Differin product is proposed for the cutaneous treatment of mild to moderate acne vulgaris where comedones, papules and pustules predominate. Acne of the face, chest or back is appropriate for treatment.

Topical route.

Apply a pea-sized amount of Differin to a clean and dry face, and spread over the acne lesions, once per day before retiring. Avoid contact with the eyes and lips.

Clinical improvement should be visible after 4 to 8 weeks' treatment, with a clear improvement visible after 3 months' treatment. Tolerance to adapalene cream or gel has been demonstrated over 6-month treatment periods. Improvement in the patient's condition should be evaluated after 3 months' treatment.

If irritation occurs and the treatment has to be interrupted or applied less frequently, it may then be resumed or applied more frequently, depending on patient tolerance to treatment.

Increasing the quantities applied will improve neither the activity nor the rapidity of action of the product but may cause redness, desquamation and discomfort.

 If patients use cosmetics, these should be non-comedogenic and non-astringent.

The safety and effectiveness of Differin Cream have not been studied in children below 12 years of age.

Special warnings

Differin cream: contains methyl parahydroxybenzoate (E218) and propyl parahydroxybenzoate (E216) and may cause allergic reactions (possibly delayed).

Differin gel: contains methyl parahydroxybenzoate (E218) and may cause allergic reactions (possibly delayed). This medicine contains propylene glycol and may cause skin irritation.

Precautions for use

If a hypersensitivity reaction or severe irritation occur, application of the Differin must be interrupted temporarily or indefinitely.

In the event of accidental application to mucous membranes (eyes, mouth and nostrils) or to open wounds, rinse thoroughly in warm water.

Due to the slightly irritant nature of Differin, the concomitant use of astringent cleansing cosmetic products and drying or irritant agents (such as fragranced products or products containing alcohol) should be avoided.

Adapalene when applied in the evening, can also be used with other acne treatments applied in the morning, such as erythromycin lotion (4 %) or clindamycin lotion (1%), or benzoyl peroxide aqueous gels at concentrations up to 10%.

Differin Cream should not come into contact with the eyes, mouth, angles of the nose or mucous membranes.

The treatment may however be continued if exposure to sun is reduced to the strict minimum (by wearing a hat and using a sun cream) and application frequency adjusted.

In the event of exceptional exposure to sun (e.g. a day at the seaside), do not apply either the day before, the same day or the next day.

If previous exposure has resulted in a sunburn, wait until completely healed before starting the treatment again.

 If the degree of local irritation warrants, patients should be directed to use the medication less frequently, to discontinue use temporarily, or to discontinue use altogether.

The product should not be applied to either broken (cuts and abrasions) or eczematous skin, nor should it be used in patients with severe acne involving large areas of the body.

Adapalene is stable in oxygen and light, and is chemically non-reactive. The concomitant use of adapalene with other topical acne treatments, such as clindamycin phosphate or benzoyl peroxide, does not cause mutual degradation.

Adapalene is only absorbed by the skin in small amounts, interaction with other medicinal products administered by systemic route is therefore not likely.

 There are no known interactions with other medications which might be used cutaneously and concurrently with Differin; however, other retinoids or drugs with a similar mode of action should not be used concurrently with adapalene.

 Absorption of adapalene through human skin is low and therefore interaction with systemic medications is unlikely. There is no evidence that the efficacy of oral drugs such as contraceptives and antibiotics is influenced by the cutaneous use of Differin .

Breastfeeding

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 in 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

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

Animal studies by the oral route have shown reproductive toxicity at high systemic exposure.

Clinical experience with locally applied adapalene in pregnancy is limited and the safe use of Differin in pregnancy has not been established, but the limited available data do not indicate harmful effects on pregnancy or on the health of the foetus exposed in early pregnancy

Due to the limited data available and the fact that slight cutaneous passage of adapalene is possible, DIFFERIN must not be used during pregnancy.

Physicians should ensure that female patients are not pregnant or trying to conceive before prescribing Differin. In case of unexpected pregnancy, treatment should be discontinued.

Breastfeeding

No study on animal or human milk transfer was conducted after cutaneous application of Differin.

No effects on the suckling child are anticipated since the systemic exposure of the breast-feeding woman to Differin is negligible.

Not applicable.

Differin may cause the following adverse drug reactions:

*Post marketing surveillance data.

** Most of the cases of “application site burn” were superficial burns but cases with second degree burn reactions have been reported.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after authorization 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:

Saudi Arabia

The National Pharmacovigilance Center (NPC):

- Fax: +966-11-205-7662

- Call NPC at +966-11-2038222, Ext 2317-2356-2340

- SFDA Call Center: 19999

- E-mail: npc.drug@sfda.gov.sa

- Website: https://ade.sfda.gov.sa/

Other GCC States

- Please contact the relevant competent authority.

Oral toxicity occurs in mice at doses higher than 10 mg/kg. Despite the low risk of accidental ingestion, gastric lavage should be envisaged in this eventuality.

Pharmacotherapeutic group: D10A Anti-Acne Preparations for Topical Use, ATC code: D10AD03

Although combination therapy in acne treatment is frequent, the classifications of severe acne, moderate acne and mild to moderate acne were established for application to monotherapy.

Adapalene is a chemically-stable, retinoid compound, which also has anti-inflammatory properties. The mechanism of action of adapalene, like tretinoin, relies on its binding to specific nuclear receptors, but not to the cytosolic receptor protein.

Adapalene has a comedolytic effect in rhino mice models, and also has effects on abnormal keratinisation and epidermal differentiation processes, both present in acne pathogenesis. The method of action of adapalene would appear to involve normalisation of cohesiveness of follicular epithelial cells, leading to a reduction in microcomedo formation.

Adapalene has an anti-inflammatory effect in vivo and in vitro (standard anti-inflammatory tests). Adapalene acts by inhibiting the chemotactic and chemokinetic responses of human polynuclear leukocytes, along with arachidonic acid metabolism by lipo-oxidation in the presence of inflammatory stimuli. The pharmacological profile may suggest that adapalene has an effect on the inflammatory component of acne.

Adapalene is little-absorbed by the skin (approximately 4% of the dose applied). The metabolism involves mainly o-demethylation, hydroxylation and conjugation and excretion is mainly by biliary route.

Prelinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

Following oral administration corresponding to significant plasma exposure, effects similar to hypervitaminosis A syndrome have been observed.

Reproductive toxicology studies have been conducted with adapalene administered orally and cutaneously in rats and rabbits. A teratogenic effect was demonstrated at high systemic doses (oral doses of 25 mg/kg/day). At lower exposures (cutaneous dose of 6 mg/kg/day), a change in the number of ribs and vertebrae was observed.

DIFFERIN Cream:

Carbomer  934P (Carbopol 974P®)., PEG-20 methyl glucose sesquistearate , glycerol, Squalane natural, methyl parahydroxybenzoate (E218), propyl parahydroxybenzoate (E216), Disodium edatate methyl glucose sesquistearate , phenoxyethanol, cyclomethicone, sodium hydroxide solution in 10 percent, purified water.

DIFFERIN Gel:

Carbomer 980, propylene glycol, poloxamer 182, sodium edetate, methyl parahydroxybenzoate (E218), phenoxyethanol, sodium hydroxide or hydrochloric acid, purified water.

Not applicable.

Store below 25°C.

Do not refrigerate.

Differin Gel: After first opening, product can be used for a period of 6 months.

Differin Cream: After first opening, product can be used for a period of 4 months.

Differin Cream: 30g tube (Varnished aluminium), with cap (Polypropylene).

Differin Gel: 30 g tube (polyethylene).

No special requirements.