose container with airless pump and snap on cap, made of polypropylene and high density polyethylene.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
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) Limited Meridien House 69-71 Clarendon Road Watford Herts
WD17 1DS UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 10590/0067
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
30/09/2016
10 DATE OF REVISION OF THE TEXT
30/09/2016