4.1. Therapeutic indications

Clobetasol propionate is a highly active topical corticosteroid which is of particular value when used in short courses for the treatment of recalcitrant eczemas, neurodermatoses, and other conditions which do not respond satisfactorily to less active steroids.

Clobetasol/neomycin/nystatin Ointment is indicated in more resistant dermatoses such as recalcitrant eczemas and psoriasis (excluding widespread plaque psoriasis) where secondary bacterial or candidal infection is present, suspected or likely to occur, as when using occlusive dressings.

4.2. Posology and method of administration

Clobetasol propionate belongs to the most potent class of topical corticosteroids (Group IV) and prolonged use may result in serious undesirable effects (see section 4.4). If treatment with a local corticosteroid is clinically justified beyond 4 weeks, a less potent corticosteroid preparation should be considered. Repeated but short courses of clobetasol propionate may be used to control exacerbations (see details below).

Posology:

Adults and adolescents

Apply sparingly to the affected area once or twice daily until improvement occurs. As with other highly active topical steroid preparations therapy should be discontinued when control is achieved. In the more responsive conditions this may be within a few days.

In very resistant lesions, especially where there is hyperkeratosis, the anti-inflammatory effects of Clobetasol/neomycin/nystatin Ointment can be enhanced, if necessary, by occluding the treatment area with polythene. Overnight occlusion only is usually adequate to bring about a satisfactory response, thereafter improvement can be usually maintained by application without occlusion.

Treatment should not be continued for more than 7 days without medical supervision. If a longer course is necessary, it is recommended that treatment should not be continued for more than 4 weeks without the patient's condition being reviewed.

Repeat short courses of Clobetasol/neomycin/nystatin Ointment may be used to control exacerbations. If continuous steroid treatment is necessary, a less potent preparation should be used.

The maximum weekly dose should not exceed 50 g/week.

Dosage in Renal Impairment

Dosage should be reduced in patients with reduced renal function (see section 4.4).

Elderly

Clobetasol/neomycin/nystatin Ointment is suitable for use in the elderly. Caution should be exercised in cases where a decrease in renal function exists and significant systemic absorption of neomycin sulfate may occur (see section 4.4). The minimum quantity should be used for the shortest duration to achieve the desired clinical benefit.

Paediatric population

Clobetasol/neomycin/nystatin Ointment is suitable for use in children (2 years and over) at the same dose as adults. A course of treatment for a child should be limited to 5 days and occlusion should not be used. It should be noted that the child's napkin may act as an occlusive dressing. A possibility of increased absorption exists in very young children; thus, this ointment is not recommended for use in neonates and infants (younger than 2 years) (see section 4.3 and 4.4).

Care should be taken when using clobetasol propionate with neomycin sulfate and nystatin to ensure the amount applied is the minimum that provides therapeutic benefit.

Method of administration

For cutaneous use.

4.3. Contraindications

Hypersensitivity to the active substances (clobetasol propionate, neomycin sulfate and nystatin) or any of the excipients listed in section 6.1 (see section 4.8).

Rosacea, acne vulgaris and perioral dermatitis.

Primary cutaneous viral infections (e.g. herpes simplex, chickenpox).

Pruritus without inflammation.

Use of Clobetasol/neomycin/nystatin skin preparations is not indicated in the treatment of primary infected skin lesions caused by infection with fungi (e.g. candidiasis, tinea), bacteria (e.g. impetigo), or yeast; secondary infections due to Pseudomonas or Proteus species; perianal and genital pruritus, dermatoses in children under 2 years of age, including dermatitis and napkin eruptions.

Preparations containing neomycin should not be used for the treatment of otitis externa when the eardrum is perforated, because of the risk of ototoxicity. Due to the known ototoxic and nephrotoxic potential of neomycin sulfate the use of this medicinal product in large quantities or on large areas for prolonged periods is not recommended in circumstances where significant systemic absorption may occur.

A possibility of increased absorption exists in very young children; therefore Clobetasol/neomycin/nystatin Ointment is not recommended for use in neonates and infants (up to 2 years). In neonates and infants, absorption by immature skin may be enhanced, and renal function may be immature.

4.4. Special warnings and precautions for use

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 neomycin, if prolonged or significant diarrhoea occurs or the patient experiences abdominal cramps, treatment should be discontinued immediately, and the patient 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 the above is 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 section 4.8).

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 (nappies 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

Local hypersensitivity

Local hypersensitivity reactions may resemble symptoms of the condition under treatment (see section 4.8). If signs of hypersensitivity appear, application should be stopped immediately.

Paediatric population

In comparison with adults, children 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 bodyweight ratio compared with adults.

Long term continuous topical therapy should be avoided where possible, particularly in infants and children, as adrenal suppression can occur readily even without occlusion.

If used in childhood, or on the face, courses should be limited to 5 days and occlusion should not be used. It should be noted that the child's napkin may act as an occlusive dressing.

Application to the face

Application to the face is undesirable as, more than other areas of the body, this area may exhibit atrophic changes after prolonged treatment with potent topical corticosteroids. If used on the face, treatment should be limited to only a few days. This must be borne in mind when treating such conditions as psoriasis and severe eczema.

Topical steroid withdrawal syndrome

Long term continuous or inappropriate use of topical steroids can result in the development of rebound flares after stopping treatment (topical steroid withdrawal syndrome). A severe form of rebound flare can develop which takes the form of a dermatitis with intense redness, stinging and burning that can spread beyond the initial treatment area. It is more likely to occur when delicate skin sites such as the face and flexures are treated. Should there be a reoccurrence of the condition within days to weeks after successful treatment a withdrawal reaction should be suspected. Reapplication should be with caution and specialist advise is recommended in these cases or other treatment options should be considered.

Application to 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. If the ointment does enter the eye, the affected eye should be bathed in copious amounts of water.

Use in Psoriasis

Topical corticosteroids may be hazardous in psoriasis for a number of reasons, including rebound relapses, development of tolerance, risk of generalized pustular psoriasis and development of local or systemic toxicity due to impaired barrier function of the skin. If used in psoriasis careful patient supervision is important.

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Osteonecrosis, serious infections and immunosuppression

Cases of osteonecrosis serious infections (including necrotizing fasciitis) and systemic immunosuppression (sometimes resulting in reversible Kaposi's sarcoma lesions) have been reported with long-term use of clobetasol propionate beyond the recommended doses (see section 4.2). In some cases patients used concomitantly other potent oral/topical corticosteroids or immunosuppressors (e.g. methotrexate, mycophenolate mofetil). If treatment with local corticosteroids is clinically justified beyond 4 weeks, a less potent corticosteroid preparation should be considered.

Infection

Extension of the infection may occur due to the masking effect of the steroid.

If infection persists, systemic chemotherapy is required. Any spread of infection requires withdrawal of topical corticosteroid therapy.

Infection risk with occlusion

Bacterial infection is encouraged by the warm, moist conditions induced by occlusive dressings, and the skin should be cleansed before a fresh dressing is applied.

Ototoxicity and nephrotoxicity

Following significant systemic absorption, aminoglycosides such as neomycin can cause irreversible ototoxicity; and neomycin has nephrotoxic potential (see section 4.3).

Renal impairment

In renal impairment, the plasma clearance of neomycin is reduced (see section 4.2).

Contact sensitisation

Extended or recurrent application may increase the risk of contact sensitization.

Dilution

Products which contain antimicrobial agents should not be diluted.

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.

Fire hazard in contact with dressings, clothing and bedding

Instruct patients not to smoke or go near naked flames - risk of severe burns. Fabric (clothing, bedding, dressings etc) that has been in contact with this product burns more easily and is a serious fire hazard. Washing clothing and bedding may reduce product build-up but not totally remove it.

The label will state very strong steroid.

4.5. Interaction with other medicinal products and other forms of interaction

CYP3A4 inhibitors

Co-administered drugs that can inhibit CYP3A4 (e.g. ritonavir and itraconazole) have been shown to inhibit the metabolism of corticosteroids leading to increased systemic exposure. The extent to which this interaction is clinically relevant depends on the dose and route of administration of the corticosteroids and the potency of the CYP3A4 inhibitor.

Systemic aminoglycoside therapy

Possibility of cumulative toxicity should be considered when neomycin sulfate is applied topically in combination with systemic aminoglycoside therapy.

Neuromuscular blocking agents

Following significant systemic absorption neomycin sulfate can intensify and prolong the respiratory depressant effects of neuromuscular blocking agents following systemic absorption. However, if used in accordance with the recommendations systemic exposure to neomycin sulfate is expected to be minimal and drug interactions are unlikely to be significant. No hazardous interactions have been reported with the use of clobetasol propionate or nystatin.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are limited data from the use of clobetasol propionate with neomycin sulfate and nystatin in pregnant women.

Topical administration of corticosteroids to pregnant animals can cause abnormalities of foetal development (see section 5.3). The relevance of this finding to humans has not been established.

Breast-feeding

The safe use of clobetasol propionate with neomycin sulfate and nystatin during lactation has not been established. It is not known whether the topical administration of corticosteroids could result in sufficient systemic absorption to product detectable amounts in breast milk. Thus, the use of clobetasol propionate with neomycin sulfate and nystatin is not recommended in lactation.

Fertility

There are no data in humans to evaluate the effect of topical clobetasol propionate with neomycin sulfate and nystatin on fertility.

Clobetasol propionate administered subcutaneously to rats had no effect upon mating performance; however, fertility was decreased at the highest dose (see section 5.3). The relevant of this finding to humans has not been established.

4.7. Effects on ability to drive and use machines

Clobetasol/neomycin/nystatin Ointment has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Adverse drug reactions (ADRs) are listed below by MedDRA system organ class and by frequency. Frequencies are defined as: 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) and not known (cannot be estimated from the available data).

Clinical trial data

Skin and subcutaneous tissue disorders

Common:

Skin atrophy*, telangiectasis*

Uncommon:

Striae*

*Skin features related to hypothalamic-pituitary adrenal (HPA) axis suppression.

Post-marketing data

Infections and infestations

Very rare:

Opportunistic infection

Immune system disorders

Very rare:

Allergic reactions including anaphylaxis and hypersensitivity

Endocrine disorders

Very rare:

Hypothalamic-pituitary adrenal (HPA) axis suppression: 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

Eye disorders

Not known (cannot be estimated from the available data):

Vision, blurred (see also section 4.4)

Skin and subcutaneous tissue disorders

Very rare:

Skin thinning*, skin wrinkling*, skin dryness*, pigmentation changes*, hypertrichosis, exacerbation of underlying symptoms, allergic contact dermatitis/dermatitis, pustular psoriasis (see section 4.4), erythema, rash, urticaria, alopecia*, trichorrhexis*, pruritus, local skin burning/skin pain

Not known:

Withdrawal reactions - redness of the skin which may extend to areas beyond the initial affected area, burning or stinging sensation, itch, skin peeling, oozing pustules. (see section 4.4)

*Skin features related to hypothalamic-pituitary adrenal (HPA) axis suppression.

General disorders and administration site conditions

Very rare:

Application site irritation/pain

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms and signs

Topically applied clobetasol propionate 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 appear (see section 4.4 and 4.8).

Treatment

In the event of chronic overdosage or misuse topical steroids should be withdrawn gradually under medical supervision by reducing the frequency of application or by substituting a less potent corticosteroid because of the risk of adrenal insufficiency.

Also, consideration should be given to significant systemic absorption of neomycin sulfate (see section 4.4 and 4.5). 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 sulfate should also be determined. Haemodialysis may reduce the serum level of neomycin sulfate.

Further management should be as clinically indicated or as recommended by the National Poisons Centre, where available.