Epiduo 0,1 %/2,5 % Gel

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Köp det nu

Produktens egenskaper Produktens egenskaper (SPC)

27-06-2019

Aktiva substanser:
adapalen; bensoylperoxid, hydratiserad
Tillgänglig från:
Orifarm AB
ATC-kod:
D10AD53
INN (International namn):
adapalene; benzoyl peroxide, hydrated
Dos:
0,1 %/2,5 %
Läkemedelsform:
Gel
Sammansättning:
adapalen 1 mg Aktiv substans; propylenglykol Hjälpämne; glycerol Hjälpämne; bensoylperoxid, hydratiserad 25 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Bemyndigande status:
Avregistrerad
Godkännandenummer:
55535
Tillstånd datum:
2017-06-21

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

19-07-2021

Produktens egenskaper Produktens egenskaper - engelska

19-07-2021

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

28-01-2013

Läs hela dokumentet

S

UMMARY OF

P

RODUCT

C

HARACTERISTICS

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 (E1520; 4.00 %).

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).

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

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

Pregnancy (see section 4.6)

Women planning a pregnancy (see section 4.6)

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), eczematous

or sunburned.

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 medicine contains 40 mg propylene glycol (E1520) in each gram which is equivalent to 4

%w/w, it 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 performed.

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

Orally administered retinoids have been associated with congenital abnormalities. When used in

accordance

with

prescribing

information,

topically

administered

retinoids

generally

assumed to result into low systemic exposure due to minimal dermal absorption. However, there

could be individual factors (e.g. damaged skin barrier, excessive use) that contribute to an

increased systemic exposure.

Pregnancy

Epiduo is contraindicated (see section 4.3) in pregnancy, or in women planning a pregnancy.

There are no or limited amount of data from the use of adapalene topically in pregnant women.

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.

If the product is used during pregnancy, or if the patient becomes pregnant while taking this drug,

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 breast-feeding.

To avoid contact exposure of the infant, application of Epiduo to the chest should be avoided

when used during breast-feeding.

Fertility

No human fertility studies were conducted with Epiduo gel.

However, no effects of adapalene or benzoyl peroxide on fertility were found in rats in

reproductive studies (See section 5.3).

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:

System organ class

(MedDRA)

Frequency

Adverse Drug Reaction

Eye disorders

Not known (cannot be estimated

from the available data)*

Eyelid oedema

Immune system

Not known (cannot be estimated

from the available data)*

Anaphylactic reaction

Respiratory, thoracic

and mediastinal

Not known (cannot be estimated

from the available data)*

Throat tightness, dyspnoea

System organ class

(MedDRA)

Frequency

Adverse Drug Reaction

disorders

Common (≥1/100 to <1/10)

Dry skin, irritative contact

dermatitis, skin irritation, skin

burning sensation, erythema, skin

exfoliation (scaling)

Uncommon (≥1/1000 to <1/100)

Pruritus, sunburn

Skin and

subcutaneous tissue

disorders

Not known (cannot be estimated

from the available data)*

Allergic contact dermatitis,

swelling face, pain of skin

(stinging pain), blisters

(vesicles), skin discolouration

(hyperpigmentation and

hypopigmentation), urticaria,

application site burn**

*Post marketing surveillance data

**Most of the cases of “application site burn” were superficial burns but cases with second degree

burn or severe burn reactions have been reported.

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 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 national reporting system

listed in Appendix V*.

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

5.1.

Pharmacodynamic properties

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

combines

active

substances,

which

through

different,

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

anti-inflammatory

properties.

Mechanistically,

adapalene

binds

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

abnormally

present

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:

Success rate, percentage of patients rated ‘Clear’ and ‘Almost Clear’ at Week 12

based on the Investigator’s Global Assessment (IGA);

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

Week

treatment.

Noninflammatory

lesions

(open

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

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 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 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

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

rapidly

completely converted to benzoic acid in the skin and after absorption is eliminated in the urine,

with limited systemic exposure.

Reproductive toxicity of adapalene was tested by the oral route in rats for fertility.

There were no adverse effects upon reproductive performance and fertility, F1 litter survival,

growth

development

weaning,

subsequent

reproductive

performance

following

treatment with adapalene oral at doses up to 20 mg/kg/day.

A reproductive and developmental toxicity study conducted in rats exposed groups to oral doses

of benzoyl peroxide of up 1000 mg/kg/day (5 mL/kg) showed that Benzoyl peroxide did not

induce teratogenicity or effects on reproductive function at doses up to 500 mg/kg/day.

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.

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:

15 g, 30 g, 45 g and 60 g 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

[To be completed nationally]

8.

MARKETING

AUTHORISATION

NUMBER(S)

[To be completed nationally]

9.

DATE

OF

FIRST

AUTHORISATION/RENEWAL

OF

THE

AUTHORISATION

[To be completed nationally]

10.

DATE

OF

REVISION

OF

THE

TEXT

8 July 2021

Liknande Produkter

Sök varningar relaterade till denna produkt

Visa dokumenthistorik

Dela den här informationen