Betamethasone-17-valerate, neomycin sulphate.
BETNOVATE-N Cream is a smooth white to off-white cream containing 0.1% w/w betamethasone 17-valerate with 0.5% w/w neomycin sulphate. BETNOVATE-N Cream also contains 0.1% w/w chlorocresol as preservative.
Excipients/Inactive Ingredients: Chlorocresol, Sodium dihydrogen phosphate Dihydrate, Cetomacrogol 1000, Liquid paraffin, Cetostearyl alcohol, White soft paraffin, Phosphoric acid, Sodium hydroxide, Purified water.
Pharmacotherapeutic Group: Corticosteroids, potent, combinations with antibiotics - Betamethasone and antibiotics. ATC Code: D07CC01.
Pharmacology: Pharmacodynamics: Mechanism of action: Topical corticosteroids act as anti-inflammatory agents via multiple mechanisms to inhibit late phase allergic reactions including decreasing the density of mast cells, decreasing chemotaxis and activation of eosinophils, decreasing cytokine production by lymphocytes, monocytes, mast cells and eosinophils, and inhibiting the metabolism of arachidonic acid.
Neomycin interferes with bacterial protein synthesis by binding to 30S ribosomal subunits.
Pharmacodynamic effects: Topical corticosteroids have anti-inflammatory, antipruritic, and vasoconstrictive properties.
Neomycin has a bactericical action against many Gram-negative bacteria but it lacks activity against Pseudomonas aeruginosa. It has partial activity against Gram-positive bacteria. It is used topically in the treatment of infections of the skin, ear, and eye due to susceptible staphylococci and other organisms.
Pharmacokinetics: Absorption: Topical corticosteroids can be systemically absorbed from intact healthy skin. The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the vehicle and the integrity of the epidermal barrier. Occlusion, inflammation and/or other disease processes in the skin may also increase percutaneous absorption.
The use of pharmacodynamic endpoints for assessing the systemic exposure of topical corticosteroids is necessary due to the fact that circulating levels are well below the level of detection.
Absorption of neomycin has been reported to occur from wounds and inflamed skin. It is poorly absorbed from the gastrointestinal tract when administered orally.
Distribution: Absorbed neomycin distributes to tissues and concentrates in the renal cortex.
Metabolism: Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. They are metabolized, primarily in the liver.
Elimination: Topical corticosteroids are excreted by the kidneys. In addition, some corticosteroids and their metabolites are also excreted in the bile.
Absorbed neomycin is rapidly excreted by the kidneys as parent compound. It has been reported to have a half-life of 2 to 3 hours.
Toxicology: Pre-clinical Safety Data: Nonclinical studies have not been conducted with BETNOVATE-N.
Betamethasone valerate and neomycin sulphate individually have been evaluated in animal toxicity tests, and the following statements reflect the information available on the individual components.
Genotoxicity: Neomycin sulphate: Neomycin was negative in the Ames test, HGPRT mutations assay in Chinese hamster ovary (CHO) cells and mouse bone marrow micronucleus test.
Pregnancy: Betamethasone 17-valerate: Subcutaneous administration of betamethasone 17-valerate to mice or rats at doses ≥0.1 mg/kg/day or rabbits at doses ≥12 micrograms/kg/day during pregnancy produced foetal abnormalities including cleft palate.
Betamethasone valerate is a potent topical corticosteroid indicated for the relief of the inflammatory and pruritic manifestations of steroid responsive dermatoses. Neomycin sulphate is an aminoglycoside broad spectrum antibiotic.
Topical preparations combining betamethasone valerate and neomycin sulphate are indicated for the treatment of the following conditions where secondary bacterial infection is present, suspected, or likely to occur: Eczema including atopic infantile and discoid eczemas. Prurigo nodularis. Psoriasis (excluding widespread plaque psoriasis). Neurodermatoses including lichen simplex, lichen planus. Seborrhoeic dermatitis. Contact sensitivity reactions. Insect bites reactions. Betnovate-N preparations can also be used in the management of secondary infected insect bites and anal and genital intertrigo.
Cream: BETNOVATE-N cream is especially appropriate for moist or weeping surfaces.
Adults and adolescents: Apply thinly and gently rub in using enough to cover the entire affected area once or twice daily for up to seven days, then change to another corticosteroid preparation not containing neomycin sulphate if further treatment is required. Allow adequate time for absorption after each application before applying an emollient.
In the more resistant lesions, such as the thickened plaques of psoriasis on elbows and knees, the effect of BETNOVATE-N can be enhanced, if necessary, by occluding the treatment area with polythene film. Overnight occlusion only is usually adequate to bring about a satisfactory response in such lesions, thereafter improvement can usually be maintained by regular application without occlusion.
Treatment should not be continued for more than seven days without medical supervision. If the condition worsens or does not improve within seven days, treatment and diagnosis should be re-evaluated.
Children aged 2 years and over: BETNOVATE-N is suitable for use in children (2 years and over) at the same dose as adults. A possibility of increased absorption exists in very young children, thus BETNOVATE-N is contraindicated in neonates and infants (less than 2 years) (see Contraindications).
Children are more likely to develop local and systemic side effects of topical corticosteroids and, in general, require shorter courses and less potent agents than adults.
Care should be taken when using BETNOVATE-N to ensure the amount applied is the minimum that provides therapeutic benefit.
Elderly: BETNOVATE-N is suitable for use in the elderly. Clinical studies have not identified difference in responses between the elderly and younger patients. The greater frequency of decreased hepatic and renal function in the elderly may delay elimination if systemic absorption occurs. Therefore the minimum quantity should be used for the shortest duration to achieve the desired clinical benefit.
Renal Impairment: Dosage should be reduced in patients with reduced renal function (see Precautions).
Symptoms and Signs: Topically applied BETNOVATE-N may be absorbed in sufficient amounts to produce systemic effects. Acute overdosage is very unlikely to occur, however, in the case of chronic overdosage or misuse the features of hypercortisolism may occur (see Adverse Reactions).
Treatment: In the event of chronic overdose or misuse, topical corticosteroids should be withdrawn gradually by reducing the frequency of application, or by substituting a less potent steroid because of the risk of adrenal insufficiency.
Consideration should also be given to significant systemic absorption of neomycin sulphate (see Precautions). If this is suspected, use of the product should be stopped and the patient's general status, hearing acuity, renal and neuromuscular functions should be monitored.
Blood levels of neomycin sulphate should also be determined. Haemodialysis may reduce the serum level of neomycin sulphate.
Further management should be as clinically indicated or as recommended by the National Poisons Centre, where available.
BETNOVATE-N is contraindicated in children under 2 years of age.
Due to the known ototoxic and nephrotoxic potential of neomycin sulphate, the use of BETNOVATE-N in large quantities or on large areas for prolonged periods of time is contraindicated in circumstances where significant systemic absorption may occur.
The following conditions should not be treated with BETNOVATE-N: Rosacea; Acne vulgaris; Perioral dermatitis; Pruritus without inflammation; Perianal and genital pruritus; Primary cutaneous viral infections; Primary infected skin lesions caused by infection with fungi, or bacteria; Primary or secondary infections due to yeasts; Secondary infections due to Pseudomonas or Proteus species; Otitis externa when the ear drum is perforated, because of the risk of ototoxicity.
Hypersensitivity: BETNOVATE-N should be used with caution in patients with a history of local hypersensitivity to betamethasone, neomycin or to any of the excipients in the preparation. Local hypersensitivity reactions (see Adverse Reactions) may resemble symptoms of the condition under treatment.
Pseudomembranous colitis: Pseudomembranous colitis has been reported with the use of antibiotics and may range in severity from mild to life-threatening. Therefore, it is important to consider its diagnosis in patients who develop diarrhoea during or after antibiotic use. Although this is less likely to occur with topically applied BETNOVATE-N. If prolonged or significant diarrhoea occurs or the patient experiences abdominal cramps, treatment should be discontinued immediately and the patients investigated further.
Reversible hypothalamic-pituitary-adrenal (HPA) axis suppression: Manifestations of hypercortisolism (Cushing's syndrome) and reversible hypothalamic-pituitary-adrenal (HPA) axis suppression can occur in some individuals as a result of increased systemic absorption of topical corticosteroids. If either of the above are observed, withdraw the drug gradually by reducing the frequency of application, or by substituting a less potent corticosteroid. Abrupt withdrawal of treatment may result in glucocorticosteroid insufficiency (see Adverse Reactions).
Risk factors for increased corticosteroidal systemic effects are: Potency and formulation of topical corticosteroid; Duration of exposure; Application to a large surface area; Use on occluded areas of skin (e.g. on intertriginous areas or under occlusive dressings (napkins may act as an occlusive dressing); Increasing hydration of the stratum corneum; Use on thin skin areas such as the face; Use on broken skin or other conditions where the skin barrier may be impaired.
Visual disturbances: Visual disturbance has been reported by patients using systemic and / or topical corticosteroids. If a patient has blurred vision or other visual disturbances, consider evaluation of possible causes which may include cataract, glaucoma or central serous chorioretinopathy.
Dilution: Products which contain antimicrobial agents should not be diluted.
Contact sensitisation: Extended or recurrent application of BETNOVATE-N may increase the risk of contact sensitisation.
Ototoxicity and nephrotoxicity: Following significant systemic absorption, aminoglycosides such as neomycin can cause irreversible ototoxicity. Neomycin has nephrotoxic potential.
Renal impairment: In renal impairment the plasma clearance of neomycin is reduced (see Dosage & Administration).
Application to the face: Prolonged application to the face is undesirable as this area is more susceptible to atrophic changes.
Application to the eyelids: If applied to the eyelids, care is needed to ensure that the preparation does not enter the eye, as cataract and glaucoma might result from repeated exposure.
Infection: Extension of infection may occur due to the masking effect of the steroid. Any spread of infection requires withdrawal of topical corticosteroid therapy and administration of appropriate systemic antimicrobial therapy.
Infection risk with occlusion: Bacterial infection is encouraged by the warm, moist conditions within skin folds or induced by occlusive dressings. When using occlusive dressings, the skin should be cleansed before a fresh dressing is applied.
Chronic leg ulcers: Topical corticosteroids are sometimes used to treat the dermatitis around chronic leg ulcers. However, this use may be associated with a higher occurrence of local hypersensitivity reactions and an increased risk of local infection.
Effects on Ability to Drive and Use Machines: There have been no studies to investigate the effect of BETNOVATE-N on driving performance or the ability to operate machinery. A detrimental effect on such activities would not be anticipated from the adverse reaction profile of topical BETNOVATE-N.
Use in children: In comparison with adults, children and infants may absorb proportionally larger amounts of topical corticosteroids and thus be more susceptible to systemic adverse effects. This is because children have an immature skin barrier and a greater surface area to body weight ratio compared with adults.
In children under 12 years of age, long-term continuous topical corticosteroid therapy should be avoided where possible, as adrenal suppression can occur.
Fertility: There are no data in humans to evaluate the effect of BETNOVATE-N fertility.
Pregnancy: There are limited data from the use of BETNOVATE-N in pregnant women.
Topical administration of corticosteroids to pregnant animals can cause abnormalities of foetal development (see Pharmacology: Toxicology: Pre-clinical safety data under Actions). The relevance of this finding to humans has not been established.
However, neomycin present in maternal blood can cross the placenta and may give rise to a theoretical risk of foetal toxicity (see Pharmacology: Toxicology: Pre-clinical safety data under Actions). Thus use of BETNOVATE-N is not recommended in pregnancy.
Lactation: The safe use of BETNOVATE-N during lactation has not been established.
It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable amounts in breast milk. Thus use of BETNOVATE-N is not recommended in lactation.
Clinical Trial and Post-marketing Data:
Adverse drug reactions (ADRs) are listed as follows by MedDRA system organ class and by frequency. Frequencies are defined as: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1,000 and <1/100), rare (≥1/10,000 and <1/1,000) and very rare (<1/10,000), including isolated reports.
Infections and Infestations:
Very rare: Opportunistic infection.
Immune System Disorders:
Very rare: Local hypersensitivity.
Very rare: Hypothalamic-pituitary adrenal (HPA) axis suppression: (see also Skin and Subcutaneous Tissue Disorders as follows) Cushingoid features (e.g. moon face, central obesity), delayed weight gain/growth retardation in children, osteoporosis, glaucoma, hyperglycaemia/glucosuria, cataract, hypertension, increased weight/obesity, decreased endogenous cortisol levels.
Skin and Subcutaneous Tissue Disorders:
Common: Pruritus, local skin burning/pain of skin. Very rare: Allergic contact dermatitis/dermatitis, erythema, rash, urticaria, pustular psoriasis, skin thinning* / skin atrophy* skin wrinkling*, skin dryness*, striae*, telangiectasias*, pigmentation changes*, hypertrichosis, exacerbation of underlying symptoms, alopecia*. trichorrhexis*.
General Disorders and Administration Site Conditions:
Very rare: Application site irritation/pain.
*Skin features of hypothalamic-pituitary-adrenal (HPA) axis suppression.
Co-administered drugs that can inhibit CYP3A4 (e.g. ritonavir, itraconazole) have been shown to inhibit the metabolism of corticosteroids and the potency of the CYP3A4 inhibitor. The extent to which this interaction is clinically relevant depends on the dose and route of administatrion of the corticosteroids and the potency of the CYP3A4 inhibitor.
Following significant systemic absorption, neomycin sulphate can intensify and prolong the respiratory depressant effects of neuromuscular blocking agents.
Possibility of cumulative toxicity should be considered when neomycin is applied topically in combination with systemic aminoglycoside therapy.
Instructions for Use/Handling: Do not dilute.
D07CC01 - betamethasone and antibiotics ; Belongs to the class of potent (group III) corticosteroids, in combination with antibiotics. Used in the treatment of dermatological diseases.
Cream (smooth white to off-white) x 15 g.