NAME OF THE MEDICINAL PRODUCT BELOGENT® cream BELOGENT® ointment betamethasonum, gentamicinum QUALITATIVE AND QUANTITATIVE COMPOSITION
1 g of cream contains 0.5 mg of betamethasone in the form of dipropionate and 1 mg of gentamicin in the form of sulphate.
1 g of ointment contains 0.5 mg of betamethasone in the form of dipropionate and 1 mg of gentamicin in the form of sulphate.
PHARMACEUTICAL FORM CLINICAL PARTICULARS THERAPEUTİC İNDİCATİONS Skin diseases responsive to local therapy with corticosteroids which have or may develop primary or secondary bacterial infection:
Infected allergic and non-allergic skin diseases: acute, subacute and chronic types
of contact allergic dermatitis and occupational dermatitis, seborrheic dermatitis, diaper dermatitis, atopic dermatitis (neurodermatitis), intertrigo, eczematous nummular dermatitis, dyshidrotic dermatitis, pyodermatous acute non-allergic dermatitis, acute photodermatitis, x-ray dermatitis, infected dermatitis caused by insect bites;
Infected dermatoses such as psoriasis vulgaris, exfoliative dermatitis, lichen ruber
Belogent cream and ointment are used on skin lesions infected by bacteria responsive to gentamicin, such as: certain strains of streptococci (alfa- and beta-haemolytic streptococcus), Staphylococcus aureus (coagulase-positive, coagulase-negative and certain penicillinase producing strains), and gram-negative bacteria: Pseudomonas aeruginosa, Aerobacter aerogenes, E. coli, Proteus vulgaris and Klebsiella pneumoniae.
POSOLOGY AND METHOD OF ADMİNİSTRATİON Belogent cream and ointment are for topical application only. The cream is used in the therapy of acute moist skin lesions, while ointment is beneficial in the treatment of chronic dermatoses, e.g. dry, lichenified and scaly lesions, i.e. in cases when occlusive effect of ointment as vehicle is required. The required amount of Belogent cream or ointment is applied to the affected skin in a thin layer and gently rubbed in twice daily. On parts of skin with thick stratum corneum and on which the preparation is easily removed (e.g. palms and soles of the feet) treatment should be repeated more frequently. The treatment should not exceed 3 weeks. In the chronic skin conditions, to prevent relapses, treatment should continue for some time even after the disappearance of all symptoms, under constant supervision of a physician. CONTRAİNDİCATİONS
Belogent cream, or ointment, should not be used in patients hypersensitive to betamethasone, gentamicin or any of the excipients. Also, the preparation should not be used in skin tuberculosis, vaccinia, varicella, perioral dermatitis and rosacea.
SPECİAL WARNİNG AND PRECAUTİONS FOR USE
If upon the first application of Belogent cream or ointment hypersensitivity reaction occurs on the skin (itching, burning, redness), administration should be immediately discontinued. Belogent cream and ointment should not be used under occlusive dressing, except if necessary. Prolonged use of Belogent cream or ointment on the face is not recommended due to possible occurrence of rosacea-like dermatitis, perioral dermatitis and acne.
Belogent cream or ointment should not be applied in the eye and periorbital region due to possible development of cataract, glaucoma, fungal eye infections and exacerbation of herpes. Belogent cream and ointment are not used in the treatment of varicose ulcers in the lower leg (ulcus cruris).
Children: due to larger skin surface to total body weight ratio and under-developed stratum corneum, increased absorption of betamethasone and gentamicin may occur in children during topical application. This may lead to manifestation of systemic toxicity. The preparation should not be used under the diapers because these garments (especially those made of plastic) work like occlusive dressing and increase absorption. Consequently, this preparation should be administered to children with great caution and for the shortest period of time possible. Children, patients with hepatic insufficiency, and patients requiring long-term topical application of Belogent cream or ointment, especially if occlusive dressings are indispensable, should be carefully monitored because, due to increased absorption of betamethasone, systemic manifestations may occur (see section OVERDOSE). These patients should be periodically tested for the functioning of hypothalamic- pituitary-adrenal axis (the test of urine and plasma free cortisol, and ACTH stimulation test). If suppression of the above mentioned axis occurs, the therapy should be discontinued or given less frequently or substituted with less potent corticosteroid. Rarely, symptoms of withdrawal may occur (fever, myalgia, arthralgia, weakness) which require administration of systemic corticosteroid substitute therapy. Certain parts of the body, e.g. groins, axillae and perianal region, where natural occlusion exists, are more susceptible to the development of striae during therapy with Belogent cream or ointment; application to these parts should be very limited.
In cases of fungal superinfection of skin lesions, additional topical application of
It should be remembered that a long-term local therapy with gentamicin could cause development of microorganisms resistant to aminoglycosides. Therefore, topical administration is not recommended in immunocompromised patients or other high-risk groups of patients. If during treatment resistance or superinfection develops, administration of gentamicin should be discontinued and appropriate treatment applied.
INTERACTİON WİTH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF İNTERACTİON
Interactions of Belogent cream or ointment with other drugs are not known.
PREGNANCY AND LACTATION Pregnancy
There are no adequate and well-controlled studies on the teratogenic effects of locally applied corticosteroids in pregnant women. Also, there are no adequate and well controlled studies about teratogenic effects of locally applied gentamicin. Therefore, local application of Belogent cream and ointment in pregnant women is allowed only if, to the physician’s opinion, benefit for a pregnant woman outweighs possible risks to the foetus. In these cases the therapy should be short and limited to a small body surface.
It is not known whether locally applied corticosteroids, including betamethasone, are
sufficiently absorbed to produce measurable concentrations in the breast milk. It has been reported that systemically administered corticosteroids are distributed into breast milk in quantities which are not harmful for infants.
Systemically administered gentamicin is excreted into breast milk, but it probably does not cause adverse effects in infants. Upon doctor’s decision, Belogent cream or ointment can be used in nursing mothers, but the preparation should not be applied on the breast skin before nursing.
EFFECTS ON ABİLİTY TO DRİVE AND USE MACHİNES
There is no evidence that Belogent cream and ointment have effect on the ability to
UNDESIRABLE EFFECTS Topical administration of betamethasone may reduce collagen content in the subcutaneous tissue and cause atrophic changes in the skin, irreversible striae, ecchymoses, telangiectasia, folliculitis, hypertrichosis and allergic contact dermatitis. Prolonged therapy may lead to development of rash, pruritus, local hyperpigmentation or depigmentation of the skin, depigmentation of the hair, and inhibition of sebaceous glands function. Secondary skin infections may occur due to depression of immunity system. Systemic side effects of topical administration of betmethasone are due to absorption of the drug into circulation. They occur very rarely, in most cases upon overdosage and usually withdraw immediately upon discontinuation of treatment (see section OVERDOSE). Local reactions to gentamicin are usually manifested as hypersensitivity skin reactions characterised by rash, pruritus, erythema, swelling and other signs of irritation that have not existed before the therapy was started. OVERDOSE When betamethasone is applied to large surfaces of damaged, and therefore more permeable skin over longer period of time (more than three weeks), under the occlusive dressing, and if it is used in children for longer period of time or in patients with hepatic insufficiency, increased absorption into circulatory system and manifestation of systemic effects may occur - suppression of hypothalamic-pituitary- adrenal axis with growth retardation and intracranial hypertension (occurring only in children), hyperglycemia, glycosuria, and Cushing’s syndrome. Manifestations of suppression of the above mentioned axis in children include growth retardation, delayed weight gain, lower plasma and urine cortisol concentration and lack of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. Over use or prolonged administration of gentamicin may lead to exacerbation of lesion due to overgrowth of fungi or unsusceptible bacteria. Consequently, appropriate antifungal or antibacterial treatment might be needed. Therapy in case of overdose is symptomatic with usual measures for maintenance of normal body functions. The therapy should be immediately discontinued. The symptoms of withdrawal are very rare (fever, myalgia, arthralgia, weakness). If they do occur, substitute systemic administration of corticosteroids is required. PHARMACOLOGICAL PROPERTIES PHARMACODYNAMİC PROPERTİES As active ingredients, Belogent cream and ointment contain betamethasone in the form of dipropionate and gentamicin in the form of sulphate. Betamethasone, is a synthetically fluorinated adrenocorticosteroid for topical use in dermatology, which has potent anti-inflammatory, immunosuppressive and anti-proliferative effects. It is a synthetic analogue of prednisolone that exhibits high degree of corticosteroid actions with negligible mineralocorticoid effect. The exact mechanism of topical corticosteroid activity is not known, however, it is thought that it is actually a combination of anti-inflammatory, immunosuppressive and anti-proliferative effects, of which the non-specific, anti-inflammatory effect is the most important. Corticosteroids actually reduce the formation, release and activity of chemical mediators of inflammation (quinines, histamines, lyposomal enzymes and prostaglandines). Since for the beginning of an inflammatory response, which is mediated by the above mentioned mediators, presence of leukocytes and macrophages is necessary, corticosteroids also inhibit the migration of cells to the site of injury and reduce vasodilatation and increased permeability of blood vessels in that area. This vasoconstrictive effect decreases extravasation of serum and formation of oedema. Corticosteroids also exhibit immunosuppressive effect on types III and IV hypersensitivity reactions by inhibiting toxic activity of antigen-antibody complex which deposits on the wall of blood vessels, causing allergic skin vasculitis. Corticosteroids also inhibit the activity of lymphokines, the target cells and macrophages which together cause allergic reaction, e.g. occurrence of allergic contact dermatitis. Besides, corticosteroids prevent the access of sensitised T-lymphocytes and macrophages to target cells. Gentamicin is an aminoglycoside antibiotic with marked bactericidal activity. It inhibits protein synthesis in bacteria by binding to a specific receptor protein in 30S subunit of bacterial ribosomes, and interferes with the initial complex between mRNA and 30S subunit, by inhibiting protein synthesis. Erroneous reading of DNA occurs, which results in the formation of non-functional proteins. PHARMACOKİNETİC PROPERTİES The extent of percutaneous absorption of locally administered betamethasone is influenced by many factors, including the vehicle, epidermal condition, and presence of occlusion. Topically applied corticosteroids, can be to a lesser degree, also absorbed through normal, intact skin. However, presence of inflammatory processes on the skin increases the absorption and so does the use of occlusive dressings. Once absorbed through the skin, topically applied corticosteroids exhibit similar pharmacokinetic properties as those administered systemically. Systemic absorption, following local application, is about 12 to 14%. About 64% of betamethasone is reversibly bound to plasma proteins; distribution volume is 1.4 L/kg. Betamethasone is metabolised in the liver, the half-life is 5.6 h and metabolites are primarily excreted in the bile and smaller quantity by the kidneys (only about 5%). Gentamicin is absorbed in insignificant amounts through intact skin; absorption through damaged skin is up to 5%. As is the case with other aminoglycosides, gentamicin poorly binds to plasma proteins and is excreted almost entirely by glomerular filtration. PRECLİNİCAL SAFETY DATA Acute toxicity of orally administered betamethasone was studied in mouse and rats. The observed average lethal doses (LD50) were more than 5 g/kg in mouse and more than 4 g/kg in rats. In trials with mouse who were administered oral gentamicin it was showen that LD50 was more than 11g/kg. During the test for subacute toxicity of gentamicin in dogs, death occurred between sixth and tenth day of intramuscular administration of 66 mg/kg dose of gentamicin.
Multiple administration of betamethasone in doses much higher than the therapeutic ones, no signs of chronic toxicity were observed in cases of percutaneous administration of the drug. Similar observations have been reported for gentamicin. When corticosteroids were systemically administered to laboratory animals, their teratogenic effect was observed already after relatively low doses. More potent corticosteroids exhibited teratogenic effects in laboratory animals even after percutaneous administration. However, teratogenicity of betamethasone, which is also classified among potent corticosteroids, has not been tested in this way. In rabbits treated with intramuscular dose of 0.05 mg/kg of betamethasone dipropionate, teratogenic potential of betamethasone dipropionate was demonstrated. This dose is 26 times higher than the topical human betamethasone-dipropionate dose. Foetal abnormalities include umbilical hernia, cephalocele and cleft palate.
Certain aminoglycosides may cause foetal damages. Tests in rats and rabbits have not
shown teratogenic effects of gentamicin. However, it is well known that gentamicin crosses the placenta; concentrations in foetal serum are similar to those found in the mother.
Information on mutagenic and carcinogenic activity of betamethasone and gentamicin is not available. Results of animal toxicological studies have shown good local tolerance of combination betamethasone and gentamicin.
PHARMACEUTICAL PARTICULARS LİST OF EXCİPİENTS Belogent cream: chlorcresol, sodium dihydrogen phosphate monohydrate, phosphoric acid, macrogol cetostearyl ether, cetostearyl alcohol, liquid paraffin, white soft paraffin, sodium hydroxide and purified water. Belogent ointment: liquid paraffin and white soft paraffin. INCOMPATİBİLİTİES SHELF LİFE Belogent cream: 4 years Belogent ointment: 4 years SPECİAL PRECAUTİONS FOR STORAGE NATURE AND CONTENTS OF CONTAİNER
Aluminium tube containing 15 g, i.e. 30 g of ointment or cream, with polyethylene
INSTRUCTİONS FOR USE AND HANDLİNG - / - NAME AND ADDRESS OF MANUFACTURER BELUPO Pharmaceuticals and Cosmetics Ulica Danica 5 48000 Koprivnica Croatia PRESCRIPTION STATUS AND DISPENSING
Available on prescription, in pharmacies only!
NUMBER AND DATE OF MARKETING AUTHORISATION
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