Advantan

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ADVANTANÒ (ADVANTANÒ)

Composition:

Active substance: methylprednisolone aceponate;

1 g of cream contains 1 mg of methylprednisolone aceponate;

Excipients: decyl oleate, glyceryl monostearate 40–55%, cetylstearyl alcohol, hard fat, Softisan-378, polyoxyl 40 stearate, glycerol 85%, edetate disodium, benzyl alcohol, butylhydroxytoluene, purified water.

Pharmaceutical form. Cream.

Main physicochemical characteristics: white, opaque cream.

Pharmacotherapeutic group. Corticosteroids for dermatological use.

ATC code D07AC14.

Pharmacological Properties.

Pharmacodynamics.

Advantan® suppresses inflammatory and allergic reactions of the skin, as well as reactions associated with cellular hyperproliferation when applied topically, thereby alleviating both objective symptoms (erythema, edema, maceration) and subjective complaints (itching, burning, pain).

It is known that methylprednisolone aceponate binds directly to intracellular glucocorticoid receptors. This particularly applies to its main metabolite—6α-methylprednisolone-17-propionate—formed after cleavage in the skin.

Binding of the steroid-receptor complex to a specific region of the DNA molecule initiates a cascade of biological effects.

The binding of the steroid-receptor complex leads to the induction of macrocortin synthesis. Macrocortin inhibits the release of arachidonic acid and thus reduces the formation of inflammatory mediators such as prostaglandins and leukotrienes.

The immunosuppressive effect of glucocorticosteroids can be explained by inhibition of cytokine synthesis and by an antimitotic effect, which is not yet fully understood.

Inhibition of the synthesis of vasodilatory prostaglandins or potentiation of the vasoconstrictive effect of adrenaline ultimately results in the vasoconstrictive activity of glucocorticosteroids.

Methylprednisolone aceponate (6α-methylprednisolone aceponate) is a non-halogenated synthetic corticosteroid molecule characterized by a high degree of dissociation between its local and systemic effects.

The 6α-methyl group exerts a potentiating effect, while the lipophilic ester groups ensure better penetration through the skin.

The local anti-inflammatory effect, confirmed by pharmacological and clinical-pharmacological studies, is comparable to that of more potent corticosteroids. Systemic effects of methylprednisolone aceponate following topical application are minimal, according to study data.

Pharmacokinetics.

Methylprednisolone aceponate is hydrolyzed in the epidermis and dermis to form 6α-methylprednisolone-17-propionate, its main metabolite, which binds more strongly to corticosteroid receptors than the parent compound—clear evidence of cutaneous bioactivation.

The percentage and overall extent of transdermal absorption of a topical corticosteroid depends on several factors, including the chemical structure of the compound, excipients, concentration of the compound in the vehicle, conditions of application (surface area treated, duration of exposure, open versus occlusive treatment), and skin characteristics (type and severity of pathology, anatomical location).

Transdermal absorption of methylprednisolone aceponate in cream form was studied in healthy volunteers. With application of occlusive dressings using 15 g of Advantan**®** cream twice daily for 7 days, the mean transdermal absorption was approximately 2.5%, corresponding to a systemic corticosteroid load of about 10 μg/kg/day. Transdermal absorption of methylprednisolone aceponate was significantly increased under experimental conditions of skin damage induced by removal of the stratum corneum.

After entering the bloodstream, the main hydrolysis product of methylprednisolone aceponate, 6α-methylprednisolone-17-propionate, is rapidly conjugated with glucuronic acid and thus inactivated.

Metabolites of methylprednisolone aceponate (main metabolite: 6α-methylprednisolone-17-propionate-21-glucuronide) are primarily excreted via urine, with a half-life of elimination of approximately 16 hours. After intravenous administration, complete excretion via urine and feces occurs within 7 days. No accumulation of the active substance or its metabolites in the body occurs.

Clinical characteristics.

Indications.

Atopic dermatitis (neurodermatitis, endogenous eczema); true eczema; simple contact dermatitis and allergic contact dermatitis; dyshidrotic eczema, infantile eczema.

Contraindications.

Hypersensitivity to methylprednisolone aceponate or to any other component of the medicinal product; tuberculosis or syphilis lesions in the area of application; viral infections (e.g. varicella, herpes zoster), rosacea, perioral dermatitis, ulcerative skin lesions, common acne, atrophic dermatitis, skin reactions following vaccination in the area of application; skin diseases associated with bacterial or fungal infections (see section "Special precautions for use").

Interaction with other medicinal products and other forms of interaction.

No data available.

Due to absorption when treating large skin areas or prolonged treatment, interactions similar to those observed during systemic therapy may occur. However, such interactions have not been reported to date.

If simultaneous use of any other medicinal products is necessary, consult a physician.

Special precautions for use

Glucocorticoids should be used only in the smallest possible doses, especially in children, and only for as long as absolutely necessary to achieve and maintain the desired therapeutic effect.

When treating pathological processes affecting a large skin area, the duration of therapy should be clearly defined by the physician.

In bacterial skin infections and/or in case of fungal involvement, additional specific treatment with antibacterial and/or antifungal agents is required.

Local skin infections may worsen during local application of glucocorticoids.

The use of the medicinal product should be avoided in the facial area in cases of rosacea or perioral dermatitis.

When using Advantan**®**, care should be taken to avoid contact of the product with the eyes and with deep open wounds or mucous membranes.

In healthy adult volunteers, application of methylprednisolone aceponate (Advantan**®** 0.1% hydrophobic cream) over 60% of the body surface under occlusive dressing for 22 hours resulted in reduced plasma cortisol levels and effects on its circadian rhythm. This mode of application should be used as infrequently as possible. When Advantan**®** is applied over a large skin area (40–90% of body surface) without occlusion in children (in newborns, diapers may act as occlusive dressings), no impairment of adrenal cortex function has been observed. Nevertheless, when applying the product over a large skin area, treatment duration should be kept as short as possible.

The risk of adverse effects significantly increases when topical corticosteroids are applied over large body areas or for prolonged periods, particularly under occlusive dressings. Treatment with occlusive dressings should be avoided unless specifically indicated. It should be remembered that diapers and nappies, as well as areas affected by intertrigo, may produce the same effect as occlusive dressings.

When treating large areas of the body, treatment duration should be kept as short as possible, since it is not possible to completely exclude the possibility of systemic absorption or systemic effects.

As with all corticosteroids, inappropriate use of this medicinal product may mask clinical symptoms.

If excessive skin dryness occurs during prolonged application of Advantan**®** cream, it is recommended to switch to another pharmaceutical form of the product with a higher fat content (Advantan**®** ointment or Advantan**®** fatty ointment).

As with systemic corticosteroid use, glaucoma may occur during topical application (e.g., after high-dose use or prolonged application over large areas, use under occlusive dressings, or application to the skin around the eyes).

Prolonged use of topically applied products may lead to sensitization. In such cases, treatment should be discontinued and appropriate therapy initiated.

The product contains cetostearyl alcohol and butylated hydroxytoluene (BHT), which may cause local skin reactions such as contact dermatitis. BHT may also cause eye and mucous membrane irritation.

Use during pregnancy or breastfeeding

Currently, there are no reliable data on the use of Advantan**®** in pregnant women; however, the risk is expected to be minimal due to the very low likelihood of systemic effects of topically applied corticosteroids.

Animal studies with methylprednisolone aceponate administered at doses exceeding the therapeutic dose have shown embryotoxic and/or teratogenic effects.

This product should not be used during pregnancy or breastfeeding unless clearly needed and under strict medical supervision.

During the first trimester of pregnancy, topical use of corticosteroid-containing products should preferably be avoided. Throughout pregnancy, treatment of large skin areas, prolonged use of the product, or use under occlusive dressings should be avoided.

Some epidemiological studies suggest a possible increased risk of cleft palate in newborns whose mothers received corticosteroid treatment during the first trimester of pregnancy.

Advantan**®** cream may be prescribed to pregnant women only after careful assessment of the benefit-risk ratio.

Studies in mice have shown that methylprednisolone aceponate does not penetrate into milk. However, it is unknown whether methylprednisolone aceponate passes into human breast milk, since systemically administered corticosteroids have been detected in women's breast milk. It is also unknown whether topical application of Advantan**®** cream could lead to systemic absorption of methylprednisolone aceponate in amounts detectable in human breast milk. Therefore, Advantan**®** cream should be used with caution in breastfeeding women.

During breastfeeding, the product should not be applied to the mammary glands. Particular care should be taken to avoid prolonged use, application over large skin areas, or use under occlusive dressings.

There is no information available on the effects of methylprednisolone aceponate on fertility.

Ability to affect reaction speed when driving or operating machinery

Not established.

Method of Administration and Dosage

The medication should usually be applied once daily as a thin layer to the affected areas of skin, unless otherwise directed by a physician.

The formulation of Advantan® cream (1 g of Advantan® cream contains 1 mg of methylprednisolone aceponate), due to its increased water content, promotes exudate drainage and is therefore particularly suitable for the treatment of weeping eczematous lesions in the acute phase, as well as skin areas with maceration, whether hairy or non-hairy.

Duration of treatment in typical cases should not exceed 12 weeks for adults and 4 weeks for children. There are no safety data available regarding the use of Advantan® cream in children under 4 months of age.

When using Advantan® cream to treat children aged 4 months and older, no dose adjustment is required.

Children.

There are no safety data available for the use of Advantan® cream in children under 4 months of age. Prior to use in children aged from 4 months to 3 years, medical advice is recommended.

When using Advantan® cream to treat children aged 4 months and older, no dose adjustment is required.

Duration of treatment in children should not exceed 4 weeks in typical cases.

Advantan® cream must not be used under occlusive dressings in children. It should be noted that diapers and nappies may produce the same effect as occlusive dressings.

Overdose.

In cases of cutaneous atrophoderma associated with overdose following topical application of the medication, treatment should be discontinued. Symptoms usually resolve within 10–14 days.

Acute toxicity studies with methylprednisolone aceponate have shown no risk of acute intoxication following a single excessive topical application (application over a large body surface area under conditions favoring absorption) or after accidental oral ingestion of the medication.

Adverse Reactions

During clinical studies, the most commonly reported adverse effects with the use of Advantan® cream were burning and itching at the application site.

The frequency of adverse reactions observed during clinical studies, listed in the table below, was determined according to MedDRA (version 12.0): very common (>1/10); common (>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10,000, <1/1000); very rare (<1/10,000); unknown (frequency cannot be estimated based on available data).

Also, when using Advantan® cream, rare side effects such as bacterial cellulitis and skin infections may occur.

As with topical use of other corticosteroids, the following adverse effects (frequency not known) may be observed: skin thinning (skin atrophy), appearance of striae, inflammation of hair follicles (folliculitis) at the application site, excessive hair growth (hypertrichosis), telangiectasias, perioral dermatitis, skin discoloration, contact dermatitis, and allergic skin reactions to any component of the medicinal product.

In individual cases, systemic effects of corticosteroids due to their absorption are possible.

The product contains cetyl stearyl alcohol and butylhydroxytoluene, which may cause local reactions such as contact dermatitis. Butylhydroxytoluene may also cause eye irritation and irritation of mucous membranes.

If any adverse reactions occur, use of the product should be discontinued and medical advice must be sought immediately.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not above 25 °C in a place inaccessible to children.

Packaging. 5 g or 15 g in a tube; 1 tube per cardboard box.

Availability. Over-the-counter (without prescription).

Manufacturer.

LEO Pharma Manufacturing Italia S.R.L.

Manufacturer's address and place of business.

Via E. Schering, 21, 20054 Segrate (MI), Italy