DIFFERIN Adapalene 1mg / g (0.1%) Cream 30g
RXDRUG-DR-XY27030
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Features
Brand
Differin
Full Details
Dosage Strength
0.1% (1mg / g)
Drug Ingredients
- Adapalene
Drug Packaging
Cream 30g
Generic Name
Adapalene
Dosage Form
Cream
Registration Number
DR-XY27030
Drug Classification
Prescription Drug (RX)
Description
Indications/Uses
Gel 0.1% and Cream: Differin Gel and Differin Cream are 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.
Gel 0.3%: Adapalene (Differin) 0.3% gel for topical use is indicated for the treatment of mild to moderate acne where comedones, papules and pustules predominate.
Adapalene (Differin) 0.3% gel for topical use is indicated for the treatment of photodamage skin including wrinkles and hyperpigmentation.
Geriatrics (> 65 years of age): Safety and effectiveness in geriatric patients age 65 and above have not been established.
Pediatrics (< 12 years of age): Safety and effectiveness in children below the age of 12 have not been established.
Gel 0.3%: Adapalene (Differin) 0.3% gel for topical use is indicated for the treatment of mild to moderate acne where comedones, papules and pustules predominate.
Adapalene (Differin) 0.3% gel for topical use is indicated for the treatment of photodamage skin including wrinkles and hyperpigmentation.
Geriatrics (> 65 years of age): Safety and effectiveness in geriatric patients age 65 and above have not been established.
Pediatrics (< 12 years of age): Safety and effectiveness in children below the age of 12 have not been established.
Dosage/Direction for Use
Gel 0.1% and Cream: Differin Gel and 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 Precautions). 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 Gel and Differin Cream have not been studied in neonates and young children.
Gel 0.3%: Adapalene (Differin) 0.3% gel should be applied to the affected areas of the face, chest and back once a day before retiring and after washing. A small amount should be applied to provide a thin film, avoiding eyes, lips and mucous membranes. This medication should not be applied to cuts, abrasions, eczematous, or sunburned skin.
Discontinue treatment if a severe local inflammatory response is experienced. Reinstitute therapy when the reaction has subsided, initially applying the preparation less frequently. Once daily application may be resumed if it is judged that the patient is able to tolerate the treatment.
Clinical improvement is expected to be clearly evident after four to eight weeks of treatment, with further improvement expected with continued use. Cutaneous safety of Adapalene (Differin) 0.3% gel has been demonstrated over a 12-month period of treatment.
Missed Dose: Dosing should continue as per usual the following evening, and the usual amount should be applied.
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 Gel and Differin Cream have not been studied in neonates and young children.
Gel 0.3%: Adapalene (Differin) 0.3% gel should be applied to the affected areas of the face, chest and back once a day before retiring and after washing. A small amount should be applied to provide a thin film, avoiding eyes, lips and mucous membranes. This medication should not be applied to cuts, abrasions, eczematous, or sunburned skin.
Discontinue treatment if a severe local inflammatory response is experienced. Reinstitute therapy when the reaction has subsided, initially applying the preparation less frequently. Once daily application may be resumed if it is judged that the patient is able to tolerate the treatment.
Clinical improvement is expected to be clearly evident after four to eight weeks of treatment, with further improvement expected with continued use. Cutaneous safety of Adapalene (Differin) 0.3% gel has been demonstrated over a 12-month period of treatment.
Missed Dose: Dosing should continue as per usual the following evening, and the usual amount should be applied.
Overdosage
Gel 0.1% and Cream: Differin Gel and Differin Cream are not to be taken orally and are 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 Gel and 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.
Gel 0.3%: Adapalene (Differin) 0.3% gel is intended 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 toxicity of adapalene topical gel, 0.1% in mice and rats is greater than 10 mL/kg (10 mg/kg). Inadvertent oral ingestion of adapalene may lead to the same adverse effects as those associated with excessive oral intake of Vitamin A including teratogenesis in women of childbearing years. Therefore, in such cases, pregnancy testing should be carried out in women of childbearing years. In the event of accidental ingestion of the product, an appropriate method of gastric emptying might be considered.
The acute oral dose of Differin Gel and 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.
Gel 0.3%: Adapalene (Differin) 0.3% gel is intended 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 toxicity of adapalene topical gel, 0.1% in mice and rats is greater than 10 mL/kg (10 mg/kg). Inadvertent oral ingestion of adapalene may lead to the same adverse effects as those associated with excessive oral intake of Vitamin A including teratogenesis in women of childbearing years. Therefore, in such cases, pregnancy testing should be carried out in women of childbearing years. In the event of accidental ingestion of the product, an appropriate method of gastric emptying might be considered.
Contraindications
Gel 0.1% and Cream: Hypersensitivity to any ingredient of the product.
Gel 0.3%: Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container.
Patients with eczema or seborrheic dermatitis.
Gel 0.3%: Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container.
Patients with eczema or seborrheic dermatitis.
Special Precautions
Gel 0.1% and 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, or to discontinue use altogether. Differin Gel and 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) or eczematous skin, nor should it be used in patients with severe acne.
Effects on The Ability to Drive and Use Machines: Based upon the pharmacodynamic profile and clinical experience, performance related to driving and using machines should not be affected.
Gel 0.3%: General: For external use only.
Avoid contact with the eyes, lips, angles of the nose, mucous membranes and open wounds. Certain cutaneous signs and symptoms such as erythema, dryness, scaling, burning or pruritus are associated with the topical application of retinoids and can also be expected with the use of Adapalene (Differin) 0.3% gel. These treatment-related effects generally occur during the first two to four weeks of therapy and usually resolve as the skin undergoes adjustment with continued use. Depending on the degree of the side effects, patients can be directed to use the medication less frequently or temporarily discontinue use until the symptoms subside (see DOSAGE & ADMINISTRATION).
Patients should be advised to use non-comedogenic cosmetics. Colour cosmetics such as blushers and powders are acceptable, however, make-up cosmetics should be water based only. Cosmetics must be removed by thorough cleansing before the area is treated.
As with any retinoid, exposure to excessive sunlight, including sunlamps, should be avoided while using the preparation, or a suitably effective sunscreen product and protective clothing over the 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. As with other retinoids, use of waxing as a depilatory method should be avoided on skin treated with adapalene.
Special Populations: Use in Pregnancy: It is recommended that topical adapalene should not be used by pregnant women. Topical adapalene should be used by women of childbearing years only after contraceptive counselling.
There have been rare reports of birth defects among babies born to women exposed to topical retinoids during pregnancy. However, there are no well controlled prospective studies of the use of topical retinoids, including adapalene, in pregnant women. A retrospective study of mothers exposed to topical tretinoin during the first trimester of pregnancy found no increase in the incidence of birth defects.
Adapalene administered orally at doses of ≥ 25 mg/kg/day (38 times the Maximum Recommended Human Dose [MRHD] based on mg/m2 comparisons for rats or 65 times MRHD for rabbits) has been shown to be teratogenic. No teratogenic effects were seen in rats at oral doses of up to 5.0 mg/kg/day adapalene (7.6 times the MRHD). Cutaneous teratology studies in rats and rabbits at doses of 0.6 (0.03 %), 2.0 (0.1 %) and 6.0 (0.3 %) mg/kg/day (17 times the MRHD for rats or 32 times the MRHD for rabbits) exhibited no teratogenicity. At 2 mg/kg/day (0.1% adapalene gel), no adverse events were observed in rabbits and only a marginal increase in the incidence of additional lumbar ribs was observed in rats. However, at 6 mg/kg/day (0.3% adapalene gel), in addition to the recorded increase in foetal rib numbers in the rat and rabbit, there were also other skeletal anomalies in both species. There are no adequate and well-controlled studies in pregnant women.
Use in Lactation: It is not known whether this drug is excreted in human milk. Animal pharmacology studies indicate that adapalene is excreted in milk at levels lower than plasma levels. Because many drugs are excreted in human milk, caution should be exercised when Adapalene (Differin) 0.3% gel is administered to a nursing mother.
Use in Children (12-16 years of age): No specific monitoring or hazards are associated with the use of the product in pediatric patients between the ages of 12 and 16 years. Safety and effectiveness in children below the age of 12 have not been established.
Use in Elderly (> 65 years of age): Safety and effectiveness in geriatric patients age 65 and above have not been established.
Effects on The Ability to Drive and Use Machines: Based upon the pharmacodynamic profile and clinical experience, performance related to driving and using machines should not be affected.
Gel 0.3%: General: For external use only.
Avoid contact with the eyes, lips, angles of the nose, mucous membranes and open wounds. Certain cutaneous signs and symptoms such as erythema, dryness, scaling, burning or pruritus are associated with the topical application of retinoids and can also be expected with the use of Adapalene (Differin) 0.3% gel. These treatment-related effects generally occur during the first two to four weeks of therapy and usually resolve as the skin undergoes adjustment with continued use. Depending on the degree of the side effects, patients can be directed to use the medication less frequently or temporarily discontinue use until the symptoms subside (see DOSAGE & ADMINISTRATION).
Patients should be advised to use non-comedogenic cosmetics. Colour cosmetics such as blushers and powders are acceptable, however, make-up cosmetics should be water based only. Cosmetics must be removed by thorough cleansing before the area is treated.
As with any retinoid, exposure to excessive sunlight, including sunlamps, should be avoided while using the preparation, or a suitably effective sunscreen product and protective clothing over the 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. As with other retinoids, use of waxing as a depilatory method should be avoided on skin treated with adapalene.
Special Populations: Use in Pregnancy: It is recommended that topical adapalene should not be used by pregnant women. Topical adapalene should be used by women of childbearing years only after contraceptive counselling.
There have been rare reports of birth defects among babies born to women exposed to topical retinoids during pregnancy. However, there are no well controlled prospective studies of the use of topical retinoids, including adapalene, in pregnant women. A retrospective study of mothers exposed to topical tretinoin during the first trimester of pregnancy found no increase in the incidence of birth defects.
Adapalene administered orally at doses of ≥ 25 mg/kg/day (38 times the Maximum Recommended Human Dose [MRHD] based on mg/m2 comparisons for rats or 65 times MRHD for rabbits) has been shown to be teratogenic. No teratogenic effects were seen in rats at oral doses of up to 5.0 mg/kg/day adapalene (7.6 times the MRHD). Cutaneous teratology studies in rats and rabbits at doses of 0.6 (0.03 %), 2.0 (0.1 %) and 6.0 (0.3 %) mg/kg/day (17 times the MRHD for rats or 32 times the MRHD for rabbits) exhibited no teratogenicity. At 2 mg/kg/day (0.1% adapalene gel), no adverse events were observed in rabbits and only a marginal increase in the incidence of additional lumbar ribs was observed in rats. However, at 6 mg/kg/day (0.3% adapalene gel), in addition to the recorded increase in foetal rib numbers in the rat and rabbit, there were also other skeletal anomalies in both species. There are no adequate and well-controlled studies in pregnant women.
Use in Lactation: It is not known whether this drug is excreted in human milk. Animal pharmacology studies indicate that adapalene is excreted in milk at levels lower than plasma levels. Because many drugs are excreted in human milk, caution should be exercised when Adapalene (Differin) 0.3% gel is administered to a nursing mother.
Use in Children (12-16 years of age): No specific monitoring or hazards are associated with the use of the product in pediatric patients between the ages of 12 and 16 years. Safety and effectiveness in children below the age of 12 have not been established.
Use in Elderly (> 65 years of age): Safety and effectiveness in geriatric patients age 65 and above have not been established.
Use In Pregnancy & Lactation
Gel 0.1% and Cream: Pregnancy: No information on the effects of adapalene in pregnant women is available. Consequently adapalene should not be used during pregnancy, especially during the first three months.
Lactation: It is not known whether this drug is excreted in animal or human milk. Because many drugs are excreted in human milk, caution should be exercised when Differin Gel and Differin Cream are administrated to nursing mothers. In this event, the product should not be used on the chest.
Lactation: It is not known whether this drug is excreted in animal or human milk. Because many drugs are excreted in human milk, caution should be exercised when Differin Gel and Differin Cream are administrated to nursing mothers. In this event, the product should not be used on the chest.
Adverse Reactions
Gel 0.1% and Cream: Differin may cause the following adverse drug reactions: See Table 6.
Seek medical attention immediately at the first sign of ADR.
Gel 0.3%: Adverse Drug Reaction Overview: Treatment-related adverse reactions typically associated with use of Adapalene (Differin) 0.3% includes mild to moderate application site reactions, such as skin irritation characterized by scaling, dryness, erythema, burning and stinging. Adapalene (Differin) 0.3% gel results in a slightly greater incidence of these events, as would be expected with the higher concentration of adapalene. These reactions usually occur early in the treatment, and tend to resolve after 2 to 4 weeks of therapy (see PRECAUTIONS).
The uncommon adverse events, occurring in 0.1% to 1% of patients, are: contact dermatitis, skin discomfort, itching, peeling skin and acne and reactions such as skin edema, pain, swelling at the site of application, irritation, itching and eyelid swelling are effects without an established frequency.
The rate of adverse events obtained in studies may not reflect clinical practice.
In a Phase III multicenter study with placebo and active drug control, the signs and symptoms of local cutaneous irritation were monitored in 258 adult patients with acne that used adapalene 0.3% for 12 weeks. In patients that presented cutaneous irritation (erythema, scaling, dryness and/or burning/stinging sensation), most of cases had mild to moderate severity and occurred in the first week of treatment, decreasing as the treatment continued.
In an open label safety study, with 1 year duration, involving 551 patients with acne vulgaris using Adapalene (Differin), the pattern of adverse events was similar to the 12 weeks controlled study. The percentage of patients that experienced cutaneous irritation, with the same signs and symptoms, higher than the basal line, was higher after one week of treatment, then decreasing continuously along the period of 1 year treatment. (See Table 7.)
Gel 0.3%: Adverse Drug Reaction Overview: Treatment-related adverse reactions typically associated with use of Adapalene (Differin) 0.3% includes mild to moderate application site reactions, such as skin irritation characterized by scaling, dryness, erythema, burning and stinging. Adapalene (Differin) 0.3% gel results in a slightly greater incidence of these events, as would be expected with the higher concentration of adapalene. These reactions usually occur early in the treatment, and tend to resolve after 2 to 4 weeks of therapy (see PRECAUTIONS).
The uncommon adverse events, occurring in 0.1% to 1% of patients, are: contact dermatitis, skin discomfort, itching, peeling skin and acne and reactions such as skin edema, pain, swelling at the site of application, irritation, itching and eyelid swelling are effects without an established frequency.
The rate of adverse events obtained in studies may not reflect clinical practice.
In a Phase III multicenter study with placebo and active drug control, the signs and symptoms of local cutaneous irritation were monitored in 258 adult patients with acne that used adapalene 0.3% for 12 weeks. In patients that presented cutaneous irritation (erythema, scaling, dryness and/or burning/stinging sensation), most of cases had mild to moderate severity and occurred in the first week of treatment, decreasing as the treatment continued.
In an open label safety study, with 1 year duration, involving 551 patients with acne vulgaris using Adapalene (Differin), the pattern of adverse events was similar to the 12 weeks controlled study. The percentage of patients that experienced cutaneous irritation, with the same signs and symptoms, higher than the basal line, was higher after one week of treatment, then decreasing continuously along the period of 1 year treatment. (See Table 7.)
Less Common Clinical Trial Adverse Drug Reactions (<1%): The following less common events have been designated as related (possibly, probably, definitely) to treatment with Adapalene (Differin) 0.1% Cream/Gel AND Adapalene (Differin) 0.3% gel, considering all patients in the clinical trials in acne vulgaris: Skin and Appendages: Eczema, contact dermatitis, atopic dermatitis, skin edema, dermatitis, acne, worsening of treated disease, urticaria, skin discolouration, seborrhea, herpes simplex, vesicular rash, eyelid edema, burning/stinging.
Body as a Whole: Pain, facial edema.
Special Senses: Eye pain, keratoconjunctivitis.
Abnormal Haematology and Clinical Chemistry: No significant abnormal values were observed in the short term controlled studies or the long term safety study.
Post-Market Adverse Drug Reactions: The following isolated (one report each) serious, unexpected adverse events have been designated as probably/possibly related to treatment with an adapalene topical formulation: Papilloedema, hepatitis/cholectasis, convulsions, foetal disorders.
Body as a Whole: Pain, facial edema.
Special Senses: Eye pain, keratoconjunctivitis.
Abnormal Haematology and Clinical Chemistry: No significant abnormal values were observed in the short term controlled studies or the long term safety study.
Post-Market Adverse Drug Reactions: The following isolated (one report each) serious, unexpected adverse events have been designated as probably/possibly related to treatment with an adapalene topical formulation: Papilloedema, hepatitis/cholectasis, convulsions, foetal disorders.
Drug Interactions
Gel 0.1% and Cream: There are no known interactions with other medications which might be used cutaneously and concurrently with Differin Gel and 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. While 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 Gel and Differin Cream.
Differin Gel and Differin Cream have 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 anti-acne treatments, e.g. erythromycin (up to 4%) or clindamycin phosphate (1% as the base) solutions or benzoyl peroxide water based gels/creams up to 10%, may be used in the morning when Differin Gel and Differin Cream are used at night as there is no mutual degradation or cumulative irritation.
Gel 0.3%: Overview: There are no known interactions with other medications which are likely to be used topically and concurrently with Adapalene (Differin) gel. Absorption of adapalene through human skin is low, and therefore interaction with systemic medications is unlikely.
Drug-Drug Interactions: As Adapalene (Differin) have the potential for local irritation, it is possible that concomitant use of abrasive cleansers, strong drying agents, or irritant products may produce additive irritant effects. Particular caution should be exercised in using preparations containing sulfur, resorcinol, or salicylic acid in combination with Adapalene (Differin) 0.3% gel. If these preparations have been used, it is advisable not to start therapy with Adapalene (Differin) until the effects of such preparations have subsided.
Other cutaneous anti-acne treatments (e.g., erythromycin topical solution, clindamycin phosphate topical solution 1% or benzoyl peroxide products in concentrations up to 10%) may be used in the morning when Adapalene (Differin) 0.3% gel is used at night.
Adapalene is essentially stable to oxygen and light and is chemically non-reactive. While 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 Gel and Differin Cream.
Differin Gel and Differin Cream have 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 anti-acne treatments, e.g. erythromycin (up to 4%) or clindamycin phosphate (1% as the base) solutions or benzoyl peroxide water based gels/creams up to 10%, may be used in the morning when Differin Gel and Differin Cream are used at night as there is no mutual degradation or cumulative irritation.
Gel 0.3%: Overview: There are no known interactions with other medications which are likely to be used topically and concurrently with Adapalene (Differin) gel. Absorption of adapalene through human skin is low, and therefore interaction with systemic medications is unlikely.
Drug-Drug Interactions: As Adapalene (Differin) have the potential for local irritation, it is possible that concomitant use of abrasive cleansers, strong drying agents, or irritant products may produce additive irritant effects. Particular caution should be exercised in using preparations containing sulfur, resorcinol, or salicylic acid in combination with Adapalene (Differin) 0.3% gel. If these preparations have been used, it is advisable not to start therapy with Adapalene (Differin) until the effects of such preparations have subsided.
Other cutaneous anti-acne treatments (e.g., erythromycin topical solution, clindamycin phosphate topical solution 1% or benzoyl peroxide products in concentrations up to 10%) may be used in the morning when Adapalene (Differin) 0.3% gel is used at night.
Caution For Usage
Gel 0.1% and Cream: Instruction 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.
Storage
Gel 0.1%: Store at temperature not exceeding 25°C. Avoid freezing during transport and storage.
Gel 0.3%: Store at temperatures not exceeding 30°C. Keep from freezing. Keep container tightly closed.
Cream: Store at room temperature (not exceeding 30°C).
Avoid freezing during transport and storage.
Gel 0.3%: Store at temperatures not exceeding 30°C. Keep from freezing. Keep container tightly closed.
Cream: Store at room temperature (not exceeding 30°C).
Avoid freezing during transport and storage.
Action
ATC Code: D10AD03.
Pharmacology: Gel 0.1% and 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 normalization 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 a hypervitaminosis A syndrome, and included bone dissolution, elevated alkaline phosphatase and a slight anemia. 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.
Gel 0.3%: Pharmacodynamics: Studies in acne patients provide clinical evidence that topical adapalene is effective in reducing the noninflammatory acne lesions (open and closed comedones). 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, by lipoxidation, to inflammatory mediators. This profile suggests that the cell mediated inflammatory component of acne is modified by adapalene. Studies in human patients provide clinical evidence that topical adapalene is effective in reducing the inflammatory components of acne (i.e., papules and pustules).
Mechanism of Action: Adapalene is a chemically stable, retinoid-like compound. Biochemical and pharmacological profile studies have demonstrated that adapalene is a potent modulator of cellular differentiation, keratinization and inflammatory processes all of which represent important features in the pathology of acne vulgaris. Mechanistically, adapalene binds to specific retinoic acid nuclear receptors but, unlike tretinoin, does not bind to the cytosolic receptor protein. Although the exact mode of action of adapalene is unknown, current evidence suggests that topical adapalene normalizes the differentiation of follicular epithelial cells resulting in decreased microcomedone formation.
Clinical Trials: Study demographics and trial design: See Table 1.
Pharmacology: Gel 0.1% and 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 normalization 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 a hypervitaminosis A syndrome, and included bone dissolution, elevated alkaline phosphatase and a slight anemia. 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.
Gel 0.3%: Pharmacodynamics: Studies in acne patients provide clinical evidence that topical adapalene is effective in reducing the noninflammatory acne lesions (open and closed comedones). 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, by lipoxidation, to inflammatory mediators. This profile suggests that the cell mediated inflammatory component of acne is modified by adapalene. Studies in human patients provide clinical evidence that topical adapalene is effective in reducing the inflammatory components of acne (i.e., papules and pustules).
Mechanism of Action: Adapalene is a chemically stable, retinoid-like compound. Biochemical and pharmacological profile studies have demonstrated that adapalene is a potent modulator of cellular differentiation, keratinization and inflammatory processes all of which represent important features in the pathology of acne vulgaris. Mechanistically, adapalene binds to specific retinoic acid nuclear receptors but, unlike tretinoin, does not bind to the cytosolic receptor protein. Although the exact mode of action of adapalene is unknown, current evidence suggests that topical adapalene normalizes the differentiation of follicular epithelial cells resulting in decreased microcomedone formation.
Clinical Trials: Study demographics and trial design: See Table 1.
Male and female subjects, 12 years of age or older, were eligible to enroll in this controlled clinical trial. In study RD.06.SRE.18081, subjects with acne vulgaris with 20 to 50 inflammatory and 20 to 100 non-inflammatory lesions and no nodules or cysts were eligible to enroll in this study. (See Table 2.)
Male and female subjects, 12 years of age or older, were eligible to enroll in this controlled clinical trial. In study RD.03.SRE.2673, subjects with acne vulgaris with 15 to 50 inflammatory and 30 to 200 non-inflammatory lesions and a maximum of two nodules/cysts were eligible to enroll in this study.
Study results: See Tables 3 and 4.
Study results: See Tables 3 and 4.
Pharmacokinetics: See Table 5.
Absorption: Absorption of adapalene through human skin is low. No quantifiable levels of parent substance have been found in the plasma of patients following chronic adapalene gel 0.1% application in controlled clinical trials (limit of quantification = 0.25 ng/mL). In adult patients with acne vulgaris who received daily applications of 0.3% gel for 10 days, the mean AUC(0-24h) on Day 10 was 8.94 ngAh/mL (SD: 8.99) and the mean Cmax was 0.553 ng/mL (SD: 0.466). The Cmax ranged from < 0.1 to 2 ng/mL and the maximum AUC(0-24h) value obtained was 36.1 ngAh/mL. The terminal apparent half-life ranged from 13 to 16 hours, thereby indicating that a pharmacokinetic steady-state was reached before Day 10.
Distribution: Classical plasma protein binding techniques were not feasible for adapalene due to the physiochemical properties of the molecule. However, an alternative method was adopted which measures the partitioning of the drug between plasma or protein solutions and erythrocytes. When 3H-adapalene was incubated with human whole blood, 26% was bound to erythrocytes and total binding of adapalene in blood was > 99%. Adapalene bound primarily to lipoproteins and human serum albumin.
Metabolism: Following 24-hour incubation with human hepatocytes, more than 90% of adapalene has been metabolized. Both metabolites and adapalene showed a possibility for conjugation - predominantly glucuronidation and sulfatation.
Excretion: Excretion appears to be primarily by the biliary route. The majority of an administered dose of 0.3% gel was excreted by 144 hours post dose and no drug was detected after the 6th day following last application. Under maximized conditions, the mean total unchanged drug substance excreted in the faeces was 0.07% ± 0.06% of the total dose applied (range, 0.02% to 0.19%).
Distribution: Classical plasma protein binding techniques were not feasible for adapalene due to the physiochemical properties of the molecule. However, an alternative method was adopted which measures the partitioning of the drug between plasma or protein solutions and erythrocytes. When 3H-adapalene was incubated with human whole blood, 26% was bound to erythrocytes and total binding of adapalene in blood was > 99%. Adapalene bound primarily to lipoproteins and human serum albumin.
Metabolism: Following 24-hour incubation with human hepatocytes, more than 90% of adapalene has been metabolized. Both metabolites and adapalene showed a possibility for conjugation - predominantly glucuronidation and sulfatation.
Excretion: Excretion appears to be primarily by the biliary route. The majority of an administered dose of 0.3% gel was excreted by 144 hours post dose and no drug was detected after the 6th day following last application. Under maximized conditions, the mean total unchanged drug substance excreted in the faeces was 0.07% ± 0.06% of the total dose applied (range, 0.02% to 0.19%).
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Acne Treatment Preparations
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