This information is intended for use by health professionals

1. Name of the medicinal product

Audavate 0.1% w/w Cream

2. Qualitative and quantitative composition

One gram of cream contains 1 mg of betamethasone (0.1% w/w) as valerate.

Excipients with known effect:

One gram of cream also contains 72 mg of cetostearyl alcohol and 1 mg of chlorocresol.

For a full list of excipients, see section 6.1.

3. Pharmaceutical form

Cream

White to almost white cream.

4. Clinical particulars
4.1 Therapeutic indications

Audavate 0.1% cream is indicated; adults, the elderly and children over 1 year of age, for the treatment of corticosteroidresponsive dermatoses including: atopic and discoid eczemas; prurigo nodularis; psoriasis (excluding widespread plaque psoriasis); neurodermatoses, including lichen simplex, lichen planus; seborrhoeic dermatitis; contact sensitivity reactions; discoid lupus erythematosus and they may be used as an adjunct to systemic steroid therapy in generalised erythroderma; insect bite reactions.

Audavate cream is most suitable in the case of moist or weeping lesions whereas an ointment preparation may be more appropriate for dry, lichenified or scaly skin conditions.

4.2 Posology and method of administration

For topical, cutaneous use only.

Apply thinly and gently rub in using only enough to cover the entire affected area once or twice daily for up to 4 weeks (up to 5 days only, in children) until improvement occurs. Once control of the condition has been achieved, treatment should be tapered off gradually by reducing the frequency of application and/or changing to a lower strength formulation such as Audavate 0.025% Cream, or a less potent corticosteroid.

If no improvement is seen after two to four weeks, the diagnosis should be reconsidered and specialist referral may be necessary. Long term, continuous treatment with Audavate 0.1% Cream should be avoided (see Section 4.4).

In adults with more recalcitrant lesions, such as thickened plaques of psoriasis on elbows and knees, the effect of Audavate 0.1% Cream can be enhanced, if necessary, by occluding the treatment area with polythene film, overnight; thereafter, improvement can usually be maintained without occlusion.

Audavate 0.1% Cream can be combined with routine daily use of emollients but adequate time (at least 30 minutes) should be allowed for penetration of the corticosteroid into the skin, before application of the emollient.

Paediatric population

Betamethasone valerate is contraindicated in children under one year of age.

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; therefore, courses should be limited to five days. Occlusion should not be used.

Care should be taken when using betamethasone valerate to ensure the amount applied is the minimum that provides therapeutic benefit.

Elderly

Clinical studies have not identified differences in responses between the elderly and younger patients. The greater frequency of decreased hepatic or 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 / Hepatic Impairment

In case of systemic absorption (when application is over a large surface area for a prolonged period) metabolism and elimination may be delayed therefore increasing the risk of systemic toxicity. Therefore the minimum quantity should be used for the shortest duration to achieve the desired clinical benefit.

Rebound of pre-existing dermatoses can occur with abrupt discontinuation of betamethasone valerate.

Recalcitrant dermatoses

Patients who frequently relapse

Once an acute episode has been treated effectively with a continuous course of topical corticosteroid, intermittent dosing (apply once a day twice a week without occlusion) may be considered. This has been shown to be helpful in reducing the frequency of relapse.

Application should be continued to all previously affected sites or to known sites of potential relapse. This regimen should be combined with routine daily use of emollients. The condition and the benefits and risks of continued treatment must be re-evaluated on a regular basis.

4.3 Contraindications

Rosacea, acne vulgaris, pruritus without inflammation, perioral dermatitis and use in widespread plaque psoriasis. Primary cutaneous viral infections (e.g. herpes simplex, chickenpox). Hypersensitivity to any component of the preparation.

The use of Audavate skin preparations is not indicated in the treatment of primarily infected skin lesions caused by infections with fungi (e.g. candidiasis, tinea); or bacteria (e.g. impetigo); primary or secondary infections due to yeast; peri-anal and genital pruritus; dermatoses in children under 1 year of age, including dermatitis and napkin eruptions.

4.4 Special warnings and precautions for use

Long-term continuous topical therapy should be avoided where possible, particularly in infants and children, as adrenal suppression, with or without clinical features of Cushing's syndrome and reversible hypothalamic-pituitary-adrenal (HPA) axis, can occur even without occlusion. In this situation, topical steroids should be discontinued gradually under medical supervision by reducing the frequency of application, or by substituting a less potent corticosteroid because of the risk of adrenal insufficiency (see section 4.8 Undesirable Effects and Section 4.9 Overdose).

Risk factors for increased systemic effects are:

o Potency and formulation of topical steroid

o Duration of exposure

o Application to a large surface area

o Use on occluded areas of skin e.g. on intertriginous areas or under occlusive dressings (in infants the nappy may act as an occlusive dressing)

o Increasing hydration of the stratum corneum

o Use on thin skin areas such as the face

o Use on broken skin or other conditions where the skin barrier may be impaired

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 body weight ratio compared with adults.

The face, more than other areas of the body, may exhibit atrophic changes after prolonged treatment with potent topical corticosteroids. This must be borne in mind when treating such conditions as psoriasis, discoid lupus erythematosus and severe eczema. Therefore, treatment courses should be limited to five days and occlusion should not be used. If applied to the eyelids, care is needed to ensure that the preparation does not enter the eye, as glaucoma and cataract might result from repeated exposure.

If used in childhood, or on the face, courses should be limited to five days and occlusion should not be used.

Topical corticosteroids may be hazardous in psoriasis for a number of reasons including rebound relapses, development of tolerance, risk of generalised 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.

Appropriate antimicrobial therapy should be used whenever treating inflammatory lesions which have become infected. Any spread of infection requires withdrawal of topical corticosteroid therapy and systemic administration of antimicrobial agents. Bacterial infection is encouraged by the warm, moist conditions within skin folds or caused by induced by occlusive dressings, and so the skin should be cleansed before a fresh dressing is applied.

In rare instances, treatment of psoriasis with corticosteroids (or its withdrawal) is thought to have provoked the pustular form of the disease. Betamethasone valerate should be used with caution in patients with a history of local hypersensitivity to other corticosteroids. Audavate RD is usually well tolerated but if signs of hypersensitivity appear, application should stop immediately. Local hypersensitivity reactions (see section 4.8) may resemble symptoms of the condition under treatment.Exacerbation of symptoms may occur.

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.

There have been a few reports in the literature of the development of cataracts in patients who have been using corticosteroids for prolonged periods of time. Although it is not possible to rule out systemic corticosteroids as a known factor, prescribers should be aware of the possible role of corticosteroids in cataract development.

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.

Healthcare professionals should be aware that if this product comes into contact with dressings, clothing and bedding, the fabric can be easily ignited with a naked flame. Patients should be warned of this risk and advised to keep away from fire when using this product.

Audavate RD Cream contains cetostearyl alcohol which can cause local skin reactions (e.g. contact dermatitis) and chlorocresol which may cause allergic reactions.

4.5 Interaction with other medicinal products and other forms of interaction

Co-administered drugs that can inhibit CYP3A4 (e.g. ritonavir, 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.

4.6 Pregnancy and lactation

Avoid extensive use in pregnancy. There is inadequate evidence of safety. Topical administration of corticosteroids to pregnant animals can cause abnormalities of fetal development including cleft palate and intrauterine growth retardation. There might therefore be a very small risk of such effects in the human fetus. Administration of Betamethasone valerate during pregnancy should only be considered if the expected benefit to the mother outweighs the risk to the fetus. The minimum quantity should be used for the minimum duration.

This product should not be used during pregnancy or lactation unless considered essential by the physician.

Lactation

The safe use of topical corticosteroids 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. Administration of betamethasone valerate during lactation should only be considered if the expected benefit to the mother outweighs the risk to the infant. If used during lactation betamethasone valerate should not be applied to the breasts to avoid accidental ingestion by the infant.

4.7 Effects on ability to drive and use machines

There have been no studies to investigate the effect of betamethasone valerate 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 betamethasone valerate.

4.8 Undesirable effects

Adverse events are listed below by MeDRA system organ class and frequency. Frequencies are defined as: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000) and very rare (<1/10,000) including isolated reports. Very common, common and uncommon events were generally determined from clinical trial data. The background rates in placebo and comparator groups were not taken into account when assigning frequency categories to adverse events derived from clinical trial data, since these rates were generally comparable to those in the active treatment group. Rare and very rare events were generally determined from spontaneous data.

Infections and Infestations

Very rare: Opportunistic infection

Immune system disorders

Very rare: Hypersensitivity, generalised rash

If signs of hypersensitivity appear, application should be stopped immediately.

Endocrine disorders

Very rare: Features of Cushing's syndrome.

Delayed weight gain/growth retardation in children, osteoporosis, glaucoma, hyperglycaemia/glucosuria, cataract, hypertension, increased weight/obesity, decreased endogenous cortisol levels, alopecia, trichorrhexis

As with other topical corticosteroids, prolonged use of large amounts or treatment of extensive areas can result in sufficient systemic absorption to produce suppression of the HPA axis and the clinical features of Cushing's syndrome (see Section 4.4 Special Warnings and Precautions for use). These effects are more likely to occur in infants and children, and if occlusive dressings are used. In infants the napkin may act as an occlusive dressing.

Ophthalmic disorders

Frequency not known: Vision, blurred (see also section 4.4)

Skin and subcutaneous tissue disorders

Common: Local skin burning/skin pain and pruritus.

Very rare: erythema, rash, urticaria, local atrophic changes in the skin such as thinning*, skin wrinkling*, skin dryness*, striae* and dilatation of the superficial blood vessels (telangiectasias)* may be caused by prolonged and intensive treatment with highly active corticosteroid preparations, particularly when occlusive dressings are used or when skin folds are involved.

Pigmentation changes, hypertrichosis, allergic contact dermatitis, exacerbation of symptoms, pustular psoriasis (due to treatment of psoriasis with corticosteroids or its withdrawal: see Section 4.4. Special Warnings and Precautions for use)

General Disorders and Administration Site Conditions

Very rare: Application site irritation/pain

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

Reporting of suspected 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.

4.9 Overdose

Acute overdosage is very unlikely to occur. However, in the case of chronic overdosage or misuse the features of Cushing's syndrome may appear and in this situation topical steroids should be discontinued gradually under medical supervision (see Section 4.4 Special Warnings and Precautions for use).

Treatment

In the event of overdose, betamethasone valerate should be withdrawn gradually by reducing the frequency of application, or by substituting a less potent corticosteroid because of the risk of glucocorticosteroid insufficiency.

Further management should be as clinically indicated or as recommended by the national poisons centre, where available.

5. Pharmacological properties
5.1 Pharmacodynamic properties

ATC Code: D07 AC01 (Corticosteroid, potent,(group III))

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.

Betamethasone is a corticosteroid with topical anti-inflammatory, antipruritic and vasoconstrictive properties.

5.2 Pharmacokinetic properties

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.

Distribution

The use of pharmacodynamic endpoints for assessing the systemic exposure of topical corticosteroids is necessary because circulating levels are well below the level of detection.

Metabolism

Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. They are metabolised, 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.

5.3 Preclinical safety data

Subcutaneous administration of betamethasone valerate to mice or rats at doses ≥0.1mg/kg/day or rabbits at doses ≥12 micrograms/kg/day during pregnancy produced fetal abnormalities including cleft palate and intrauterine growth retardation.

The effect on fertility of betamethasone valerate has not been evaluated in animals.

6. Pharmaceutical particulars
6.1 List of excipients

Liquid paraffin

White soft paraffin

Macrogol cetostearyl ether 20

Cetostearyl alcohol

Chlorocresol

Sodium dihydrogen phosphate dihydrate

Phosphoric acid 10%

Sodium hydroxide 50%

Purified water

6.2 Incompatibilities

None known.

6.3 Shelf life

24 months.

In-use shelf life: 3 months.

6.4 Special precautions for storage

Do not store above 30°C

6.5 Nature and contents of container

Collapsible aluminium tubes internally coated with an epoxy resin-based lacquer and closed with a polypropylene cap.

Pack sizes: 30g, 100g

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special instructions.

7. Marketing authorisation holder

Actavis Group PTC ehf

Reykjavikurvegur 76-78

Hafnarfjordur

IS-220

Iceland

8. Marketing authorisation number(s)

PL 30306/0721

9. Date of first authorisation/renewal of the authorisation

28/04/2017

10. Date of revision of the text

1st August 2017