Differin

Adapalene (Differin) 0.1% (1mg/g) Gel: One gram contains: Adapalene Ph. Eur. 1 mg.
Adapalene (Differin) 0.3% (3mg/g) Topical Gel: One gram contains: Adapalene Ph. Eur. 3 mg.
Adapalene (Differin) 0.1% (1mg/g) Cream: One gram contains: Adapalene Ph. Eur. 1 mg.
Differin Cream contains 0.1% w/w adapalene (BAN, INN, USAN), as the active ingredient in a cream base containing carbomer, PEG-20 methylglucose sesquistearate, glycerol, natural squalane, methyl parahydroxybenzoate, propyl parahydroxybenzoate, disodium edetate, methylglucose sesquistearate, phenoxyethanol, cyclomethicone, sodium hydroxide to adjust the pH to 6.5 ± 0.2 and purified water to complete the formulation.
Excipients with known effect: Topical gel 0.1%: Methyl parahydroxybenzoate (E218), propylene glycol: One gram of gel contains 40mg of Propylene glycol (E1520).
Topical gel 0.3% and Cream: Methyl parahydroxybenzoate (E218) and propyl parahydroxybenzoate (E216).
Excipients/Inactive Ingredients: Topical gel 0.1%: Carbomer 940, Propylene Glycol, Poloxamer 182, Disodium edetate, Methyl para-hydroxybenzoate, Phenoxyethanol, Sodium hydroxide solution (qs pH = 5.0) and Purified water.
Topical gel 0.3% and Cream: Carbomer 934P, PEG-20 methyl glucose sesquistearate, Glycerol, Natural squalane, Methyl parahydroxybenzoate, Propyl parahydroxybenzoate, Disodium edetate, Methyl glucose sesquistearate, Phenoxyethanol, Cyclomethicone, Sodium hydroxide solution (qs pH = 6.3 to 6.7) and Purified water.

Pharmacology: Cream: Adapalene is a retinoid-like compound which, in in vivo and in vitro models of inflammation, has been demonstrated to possess anti-inflammatory properties; Adapalene is essentially stable to oxygen and light and is chemically non-reactive. Mechanistically, adapalene binds like tretinoin to specific retinoic acid nuclear receptors but, unlike tretinoin, not to cytosolic receptor binding proteins. Adapalene applied cutaneously is comedolytic in the rhino mouse model and also has effects on the abnormal processes of epidermal keratinization and differentiation, both of which are present in the pathogenesis of acne vulgaris. The mode of action of adapalene is suggested to be a normalisation of differentiation of follicular epithelial cells resulting in decreased microcomedone formation.
Adapalene is superior to reference retinoids in standard anti-inflammatory assays, both in vivo and in vitro. Mechanistically, it inhibits chemotactic and chemokinetic responses of human polymorphonuclear leucocytes and also the metabolism by lipoxidation of arachidonic acid to pro-inflammatory mediators. This profile suggests that the cell mediated inflammatory component of acne may be modified by adapalene. Studies in human patients provide clinical evidence that cutaneous adapalene is effective in reducing the inflammatory components of acne (papules and pustules).
Absorption of adapalene through human skin is low; in clinical trials measurable plasma adapalene levels were not found following chronic cutaneous application to large areas of acneic skin with an analytical sensitivity of 0.15 ng.mL-1. After administration of [14C]-adapalene in rats (IV, IP, oral and cutaneous), rabbits (IV, oral and cutaneous) and dogs (IV and oral), radioactivity was distributed in several tissues, the highest levels being found in liver, spleen, adrenals and ovaries. Metabolism in animals has been tentatively identified as being mainly by O-demethylation, hydroxylation and conjugation, and excretion is primarily by the biliary route.
In animal studies, adapalene was well tolerated on cutaneous application for periods of up to six months in rabbits and for up to two years in mice. The major symptoms of toxicity found in all animal species by the oral route were related to hypervitaminosis A syndrome, and included bone dissolution, elevated alkaline phosphatase and a slight anaemia. Large oral doses of adapalene produced no adverse neurological, cardiovascular or respiratory effects in animals. Adapalene is not mutagenic. Lifetime studies with adapalene have been completed in mice at cutaneous doses of 0.6, 2 and 6 mg.kg-1.d-1 and in rats at oral doses of 0.15, 0.5 and 1.5 mg.kg-1.d-1.
The only significant finding was a statistically significant increase of benign phaeochromocytomas of the adrenal medulla among male rats receiving adapalene at 1.5 mg.kg-1.d-1. These changes are considered to have no relevance to the cutaneous use of adapalene.
Pharmacodynamics: 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.
The clinical significance of these findings for the mitigation of facial photoaging is unknown.
Pharmacokinetics: A pharmacokinetic trial was conducted in 50 adults with acne vulgaris who were treated with once-daily applications during a 4-week period with 2 grams/day of Adapalene (Differin) 0.1 % GEL or Adapalene (Differin) 0.3 % GEL applied as a thin layer to the face, shoulders, upper chest and upper back.
Over the 4-week treatment with Adapalene (Differin) 0.1 % GEL, only 4 to 7 subjects out of 25 had quantifiable adapalene plasma concentrations above the limit of quantification of 0.1 ng/mL at steady state, with a mean Cmax of 0.04 ± 0.08 ng/mL and a mean AUC0-24h of 0.50 ± 0.99 ng.h/mL The most exposed subject had adapalene Cmax and AUC0-24h of 0.31 ng/mL and 3.47 ng.h/mL, respectively.
Over the 4-week treatment with Adapalene (Differin) 0.3 % GEL, 20 to 22 subjects out of 25 had quantifiable adapalene plasma concentrations above the limit of quantification of 0.1 ng/mL at steady state, with a mean Cmax of 0.18 ± 0.09 ng/mL and a mean AUC0-24h of 2.84 ± 1.75 ng.h/mL. The most exposed subject had adapalene Cmax and AUC0-24h of 0.40 ng/mL and 5.99 ng.h/mL, respectively.
Similar results were observed in adult and adolescent subjects (12 years of age and older) with acne vulgaris who were treated with once-daily applications during a 4-week period with, on average, 1.95 grams/day (range 1.2 - 2.9 grams/day) of Differin 0.1 % gel or with on average, 2.3 grams/day (range 1.4 - 3.2 grams/day) of Differin 0.3 % gel applied as a thin layer to the face, shoulders, upper chest and upper back.
Over the 4-week treatment with Adapalene (Differin) 0.1 % GEL in 24 adult and adolescent subjects (12 years of age and older) with moderate to severe acne vulgaris, all the subjects had quantifiable adapalene plasma concentrations above the limit of quantification of 0.02 ng/mL at steady state, with a mean Cmax of 0.05 ± 0.03 ng/mL and a mean AUC0-24h of 0.87 ± 0.43 ng.h/mL. The most exposed subject had adapalene Cmax and AUC0-24h of 0.17 ng/mL and 2.90 ng.h/mL, respectively.
Over the 4-week treatment with Adapalene (Differin) 0.3 % GEL in 30 adult and adolescent subjects (12 years of age and older) with severe acne vulgaris, 14 to 16 subjects had quantifiable adapalene plasma concentrations above the limit of quantification of 0.1 ng/mL at steady state, with a mean Cmax of 0.15 ± 0.08 ng/mL and a mean AUC0-24h of 2.47 ± 1.31 ng.h/mL. The most exposed subject had adapalene Cmax and AUC0-24h of 0.46 ng/mL and 7.40 ng.h/mL, respectively.
Excretion of adapalene appears to be primarily by the biliary route.

Adapalene (Differin) 0.1% (1mg/g) Gel, 0.3% (3mg/g) Topical Gel, and 0.1% (1mg/g) Cream: Adapalene (Differin) products are indicated for the topical treatment of facial acne vulgaris. Acne on the chest or back is appropriate for treatment.
Adapalene (Differin) 0.3% (3mg/g) Topical Gel: Indicated also for the treatment of facial skin photoaging which is a consequence of exposure to the sun. It helps to minimize the signs of photodamage skin which may include fine wrinkles and some types of hyperpigmentation such as blemishes, related to sun exposures, and when use together with appropriate skin care and sunlight avoidance programs.
Cream: Differin Cream is proposed for the cutaneous treatment of acne vulgaris where comedones, papules and pustules predominate. Acne of the face, chest or back is appropriate for treatment.

Adapalene (Differin) products should be applied to the face acne affected areas once a day at bedtime and after washing. Ensure that the affected areas are dry before application. A thin film of the product should be applied avoiding the eyes, lips and mucous membranes and the angles of the nose. (See PRECAUTIONS).
Clinical improvement for acne vulgaris is expected to be evident in four to eight weeks of treatment. Further improvement may be assessed after three months of treatment with Adapalene (Differin).
Clinical improvement for facial photoaging, periorbital wrinkles, ephelides/melanosis and forehead wrinkles is expected in 12 weeks. Further improvement may be assessed after 24 weeks of treatment with Adapalene (Differin) 0.3%.
Cutaneous safety of Adapalene (Differin) products has been demonstrated over a 12- months period.
If patients use cosmetics, these should be non-comedogenic and non-astringent.
The safety and effectiveness of Adapalene (Differin) products have not been studied in children below 12 years of age.
The safety and effectiveness of Adapalene (Differin) 0.3% has not been established in patients under the age of 35 years of age with facial photoaging.
Safety and effectiveness in geriatric patients age 65 and above have not been established.
Cream: Differin Cream should be applied to the acne affected areas once a day before retiring and after washing. A thin film of the product should be applied avoiding the eyes and lips (see Special Warnings and Special Precautions for Use). Ensure that the affected areas are dry before application.
With patients for whom it is necessary to reduce the frequency of application or to temporarily discontinue treatment, frequency of application may be restored or therapy resumed once it is judged that the patient can again tolerate the treatment.
If patients use cosmetics, these should be non-comedogenic and non-astringent.
The safety and effectiveness of Differin Cream has not been studied in neonates and young children.

Adapalene (Differin) products are not to be taken orally and are for cutaneous use only.
The oral route toxicity for Adapalene (Differin) products in mice is greater than 10 mL/kg. Unless the amount accidentally ingested is small, an appropriate method of gastric emptying should be considered.
Cream: Differin Cream is not to be taken orally and is for cutaneous use only. If the medication is applied excessively, no more rapid or better results will be obtained and marked redness, peeling or discomfort may occur.
The acute oral dose of Differin Cream required to produce toxic effects in mice is greater than 10 g/kg. Nevertheless, unless the amount accidentally ingested is small, an appropriate method of gastric emptying should be considered.

Hypersensitivity to the active substance or to any of the excipients.
Cream: Pregnancy (see Use in Pregnancy & Lactation).
Women planning a pregnancy.

If a reaction suggesting sensitivity or severe irritation occurs, use of the medication should be discontinued. If the degree of local irritation warrants, the patient should be directed to use the medication less frequently, should be instructed to either use a moisturizer, to discontinue use temporarily until symptoms subside or to discontinue use altogether. Once daily application may be resumed if it is judged that the patient is able to tolerate the treatment.
Adapalene (Differin) products should not come into contact with the eyes, mouth, angles of the nose or mucous membranes. If product enters the eye, wash immediately with warm water. The product should not be applied to either broken (cuts and abrasions), sunburn or eczematous skin.
Adapalene (Differin) products should not be used in patients with severe acne involving large areas of the body. As with other retinoids, use of "waxing" as a depilatory method should be avoided on skin treated with adapalene.
As Adapalene (Differin) products have the potential to induce local irritation in some patients, concomitant use of other potentially irritating topical products (medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect and products with high concentrations of alcohol, astringents, spices, or lime) should be considered with caution. Particular caution should be exercised in using preparations containing sulfur, resorcinol, or salicylic acid in combination with Adapalene (Differin) products. If these preparations have been used, it is advisable not to start therapy with Adapalene (Differin) products until the effects of such preparations have subsided.
Exposure to sunlight and artificial UV irradiation, including sunlamps, should be minimized during use of adapalene. Use of sunscreen products and protective clothing over treated areas is recommended when exposure cannot be avoided.
Weather extremes, such as wind or cold, also may be irritating to patients under treatment with Adapalene (Differin) products.
Allergic/hypersensitivity reactions have been reported during postmarketing use of adapalene. A patient should stop using Adapalene (Differin) products and consult a doctor if allergic or anaphylactoid/anaphylactic reactions (e.g., skin rash, pruritus, hives, chest pain, edema, and shortness of breath) occur during treatment.
Adapalene (Differin) 0.1% and 0.3% Gel contain: methyl parahydroxybenzoate (E218). It may cause allergic reactions which can possibly be delayed.
Adapalene (Differin) 0.1% Cream contains: methyl parahydroxybenzoate (E218) and propyl parahydroxybenzoate (E216) that can cause allergic reactions (can arise after the treatment is completed).
Cream: General: If a reaction suggesting sensitivity or severe irritation occurs, use of the medication should be discontinued. If the degree of local irritation warrants, patients should be directed to use the medication less frequently, to discontinue use temporarily until symptoms subside, or to discontinue use altogether. Differin Cream should not come into contact with the eyes, mouth, angles of the nose or mucous membranes.
If product enters the eye, wash immediately with warm water. The product should not be applied to either broken (cuts and abrasions), sunburn or eczematous skin, nor should it be used in patients with severe acne.
Effects on ability to drive and use machines: Adapalene (Differin) products have no influence on the ability to drive and use machines.

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: Animal studies by the oral route have shown reproductive toxicity at high systemic exposure.
Clinical experience with locally applied Differin products in pregnancy is limited but the few available data do not indicate harmful effects on pregnancy or on the health of the foetus exposed in early pregnancy. Differin products should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Due to the limited available data and because a very weak cutaneous passage of adapalene is possible, Adapalene (Differin) should not be used during pregnancy. In case of unexpected pregnancy, treatment should be discontinued.
Physicians should ensure that female patients are not pregnant or trying to conceive before prescribing Adapalene (Differin) products.
Cream: Differin is contraindicated (see Contraindications) in pregnancy, or in women planning a pregnancy. If the product is used during pregnancy, or if the patient becomes pregnant while taking this drug, treatment should be discontinued.
Lactation: It is not known whether Adapalene (Differin) products are excreted in animal or human milk after cutaneous application of Adapalene (Differin) products. In animal studies, infant rats suckled by mother with circulating levels of adapalene at least 300 times those demonstrated in clinical use developed normally. Because many drugs are excreted in human milk, caution should be exercised when Adapalene (Differin) products are administered to a nursing woman.
Adapalene (Differin) can be used during breastfeeding. To avoid contact exposure of the infant, application of Adapalene (Differin) to the chest should be avoided when used during breast-feeding.

Adapalene (Differin) products may cause the following adverse drug reactions: See Table.

Click on icon to see table/diagram/image

Absorption of adapalene through human skin is low (see Pharmacokinetics properties), and therefore interaction with systemic medications is unlikely.
There are no formal drug-drug interaction studies conducted with other medications which might be used cutaneously and concurrently with Adapalene (Differin) products.
Cutaneous antiacne treatments such as erythromycin (up to 4%) or clindamycin phosphate (1% as the base) solutions or benzoyl peroxide water-based gels (up to 10%) may be used in the morning with Adapalene (Differin) products used at night as there is no mutual degradation or cumulative irritation. However, other retinoids or drugs with a similar mode of action should not be used concurrently with Adapalene (Differin) products.
Adapalene (Differin) products are essentially stable to oxygen and light and is chemically non-reactive. Whilst extensive studies in animals and man have shown neither phototoxic nor photoallergic potential for Adapalene (Differin) products, the safety of using Adapalene (Differin) products during repeated exposure to sunlight or UV irradiation has not been established in either animals or man. Exposure to excessive sunlight or UV irradiation should be avoided.
Adapalene (Differin) products have a potential for mild local irritation, and therefore it is possible that concomitant use of peeling agents, abrasive cleansers, strong drying agents, astringents or irritant products (aromatic and alcoholic agents) may produce additive irritant effects.
Cream: There are no known interactions with other medications which might be used cutaneously and concurrently with Differin Cream; however, other retinoids or drugs with a similar mode of action should not be used concurrently with adapalene.
Adapalene is essentially stable to oxygen and light and is chemically non-reactive. Whilst extensive studies in animals and man have shown neither phototoxic nor photoallergic potential for adapalene, the safety of using adapalene during repeated exposure to sunlight or UV irradiation has not been established in either animals or man. Exposure to excessive sunlight or UV irradiation should be avoided.
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 Cream.
Differin Cream has a potential for mild local irritation, and therefore it is possible that concomitant use of peeling agents, astringents or irritant products may produce additive irritant effects. However, cutaneous antiacne treatments, e.g. erythromycin (up to 4%) or clindamycin phosphate (1% as the base) solutions or benzoyl peroxide water based gels up to 10%, may be used in the morning when Differin Cream is used at night as there is no mutual degradation or cumulative irritation.

Cream: Instructions for Use: Squeeze the tube gently at its base to place a quantity of product on the fingertips sufficient to cover the affected areas. Replace the cap tightly after use.

Adapalene (Differin) 0.1% Gel: Store at temperatures not exceeding 25°C. Avoid freezing during transport and storage.
Adapalene (Differin) 0.3% Topical Gel: Store at temperatures not exceeding 30°C. Keep from freezing. Keep container tightly closed. Keep in a safe place.
Adapalene (Differin) 0.1% Cream: Store at temperatures not exceeding 30°C. Avoid freezing during transport and storage.

Acne Treatment Preparations

D10AD03 - adapalene ; Belongs to the class of topical retinoid preparations used in the treatment of acne.

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