EPIDUO FORTE Adapalene / Benzoyl Peroxide 0.3% / 2.5% per g Topical Gel 15g
RXDRUG-DR-XY46058-15
Discreet Packaging
FDA-registered Products
FDA-licensed Pharmacies
Indications/Uses
Epiduo: Cutaneous treatment of Acne vulgaris when comedones, papules and pustules are present.
Epiduo Forte: Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel is indicated for: Treatment of moderate and severe acne vulgaris, characterized by comedones, inflammatory papules/pustules with or without occasional nodules in patients 12 years of age and older.
Epiduo Forte: Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel is indicated for: Treatment of moderate and severe acne vulgaris, characterized by comedones, inflammatory papules/pustules with or without occasional nodules in patients 12 years of age and older.
Dosage/Direction for Use
Epiduo: Epiduo should be applied to the entire acne affected areas once a day in the evening on a clean and dry skin. A thin film of gel should be applied, with the fingertips, avoiding the eyes and lips (see Precautions).
If irritation occurs, the patient should be directed to apply non-comedogenic moisturizers, to use the medication less frequently (e.g. every other day), to suspend use temporarily, or to discontinue use altogether.
The duration of treatment should be determined by the Doctor on the basis of the clinical condition. Early signs of clinical improvement usually appear after 1 to 4 weeks of treatment.
The safety and effectiveness of Epiduo have not been studied in children below 9 years of age.
Epiduo Forte: Recommended Dose and Dosage Adjustment: Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel (patients 12 years of age and older), should be applied to affected areas of the face, chest and back once daily in the evening, after washing gently with a non-medicated cleanser.
A small amount of either Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel should be applied to provide a thin film, avoiding eyes, lips and mucous membranes. These medications should not be applied to cuts, abrasions, eczematous, or sunburned skin.
If irritation occurs, the patient should be directed to apply non-comedogenic moisturizers. Discontinue treatment if a severe local inflammatory response is experienced. Reinstitute therapy when the reaction has subsided, initially applying the preparation less frequently (e.g. every other day). Once-daily application may be resumed if it is judged that the patient is able to tolerate the treatment.
Missed Dose: If a single dose is missed, dosing should continue as per usual the following day, and the usual amount should be applied.
If irritation occurs, the patient should be directed to apply non-comedogenic moisturizers, to use the medication less frequently (e.g. every other day), to suspend use temporarily, or to discontinue use altogether.
The duration of treatment should be determined by the Doctor on the basis of the clinical condition. Early signs of clinical improvement usually appear after 1 to 4 weeks of treatment.
The safety and effectiveness of Epiduo have not been studied in children below 9 years of age.
Epiduo Forte: Recommended Dose and Dosage Adjustment: Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel (patients 12 years of age and older), should be applied to affected areas of the face, chest and back once daily in the evening, after washing gently with a non-medicated cleanser.
A small amount of either Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel should be applied to provide a thin film, avoiding eyes, lips and mucous membranes. These medications should not be applied to cuts, abrasions, eczematous, or sunburned skin.
If irritation occurs, the patient should be directed to apply non-comedogenic moisturizers. Discontinue treatment if a severe local inflammatory response is experienced. Reinstitute therapy when the reaction has subsided, initially applying the preparation less frequently (e.g. every other day). Once-daily application may be resumed if it is judged that the patient is able to tolerate the treatment.
Missed Dose: If a single dose is missed, dosing should continue as per usual the following day, and the usual amount should be applied.
Overdosage
Epiduo: Epiduo is for once-daily cutaneous use only.
In case of accidental ingestion, appropriate symptomatic measures should be taken.
Epiduo Forte: For management of a suspected drug overdose, contact the regional Poison Control Centre.
In the event of an acute oral overdose, activated charcoal may be administered to aid in the removal of unabsorbed drug. General supportive measures are recommended.
Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel is intended for cutaneous use only. Acute overdosage with the topical use is unlikely. If the medications are 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, pregnancy testing should be carried out in women of childbearing potential who have ingested the product.
In case of accidental ingestion, appropriate symptomatic measures should be taken.
Epiduo Forte: For management of a suspected drug overdose, contact the regional Poison Control Centre.
In the event of an acute oral overdose, activated charcoal may be administered to aid in the removal of unabsorbed drug. General supportive measures are recommended.
Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel is intended for cutaneous use only. Acute overdosage with the topical use is unlikely. If the medications are 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, pregnancy testing should be carried out in women of childbearing potential who have ingested the product.
Contraindications
Epiduo: Hypersensitivity to the active substances or to any of the excipients.
Epiduo Forte: Patients who are hypersensitive to adapalene, benzoyl peroxide or to any ingredient in the formulation or component of the container. For a complete listing, see Description.
Application to areas of skin affected by eczema or seborrhoeic dermatitis.
Epiduo Forte: Patients who are hypersensitive to adapalene, benzoyl peroxide or to any ingredient in the formulation or component of the container. For a complete listing, see Description.
Application to areas of skin affected by eczema or seborrhoeic dermatitis.
Special Precautions
Epiduo: Epiduo Gel should not be applied to damaged skin, either broken (cuts or abrasions) or eczematous skin.
Epiduo should not come into contact with the eyes, mouth, nostrils or mucous membranes. If product enters the eye, wash immediately with warm water.
This product contains propylene glycol (E1520) that may cause skin irritation.
If a reaction suggesting sensitivity to any component of the formula occurs, the use of Epiduo should be discontinued.
Excessive exposure to sunlight or UV radiation should be avoided.
Epiduo should not come into contact with any coloured material including hair and dyed fabrics as this may result in bleaching and discoloration.
Effects on ability to drive and use machines: Not relevant.
Epiduo Forte: General: For external use only. Not for ophthalmic use.
Avoid contact with the eyes, lips, angles of the nose, mucous membranes, abraded skin and open wounds. If contact occurs, rinse thoroughly with water.
If a reaction suggesting allergic/hypersensitivity reactions to any component of the formula occurs, the use of the product should be discontinued.
Concomitant topical acne therapy is not recommended because a possible cumulative irritancy effect may occur, especially with the use of peeling, desquamating, or abrasive agents (see Drug-Drug Interactions under Interactions). Avoid concomitant use of other potentially irritating topical products (medicated or abrasive soaps and cleansers, soaps and cosmetics that have strong skin-drying effect and products with high concentrations of alcohol, astringents, spices, or limes).
The product should not be applied to cuts, abrasions, eczematous or sunburned skin. As with other retinoids, use of electrolysis, "waxing" and chemical depilatories for hair removal should be avoided on skin treated with Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel (see Drug-Lifestyle Interactions under Interactions).
Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel may bleach hair and coloured fabric. Use caution when applying near hairline (see Drug-Lifestyle Interactions under Interactions).
Patients should be advised to use non-comedogenic cosmetics (see Drug-Lifestyle Interactions under Interactions).
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 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel. These treatment-related effects generally occur during the first four weeks of therapy, are mostly mild to moderate in intensity, and usually lessen as the skin adjusts with continued use. Depending on the degree of the side effects, patients can be directed to use a moisturizer, use the medication less frequently or temporarily discontinue use until the symptoms subside (see Dosage & Administration).
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. In case of sunburn, allow the skin to heal before using Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel. Weather extremes, such as wind or cold, may also be irritating to patients under treatment with adapalene.
Special Populations: Use in Pregnancy: It is recommended that topical adapalene/benzoyl peroxide should not be used by pregnant women. Topical adapalene/benzoyl peroxide should be used by women of childbearing years only after contraceptive counselling.
There are no well-controlled trials in pregnant women treated with Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel. Animal reproduction studies have not been conducted with the combination gel or benzoyl peroxide. Furthermore, such studies are not always predictive of human response; therefore, Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel should not be used by pregnant women.
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 has been shown to be teratogenic. No teratogenic effects were seen in rats at oral doses of up to 5.0 mg/kg/day.
Dermal teratology studies conducted in rats and rabbits at doses of 0.6-6.0 mg adapalene/kg/day exhibited no foetotoxicity and only minimal increases in supernumerary ribs in both species and delayed ossification in rabbits. The AUC at the No Observable Adverse Effect Level in the rat (6.0 mg/kg/day, the most sensitive species) corresponds to safety margins of 32 and 102 when compared respectively to the exposure data in humans with Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel.
Use in Lactation: It is not known whether adapalene or benzoyl peroxide is excreted in human milk following use of Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel. 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 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel are administered to a nursing mother. If applied to the chest, facial contact and oral ingestion by the infant from maternal skin may occur.
Use in Children (9-16 years of age): Safety and effectiveness of Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel in children below the age of 12 years have not been established.
Safety and effectiveness Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel in geriatric patients age 65 years and above have not been established.
Epiduo should not come into contact with the eyes, mouth, nostrils or mucous membranes. If product enters the eye, wash immediately with warm water.
This product contains propylene glycol (E1520) that may cause skin irritation.
If a reaction suggesting sensitivity to any component of the formula occurs, the use of Epiduo should be discontinued.
Excessive exposure to sunlight or UV radiation should be avoided.
Epiduo should not come into contact with any coloured material including hair and dyed fabrics as this may result in bleaching and discoloration.
Effects on ability to drive and use machines: Not relevant.
Epiduo Forte: General: For external use only. Not for ophthalmic use.
Avoid contact with the eyes, lips, angles of the nose, mucous membranes, abraded skin and open wounds. If contact occurs, rinse thoroughly with water.
If a reaction suggesting allergic/hypersensitivity reactions to any component of the formula occurs, the use of the product should be discontinued.
Concomitant topical acne therapy is not recommended because a possible cumulative irritancy effect may occur, especially with the use of peeling, desquamating, or abrasive agents (see Drug-Drug Interactions under Interactions). Avoid concomitant use of other potentially irritating topical products (medicated or abrasive soaps and cleansers, soaps and cosmetics that have strong skin-drying effect and products with high concentrations of alcohol, astringents, spices, or limes).
The product should not be applied to cuts, abrasions, eczematous or sunburned skin. As with other retinoids, use of electrolysis, "waxing" and chemical depilatories for hair removal should be avoided on skin treated with Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel (see Drug-Lifestyle Interactions under Interactions).
Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel may bleach hair and coloured fabric. Use caution when applying near hairline (see Drug-Lifestyle Interactions under Interactions).
Patients should be advised to use non-comedogenic cosmetics (see Drug-Lifestyle Interactions under Interactions).
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 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel. These treatment-related effects generally occur during the first four weeks of therapy, are mostly mild to moderate in intensity, and usually lessen as the skin adjusts with continued use. Depending on the degree of the side effects, patients can be directed to use a moisturizer, use the medication less frequently or temporarily discontinue use until the symptoms subside (see Dosage & Administration).
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. In case of sunburn, allow the skin to heal before using Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel. Weather extremes, such as wind or cold, may also be irritating to patients under treatment with adapalene.
Special Populations: Use in Pregnancy: It is recommended that topical adapalene/benzoyl peroxide should not be used by pregnant women. Topical adapalene/benzoyl peroxide should be used by women of childbearing years only after contraceptive counselling.
There are no well-controlled trials in pregnant women treated with Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel. Animal reproduction studies have not been conducted with the combination gel or benzoyl peroxide. Furthermore, such studies are not always predictive of human response; therefore, Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel should not be used by pregnant women.
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 has been shown to be teratogenic. No teratogenic effects were seen in rats at oral doses of up to 5.0 mg/kg/day.
Dermal teratology studies conducted in rats and rabbits at doses of 0.6-6.0 mg adapalene/kg/day exhibited no foetotoxicity and only minimal increases in supernumerary ribs in both species and delayed ossification in rabbits. The AUC at the No Observable Adverse Effect Level in the rat (6.0 mg/kg/day, the most sensitive species) corresponds to safety margins of 32 and 102 when compared respectively to the exposure data in humans with Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel.
Use in Lactation: It is not known whether adapalene or benzoyl peroxide is excreted in human milk following use of Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel. 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 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel are administered to a nursing mother. If applied to the chest, facial contact and oral ingestion by the infant from maternal skin may occur.
Use in Children (9-16 years of age): Safety and effectiveness of Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel in children below the age of 12 years have not been established.
Safety and effectiveness Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel in geriatric patients age 65 years and above have not been established.
Use In Pregnancy & Lactation
Epiduo: Pregnancy: Animal studies by the oral route have shown reproductive toxicity at high systemic exposure (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Clinical experience with locally applied adapalene and benzoyl peroxide in pregnancy is limited but the few available data do not indicate harmful effects in patients exposed in early pregnancy.
Due to the limited available data and because a very weak cutaneous passage of adapalene is possible, Epiduo should not be used during pregnancy.
In case of unexpected pregnancy, treatment should be discontinued.
Breastfeeding: No study on animal or human milk transfer was conducted after cutaneous application of Epiduo (adapalene/benzoyl peroxide) Gel.
No effects on the suckling child are anticipated since the systemic exposure of the breast-feeding woman to Epiduo is negligible. Epiduo can be used during breast-feeding.
To avoid contact exposure of the infant, application of Epiduo to the chest should be avoided when used during breast-feeding.
Clinical experience with locally applied adapalene and benzoyl peroxide in pregnancy is limited but the few available data do not indicate harmful effects in patients exposed in early pregnancy.
Due to the limited available data and because a very weak cutaneous passage of adapalene is possible, Epiduo should not be used during pregnancy.
In case of unexpected pregnancy, treatment should be discontinued.
Breastfeeding: No study on animal or human milk transfer was conducted after cutaneous application of Epiduo (adapalene/benzoyl peroxide) Gel.
No effects on the suckling child are anticipated since the systemic exposure of the breast-feeding woman to Epiduo is negligible. Epiduo can be used during breast-feeding.
To avoid contact exposure of the infant, application of Epiduo to the chest should be avoided when used during breast-feeding.
Adverse Reactions
Epiduo: Epiduo may cause the following adverse reactions at the site of application: See Table 7.
If skin irritation appears after application of Epiduo, the intensity is generally mild or moderate, with local tolerability signs and symptoms (erythema, dryness, scaling, burning and pain of skin (stinging pain)) peaking during the first week and then subsiding spontaneously.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after 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.
Epiduo Forte: Treatment-related adverse reactions typically associated with use of Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel include mild to moderate application site reactions, such as skin irritation characterized by scaling, dryness, erythema, and burning/stinging. 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 in vehicle-controlled Phase 3 study with Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel. (See Table 8.)
Reporting of 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.
Epiduo Forte: Treatment-related adverse reactions typically associated with use of Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel include mild to moderate application site reactions, such as skin irritation characterized by scaling, dryness, erythema, and burning/stinging. 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 in vehicle-controlled Phase 3 study with Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel. (See Table 8.)
If skin irritation appears after application of Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel, the intensity is generally mild or moderate, with local tolerability signs and symptoms (erythema, dryness, scaling, burning and pain of skin (stinging pain)) peaking during the first week and then subsiding spontaneously.
In addition to some of the previously mentioned, other adverse drug reactions were reported with Adapalene 0.1%/Benzoyl peroxide 2.5% (EPIDUO) Gel, the previously approved fixed combination of adapalene and benzoyl peroxide: Clinical trials: Other adverse drug reactions reported in clinical trials with Adapalene 0.1%/Benzoyl peroxide 2.5% (EPIDUO) Gel are irritative contact dermatitis (common) and sunburn (uncommon).
Post-Marketing surveillance data: The following events have been reported since the global launch of Adapalene 0.1%/Benzoyl peroxide 2.5% (EPIDUO) Gel. These events have been chosen for inclusion due to either their seriousness, causal connection to Adapalene 0.1%/Benzoyl peroxide 2.5% (EPIDUO) Gel or frequency of reporting. Post-market adverse events are reported spontaneously from a population of unknown size, thus estimates of frequency cannot be made.
Eye disorders: Eyelid oedema.
Respiratory, thoracic and mediastinal disorders: Throat tightness.
Skin and subcutaneous tissue disorders: Pain of skin, allergic contact dermatitis, swelling of face, blister (vesicles).
In addition to some of the previously mentioned, other adverse drug reactions were reported with Adapalene 0.1%/Benzoyl peroxide 2.5% (EPIDUO) Gel, the previously approved fixed combination of adapalene and benzoyl peroxide: Clinical trials: Other adverse drug reactions reported in clinical trials with Adapalene 0.1%/Benzoyl peroxide 2.5% (EPIDUO) Gel are irritative contact dermatitis (common) and sunburn (uncommon).
Post-Marketing surveillance data: The following events have been reported since the global launch of Adapalene 0.1%/Benzoyl peroxide 2.5% (EPIDUO) Gel. These events have been chosen for inclusion due to either their seriousness, causal connection to Adapalene 0.1%/Benzoyl peroxide 2.5% (EPIDUO) Gel or frequency of reporting. Post-market adverse events are reported spontaneously from a population of unknown size, thus estimates of frequency cannot be made.
Eye disorders: Eyelid oedema.
Respiratory, thoracic and mediastinal disorders: Throat tightness.
Skin and subcutaneous tissue disorders: Pain of skin, allergic contact dermatitis, swelling of face, blister (vesicles).
Drug Interactions
Epiduo: No interaction studies have been conducted with Epiduo.
From previous experience with adapalene and benzoyl peroxide, there are no known interactions with other medicinal products which might be used cutaneously and concurrently with Epiduo. However, other retinoids or benzoyl peroxide or drugs with a similar mode of action should not be used concurrently.
Caution should be exercised if cosmetics with desquamative, irritant or drying effects are used, as they may produce additive irritant effects with Epiduo.
Absorption of adapalene through human skin is low (see Pharmacology: Pharmacokinetics under Actions), 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.
Epiduo Forte: Overview: There are no known interactions with other medications which are likely to be used topically and concurrently with Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel. Absorption of adapalene through human skin is low, and therefore interaction with systemic medications 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.
Drug-Drug Interactions: No formal drug-drug interaction studies were conducted with Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel.
As Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel has 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 sulphur, resorcinol, or salicylic acid in combination with Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel. If these preparations have been used, it is advisable not to start therapy with Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel until the effects of such preparations have subsided.
Drug-Food Interactions: Interactions of Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel with food products have not been established.
Drug-Herb Interactions: Interactions of Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel with herbal products have not been established.
Drug-Laboratory Interactions: Interactions of Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel with laboratory tests have not been established.
Drug-Lifestyle Interactions: Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel should not come into contact with any coloured material including hair and fabrics as this may result in bleaching and discolouration.
As with other retinoids, use of electrolysis, "waxing" and chemical depilatories for hair removal should be avoided on skin treated with Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel.
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. Cosmetics must be removed by thorough cleansing before the area is treated.
From previous experience with adapalene and benzoyl peroxide, there are no known interactions with other medicinal products which might be used cutaneously and concurrently with Epiduo. However, other retinoids or benzoyl peroxide or drugs with a similar mode of action should not be used concurrently.
Caution should be exercised if cosmetics with desquamative, irritant or drying effects are used, as they may produce additive irritant effects with Epiduo.
Absorption of adapalene through human skin is low (see Pharmacology: Pharmacokinetics under Actions), 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.
Epiduo Forte: Overview: There are no known interactions with other medications which are likely to be used topically and concurrently with Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel. Absorption of adapalene through human skin is low, and therefore interaction with systemic medications 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.
Drug-Drug Interactions: No formal drug-drug interaction studies were conducted with Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel.
As Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel has 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 sulphur, resorcinol, or salicylic acid in combination with Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel. If these preparations have been used, it is advisable not to start therapy with Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel until the effects of such preparations have subsided.
Drug-Food Interactions: Interactions of Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel with food products have not been established.
Drug-Herb Interactions: Interactions of Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel with herbal products have not been established.
Drug-Laboratory Interactions: Interactions of Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel with laboratory tests have not been established.
Drug-Lifestyle Interactions: Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel should not come into contact with any coloured material including hair and fabrics as this may result in bleaching and discolouration.
As with other retinoids, use of electrolysis, "waxing" and chemical depilatories for hair removal should be avoided on skin treated with Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel.
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. Cosmetics must be removed by thorough cleansing before the area is treated.
Caution For Usage
Epiduo: Incompatibilities: Not applicable.
Epiduo Forte: Special Handling Instructions: There are no special handling instructions for Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel.
Epiduo Forte: Special Handling Instructions: There are no special handling instructions for Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel.
Storage
Epiduo: Store at temperatures not exceeding 30°C. Protect from light.
Epiduo Forte: Keep container tightly closed. Do not store above 25°C.
Shelf-Life: The product should be used within a period of 3 months after first opening.
Epiduo Forte: Keep container tightly closed. Do not store above 25°C.
Shelf-Life: The product should be used within a period of 3 months after first opening.
Action
Pharmacotherapeutic group: D10A Anti-Acne Preparations for Topical Use. ATC code: D10AD53.
Pharmacology: Pharmacodynamics: Epiduo: Mechanism of action and Pharmacodynamic effects: Epiduo combines two active substances, which act through different, but 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 P. acnes, which is abnormally present in the acne-affected pilosebaceous unit. Additionally benzoyl peroxide has demonstrated exfoliative and keratolytic activities. Benzoyl peroxide is also sebostatic, counteracting the excessive sebum production associated with acne.
Epiduo Forte: Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel combine two active substances, which have complementary mechanisms of action. The targets of this action are distinct, with no known pharmacodynamic interactions.
Adapalene: Studies in acne patients provide clinical evidence that topical adapalene is effective in reducing non-inflammatory 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 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).
Benzoyl Peroxide: Benzoyl peroxide is an oxidizing agent with bactericidal and keratolytic effects. As it exerts its antimicrobial effect through its oxidizing properties, resistance to this agent is unlikely to develop and has not been reported in the literature. In addition, benzoyl peroxide has keratolytic properties, which may improve efficacy.
Mechanism of Action: Adapalene and benzoyl peroxide, have complementary mechanisms of action targeting the pathology of acne vulgaris. The actives have an effect on three pathophysiologic factors known to contribute to acne vulgaris: altered follicular growth and differentiation (comedogenesis), colonization of the pilosebaceous unit with Propionibacterium acnes (P. acnes), and inflammation.
Adapalene: 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. In vitro studies with adapalene 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 (BPO): Benzoyl peroxide is an oxidizing agent with a broad spectrum bactericidal activity, in particular against Propionibacterium acnes (P. acnes), which is abnormally present in the acne-affected pilosebaceous unit. Additionally benzoyl peroxide has demonstrated exfoliative and keratolytic activities.
Clinical Studies: Epiduo: Clinical efficacy of Epiduo in patients aged 12 years and older: The safety and efficacy of Epiduo applied once daily for the treatment of acne vulgaris were assessed in two 12-week, multicenter, controlled clinical studies of similar design, comparing Epiduo to its individual active components, adapalene and benzoyl peroxide, and to the gel vehicle in acne patients. A total of 2185 patients were enrolled in Study 1 and Study 2. The distribution of patients in the two studies was approximately 49% male and 51% female, 12 years of age or older (mean age: 18.3 years; range 12 - 50), presenting 20 to 50 inflammatory lesions and 30 to 100 noninflammatory lesions at baseline.
The patients treated the face and other acne affected areas as needed once daily in the evening.
The efficacy criteria were: (1) Success rate, percentage of patients rated 'Clear' and 'Almost Clear' at Week 12 based on the Investigator's Global Assessment (IGA); (2) Change and Percent Change from baseline at Week 12 in Inflammatory lesion counts, Non-inflammatory lesion counts, Total lesion count.
The efficacy results are presented for each study in Table 1 and combined results in Table 2. Epiduo was shown to be more effective compared to its monads and gel vehicle in both studies. Overall, the net beneficial effect (active minus vehicle) obtained from Epiduo was greater than the sum of the net benefits obtained from the individual components, thus indicating a potentiation of the therapeutic activities of these substances when used in a fixed-dose combination. An early treatment effect of Epiduo was consistently observed in Study 1 and Study 2 for Inflammatory Lesions at Week 1 of treatment. Noninflammatory lesions (open and closed comedones) noticeably responded between the first and fourth week of treatment. The benefit on nodules in acne has not been established. (See Tables 1 and 2.)
Pharmacology: Pharmacodynamics: Epiduo: Mechanism of action and Pharmacodynamic effects: Epiduo combines two active substances, which act through different, but 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 P. acnes, which is abnormally present in the acne-affected pilosebaceous unit. Additionally benzoyl peroxide has demonstrated exfoliative and keratolytic activities. Benzoyl peroxide is also sebostatic, counteracting the excessive sebum production associated with acne.
Epiduo Forte: Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel combine two active substances, which have complementary mechanisms of action. The targets of this action are distinct, with no known pharmacodynamic interactions.
Adapalene: Studies in acne patients provide clinical evidence that topical adapalene is effective in reducing non-inflammatory 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 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).
Benzoyl Peroxide: Benzoyl peroxide is an oxidizing agent with bactericidal and keratolytic effects. As it exerts its antimicrobial effect through its oxidizing properties, resistance to this agent is unlikely to develop and has not been reported in the literature. In addition, benzoyl peroxide has keratolytic properties, which may improve efficacy.
Mechanism of Action: Adapalene and benzoyl peroxide, have complementary mechanisms of action targeting the pathology of acne vulgaris. The actives have an effect on three pathophysiologic factors known to contribute to acne vulgaris: altered follicular growth and differentiation (comedogenesis), colonization of the pilosebaceous unit with Propionibacterium acnes (P. acnes), and inflammation.
Adapalene: 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. In vitro studies with adapalene 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 (BPO): Benzoyl peroxide is an oxidizing agent with a broad spectrum bactericidal activity, in particular against Propionibacterium acnes (P. acnes), which is abnormally present in the acne-affected pilosebaceous unit. Additionally benzoyl peroxide has demonstrated exfoliative and keratolytic activities.
Clinical Studies: Epiduo: Clinical efficacy of Epiduo in patients aged 12 years and older: The safety and efficacy of Epiduo applied once daily for the treatment of acne vulgaris were assessed in two 12-week, multicenter, controlled clinical studies of similar design, comparing Epiduo to its individual active components, adapalene and benzoyl peroxide, and to the gel vehicle in acne patients. A total of 2185 patients were enrolled in Study 1 and Study 2. The distribution of patients in the two studies was approximately 49% male and 51% female, 12 years of age or older (mean age: 18.3 years; range 12 - 50), presenting 20 to 50 inflammatory lesions and 30 to 100 noninflammatory lesions at baseline.
The patients treated the face and other acne affected areas as needed once daily in the evening.
The efficacy criteria were: (1) Success rate, percentage of patients rated 'Clear' and 'Almost Clear' at Week 12 based on the Investigator's Global Assessment (IGA); (2) Change and Percent Change from baseline at Week 12 in Inflammatory lesion counts, Non-inflammatory lesion counts, Total lesion count.
The efficacy results are presented for each study in Table 1 and combined results in Table 2. Epiduo was shown to be more effective compared to its monads and gel vehicle in both studies. Overall, the net beneficial effect (active minus vehicle) obtained from Epiduo was greater than the sum of the net benefits obtained from the individual components, thus indicating a potentiation of the therapeutic activities of these substances when used in a fixed-dose combination. An early treatment effect of Epiduo was consistently observed in Study 1 and Study 2 for Inflammatory Lesions at Week 1 of treatment. Noninflammatory lesions (open and closed comedones) noticeably responded between the first and fourth week of treatment. The benefit on nodules in acne has not been established. (See Tables 1 and 2.)
Clinical efficacy of Epiduo in children 9 to 11 years old: During a paediatric clinical trial, 285 children with acne vulgaris, aged 9-11 years (53% of subjects were 11 years old, 33% were 10 years old and 14% were 9 years old) with a score of 3 (moderate) on the IGA scale and a minimum of 20 but not more than 100 total lesions (Noninflammatory and/or Inflammatory) on the face (including the nose) at baseline were treated with Epiduo Gel once daily for 12 weeks.
The study concludes that the efficacy and safety profiles of Epiduo Gel in this specific younger age group are consistent with results of other pivotal studies in subjects with acne vulgaris aged 12 years and older showing significant efficacy with an acceptable tolerability.
A sustained early treatment effect of Epiduo Gel compared to Gel Vehicle was consistently observed for all Lesions (Inflammatory, Non-Inflammatory, and Total) at Week 1 and continuing to Week 12. (See Table 3.)
The study concludes that the efficacy and safety profiles of Epiduo Gel in this specific younger age group are consistent with results of other pivotal studies in subjects with acne vulgaris aged 12 years and older showing significant efficacy with an acceptable tolerability.
A sustained early treatment effect of Epiduo Gel compared to Gel Vehicle was consistently observed for all Lesions (Inflammatory, Non-Inflammatory, and Total) at Week 1 and continuing to Week 12. (See Table 3.)
Epiduo Forte: Study demographics and trial design: See Table 4.
Treatment response was 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), and mean absolute change from baseline at Week 12 in both inflammatory and non-inflammatory lesion counts. 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.
At Baseline, 50% of enrolled patients had acne severity assessed as "moderate" (IGA = 3) and 50% had scores of "severe" (IGA=4). 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, with 273 (54.3%) patients 12 to 17 years of age. A similar number of males (47.7%) and females (52.3%) were enrolled. (See Table 5.)
At Baseline, 50% of enrolled patients had acne severity assessed as "moderate" (IGA = 3) and 50% had scores of "severe" (IGA=4). 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, with 273 (54.3%) patients 12 to 17 years of age. A similar number of males (47.7%) and females (52.3%) were enrolled. (See Table 5.)
Superiority of Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel over vehicle gel was demonstrated in the overall study population of subjects with moderate and severe acne (IGA=3 and IGA=4) at Week 12 for Success Rate (subjects rated "Clear" or "Almost Clear" on the IGA with at least 2-grade improvement [33.7% vs. 11.0%, p<0.001]) and for changes in inflammatory (-27.8 vs -13.2, p<0.001) and non-inflammatory lesion counts (-40.5 vs -19.7, p<0.001).
The primary efficacy analyses were also confirmed in the PP analyses and sensitivity analyses using traditional imputation methodology for missing data. Results of primary efficacy analyses are shown in the previous table.
In addition, in the subjects with severe acne (IGA= 4), Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel was shown to be superior to gel vehicle for the same endpoints: see Table 6.
The primary efficacy analyses were also confirmed in the PP analyses and sensitivity analyses using traditional imputation methodology for missing data. Results of primary efficacy analyses are shown in the previous table.
In addition, in the subjects with severe acne (IGA= 4), Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel was shown to be superior to gel vehicle for the same endpoints: see Table 6.
Both Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel and Adapalene 0.1 %/Benzoyl Peroxide 2.5% (EPIDUO) Gel were superior to Vehicle in terms of each lesion type, inflammatory and non-inflammatory. However, when analyzing Success rate, where IGA required to be improved by at least 3 grades, only Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel was shown superior to Vehicle (31.9% vs 11.8%, p=0.029), while Adapalene 0.1%/Benzoyl Peroxide 2.5% (EPIDUO) Gel was not (20.5% vs 11.8%, p=0.443).
Pharmacokinetics: Epiduo: The pharmacokinetic (PK) properties of Epiduo are similar to the PK profile of Adapalene 0.1% gel alone.
In a 30-day clinical PK study, conducted in patients with acne who were tested with either the fixed-combination gel or with an adapalene 0.1% matched formula under maximised conditions (with application of 2 g gel per day), adapalene was not quantifiable in the majority of plasma samples (limit of quantification 0.1 ng/mL). Low levels of adapalene (Cmax between 0.1 and 0.2 ng/mL) were measured in two blood samples taken from the subjects treated with Epiduo and in three samples from the subjects treated with Adapalene 0.1% Gel. The highest adapalene AUC0-24h determined in the fixed-combination group was 1.99 ng.h/mL.
These results are comparable to those obtained in previous clinical PK studies on various Adapalene 0.1% formulations, where systemic exposure to adapalene was consistently low.
The percutaneous penetration of benzoyl peroxide is low; when applied on the skin, it is completely converted into benzoic acid which is rapidly eliminated.
Epiduo Forte: Absorption: A pharmacokinetic study was conducted with Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel in 28 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 Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) 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 the limit of quantification (LOQ of 0.1 ng/mL), with a mean Cmax of 0.16 ± 0.08 ng/mL and a mean AUC0-24h of 2.49 ± 1.21 ng.h/mL. The most exposed subject had adapalene Cmax and AUC0-24h values of 0.35 ng/mL and 6.41 ng.h/mL, respectively.
The percutaneous penetration of benzoyl peroxide is low; when applied topically, it is rapidly and completely converted into benzoic acid in the skin and eliminated in the urine.
Topical application of either Adapalene 0.1%/Benzoyl Peroxide 2.5% (EPIDUO) Gel or adapalene gel (at corresponding equivalent adapalene strengths, i.e. 0.1% or 0.3%) under conditions of maximized use generated similar results.
Distribution: The total binding of adapalene in the blood was greater than 99%, with adapalene bound primarily to lipoproteins and human serum albumin. In human blood with a haematocrit of 45%, the erythrocyte fraction of blood contained only 26% of the total adapalene indicating that adapalene was distributed to erythrocytes at a lesser extent.
The distribution for benzoyl peroxide could not be determined since it is converted into benzoic acid, which is an endogenous substance.
Metabolism: Following 24-hour incubation with human hepatocytes, more than 90% of adapalene was metabolized. Both metabolites and adapalene showed a possibility for conjugation - predominantly glucuronidation and sulfation.
The metabolism of benzoyl peroxide metabolism evaluated in vitro in human skin confirmed benzoyl peroxide is metabolized into benzoic acid before passing into circulation.
Excretion: Excretion of adapalene appears to be primarily by the biliary route.
After topical administration in animal models, benzoyl peroxide was mainly and rapidly excreted in urine (45% of applied dose), nearly exclusively in the form of benzoic acid.
Special Populations and Conditions: Pharmacokinetic studies have not been conducted in subjects with a medical condition which might interfere with the absorption, distribution, metabolism, or excretion of Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel, in particular, a history of hepatic or renal disease.
Toxicology: Epiduo: Preclinical safety data: Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, phototoxicity or carcinogenicity.
Reproductive toxicology studies with adapalene have been performed by the oral and dermal routes of administration in the rat and rabbit. A teratogenic effect has been demonstrated at high systemic exposures (oral doses from 25 mg/kg/day). At lower exposures (dermal dose of 6 mg/kg/day), changes in the numbers of ribs or vertebrae were seen.
Animal studies performed with Epiduo include local tolerance studies and dermal repeat-dose toxicity studies in rat, dog and minipig up to 13 weeks and demonstrated local irritation and a potential for sensitisation, as expected for a combination containing benzoyl peroxide. Systemic exposure to adapalene following repeat dermal application of the fixed combination in animals is very low, consistent with clinical pharmacokinetic data. Benzoyl peroxide is rapidly and completely converted to benzoic acid in the skin and after absorption is eliminated in the urine, with limited systemic exposure.
Pharmacokinetics: Epiduo: The pharmacokinetic (PK) properties of Epiduo are similar to the PK profile of Adapalene 0.1% gel alone.
In a 30-day clinical PK study, conducted in patients with acne who were tested with either the fixed-combination gel or with an adapalene 0.1% matched formula under maximised conditions (with application of 2 g gel per day), adapalene was not quantifiable in the majority of plasma samples (limit of quantification 0.1 ng/mL). Low levels of adapalene (Cmax between 0.1 and 0.2 ng/mL) were measured in two blood samples taken from the subjects treated with Epiduo and in three samples from the subjects treated with Adapalene 0.1% Gel. The highest adapalene AUC0-24h determined in the fixed-combination group was 1.99 ng.h/mL.
These results are comparable to those obtained in previous clinical PK studies on various Adapalene 0.1% formulations, where systemic exposure to adapalene was consistently low.
The percutaneous penetration of benzoyl peroxide is low; when applied on the skin, it is completely converted into benzoic acid which is rapidly eliminated.
Epiduo Forte: Absorption: A pharmacokinetic study was conducted with Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel in 28 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 Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) 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 the limit of quantification (LOQ of 0.1 ng/mL), with a mean Cmax of 0.16 ± 0.08 ng/mL and a mean AUC0-24h of 2.49 ± 1.21 ng.h/mL. The most exposed subject had adapalene Cmax and AUC0-24h values of 0.35 ng/mL and 6.41 ng.h/mL, respectively.
The percutaneous penetration of benzoyl peroxide is low; when applied topically, it is rapidly and completely converted into benzoic acid in the skin and eliminated in the urine.
Topical application of either Adapalene 0.1%/Benzoyl Peroxide 2.5% (EPIDUO) Gel or adapalene gel (at corresponding equivalent adapalene strengths, i.e. 0.1% or 0.3%) under conditions of maximized use generated similar results.
Distribution: The total binding of adapalene in the blood was greater than 99%, with adapalene bound primarily to lipoproteins and human serum albumin. In human blood with a haematocrit of 45%, the erythrocyte fraction of blood contained only 26% of the total adapalene indicating that adapalene was distributed to erythrocytes at a lesser extent.
The distribution for benzoyl peroxide could not be determined since it is converted into benzoic acid, which is an endogenous substance.
Metabolism: Following 24-hour incubation with human hepatocytes, more than 90% of adapalene was metabolized. Both metabolites and adapalene showed a possibility for conjugation - predominantly glucuronidation and sulfation.
The metabolism of benzoyl peroxide metabolism evaluated in vitro in human skin confirmed benzoyl peroxide is metabolized into benzoic acid before passing into circulation.
Excretion: Excretion of adapalene appears to be primarily by the biliary route.
After topical administration in animal models, benzoyl peroxide was mainly and rapidly excreted in urine (45% of applied dose), nearly exclusively in the form of benzoic acid.
Special Populations and Conditions: Pharmacokinetic studies have not been conducted in subjects with a medical condition which might interfere with the absorption, distribution, metabolism, or excretion of Adapalene 0.3%/Benzoyl Peroxide 2.5% (EPIDUO FORTE) Gel, in particular, a history of hepatic or renal disease.
Toxicology: Epiduo: Preclinical safety data: Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, phototoxicity or carcinogenicity.
Reproductive toxicology studies with adapalene have been performed by the oral and dermal routes of administration in the rat and rabbit. A teratogenic effect has been demonstrated at high systemic exposures (oral doses from 25 mg/kg/day). At lower exposures (dermal dose of 6 mg/kg/day), changes in the numbers of ribs or vertebrae were seen.
Animal studies performed with Epiduo include local tolerance studies and dermal repeat-dose toxicity studies in rat, dog and minipig up to 13 weeks and demonstrated local irritation and a potential for sensitisation, as expected for a combination containing benzoyl peroxide. Systemic exposure to adapalene following repeat dermal application of the fixed combination in animals is very low, consistent with clinical pharmacokinetic data. Benzoyl peroxide is rapidly and completely converted to benzoic acid in the skin and after absorption is eliminated in the urine, with limited systemic exposure.
MedsGo Class
Acne Treatment Preparations
Features
Brand
Epiduo Forte
Full Details
Dosage Strength
3 mg / 25 mg (0.3% / 2.5%)
Drug Ingredients
- Adapalene
- Benzoyl Peroxide
Drug Packaging
Topical Gel 15g
Generic Name
Adapalene / Benzoyl Peroxide
Dosage Form
Topical Gel
Registration Number
DR-XY46058
Drug Classification
Prescription Drug (RX)
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