INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KARIZON®

Composition:

Active substance: clobetasol;

1 g of ointment contains 0.5 mg of clobetasol propionate;

Excipients: white soft paraffin, paraffin, stearyl alcohol, sorbitan sesquioleate, polysorbate 80, sodium edetate, purified water.

Pharmaceutical form. Ointment.

Main physicochemical properties: white homogeneous ointment with a weak specific odor.

Pharmacotherapeutic group. Corticosteroids for topical use. Simple corticosteroids. Very potent corticosteroids (Group IV).

ATC code: D07AD01.

Pharmacological properties.

Pharmacodynamics.

Efficacy

Topical corticosteroids possess anti-inflammatory, antipruritic, and vasoconstrictive properties.

Based on its efficacy confirmed in animal studies and pharmacological trials in humans, 0.05% clobetasol propionate belongs to the group of very potent topical corticosteroids, intensity class IV.

Mechanism of action

Qualitatively, the mechanism of anti-inflammatory, antiproliferative, and immunomodulatory action of all glucocorticoids (according to the generally accepted, albeit partially incomplete and hypothetical understanding) can be schematically represented in simplified form as follows: glucocorticoid molecules form complexes with corticoid receptors of cells in the plasma — binding to specific genes, GRE (glucocorticoid-responsive elements).

This induces transcription of specific mRNA molecules, leading to the synthesis of lipocortin-proteins on ribosomes.

Lipocortins slow down reactions occurring in response to physical, chemical, toxic, or immunogenic influences, or the action of microbiological pathogenic factors, acting between phospholipase A2 and membrane phospholipids, thereby preventing the release of arachidonic acid.

Inhibition or slowing of arachidonic acid release normalizes, reduces, or blocks the synthesis regulated by arachidonic acid metabolism via cyclooxygenase and lipoxygenase pathways, and the subsequent release of prostaglandins, prostacyclin, leukotrienes, histamine, and thromboxane — inflammatory mediators that affect, for example, blood vessels, cell membranes, leukocytes, and macrophages, including their chemotaxis and migration, and regulate cell growth.

In addition, glucocorticoids exert antimitotic effects and slow down the synthesis of nucleic acids and proteins. Key factors in their immunomodulatory and antiallergic effects are interactions of glucocorticoids with B-cells, T-cells, and Langerhans cells, which inhibit antigen presentation and antagonize the synthesis and functions of interleukin-1, interleukin-2, and other cytokines.

Pharmacokinetics.

Studies on skin penetration of clobetasol from ointment formulations containing clobetasol propionate have not been conducted.

Clinical characteristics.

Indications.

For the treatment of localized, therapy-resistant plaques of inflammatory skin diseases where symptomatic treatment with potent topical glucocorticoids is indicated, for example, in psoriasis.

Contraindications.

Carison® is contraindicated:

• in case of hypersensitivity to the active substance, stearyl alcohol, or to any other excipient of the medicinal product;
• in rosacea, rosacea-like (perioral) dermatitis, generalized forms of chronic plaque psoriasis, common acne, pruritus without inflammation, Pruritus anogenitalis, viral skin infections (e.g., herpes simplex, varicella), specific skin conditions (e.g., cutaneous tuberculosis, cutaneous manifestations of syphilis), vaccination reactions, and untreated skin infections (caused by bacteria, fungi, or parasites);
• in infants and children under 3 years of age (including treatment of dermatoses);
• this medicinal product is not intended for use in the eye area, eyelids, or around the eyes, as under certain circumstances this may lead to the development of glaucoma or cataract.

Carison® ointment should not be applied to the face (see section "Special precautions for use").

Interaction with other medicinal products and other forms of interaction.

When used concomitantly with medicinal products that may inhibit the CYP3A4 enzyme system (e.g., ritonavir, itraconazole), inhibition of corticosteroid metabolism has been observed, which may lead to increased systemic availability. The clinical significance of such interaction depends on the dose of the medicinal product, the route of administration of the corticosteroid, and the potency of the CYP3A4 inhibitor.

Interaction of clobetasol propionate with other medicinal products has not been fully described, but possible interactions may occur, for example, with diuretics and anticoagulants, particularly under unfavorable therapeutic and absorptive conditions, such as on severely damaged skin.

Special precautions for use.

Increased systemic absorption of topical corticosteroids may in some individuals lead to manifestations of hypercorticism (Cushing's syndrome) and reversible suppression of the hypothalamic-pituitary-adrenal (HPA) axis with adrenal insufficiency. If any of the above symptoms occur, the frequency of application should be gradually reduced or the drug should be replaced with a less potent corticosteroid. Abrupt discontinuation of treatment may result in adrenal insufficiency (see section "Adverse reactions").

Factors increasing the risk of systemic effects include:

• Potency and formulation of the topical corticosteroid;
• Duration of use;
• Application over a large skin surface area;
• Application to skin areas in contact with each other, such as intertriginous areas or under occlusive dressings (in infants, diapers may act as occlusive dressings);
• Increased hydration of the stratum corneum;
• Application to areas with thin skin, such as the face;
• Application to damaged skin or areas with impaired skin barrier function;
• In infants and children compared to adults, a proportionally greater amount of topical corticosteroid may be absorbed due to their underdeveloped skin barrier and larger skin surface area relative to body weight. Therefore, systemic adverse effects are more likely in infants and children.

Carizon® ointment should not be used in children aged 3 to 12 years. Treatment in this age group should be carried out only in exceptional cases and for a few days only. Prolonged treatment with topical corticosteroids should be avoided in this age group, as adrenal cortex suppression may occur.

The risk of bacterial infections increases in warm and moist conditions in skin folds or due to the use of occlusive dressings. When occlusive dressings are used, the skin should be carefully cleansed each time the dressing is changed.

Topical steroids should be used with caution in the treatment of psoriasis, as in some cases relapses, development of tolerance, risk of generalized pustular psoriasis, and local or systemic toxicity due to impaired skin barrier function have been reported. Patients treated with this drug for psoriasis should be under close medical supervision.

For inflammatory skin conditions complicated by infection, appropriate antimicrobial therapy should be administered. Any sign of infection spreading requires discontinuation of topical glucocorticoid therapy and initiation of appropriate antimicrobial treatment.

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

Serious osteonecrotic infections (including necrotizing fasciitis) and systemic immunosuppression (sometimes leading to regression of Kaposi's sarcoma) have been reported with prolonged use of clobetasol propionate exceeding recommended doses (see section "Dosage and administration"). In some cases, patients were concurrently using other potent oral/topical corticosteroids or immunosuppressants (e.g., methotrexate, mycophenolate mofetil). If treatment with topical corticosteroids is clinically justified for longer than 2 weeks, consideration should be given to using a less potent corticosteroid.

Carizon® ointment should not be applied to the facial skin, as the face is particularly susceptible to cutaneous atrophic changes.

If application to the facial skin is necessary, treatment duration should be limited to a few days.

Visual disturbances:

Visual disturbances may occur with systemic or topical use of corticosteroids. If a patient presents with symptoms such as blurred vision or other visual disturbances, they should be referred to an ophthalmologist to evaluate possible causes (e.g., cataract, glaucoma, or rare conditions such as central serous chorioretinopathy, which has been reported after systemic or topical corticosteroid use).

Additionally, Carizon® ointment should not be applied to the skin of the neck, intertriginous areas (axillary folds and genital areas), except in the case of genital lichen sclerosus, or to eroded, weeping, abraded, or ulcerated skin surfaces. It should also be avoided in patients with hepatic impairment and in those with development of diabetes-prone metabolism.

Elderly patients should not apply Carizon® ointment over large skin surface areas.

Careful patient monitoring is required during prolonged and/or repeated use of clobetasol propionate, whether administered orally or parenterally.

When treating the genital area or perianal region, the presence of excipients such as petrolatum and paraffin in the formulation may reduce the strength and, consequently, the reliability of latex condoms if used simultaneously.

Stearyl alcohol may cause localized skin irritation (e.g., contact dermatitis).

Use during pregnancy or breastfeeding.

During pregnancy, use of Carizon® ointment should be avoided if possible. If use is necessary, duration should be as short as possible and the application area as small as possible. Clobetasol should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

Prolonged treatment with glucocorticoids during pregnancy may impair fetal development. Animal studies have shown that glucocorticoid use leads to cleft palate. It is believed that the risk of cleft palate in human fetuses is increased when glucocorticoids are taken during the first trimester of pregnancy. Furthermore, epidemiological studies and animal experiments suggest that intrauterine exposure to glucocorticoids may predispose to metabolic and cardiovascular disorders in adulthood. Synthetic glucocorticoids such as clobetasol are generally less inactivated than endogenous cortisol (hydrocortisone) and thus pose a risk to the fetus. Use of glucocorticoids late in pregnancy may lead to adrenal cortical atrophy in the fetus, which may require gradual initiation of replacement therapy in newborns.

Breastfeeding period

Glucocorticoids pass into breast milk. No adverse effects in newborns have been reported to date. However, the indication for use during breastfeeding should be clearly justified. During breastfeeding, clobetasol should be used only if the expected benefit to the mother outweighs the potential risk to the infant. Contact between the infant and areas of skin treated with the drug should be avoided. If higher doses of the drug are required due to illness, breastfeeding should be discontinued.

During breastfeeding, Carizon® ointment should not be applied to the area of the mammary glands to prevent accidental ingestion by the infant.

Ability to influence the ability to drive vehicles or operate machinery.

No negative effect on the ability to drive vehicles or operate machinery is expected following the use of Carizon® ointment.

Method of Administration and Dosage

Clobetasol propionate belongs to the class of the most potent topical corticosteroids (Group IV), and prolonged use may lead to serious adverse effects (see section "Precautions for Use"). If treatment with a topical corticosteroid is clinically justified beyond 2 weeks, consideration should be given to switching to a less potent corticosteroid agent. Repeated but short courses of clobetasol propionate may be used to control flare-ups (see details below).

Dosage

The ointment should be applied once daily in a thin layer.

The treated area should not exceed 10% of the body surface. For safety reasons, patients should not use more than 50 g of Karizon® ointment per week.

Repeated short-term treatment with Karizon® ointment may be used to manage disease flare-ups. If long-term steroid therapy is indicated, a formulation with a lower application frequency should be selected.

Elderly Patients

Clinical trial data have not demonstrated differences in efficacy between elderly and younger patients. However, the increased incidence of renal and hepatic impairment in elderly patients may reduce elimination in the event of systemic absorption. Therefore, treatment should be limited to the minimum amount and shortest duration necessary to achieve the desired clinical benefit. Regular monitoring for adverse effects should be performed at regular intervals during treatment.

Patients with Renal or Hepatic Impairment

In the event of systemic absorption (possible with use over large areas for prolonged periods), patients with renal or hepatic impairment may experience delayed metabolism and elimination, thereby increasing the risk of systemic toxicity. Therefore, treatment should be limited to the minimum amount and shortest duration necessary to achieve the desired clinical benefit. Regular monitoring for adverse effects should be performed at regular intervals during treatment.

Patients with Impaired Glucose Metabolism

Karizon® ointment should not be used in patients with impaired glucose metabolism over large skin areas. Regular monitoring for adverse effects should be performed at regular intervals during treatment.

Method of Administration

For external use only.

Patients should wash their hands after applying Karizon® ointment, unless the hands are being treated.

Duration of Treatment

The maximum duration of treatment is 2 weeks. If no improvement is observed, the patient should consult the prescribing physician again.

Once disease control is achieved, corticosteroid therapy should be gradually discontinued and replaced with basic skin care as maintenance therapy.

Sudden withdrawal of clobetasol may result in rebound recurrence of dermatoses that existed prior to treatment initiation (rebound phenomenon).

Children.

Treatment with Karizon® ointment in children should be conducted for the shortest possible duration and at the lowest possible doses that still ensure efficacy.

The product is contraindicated for use in infants and children under 3 years of age (see section "Contraindications").

Karizon® ointment should not be used in children aged 3 to 12 years. Treatment in this age group should be undertaken only in exceptional cases and for a few days only (see section "Precautions for Use").

Overdose.

Symptoms.

Acute overdose symptoms are unlikely; however, chronic overdose or abuse may manifest as clinical features of hypercortisolism (see section "Adverse Reactions").

Treatment.

In case of overdose, due to the risk of adrenal insufficiency, the dosage should be tapered gradually by reducing the frequency of application or switching to a less potent corticosteroid under medical supervision.

Further management in cases of overdose should be based on the patient's clinical condition.

Adverse reactions.

The adverse reactions listed below are classified by organ systems and by their absolute frequency of occurrence.

The following classification was used to determine the frequency of adverse reactions:

If signs of hypersensitivity occur, the drug must be discontinued immediately.

Local hypersensitivity reactions may occur during the use of the ointment, resembling symptoms caused by the underlying disease.

* Skin disorders secondary to local and/or systemic suppression of the hypothalamic-pituitary-adrenal (HPA) axis.

After prolonged use of the drug on the face, skin atrophy occurs more frequently than in other areas of the body.

Exacerbation of symptoms requiring treatment is possible.

Reporting suspected adverse reactions

Reporting suspected adverse reactions during the post-marketing period is very important. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions.

Shelf life. 3 years.

After opening the tube – 3 months.

Storage conditions.

Keep out of reach of children, at a temperature not exceeding 25 °C.

Packaging. 15 g, 30 g, or 50 g tube in a cardboard box with instructions for medical use.

Prescription status. Prescription only.

Manufacturer.

mibe GmbH & Co. KG.

Manufacturer's address and place of business.

Muenchener Strasse 15, Brehna, Saxony-Anhalt, 06796, Germany.