Xamiol 50 microgram/g + 0.5 mg/g gel

One gram of gel contains 50 microgram of calcipotriol (as monohydrate) and 0.5 mg of betamethasone (as dipropionate).

Excipient: 160 microgram butylated hydroxytoluene/g gel.

For a full list of excipients, see section 6.1.

Gel.

An almost clear, colourless to slightly off-white gel.

Topical treatment of scalp psoriasis.

Xamiol gel should be applied to affected areas of the scalp once daily. The recommended treatment period is 4 weeks. After this period repeated treatment with Xamiol gel can be initiated under medical supervision.

All the affected scalp areas may be treated with Xamiol gel. Usually an amount between 1 g and 4 g per day is sufficient for treatment of the scalp (4g corresponds to one teaspoon).

When using calcipotriol containing products, the maximum daily dose should not exceed 15 g, and the maximum weekly dose should not exceed 100 g. The body surface area treated with calcipotriol containing products should not exceed 30% (see section 4.4).

Shake the bottle before use. In order to achieve optimal effect, it is recommended that the hair is not washed immediately after application of Xamiol gel. Xamiol gel should remain on the scalp during the night or during the day.

Paediatric patients:

Xamiol gel is not recommended for use in children below 18 years due to lack of data on safety and efficacy.

Hypersensitivity to the active substances or to any of the excipients.

Due to the content of calcipotriol, Xamiol gel is contraindicated in patients with known disorders of calcium metabolism.

Due to the content of corticosteroid, Xamiol gel is contraindicated in the following conditions: Viral (e.g. herpes or varicella) lesions of the skin, fungal or bacterial skin infections, parasitic infections, skin manifestations in relation to tuberculosis or syphilis, perioral dermatitis, atrophic skin, striae atrophicae, fragility of skin veins, ichthyosis, acne vulgaris, acne rosacea, rosacea, ulcers and wounds.

Xamiol gel is contraindicated in guttate, erythrodermic, exfoliative and pustular psoriasis.

Xamiol gel is contraindicated in patients with severe renal insufficiency or severe hepatic disorders.

Xamiol gel contains a potent group III steroid and concurrent treatment with other steroids on the scalp must be avoided. Adverse effects found in connection with systemic corticosteroid treatment, such as adrenocortical suppression or impact on the metabolic control of diabetes mellitus, may occur also during topical corticosteroid treatment due to systemic absorption. Application under occlusive dressings should be avoided since it increases the systemic absorption of corticosteroids.

In a study in patients with both extensive scalp and extensive body psoriasis using a combination of high doses of Xamiol gel (scalp application) and high doses of Dovobet ointment (body application), 5 of 32 patients showed a borderline decrease in cortisol response to adrenocorticotropic hormone (ACTH) challenge after 4 weeks of treatment (see section 5.1).

Due to the content of calcipotriol, hypercalcaemia may occur if the maximum weekly dose (100 g) is exceeded. Serum calcium is, however, quickly normalised when treatment is discontinued. The risk of hypercalcaemia is minimal when the recommendations relevant to calcipotriol are followed.

Efficacy and safety of use of this product on areas other than the scalp have not been established. Treatment of more than 30% of the body surface should be avoided (see section 4.2). Application on large areas of damaged skin or on mucous membranes or in skin folds should be avoided since it increases the systemic absorption of corticosteroids (see section 4.8). Skin of the face and genitals are very sensitive to corticosteroids. These areas should only be treated with weaker corticosteroids. Uncommon local adverse reactions (such as eye irritation or irritation of facial skin) were observed, when the drug was accidentally administered in the area of face, or accidentally to the eyes or conjunctives (see sections 4.8 and 5.1). The patient must be instructed in correct use of the product to avoid application and accidental transfer to the face, mouth and eyes. Hands must be washed after each application to avoid accidental transfer to these areas.

When lesions become secondarily infected, they should be treated with antimicrobiological therapy. However, if infection worsens, treatment with corticosteroids should be stopped.

When treating psoriasis with topical corticosteroids, there may be a risk of generalised pustular psoriasis or of rebound effects when discontinuing treatment. Medical supervision should therefore continue in the post-treatment period.

With long-term use there is an increased risk of local and systemic corticosteroid undesirable effects. The treatment should be discontinued in case of undesirable effects related to long-term use of corticosteroid (see section 4.8).

There is no experience with concurrent use of other anti-psoriatic products administered systemically or with phototherapy.

During Xamiol gel treatment, physicians are recommended to advise patients to limit or avoid excessive exposure to either natural or artificial sunlight. Topical calcipotriol should be used with UVR only if the physician and patient consider that the potential benefits outweigh the potential risks (see section 5.3).

Xamiol gel contains butylated hydroxytoluene (E321), which may cause local skin reactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes.

No interaction studies have been performed.

Pregnancy

There are no adequate data from the use of Xamiol gel in pregnant women. Studies in animals with glucocorticoids have shown reproductive toxicity (see section 5.3), but a number of epidemiological studies have not revealed congenital anomalies among infants born to women treated with corticosteroids during pregnancy. The potential risk for humans is uncertain. Therefore, during pregnancy, Xamiol gel should only be used when the potential benefit justifies the potential risk.

Lactation

Betamethasone passes into breast milk, but risk of an adverse effect on the infant seems unlikely with therapeutic doses. There are no data on the excretion of calcipotriol in breast milk. Caution should be exercised when prescribing Xamiol gel to women who breast-feed.

Xamiol gel has no influence on the ability to drive and use machines.

The following terminologies have been used in order to classify the frequencies of adverse drug reactions:

Not known (cannot be estimated from the available data)

The clinical trial programme for Xamiol gel has so far included more than 4,400 patients of whom more than 1,900 were treated with Xamiol gel. Approximately 8% of patients treated with Xamiol gel experienced a non-serious adverse drug reaction.

Based on data from clinical trials the only known common adverse drug reaction is pruritus. Uncommon adverse drug reactions are burning sensation of skin, skin pain or irritation, folliculitis, dermatitis, erythema, acne, dry skin, exacerbation of psoriasis, rash, pustular rash, and eye irritation. These adverse drug reactions were all non-serious local reactions.

The adverse drug reactions are listed by MedDRA SOC, and the individual adverse drug reactions are listed starting with the most frequently reported.

•Eye disorders

•Skin and subcutaneous tissue disorders

Adverse drug reactions observed for calcipotriol and betamethasone, respectively:

Calcipotriol

Adverse drug reactions include application site reactions, pruritus, skin irritation, burning and stinging sensation, dry skin, erythema, rash, dermatitis, eczema, psoriasis aggravated, photosensitivity and hypersensitivity reactions including very rare cases of angioedema and facial oedema. Systemic effects after topical use may appear very rarely causing hypercalcaemia or hypercalciuria (see section 4.4).

Betamethasone (as dipropionate)

Local reactions can occur after topical use, especially during prolonged application, including skin atrophy, telangiectasia, striae, folliculitis, hypertrichosis, perioral dermatitis, allergic contact dermatitis, depigmentation and colloid milia. When treating psoriasis, there may be a risk of generalised pustular psoriasis.

Systemic effects due to topical use of corticosteroids are rare in adults, however, they can be severe. Adrenocortical suppression, cataract, infections and increase of intra-ocular pressure can occur, especially after long-term treatment. Systemic effects occur more frequently when applied under occlusion (plastic, skin folds), when applied on large areas and during long-term treatment (see section 4.4).

Use above the recommended dose may cause elevated serum calcium which should rapidly subside when treatment is discontinued.

Excessive prolonged use of topical corticosteroids may suppress the pituitary-adrenal functions, resulting in secondary adrenal insufficiency which is usually reversible. In such cases, symptomatic treatment is indicated.

In case of chronic toxicity, the corticosteroid treatment must be discontinued gradually.

It has been reported that due to misuse one patient with extensive erythrodermic psoriasis treated with 240 g of Dovobet ointment weekly (maximum dose 100 g weekly) for 5 months developed Cushing's syndrome and pustular psoriasis after abruptly stopping treatment.

Pharmacotherapeutic group: Other antipsoriatics for topical use, Calcipotriol, combinations

ATC Code: D05AX52

Calcipotriol is a vitamin D analogue. In vitro data suggest that calcipotriol induces differentiation and suppresses proliferation of keratinocytes. This is the proposed basis for its effect in psoriasis.

Like other topical corticosteroids, betamethasone dipropionate has anti-inflammatory, antipruritic, vasoconstrictive and immunosuppresive properties, however, without curing the underlying condition. Through occlusion the effect can be enhanced due to increased penetration of the stratum corneum. The incidence of adverse events will increase because of this. In general, the mechanism of the anti-inflammatory activity of the topical steroids is unclear.

Adrenal response to ACTH was determined by measuring serum cortisol levels in patients with both extensive scalp and body psoriasis, using up to 106 g per week combined Xamiol gel and Dovobet ointment. A borderline decrease in cortisol response at 30 minutes post ACTH challenge was seen in 5 of 32 patients (15.6%) after 4 weeks of treatment and in 2 of 11 patients (18.2%) who continued treatment until 8 weeks. In all cases, the serum cortisol levels were normal at 60 minutes post ACTH challenge. There was no evidence of change of calcium metabolism observed in these patients.

The efficacy of once daily use of Xamiol gel was investigated in two randomised, double-blind, 8-week clinical studies including a total of more than 2,900 patients with scalp psoriasis of at least mild severity according to the Investigator's Global Assessment of disease severity (IGA). Comparators were betamethasone dipropionate in the gel vehicle, calcipotriol in the gel vehicle and (in one of the studies) the gel vehicle alone, all used once daily. Results for the primary response criterion (absent or very mild disease according to the IGA at week 8) showed that Xamiol gel was statistically significantly more effective than the comparators. Results for speed of onset based on similar data at week 2 also showed Xamiol gel to be statistically significantly more effective than the comparators.

¹ Statistically significantly less effective than Xamiol gel (P<0.001)

Another randomised, investigator-blinded clinical study including 312 patients with scalp psoriasis of at least moderate severity according to the IGA investigated use of Xamiol gel once daily compared with Dovonex Scalp solution twice daily for up to 8 weeks. Results for the primary response criterion (absent or very mild disease according to the IGA at week 8) showed that Xamiol gel was statistically significantly more effective than Dovonex Scalp solution.

¹ Statistically significantly less effective than Xamiol gel (P<0.001)

A randomised, double-blind long-term clinical study including 873 patients with scalp psoriasis of at least moderate severity (according to the IGA) investigated the use of Xamiol gel compared with calcipotriol in the gel vehicle. Both treatments were applied once daily, intermittently as required, for up to 52 weeks. Adverse events possibly related to long-term use of corticosteroids on the scalp, were identified by an independent, blinded panel of dermatologists. There was no difference in the percentages of patients experiencing such adverse events between the treatment groups (2.6% in the Xamiol gel group and 3.0% in the calcipotriol group; P=0.73). No cases of skin atrophy were reported.

The systemic exposure to calcipotriol and betamethasone dipropionate from topically applied Xamiol gel is comparable to Dovobet ointment in rats and minipigs. Clinical studies with radiolabelled ointment indicate that the systemic absorption of calcipotriol and betamethasone from Dovobet ointment formulation is less than 1% of the dose (2.5 g) when applied to normal skin (625 cm²) for 12 hours. Application to psoriasis plaques and under occlusive dressings may increase the absorption of topical corticosteroids.

Following systemic exposure, both active ingredients – calcipotriol and betamethasone dipropionate – are rapidly and extensively metabolised. The main route of excretion of calcipotriol is via faeces (rats and minipigs) and for betamethasone dipropionate it is via urine (rats and mice). In rats, tissue distribution studies with radiolabelled calcipotriol and betamethasone dipropionate, respectively, showed that the kidney and liver had the highest level of radioactivity.

Calcipotriol and betamethasone dipropionate were below the lower limit of quantification in all blood samples of 34 patients treated for 4 or 8 weeks with both Xamiol gel and Dovobet ointment for extensive psoriasis involving the body and scalp. One metabolite of calcipotriol and one metabolite of betamethasone dipropionate were quantifiable in some of the patients.

Studies of corticosteroids in animals have shown reproductive toxicity (cleft palate, skeletal malformations). In reproduction toxicity studies with long-term oral administration of corticosteroids to rats, prolonged gestation and prolonged and difficult labour were detected. Moreover, reduction in offspring survival, body weight and body weight gain was observed. There was no impairment of fertility. The relevance for humans is unknown.

A dermal carcinogenicity study with calcipotriol in mice revealed no special hazard to humans.

In a photo(co)carcinogenicity study, albino hairless mice were repeatedly exposed to both UVR and dermally administered calcipotriol solution for 40 weeks at dose levels corresponding to 9, 30 and 90 µg/m²/day (equivalent to 0.25, 0.84, 2.5 times the maximum recommended daily dose for a 60 kg adult, respectively). A reduction in the time required for UVR to induce the formation of skin tumours was observed (statistically significant in males only), suggesting that calcipotriol may enhance the effect of UVR to induce skin tumours. In a supplementary study, mice of the same strain were treated repeatedly with either calcipotriol solution or calcipotriol/ betamethasone gel, followed by irradiation with UVR and measurement of recognised cellular indicators of skin photocarcinogenicity. This study showed a similar enhancing effect of calcipotriol alone on the photobiological response of the skin but indicated no effect of the calcipotriol/betamethasone combination. The clinical relevance of these findings is unknown.

No carcinogenicity or photocarcinogenicity studies have been performed with betamethasone dipropionate.

In local tolerability studies in rabbits, Xamiol gel caused mild to moderate skin irritation and a slight transient irritation of the eye.

Paraffin, liquid

Polyoxypropylene-15 stearyl ether

Castor oil, hydrogenated

Butylhydroxytoluene (E321)

All-rac-α-tocopherol

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

2 years.

After first opening: 3 months.

Do not refrigerate. Keep the bottle in the outer carton in order to protect from light.

High-density polyethylene bottles with low-density polyethylene nozzle and a high-density polyethylene screw cap. The bottles are placed in cartons.

Pack sizes: 15, 30, 60 and 2 x 60 g.

Not all pack sizes may be marketed.

Any unused product or waste material should be disposed of in accordance with local requirements.

LEO Pharmaceutical Products Ltd. A/S

Industriparken 55

DK-2750 Ballerup

Denmark

PL 05293/0006

25/09/2008

25/09/2008