Epiduo 0,3 %/2,5 % Gel

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

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Bipacksedel Bipacksedel (PIL)

19-07-2021

Produktens egenskaper Produktens egenskaper (SPC)

27-06-2019

Aktiva substanser:
adapalen; bensoylperoxid, hydratiserad
Tillgänglig från:
Galderma Nordic AB,
ATC-kod:
D10AD53
INN (International namn):
adapalene; benzoyl peroxide, hydrated
Dos:
0,3 %/2,5 %
Läkemedelsform:
Gel
Sammansättning:
adapalen 3 mg Aktiv substans; propylenglykol Hjälpämne; glycerol Hjälpämne; bensoylperoxid, hydratiserad 25 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Tub, 2 gram; Tub, 5 gram; Flaska med pump, 15 gram; Flaska med pump, 30 gram; Flaska med pump, 45 gram; Flaska med pump, 60 gram
Bemyndigande status:
Godkänd
Godkännandenummer:
53560
Tillstånd datum:
2016-11-11

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

09-10-2020

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19-07-2021

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

11-11-2016

Läs hela dokumentet

Bipacksedel: Information till patienten

Epiduo 0,3% / 2,5% gel

adapalen / bensoylperoxid

Läs noga igenom denna bipacksedel innan du börjar använda detta läkemedel. Den innehåller

information som är viktig för dig.

Spara denna information, du kan behöva läsa den igen.

Om du har ytterligare frågor vänd dig till läkare eller apotekspersonal.

Detta läkemedel har ordinerats enbart åt dig. Ge det inte till andra. Det kan skada dem, även om

de uppvisar sjukdomstecken som liknar dina.

Om du får biverkningar, tala med läkare eller apotekspersonal. Detta gäller även eventuella

biverkningar som inte nämns i denna information. Se avsnitt 4.

I denna bipacksedel finns information om följande:

Vad Epiduo är och vad det används för

Vad du behöver veta innan du använder Epiduo

Hur du använder Epiduo

Eventuella biverkningar

Hur Epiduo ska förvaras

Förpackningens innehåll och övriga upplysningar

1.

Vad Epiduo är och vad det används för

Epiduo gel tillhör en grupp läkemedel som kallas ”akneläkemedel för lokalbehandling”, dvs. det är

avsett för behandling av acne vulgaris med komedoner (pormaskar), många papler (upphöjningar på

huden) och pustler (inflammerade finnar).

Gelen kombinerar två aktiva substanser, adapalen och bensoylperoxid, som verkar tillsammans men på

olika sätt:

-

Adapalen tillhör en grupp läkemedel som kallas för retinoider och som verkar specifikt på de

processer i huden som orsakar akne.

-

Bensoylperoxid verkar som ett bakteriedödande medel samt genom att mjukgöra och flaga av

det yttersta hudlagret.

Epiduo 0,3% / 2,5% gel ska endast användas av vuxna och ungdomar från 12 års ålder.

Adapalen och bensoylperoxid som finns i Epiduo kan också vara godkänd för att behandla andra

sjukdomar som inte nämns i denna produktinformation. Fråga läkare, apotek eller annan

hälsovårdspersonal om du har ytterligare frågor och följ alltid deras instruktion.

2.

Vad du behöver veta innan du använder Epiduo

Använd inte Epiduo gel:

Om du är gravid

Om du planerar att bli gravid

Om du är allergisk mot adapalen eller bensoylperoxid eller något annat innehållsämne i detta

läkemedel (anges i avsnitt 6).

Varningar och försiktighet

Tala med läkare eller apotekspersonal innan du använder Epiduo gel.

-

Du ska inte använda Epiduo gel på områden med skärsår, skrapsår, solbränna eller eksem.

-

Se till att Epiduo gel inte kommer i ögonen, munnen, näsborrarna eller slemhinnor och andra

mycket känsliga områden på kroppen. Om detta skulle hända, skölj omedelbart området med

rikligt med varmt vatten.

-

Undvik överdriven exponering för solljus och UV-strålning.

-

Undvik att få Epiduo gel i håret eller på färgade tyger eftersom gelen kan orsaka blekning.

Tvätta också händerna noga efter att du har använt Epiduo gel.

Kontakta läkare om du upplever ihållande hudirritation när du börjar med Epiduo gel (se avsnitt 3. Hur

du använder Epiduo).

Andra läkemedel och Epiduo gel

-

Använd inte andra akneprodukter (som innehåller bensoylperoxid och/eller retinoider) samtidigt

med Epiduo gel.

-

Undvik att använda Epiduo gel samtidigt med kosmetika som är irriterande, uttorkande eller

exfolierande (avlägsnar döda hudceller).

Andra läkemedel kan påverka Epiduo gel och du ska därför tala om för läkare eller apotekspersonal

om du använder, nyligen har använt eller kan tänkas använda andra läkemedel.

Graviditet och amning

Graviditet

Använd INTE Epiduo 0,3% / 2,5% gel om du är gravid eller planerar att bli gravid. Din läkare kan ge

dig mer information.

Om du blir gravid medan du använder Epiduo 0,3% / 2,5% gel ska behandlingen avbrytas och du ska

informera din läkare så snart som möjligt för ytterligare uppföljning.

Amning

Om du ammar, rådfråga läkare innan du använder detta läkemedel. Läkaren talar om för dig om du bör

avbryta amningen eller avstå från behandling med Epiduo 0,3% / 2,5% gel.

Om läkaren råder dig att fortsätta behandlingen ska du inte applicera gel på bröstet för att undvika att

barnet kommer i kontakt med läkemedlet.

Körförmåga och användning av maskiner

Epiduo gel har ingen eller försumbar effekt på förmågan att framföra fordon och använda maskiner.

Epiduo 0,3% / 2,5% gel innehåller 40 mg propylenglykol (E1520) per gram motsvarande 4 %

w/w

, det kan orsaka hudirritation (t.ex. kontaktdermatit).

3.

Hur du använder Epiduo

Använd alltid detta läkemedel enligt läkarens anvisningar. Rådfråga läkare eller apotekspersonal om

du är osäker.

Epiduo 0,3% / 2,5% gel är endast avsett att användas av vuxna och ungdomar från 12 års ålder.

Epiduo är en gel som används på huden.

Läkaren avgör vilken styrka av Epiduo gel du behöver beroende på hur din akne ser ut och hur svår

den är. Läkaren avgör också om du behöver någon ytterligare behandling.

-

Huden ska vara ren och torr före applicering.

-

Applicera gelen i ett tunt, jämnt lager på de akneangripna områdena i ansiktet och/eller på bålen

en gång dagligen vid sänggåendet. Undvik kontakt med ögon, läppar, näsborrar och slemhinnor.

-

Vid användning i ansiktet: Tvätta och torka ansiktet och använd en ärtstor mängd gel på varje

del av ansiktet (t.ex. pannan, hakan, vardera kinden).

-

Tvätta händerna noga efter att du har använt Epiduo gel.

Läkaren kommer att tala om för dig hur länge du behöver använda Epiduo 0,3% / 2,5% gel. Om du

inte ser någon förbättring efter 4-8 veckor ska du diskutera nyttan med att fortsätta behandlingen med

din läkare.

Om du upplever ihållande hudirritation under de första veckorna när du använder Epiduo gel ska du

kontakta läkare. Du kan uppmanas att använda en fuktighetskräm, att använda gelen mindre ofta, att

göra ett kort avbrott i behandlingen eller att sluta använda gelen.

Använd inte kosmetika (t.ex. någon annan ansiktskräm eller smink) före den dagliga appliceringen av

Epiduo gel. Sådana produkter kan användas när gelen har torkat.

Användning för barn

Epiduo 0,3% / 2,5% gel ska inte användas av barn under 12 år.

Om du har använt för stor mängd av Epiduo gel

Om du använder mer Epiduo gel på huden än vad du behöver, kommer aknen inte att försvinna

snabbare, men huden kan bli irriterad och röd.

Om du fått i dig för stor mängd läkemedel eller om t.ex. ett barn fått i sig läkemedlet av misstag

kontakta läkare, sjukhus eller Giftinformationscentralen (tel. 112) för bedömning av risken samt

rådgivning.

Om du har glömt att använda Epiduo gel

Applicera inte dubbel dos för att kompensera för glömd dos.

Om du slutar att använda Epiduo gel

Det behövs flera appliceringar av detta läkemedel innan aknen (komedoner, papler och pustler) börjar

minska. Fortsätt att använda Epiduo gel så länge som läkaren har ordinerat det.

Om du har ytterligare frågor om detta läkemedel, kontakta läkare eller apotekspersonal.

4.

Eventuella biverkningar

Liksom alla läkemedel kan detta läkemedel orsaka biverkningar, men alla användare behöver inte få

dem.

Cirka 1 av 10 personer som använder Epiduo 0,3% / 2,5% gel kan få biverkningar i huden.

Sluta använda produkten och kontakta omedelbart sjukvården om du utvecklar trånghetskänsla i halsen

eller svullnad av ögonen, ansiktet, läpparna eller tungan, känner dig svag eller har svårighet att andas.

Sluta använda produkten om du får nässelutslag eller klåda i ansiktet eller på kroppen. Frekvensen med

vilka dessa biverkningar inträffar är inte känd.

Vanliga biverkningar (kan förekomma hos upp till 1 av 10 användare)

Hudirritation

Eksem

Brännande känsla i huden

Mindre vanliga biverkningar (kan förekomma hos upp till 1 av 100 användare):

Rodnad på ögonlocken

Pirrningar eller stickningar på appliceringsstället

Klåda i huden, allergisk hudreaktion

Utslag

Torr hud

Utöver de biverkningar som beskrivs ovan, har följande biverkningar rapporterats med en svagare

styrka av Epiduo gel (adapalen 0,1% / bensoylperoxid 2,5%):

Mindre vanliga (kan förekomma hos upp till 1 av 100 användare)

Solsveda

Ingen känd frekvens (kan inte beräknas från tillgängliga data)

Svullnad av ögonlock

Trånghetskänsla i halsen

Allergiska kontaktreaktioner

Svullet ansikte

Smärta i huden (stickande smärta)

Blåsor (vesiklar)

Svårighet att andas

Missfärgning av huden (förändring i hudfärg)

Brännsår vid appliceringsstället

Biverkningar som vanligen är förenade med användning av Epiduo är lindriga till måttliga reaktioner

på appliceringsstället, till exempel hudirritation med rodnad, torrhet, fjällning, sveda och/eller

brännande känsla i huden.

Brännsår vid appliceringsstället, de flesta ytliga, men även allvarligare fall med blåsbildning har

rapporterats.

Om du upplever ihållande hudirritation under de första veckorna när du använder Epiduo 0,3% / 2,5%

gel ska du kontakta läkare. Biverkningar i huden, t ex hudirritation, är vanligare med Epiduo 0,3% /

2,5% gel än med den svagare styrkan Epiduo 0,1% / 2,5% gel. Du kan uppmanas att använda en

fuktighetskräm, att använda gelen mindre ofta, att göra ett kort avbrott i behandlingen eller att sluta

använda gelen. Dessa reaktioner kommer vanligen tidigt under behandlingen och tenderar att gradvis

avta med tiden.

Rapportering av biverkningar

Om du får biverkningar, tala med läkare eller apotekspersonal.

Detta gäller även eventuella biverkningar som inte nämns i denna information. Du kan också

rapportera biverkningar direkt (se detaljer nedan). Genom att rapportera biverkningar kan du bidra till

att öka informationen om läkemedlets säkerhet.

Läkemedelsverket

Box 26

751 03 Uppsala

Webbplats: www.lakemedelsverket.se

5.

Hur Epiduo ska förvaras

Förvara detta läkemedel utom syn- och räckhåll för barn.

Används före utgångsdatum som anges på kartongen och tuben/pumpen efter EXP. Utgångsdatumet är

den sista dagen i angiven månad.

Förvaras vid högst 25 °C.

Hållbarhet efter första öppnandet: 3 månader.

Epiduo 0,3% / 2,5% gel ska inte kastas i avloppet eller bland hushållsavfall. Fråga apotekspersonalen

hur man kastar läkemedel som inte längre används. Dessa åtgärder är till för att skydda miljön.

6.

Förpackningens innehåll och övriga upplysningar

Innehållsdeklaration

aktiva substanserna

är adapalen och bensoylperoxid. Ett gram gel innehåller 3 mg (0,3%)

adapalen och 25 mg (2,5%) bensoylperoxid.

Övriga innehållsämnen

är dinatriumedetat, dokusatnatrium, glycerol, poloxamer, propylenglykol

(E1520), simulgel 600 PHA (sampolymer av akrylamid och natriumakryloyldimetyltaurat,

isohexadekan, polysorbat 80, sorbitanoleat) och renat vatten.

Se slutet av avsnitt 2 för mer

information.

Läkemedlets utseende och förpackningsstorlekar

Epiduo gel är en vit till mycket blekt gul, ogenomskinlig gel.

Epiduo gel finns i:

En plasttub innehållande 2 eller 5 gram.

En pump innehållande 15, 30, 45 eller 60 gram.

Eventuellt kommer inte alla förpackningsstorlekar att marknadsföras.

Innehavare av godkännande för försäljning och tillverkare

Innehavare av godkännande för försäljning

Galderma Nordic AB

Seminariegatan 21

752 28 Uppsala

Sverige

Tel: +46 18 444 0330

E-post: nordic@galderma.com

Tillverkare

Laboratoires Galderma

Z.I. Montdésir

74540 Alby-sur-Chéran

Frankrike

Detta läkemedel är godkänt inom Europeiska ekonomiska samarbetsområdet under namnen:

Österrike, Belgien, Tyskland, Grekland, Luxemburg, Polen: Epiduo Forte

Danmark: Epiduo

Finland, Frankrike, Island, Italien, Norge, Sverige, Storbritannien: Epiduo 0,3% / 2,5% gel

Spanien: Epiduo Forte 3 mg/g + 25 mg/g

Portugal: Epiduo 3 mg/g + 25 mg/g

Denna bipacksedel ändrades senast 2021-07-19

Läs hela dokumentet

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 of 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

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 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.

reaction

suggesting

sensitivity

component

formula

occurs,

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

it may cause skin irritation.

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

used

cutaneously

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

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

accordance with the prescribing information, topically administered retinoids are 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 0.3%/2.5% gel 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.

Breast-feeding

study

animal

human

milk

transfer

conducted

after

cutaneous

application

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 (See section 5.3).

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

Table 1: Adverse reactions

System Organ Class

Frequency

Adverse reactions

Eye disorders

Uncommon

Erythema of eyelid

System Organ Class

Frequency

Adverse reactions

Not known*

Eyelid oedema

Immune system

Not known*

Anaphylactic reaction

Nervous system disorders

Uncommon

Paresthesia (tingling at application site)

Respiratory,

thoracic

mediastinal disorders

Not known*

Throat tightness, dyspnea

Common

Atopic

dermatitis,

eczema,

skin

burning

sensation, skin irritation

Uncommon

Dry skin, pruritus, rash

Skin

subcutaneous

tissue

disorders

Not known*

Allergic contact dermatitis, swelling face, pain

of skin (stinging pain) and blisters (vesicles),

skin

discolouration

(hyperpigmentation

hypopigmentation),

urticaria,

application

site

burn**

*Post-marketing surveillance data reported since the global launch of Epiduo 0.1%/2.5% gel, from a

population of unknown size

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

burn or severe burn reactions have been reported.

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 national reporting system listed in Appendix V.*

4.9

Overdose

Epiduo

0.3%

2.5%

once-daily

cutaneous

only.

Excessive

application

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%

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 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

Cutibacterium 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

C. 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: 30-149). 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

“clear” or “almost clear”)

33.7%

27.3%

11.0%

Change

in

Inflammatory

Lesions,

Mean

absolute

(percent)

reduction

27.8

(68.7%)

26.5 (69.3%)

13.2

(39.2%)

Change

in

Non-inflammatory

Lesions,

Mean

absolute

(percent)

reduction

40.5

(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%

20.5%

11.8%

Change

in

Inflammatory

Lesions,

Mean

absolute

(percent)

reduction

37.3

(74.4%)

30.2

(68%)

14.3

(33.0%)

Change

in

Non-inflammatory

Lesions,

Mean

absolute

(percent)

reduction

46.3

(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%).

The effect of Epiduo 0.3% / 2.5% gel on acne scarring was investigated in the OSCAR study. This was

multi-centre,

randomized,

investigator-blinded,

vehicle-controlled

trial

using

intra-individual

comparison (right half-face vs. left half-face) investigating male and female subjects aged 16 to 35 years

(n=67) with moderate to severe facial acne vulgaris, with an average mean number of acne lesions of 40

acne lesions (18 inflammatory lesions, 22 non-inflammatory lesions) on each side. The vast majority of

subjects had a global moderate severity of acne (93%). Both sides were well-balanced regarding the

acne lesions, the severity of acne scars were 12 scars on each side with a majority of 2-4 mm scars.

Majority of subjects had a globally mild (63%) severity of scars and about 30% had moderate severity.

Male or female subjects, aged 16 to 35 years inclusive and with skin phototype of I to IV on

Fitzpatrick’s scale were included in this study.

The enrolled population were mainly females (65.7%), and most subjects were categorized as mostly

white by race (86.6%) and rest Asians (13.4%), ethnicity was not captured. The most frequent skin

phototypes were II (47.8%) and III (34.3%) and rest IV (13.4%) and I (4.5%).

All eligible subjects were randomized to receive Epiduo 0.3% / 2.5% on one half of the face and vehicle

gel on the other, once daily at night, for 24 weeks. The primary efficacy endpoint was atrophic acne scar

count per half-face at Week 24.

The primary endpoint analysis showed that drug therapy reduced the total number of acne scars (see

Table 4).

Table 4: Total acne scars (ITT/LOCF)

Total acne scars (ITT/LOCF)

Epiduo

0.3% / 2.5% gel

Vehicle gel

Treatment

difference

Statistical

result

Mean ± SD

Median

(Q1, Q3)

(Min, Max)

9.5 ± 5.5

(6.0, 12.0)

(0, 27)

13.3 ± 7.4

13.0

(8.0, 19.0)

(0, 36)

-3.7 ± 4.4

-3.0

(-7.0, 0.0)

(-16, 3)

p<0.0001

Epiduo 0.3% / 2.5% gel primarily reduced scars of 2-4 mm size (mean Epiduo 0.3% / 2.5% gel 9.0 ±

5.4; mean Vehicle gel 12.1 ± 7.0; mean treatment difference vs. vehicle -3.1 ± 4.1), while the reduction

in scars of >4 mm was smaller (mean Epiduo 0.3% / 2.5% gel 0.6 ± 0.8; mean Vehicle gel 1.2 ± 1.9;

mean treatment difference vs. vehicle -0.6 ± 1.5).

Figure 1 shows the percent change of total atrophic scars by visit for the Epiduo 0.3% / 2.5% gel and

vehicle face halves, respectively.

Figure 1

* nominal p-value, not adjusted for multiple testing

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

limit

quantification

(LOQ

0.1 ng/mL),

with

mean

0.16 ± 0.08 ng/mL and a mean AUC

0-24h

of 2.49 ± 1.21 ng.h/mL. The most exposed subject had

adapalene C

and AUC

0-24h

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

special

hazard

humans

based

conventional

studies

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.

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

and development to weaning, and 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.

Environmental Risk Assessment (ERA):

Environmental risk assessment studies have shown that adapalene has the potential to be very persistent,

and toxic to the environment (see section 6.6).

Environmental risk assessment studies have shown that adapalene may pose a risk for aquatic

compartment.

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 plastic tubes having a high density polyethylene body structure with a high density

polyethylene head, closed with a polypropylene screw-cap.

Multidose container with airless pump:

15 g, 30 g, 45 g and 60 g multidose container with airless pump and snap on cap, made of polypropylene

and high density polyethylene or polypropylene, high density polyethylene and very low density

polyethylene.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

This medicinal product may pose a risk to the environment (See section 5.3).

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

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