Properties
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Advantan® Cream 0.1% Product Summary 1. Name of medicinal product Advantan 0.1% cream 2. Qualitative and quantitative composition Active substance: 1 g of Advantan contains 1 mg of methylprednisolone aceponate. Excipients: For excipients, see section 6.1. 3. Pharmaceutical form Cream Oil-in-water emulsion, white to yellowish opaque cream See blog: Advantan – for the treatment of chronic and acute inflammatory skin diseases 4. Clinical features 4.1. Therapeutic indications Endogenous eczema (atopic dermatitis, neurodermatitis), contact eczema, degenerative eczema, dyshidrotic eczema, nummular eczema, unclassified eczema, pediatric eczema. 4.2. Dosage and method of administration Dosage/frequency and duration of use Advantan should be applied topically and gently in a thin layer to the affected skin once a day. In general, the duration of use in adults should not exceed 12 weeks. If excessive skin dryness occurs due to prolonged use of Advantan cream, a switch to another dosage form with a high oil content (Advantan ointment or Advantan fatty ointment) should be made. Method of administration It is used externally and applied to the affected skin. Additional information on special populations Renal/hepatic impairment The use of Advantan in patients with renal and hepatic impairment has not been studied. Pediatric population The safety of Advantan in infants under 4 months of age has not been established. Dose adjustment is not necessary when using Advantan in children. The duration of use in children should generally not exceed 4 weeks. Use in infants and young children is not recommended unless absolutely necessary. Geriatric population The use of Advantan in elderly patients has not been studied. 4.3. Contraindications Contraindicated in case of tuberculosis or syphilis lesions in the treatment area, viral diseases (e.g., varicella, herpes zoster), rosacea, perioral dermatitis, skin ulcers, vulgar acne, atrophic skin diseases, or if post-vaccination skin reactions are observed. Contraindicated in patients with hypersensitivity to the active substance or any of the excipients. 4.4. Special warnings for use and precautions Glucocorticoids should be used at the lowest dose, especially in children. It should only be used for the period necessary to achieve and maintain the desired therapeutic effect. Specific additional treatment is also required for bacterial skin diseases and/or fungal infections. The use of topical glucocorticoids may increase the potential for local skin infections. Caution is required when using Advantan to avoid contact with eyes, open deep wounds, and mucous membranes. In healthy adult volunteers, after application of Advantan ointment to 60% of the skin surface under occlusive conditions for 22 hours, suppression of plasma cortisol levels and disruption of circadian rhythm were observed. Prolonged or intensive use of topical corticosteroids over large areas, especially under occlusive dressings, significantly increases the risk of side effects. It should be noted that diapers can be occlusive. When treating large areas of skin, the duration of treatment should be as short as possible, as the possibility of absorption or systemic effects cannot be completely ruled out. As with other glucocorticoids, incorrect use can mask clinical symptoms. As with systemic corticosteroids, glaucoma may develop with the use of topical corticosteroids (e.g., at high doses for a long time or over a large area, occlusive dressing, or application to the skin around the eye). Two excipients of Advantan (cetostearyl alcohol and butylated hydroxytoluene) may cause local skin reactions (e.g., contact dermatitis). Butylated hydroxytoluene may also cause irritation to the eyes and mucous membranes. Pediatric population For use in children from four months to 3 years of age, a benefit/risk assessment is required. 4.5. Interactions with other medicinal products and other forms of interaction No known interactions. 4.6. Pregnancy and lactation General recommendations Pregnancy category C. Women of reproductive potential / Contraceptives There is no data on the effect of Advantan on the use of contraceptive methods. Pregnancy There is insufficient data on the use of Advantan in pregnant women. Methylprednisolone aceponate has shown embryotoxic and/or teratogenic effects in animal experimental studies. (See 5.3: Preclinical safety data). Epidemiological studies suggest that there may be an increased risk of cleft palate in children of women treated with systemic glucocorticoids during the first trimester of pregnancy. In general, topical preparations containing corticosteroids should not be used in the first trimester of pregnancy. Treatment of large areas, prolonged use, or occlusive dressings should be avoided during treatment, especially during pregnancy. Lactation It has not been observed in practice that methylprednisolone aceponate is transferred to milk in rat neonates. It is unknown whether methylprednisolone aceponate is excreted in breast milk: however, systemically administered corticosteroids have been detected in breast milk. It is unknown whether topical Advantan formulations cause sufficient systemic absorption of methylprednisolone aceponate to be detected in sufficient quantities in human milk. Therefore, caution is required when administering Advantan to nursing mothers. Treatment in nursing mothers should not be applied to the breast area. Use over large areas, prolonged use, or occlusive dressings should be avoided (see section 4.4 Special warnings and precautions for use). Reproductive toxicity/fertility There is no information that Advantan affects reproductive ability. 4.7. Effects on ability to drive and use machines There is no data that Advantan affects the ability to drive or operate machinery. 4.8. Undesirable effects The frequency of side effects observed in clinical trials is listed below according to MedDRA classification (MedDra version 11.1): Very common (>1/10); Common (>1/100 to <1/10); Uncommon (>1/1000 to <1/100); Rare (>1/10,000 to <1/1000); Very rare (<1/10,000), Unknown (cannot be estimated from available data). MedDRA version 11.1 was used for classification. Infections and infestations Rare: fungal skin reaction Immune system disorders Uncommon: hypersensitivity Skin and subcutaneous tissue disorders Rare: acne, skin fissures, pyoderma, telangiectasias, cracks, skin atrophy, fungal skin infections Unknown (cannot be estimated from available data): striae formation on the skin, perioral dermatitis, skin discoloration changes, allergic skin reactions General disorders and administration site conditions Common: burning sensation, itching at the application site Uncommon: dryness at the application site, vesicles, erythema, folliculitis, rash, paresthesia, Rare: cellulitis, swelling, irritation at the application site Unknown (cannot be estimated from available data): hypertrichosis With the use of topical preparations containing corticosteroids, systemic effects may occur due to absorption. Reporting of suspected adverse reactions is important after the authorization of the medicinal product. Providing information on suspected adverse reactions allows for continuous monitoring of the benefit/risk balance of the drug. 4.9. Overdose and treatment Results of acute toxicity studies do not indicate a risk of acute intoxication after a single overdose of cream on the skin (application to a large surface under conditions suitable for absorption) or accidental ingestion. 5. Pharmacological properties 5.1. Pharmacodynamic properties Pharmacotherapeutic group: Corticosteroids, potent (Group III) After topical application, Advantan suppresses inflammatory and allergic skin reactions, as well as hyperproliferative processes, leading to regression of objective symptoms (erythema, edema, weeping) and subjective complaints (itching, burning, pain). Methylprednisolone aceponate is known to bind to intracellular glucocorticoid receptors, and this also applies to the main metabolite 6a-methylprednisolone-17-propionate, which is formed in the skin after ester degradation. The steroid receptor complex binds to specific regions of DNA, leading to biological effects. Binding of the steroid receptor complex induces the synthesis of macrocortin. Macrocorin inhibits the release of arachidonic acid and, consequently, the formation of inflammatory mediators such as prostaglandins and leukotrienes. The immunosuppressive effect of glucocorticoids can be explained by the suppression of cytokine synthesis and an antimitotic effect, which is not yet fully understood. The suppression of the synthesis of vasodilatory prostaglandins and the enhancement of the vasoconstrictive effect of adrenaline lead to the vasoconstrictive effect of glucocorticoids. 5.2. Pharmacokinetic properties General characteristics Absorption Methylprednisolone aceponate can penetrate the skin from all formulations. The rate and extent of percutaneous absorption of a topical corticosteroid depend on factors such as the chemical structure of the compound, the composition of the preparation, the concentration of the preparation in the preparation, the conditions of exposure (site of treatment, duration of exposure, open or occlusive), and the condition of the skin (type and severity of skin disease, anatomical site, etc.). Percutaneous absorption was significantly higher when methylprednisolone aceponate was applied to damaged skin with removal of the stratum corneum (13-27% of the dose). Distribution Concentration in the stratum corneum and viable epidermis decreases from outside to inside. Biotransformation Methylprednisolone aceponate is hydrolyzed in the epidermis and dermis to its main metabolite, 6a-methylprednisolone-17-propionate, which has a higher affinity for the corticosteroid receptor. This hydrolysis indicates "bioactivation" in the skin. After reaching the systemic circulation, 6a-methylprednisolone-17-propionate, the main metabolite of methylprednisolone aceponate, is rapidly conjugated with glucuronic acid and finally inactivated. Elimination Metabolites of methylprednisolone aceponate (main metabolite: 6-a-methylprednisolone-17-propionate-21-glucuronide) are mainly excreted by the kidneys with a half-life of 16 hours. After intravenous administration, excretion of 14C-labeled substances is complete within 7 days via urine and feces. No accumulation of any active substance or metabolite in the body is observed. 5.3. Preclinical safety data For the assessment of systemic tolerance after repeated subcutaneous and dermal application, methylprednisolone aceponate showed a typical glucocorticoid action profile. Based on these results, effects other than typical glucocorticoid side effects are expected after therapeutic use of Advantan, even under extreme conditions such as application to large areas and/or occlusive treatment. Embryotoxicity studies with Advantan showed typical results of other glucocorticoids, i.e., embriolethal and/or teratogenic effects occurred in the respective test system. In view of these findings, particular caution is required when prescribing Advantan during pregnancy. The results of epidemiological studies are summarized in section "4.6 Pregnancy and lactation". Neither in vitro studies on bacterial and mammalian cell gene mutation screening nor in vitro and in vivo studies on chromosome and gene mutation screening showed that methylprednisolone aceponate has any genotoxic potential. Tumor-specific studies using methylprednisolone aceponate have not been conducted. Information on structure, mechanism of action, and results from systemic tolerance studies with prolonged administration do not indicate a risk of tumor formation. If the recommended conditions for the use of Advantan are observed, it is not expected to have an effect on tumor formation, as dermal application does not achieve systemic immunosuppressive effects. In local tolerance studies of methylprednisolone aceponate and Advantan formulations on skin and mucous membranes, no findings other than known local side effects of glucocorticoids were observed. In studies on guinea pigs, no potential skin sensitization effect of methylprednisolone aceponate was observed. 6. Pharmaceutical properties 6.1. List of excipients · Decyl oleate · Glyceryl monostearate 40-55% · Cetostearyl alcohol · Hard fat · Caprylic-capric-myristic-stearic triglyceride · Macrogol stearate 40 (Type I) · Glycerol 85% · Disodium edetate · Benzyl alcohol · Butylated hydroxytoluene · Purified water 6.2. Incompatibilities No known incompatibilities. 6.3. Shelf life 36 months 6.4. Special precautions for storage Store at a temperature not exceeding 25°C. 6.5. Packaging form and contents Aluminum tube 15g, 30g, 60g