Triderm®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRIDERМ® (TRIDERM®)

Composition:

Active substances: betamethasone, clotrimazole, gentamicin;

1 g of cream contains: betamethasone (as dipropionate) 0.5 mg, clotrimazole 10 mg and gentamicin (as sulfate) 1 mg;

Excipients: mineral oil; white soft paraffin; cetylstearyl alcohol; propylene glycol; polyethylene glycol cetylstearyl ether; benzyl alcohol; sodium dihydrogen phosphate dihydrate; phosphoric acid; sodium hydroxide; purified water.

Pharmaceutical form. Cream.

Main physicochemical properties: soft, homogeneous cream, white or almost white, free from foreign inclusions.

Pharmaco-therapeutic group.

Corticosteroids for dermatological use. Corticosteroids in combination with antibiotics. Betamethasone and antibiotics. ATC code D07XC01.

Pharmacological properties.

Mechanism of action.

Triderm® combines three actions: the anti-inflammatory effect of betamethasone dipropionate, the antibacterial activity of gentamicin sulfate, and the antifungal effect of clotrimazole.

Pharmacodynamics.

Betamethasone dipropionate is a potent (class III) corticosteroid with anti-inflammatory, antiallergic, and antipruritic effects.

Gentamicin is an antibiotic from the aminoglycoside group with bactericidal activity. It inhibits protein synthesis in antibiotic-sensitive microorganisms. Gentamicin is active against many aerobic gram-negative and a few gram-positive bacteria. In vitro, gentamicin at concentrations of 1–8 mcg/mL inhibits most sensitive strains of Escherichia coli, Haemophilus influenzae, Moraxella lacunata, Neisseria, indole-positive and indole-negative strains of Proteus, Pseudomonas (including most strains of Pseudomonas aeruginosa), Staphylococcus aureus, Staphylococcus epidermidis, and Serratia. Different species and strains of the same species may show significant differences in in vitro sensitivity. Moreover, in vitro sensitivity does not always correlate with in vivo sensitivity. Gentamicin is ineffective against most anaerobic bacteria, fungi, and viruses. Gentamicin has only minimal efficacy against streptococci.

Resistance to gentamicin may develop in both gram-negative and gram-positive bacteria.

Clotrimazole is a synthetic antifungal agent of the imidazole derivatives group. Its spectrum of activity includes a range of fungi pathogenic for humans and animals. Clotrimazole is effective against dermatophytes, yeasts, and molds. In vitro studies have demonstrated clotrimazole's efficacy against Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, Microsporum canis, and Candida species (including Candida albicans). Based on current knowledge, the antifungal action of clotrimazole is attributed to inhibition of ergosterol synthesis. Ergosterol is a key component of the fungal cell membrane.

Pharmacokinetics.

Studies on penetration or absorption of this medicinal product have not been conducted.

Betamethasone

Under normal conditions, only a portion of topically applied betamethasone becomes systemically available. The extent of penetration depends on the site of application, skin condition, pharmaceutical formulation used, patient's age, and method of application.

Gentamicin

Systemic absorption can be disregarded when gentamicin is applied to intact skin. However, increased transdermal absorption should be considered in cases of keratin layer loss, inflammatory skin conditions, or when used under occlusive dressing or over large skin areas.

Clotrimazole

After topical application, systemic absorption is low, with most of the clotrimazole remaining in the stratum corneum. Concentrations observed 6 hours after application of 1% radiolabeled clotrimazole on intact and acutely inflamed skin were as follows: stratum corneum – 100 mcg/cm³, reticular layer – 0.5–1 mcg/cm³, subcutaneous layer – 0.1 mcg/cm³.

Clinical characteristics.

Indications.

Treatment of dermatoses sensitive to corticosteroids, when (or suspected) bacterial and/or fungal infections caused by microorganisms sensitive to the components of the drug are present.

Contraindications.

The drug is contraindicated in patients with hypersensitivity to the active substances or to any other component of the drug, to other aminoglycoside antibiotics (cross-allergic reactions to gentamicin), or to imidazole derivatives (cross-allergic reactions to clotrimazole). Also contraindicated in cutaneous tuberculosis, cutaneous manifestations of syphilis, skin reactions following vaccination, skin ulcers, acne, widespread plaque psoriasis, viral skin infections (e.g. herpes simplex, herpes zoster), varicose veins, perioral dermatitis, rosacea, chickenpox, and other bacterial and fungal skin infections without appropriate antibacterial and antifungal therapy.

Trikderm® is not indicated for use under occlusive dressings.

Trikderm® should not be applied to mucous membranes, eyes, or the area around the eyes.

Do not use the cream for treatment of nails or infections of the scalp skin.

Interaction with other medicinal products and other forms of interaction.

When the cream is applied to the genital area or the perianal region, the presence of soft paraffin or mineral oil (excipients in the medicinal product) may weaken latex condoms, thereby reducing their reliability during use.

Clotrimazole, when applied topically, may act as an antagonist to amphotericin and other polyene antibiotics.

Special precautions for use

The cream is particularly suitable for the treatment of conditions in the exudative stage.

TriDerma® is not intended for ophthalmic use.

If skin irritation or hypersensitivity reactions develop during treatment with TriDerma® cream, the drug should be discontinued and appropriate therapy initiated.

With topical application, systemic absorption of the active substances may be increased when the drug is applied to large areas of skin, especially with prolonged use or application to damaged skin. In such cases, adverse reactions associated with systemic exposure to the active ingredients may occur.

When aminoglycoside antibiotics are administered systemically concurrently, the possibility of cumulative toxic effects (ototoxicity/nephrotoxicity) should be considered in case of increased absorption.

Cross-allergic reactions with other aminoglycoside antibiotics should also be taken into account.

Prolonged topical use of antibiotics may occasionally lead to overgrowth of resistant microorganisms. In such cases, as well as in the event of superinfection, appropriate treatment should be initiated.

The drug should be used in high doses, over large body surface areas, or with potent or very potent corticosteroids only under regular medical supervision, particularly regarding suppression of the hypothalamic-pituitary-adrenal (HPA) axis and possible metabolic effects. If HPA axis suppression develops, the drug should be discontinued or the frequency of application reduced, or the patient should be switched to a less potent corticosteroid. HPA axis function usually recovers after discontinuation of the drug. In individual cases, withdrawal symptoms may develop, requiring administration of systemic corticosteroids.

Application of the drug to open wounds or damaged skin should be avoided.

Continuous treatment for more than 2–3 weeks is not recommended.

Very potent, potent, and moderately potent corticosteroids should be used with caution when applied to facial or genital skin. In such cases, the treatment course should not exceed 1 week.

In general, only low-dose corticosteroids should be used around the eyes (due to the risk of glaucoma).

Corticosteroids may mask symptoms of an allergic reaction to one of the components of the drug.

Patients should be instructed to use the drug only for personal treatment of their existing skin condition and not to pass it on to others.

Visual disturbances may occur with systemic and topical use of corticosteroids (including intranasal, inhaled, and intraocular administration). If symptoms such as blurred vision or other visual disturbances occur, the patient should undergo an ophthalmological examination to evaluate possible causes, including cataract, glaucoma, or rare conditions such as central serous chorioretinopathy, which has been reported after systemic and topical corticosteroid use.

Children

Pediatric patients may demonstrate greater sensitivity to hypothalamic-pituitary-adrenal (HPA) axis suppression and Cushing's syndrome caused by topical corticosteroids than adult patients, due to a higher skin surface area to body mass ratio.

In children treated with topical corticosteroids, suppression of HPA axis function, Cushing's syndrome, growth retardation, inadequate weight gain, and increased intracranial pressure have been reported.

Signs of adrenal cortex suppression include low plasma cortisol levels and lack of response to adrenocorticotropic hormone (ACTH) stimulation tests. Increased intracranial pressure may manifest as bulging fontanelle, headache, and bilateral optic disc swelling.

Propylene glycol contained in this medicinal product may cause skin irritation.

Use during pregnancy or breastfeeding

Pregnancy

Animal studies have demonstrated teratogenic effects of topical corticosteroids. There are no adequate data on use in pregnant women.

Aminoglycosides cross the placental barrier and may cause fetal harm when administered to pregnant women. Cases of complete, irreversible, bilateral congenital deafness in infants whose mothers received aminoglycosides (including gentamicin) during pregnancy have been reported. Data on topical use of gentamicin in pregnant women are insufficient. Data on use of clotrimazole in pregnant women are limited.

Animal studies did not demonstrate any risk of adverse effects of the drug on the fetus.

TriDerma® should be used only if clearly needed.

TriDerma® should not be used in high doses, over large skin areas, or for prolonged periods.

Lactation

It is unknown whether gentamicin, clotrimazole, and corticosteroids, when applied topically, are excreted in breast milk. However, systemic corticosteroids are known to be excreted in breast milk.

TriDerma® should not be applied to the breasts during breastfeeding.

Ability to affect reaction rate when driving or operating machinery

The effect on the ability to drive vehicles or operate machinery has not been studied.

Method of Administration and Dosage

For adults, apply Triderm® thinly to the entire affected area and the adjacent area of intact skin twice daily, in the morning and evening, and gently rub in. The duration of treatment depends on the patient's clinical response to therapy, as well as clinical and microbiological findings.

In cases of athlete's foot, a longer treatment course may be required (2–4 weeks).

Children.

Not recommended for use in children due to lack of experience with the use of this medicinal product in this age group.

Overdose.

Symptoms. With prolonged or excessive use of topical glucocorticosteroids, suppression of the hypothalamic-pituitary-adrenal system may occur, leading to secondary adrenal insufficiency and symptoms of hypercorticism, including Cushing's syndrome.

It cannot be excluded that a single overdose of gentamicin may lead to symptoms of overdose.

Excessive and prolonged topical use of gentamicin may result in overgrowth of fungi or antibiotic-resistant microorganisms at the site of skin lesions.

Treatment. Appropriate symptomatic therapy should be administered. Symptoms of acute hypercorticism are usually reversible. If necessary, correction of electrolyte imbalance should be performed. In cases of chronic toxic effects, gradual withdrawal of corticosteroids is recommended.

If overgrowth of resistant microorganisms occurs, treatment with Triderm® should be discontinued and appropriate antifungal or antibacterial therapy should be initiated.

Side effects.

Initial treatment

Skin-related

Rare: skin irritation, burning sensation, itching, dryness of the skin, hypersensitivity reactions to one of the components of the medicinal product, and changes in skin color.

Application to large areas of skin, under occlusive dressings and/or for prolonged periods (see section "Contraindications")

When applied to large areas of skin, under occlusive dressings and/or for prolonged periods, local skin changes may occur. Systemic reactions (adrenal suppression, fainting, arterial hypotension, dyspnea, discomfort/pain, malaise) may occur when applied to large areas of skin.

One should bear in mind the increased risk of secondary infections due to decreased local resistance to infection.

Skin-related

Localized skin changes such as skin atrophy (particularly on the face), telangiectasia, exudation, blistering, swelling, urticaria, maceration of the skin, miliaria, pigmentary disturbances (hypopigmentation), hypochromia, striae, focal desquamation, pruritus, flaking of the skin, induration of the skin, skin fissures, sensation of warmth, follicular rash, erythema, stretch marks, subcutaneous hemorrhages, purpura, steroid-induced acneiform eruptions, rosacea-like/perioral dermatitis, hypertrichosis, and changes in skin color. It is unknown whether these skin color changes are reversible.

Uncommon: contact sensitization to gentamicin.

Photosensitization has been observed in some patients; however, this effect does not recur upon re-exposure to gentamicin followed by ultraviolet radiation.

Endocrine system

Suppression of endogenous corticosteroid synthesis, excessive adrenal activity with edema.

Metabolism

Development of latent diabetes mellitus.

Visual system

Blurred vision.

Auditory system, inner ear/kidneys

With concomitant systemic use of aminoglycoside antibiotics, combined ototoxicity/nephrotoxicity may occur when Triaderm® cream is applied to large body surfaces or areas of damaged skin.

Musculoskeletal system

Osteoporosis, growth retardation (in children).

Cetearyl alcohol, an ingredient of the medicinal product, may cause local skin reactions (e.g., contact dermatitis).

Shelf life: 2 years.

Storage conditions:

Store in a place inaccessible to children, at a temperature not exceeding 25 °C.

Packaging:

15 g or 30 g in aluminum tubes. 1 tube per cardboard box.

Prescription status: Prescription only.

Manufacturer:

Organon Heist bv, Belgium.

Manufacturer's address and location of its business operations:

Industriepark 30, 2220, Heist-op-den-Berg, Belgium.