Soderm

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SODERM®

Composition:

Active substance: betamethasone valerate;

1 g of cream contains betamethasone valerate 1.22 mg (equivalent to betamethasone 1 mg);

Excipients: cetostearyl alcohol; chlorocresol; polyethylene glycol (macrogol) cetostearyl ether; white soft paraffin; sodium hydroxide; mineral oil; sodium dihydrogen phosphate dihydrate; purified water.

Pharmaceutical form. Cream

Main physicochemical properties:

cream of uniform consistency, white in color.

Pharmacotherapeutic group. Simple corticosteroid preparations. Potent corticosteroids (Group III).

ATC code: D07AC01.

Pharmacological properties.

Pharmacodynamics.

Efficacy

Under experimental and therapeutic conditions, betamethasone valerate has anti-inflammatory, antiallergic, and antiproliferative effects.

When applied topically, anti-inflammatory, epidermostatic and dermostatic, as well as antiallergic effects and effects in the form of contact hypesthesia are observed.

By performing the vasoconstriction test according to McKenzie and Stoughton, whose results correlate with the therapeutic efficacy of topical corticosteroids, 23 esters of betamethasone were investigated. It was established that betamethasone valerate, recalculated relative to fluocinolone acetonide = 100, has the following vasoconstrictive activity index: 360.

Vasoconstrictive activity indices of 5 topical corticosteroids in clinical comparison:

fluocinolone acetonide: 100
hydrocortisone: < 1
triamcinolone acetonide: 75
betamethasone: < 1
betamethasone valerate: 360

Mechanism of action

The mechanisms of anti-inflammatory, antiproliferative, and immunomodulatory actions, which qualitatively are common to all glucocorticoids, can be schematically and simplistically represented according to current, albeit partially incomplete and hypothetical, knowledge as follows:

Glucocorticoid molecules form a complex with receptor proteins in the cytoplasm and are transported into the cell nucleus, where, as a corticoid-receptor complex, they bind to GRE (glucocorticoid response elements) of specific genes.

This induces transcription of specific mRNA molecules, which bind to ribosomes for the synthesis of lipocortin proteins. Lipocortins inhibit reactions between phospholipase A2 and membrane phospholipids that occur when cells are damaged by physical, chemical, toxic, immunogenic, or bacterial pathogenic factors, and suppress the release of arachidonic acid.

Inhibition or reduction of arachidonic acid release normalizes, reduces, or blocks the synthesis regulated by arachidonic acid metabolism via cyclooxygenase and lipoxygenase, and the release of prostaglandins, prostacyclin, leukotrienes, platelet-activating factor, and thromboxane. These mediators of inflammation affect, for example, blood vessels, cell membranes, leukocytes, macrophages, and their chemotaxis and migration, as well as regulate cell growth.

In addition, glucocorticoids have antimitotic effects and inhibit nucleic acid and protein synthesis. Important factors in the immunomodulatory and antiallergic effects of glucocorticoids are their interactions with B-cells, T-cells, and Langerhans cells, inhibition of antigen processing, and antagonistic effects on the synthesis and function of interleukin-1, interleukin-2, and other cytokines.

Pharmacokinetics.

When the topical medicinal product is used for a limited time and on localized areas, the amount of active substance absorbed into the body is not significant enough to produce systemic effects.

However, with prolonged use and/or application to large areas of skin, depending on the degree of impairment of the stratum corneum barrier, depending on the site of application (e.g., intertriginous areas), or under occlusive dressings, significant amounts of the drug may be absorbed into systemic circulation. Betamethasone valerate is rapidly hydrolyzed by esterases in vivo to betamethasone alcohol.

Metabolism of [3H]betamethasone was studied in healthy subjects and in patients receiving high therapeutic doses of the steroid. Approximately 70% of the dose was excreted in urine within 48 hours, with 15–30% reappearing in the unconjugated fraction. Six metabolites were identified, along with unchanged betamethasone. The transformations occurred as follows: oxidation of the 11β-hydroxyl group, hydroxylation at the 6β position, reduction of the carboxyl group at C-20, and cleavage of the side chain.

Clinical characteristics.

Indications.

For the treatment of inflammatory and allergic skin diseases or skin conditions accompanied by pruritus, in which symptomatic treatment with potent corticosteroids is indicated.

Contraindications.

• Hypersensitivity to any component of the drug;
• viral infections, including post-vaccination reactions and varicella;
• viral skin infections (e.g. herpes simplex, herpes zoster, varicella);
• untreated skin infections;
• acne;
• pruritus without inflammation;
• anogenital pruritus;
• rosacea;
• rosacea-like dermatitis;
• perioral dermatitis;
• bacterial dermatoses, including tuberculosis and syphilis of the skin;
• skin infections caused by viruses, bacteria, or fungi.

Soderm**®** cream must not be used to treat skin diseases, including dermatitis and diaper dermatitis, in infants under 1 year of age.

Use under occlusive dressings (e.g. diapers, etc.) is not recommended.

Soderm**®** cream must not be used in chronic, stable forms of psoriasis with extensive skin involvement.

Facial skin is particularly sensitive. Therefore, to avoid skin changes, prolonged topical corticosteroid therapy should be avoided in this area whenever possible. Application to the eyelids should be entirely avoided, as under certain conditions such use may lead to glaucoma and cataract. Medicinal products containing glucocorticoids are not intended for use in the periorbital area.

Interaction with other medicinal products and other forms of interaction.

When used concomitantly with medicinal products that inhibit the activity of the CYP3A4 enzyme system (e.g. ritonavir, itraconazole), inhibition of corticosteroid metabolism may occur, leading to increased systemic bioavailability. The clinical significance of this interaction depends on the dosage and route of administration of the corticosteroid, as well as the potency of the CYP3A4 inhibitors.

Special precautions for use.

Enhanced systemic absorption of topical corticosteroids in certain individuals may lead to manifestations of hypercortisolism (Cushing's syndrome) and reversible suppression of the hypothalamic-pituitary-adrenal (HPA) axis, followed by adrenal insufficiency.

If suppression occurs, the medication should be discontinued, the frequency of application reduced, or the patient should be switched to a less potent corticosteroid.

Abrupt discontinuation of treatment may result in adrenal insufficiency (see section "Adverse reactions").

Factors associated with increased risk of systemic effects include:

• Potency and formulation of the topical corticosteroid;
• Duration of treatment;
• Application over large body surface areas;
• Use of occlusive dressings, for example, in intertriginous skin areas, or application under occlusive dressings (in children, diapers may act as occlusive coverings);
• Enhanced hydration of the stratum corneum;
• Application to thin skin, such as facial skin;
• Application to damaged skin or compromised skin barrier;
• In infants and young children, compared to adults, due to an incompletely developed skin barrier and a larger body surface area relative to body weight, higher absorption of topical corticosteroids may occur. Therefore, systemic adverse effects are more likely in infants and young children.

Soderm® cream should be used in children only for short-term treatment (less than 1 week) and over small areas (less than 10% of body surface area). Particular caution should be exercised when treating children with corticosteroids, as corticosteroids may be absorbed in higher amounts through the skin in children compared to adults.

Long-term treatment in infants and children under 12 years of age should be avoided, as enhanced transdermal absorption—and consequently adrenal suppression—may occur even without the use of occlusive dressings.

Warm, moist conditions in skin folds may promote bacterial infections, or bacterial infections may result from the use of occlusive dressings. If occlusive dressings are used, the skin should be cleaned during dressing changes. Topical corticosteroids should be used with caution in psoriasis, as cases of rebound flare-ups (withdrawal syndrome), development of tolerance, risk of generalized pustular psoriasis, and local or systemic toxicity due to impaired skin barrier have been reported. When Soderm® cream is used in psoriasis, the patient's condition should be closely monitored.

Treatment of skin disorders with corticosteroids may be complicated by the development of infection, which requires appropriate antimicrobial therapy. If such an infection spreads, treatment with topical corticosteroids should be discontinued and the patient should consult a physician who will determine the need for specific further treatment. This medicinal product must not come into contact with the eyes or mucous membranes when applied to the face.

Facial skin is particularly sensitive. To avoid atrophic skin changes, long-term therapy with topical corticosteroids should not be performed on the face.

Topical corticosteroids are sometimes used to treat dermatitis around chronic leg ulcers. However, such use may be associated with a higher incidence of local hypersensitivity reactions and an increased risk of local infections.

Visual disturbances:

Visual disturbances may occur with both systemic and topical use of corticosteroids. If a patient presents with symptoms such as blurred vision or other visual disturbances, referral to an ophthalmologist should be considered to identify possible causes, including cataract, glaucoma, or rare conditions such as central serous chorioretinopathy (CSCR), which has been reported after systemic or topical corticosteroid use.

During treatment of genital or anal areas, the presence of excipients such as petrolatum and paraffin in the formulation may reduce the tensile strength of latex condoms, potentially compromising their reliability when used concurrently.

Use during pregnancy or breastfeeding.

Previous human experience with glucocorticoids has not provided evidence suggesting an increased risk of congenital malformations. However, during pregnancy, topical corticosteroids should not generally be used in high doses, over large skin areas, or for prolonged periods due to their potential systemic effects, which may impair function of the hypothalamic-pituitary-adrenal system and possibly affect fetal growth.

Animal studies have shown that glucocorticoids can cause cleft palate. There is ongoing debate regarding a potential increased risk of cleft palate in human embryos following glucocorticoid use during the first trimester of pregnancy. Furthermore, based on epidemiological data combined with animal studies, there is discussion about the possibility that in utero exposure to glucocorticoids may predispose individuals to metabolic and cardiovascular diseases in adulthood. Synthetic glucocorticoids such as betamethasone are generally less effectively inactivated in the placenta than endogenous cortisol (hydrocortisone), thus posing a risk to the fetus.

During pregnancy, especially in the first three months, prolonged topical treatment should only be initiated after careful assessment of benefit versus risk. To date, no teratogenic effects have been observed in humans, but intrauterine developmental disturbances due to glucocorticoid exposure during long-term oral therapy cannot be ruled out. When treatment is administered late in pregnancy, there is a risk of adrenal atrophy in the fetus, necessitating replacement therapy with gradual dose tapering in the newborn.

Betamethasone passes into breast milk. Harm to infants has not yet been established. However, a clear medical indication is required for use of this medicinal product during breastfeeding. Betamethasone valerate should only be used during breastfeeding when the expected benefit to the mother outweighs the potential risk to the infant. If higher doses are required due to the disease, or if the drug is applied over larger areas exceeding 20% of body surface area, breastfeeding should be discontinued. Contact between the infant and treated skin areas should be avoided. When betamethasone valerate is used during breastfeeding, it should not be applied to the breasts to prevent inadvertent ingestion by the infant.

Effect on ability to drive and use machines.

There is no experience indicating negative effects on the ability to concentrate while driving vehicles or operating machinery.

Method of Administration and Dosage

At the beginning of treatment, Soderm**®** cream should be applied in a thin layer to affected areas of the skin and gently rubbed in once or twice daily. Once improvement occurs, usually once daily application is sufficient.

For children over 1 year of age, once daily application is generally adequate in most cases.

In adults, prolonged use of Soderm**®** (more than 3 weeks) or application over large areas of skin (over 20% of body surface) should be avoided. Longer-term treatment should only be prescribed in exceptional cases and when clearly indicated.

Children.

Do not use the drug in children under 1 year of age.

In children over 1 year of age, once daily application is generally sufficient in most cases.

The cream should be applied in a thin layer to affected skin areas and, if possible, gently rubbed in. In adults, prolonged use (longer than 3 weeks) or application over large areas of skin (over 20% of body surface) should be avoided. Longer-term treatment should only be prescribed in exceptional cases when clearly indicated.

The duration of treatment with Soderm**®** cream in children should be as short as possible, using the lowest effective dose. Treatment in children should not exceed 1 week. Close monitoring of children for the development of adverse symptoms and systemic effects is recommended.

Overdose.

Acute overdose symptoms are unlikely to occur. However, following chronic overdose or improper use, clinical manifestations of hypercortisolism may develop. In such cases, the drug should be discontinued, or, due to the potential risk of adrenal insufficiency, the dosage should be gradually tapered under medical supervision by reducing the frequency of application or switching to a corticosteroid with weaker activity.

Side effects

The assessment of adverse effects is based on the following frequency data:

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 (frequency cannot be estimated from the available data)

Generally, topical medicinal products containing glucocorticoids are well tolerated. However, if signs of hypersensitivity occur, the use of these products should be discontinued.

If signs of hypersensitivity do appear, treatment should be discontinued.

Local hypersensitivity reactions may resemble symptoms caused by the underlying disease.

*Skin manifestations associated with local and/or systemic effects due to suppression of hypothalamic-pituitary-adrenal (HPA) axis activity.

§Prolonged use of corticosteroids or their application over large areas may lead to systemic absorption of the active substance. Systemic effects are more likely in infants and young children, as well as with the use of occlusive dressings. In infants, diapers may act as an occlusive dressing. Children may be more susceptible than adults to systemic absorption of topically applied glucocorticoids.

With prolonged use (more than 3 weeks) or application over large skin areas, especially under occlusive dressings or in skin folds, local skin changes such as skin atrophy, striae, steroid acne, telangiectasia, pigment alterations, and hypertrichosis may occur.

Application of topical corticosteroid-containing products to wounds may impair wound healing.

Reporting 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 strongly encouraged to report any suspected adverse reactions to the Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte), Department of Pharmacovigilance (Abt. Pharmakovigilanz), Kurt-Georg-Kiesinger-Allee 3, D-53175 Bonn, Germany, Website: www.bfarm.de.

Shelf life. 3 years.

After first opening of the tube, shelf life is 6 months.

Storage conditions.

Store out of reach of children, at a temperature not exceeding 30 °C.

Packaging.

25 g, 50 g in a tube; 1 tube per cardboard box.

Prescription status. Prescription-only.

Manufacturer. mibe GmbH Arzneimittel.

Manufacturer's address.

Muenchenstrasse 15, Brehna, Saxony-Anhalt, 06796, Germany.