XAMIOL

עעבקנהזןולעטמרופ " רשואוקדבנונכותותואירבהדרשמי

XAMIOL ®

Physician's insert.

1. NAME OF THE MEDICINAL PRODUCT

Xamiol

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One gram of gel contains 50 microgram ofcalcipotriol (as hydrate) 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.

3. PHARMACEUTICAL FORM

Gel.

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

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Topical treatment of psoriasis vulgaris onthe scalp and topical treatment of mild to

moderate “non-scalp” plaque psoriasis vulgaris in adults 18 years of age and older.

4.2 Posologyand method of administration

Posology

Xamiol gel should be applied to affected areas once daily. The recommended treatment

period is 4 weeks for scalp areas and 8 weeks for “non-scalp” areas. If it is necessary to

continue or restart treatment after this period, treatment should be continued after medical

review and under regular medical supervision.

When using calcipotriol containing products,the maximum daily dose should not exceed

15 g. The body surface area treated with calcipotriol containing products should not

exceed 30% (see section 4.4).

If used on the scalp

All the affected scalp areas may be treatedwith Xamiol. Usually an amount between 1 g

and 4 g per day is sufficient for treatment ofthe scalp (4 g corresponds to one teaspoon).

Special populations

Renal and hepatic impairment

The safety and efficacy of Xamiol gel in patients with severe renal insufficiency or severe

hepatic disorders have not been evaluated.

Paediatric population

The safety and efficacy of Xamiol gel in children below 18 years have not been

established. No data are available.

Method of administration

The bottle should be shaken before use and Xamiol gel applied to the affected area.

Xamiol gel should not be applied directly to the face or eyes. The hands should be washed

after use. In order to achieve optimal effect, it is recommended not to take a shower or a

bath, or to wash the hair in case of scalpapplication, immediately after application of

Xamiol gel. Xamiol gel should remain on the skin during the night or during the day.

4.3 Contraindications

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

Xamiol is contraindicated in erythrodermic, exfoliative and pustular psoriasis.

Due to the content of calcipotriol, Xamiolgel 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 , wounds, perianal and genital pruritus.

4.4 Special warnings and special precautions for use

Effects on endocrine system

Xamiol gel contains a potent groupIIIsteroid and concurrent treatment with other steroids

must be avoided. Adverse reactions found inconnection with systemic corticosteroid

treatment, such as adrenocortical suppressionor 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. 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).

In a study in patients with both extensivescalp and extensive body psoriasis using a

combination of high doses of Xamiol gel (scalp application) and high doses of Daivobet

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).

Effects on calcium metabolism

Due to the content of calcipotriol, hypercalcaemia may occur if the maximum daily dose

(15 g) is exceeded. Serum calcium is, however, quickly normalised when treatment is

discontinued. The risk of hypercalcaemia isminimal when the recommendations relevant

to calcipotriol are followed.

Treatment of more than 30% of the bodysurface should be avoided (see section 4.2).

Local adverse reactions

Skin of the face and genitals are very sensitive to corticosteroids. The medicinal product

should not be used in these areas. Uncommon local adverse reactions (such as eye

irritation or irritation offacial skin) were observed, when the medicinal product 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 beinstructed in correct use of the medicinal

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.

Concomitant skin infections

When lesions become secondarily infected, theyshould be treated with antimicrobiological

therapy. However, if infection worsens, treatment with corticosteroids should be stopped.

Dicontinuation of treatment

When treating psoriasis with topical corticosteroids, there may be a risk of generalised

pustular psoriasis or of rebound effects whendiscontinuing treatment. Medical supervision

should therefore continue inthe post-treatment period.

Long-term use

With long-term use there is an increased risk oflocal and systemic corticosteroid adverse

reactions. The treatment should be discontinued incase of adverse reactions related to

long-term use of corticosteroid (see section 4.8).

Unevaluated uses

There is no experience for the use of Xamiol gel in guttate psoriasis

Concurrent treatment and UV exposure

Daivobet ointment for body psoriasis lesionshas been used in combination with Xamiol gel

for scalp psoriasis lesions, but there is noexperience of Xamiol with other topical anti-

psoriatic products at the same treatment area, other anti-psoriatic medicinal products

administered systemicallyor with phototherapy.

During Xamiol gel treatment, physicians arerecommended 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).

Adverse reactions to excipients

Xamiol gel contains butylated hydroxytoluene (E321), which may cause local skin

reactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes.

4.5 Interaction with othermedicaments or other forms of interaction

No interaction studies have been performed.

4.6 Pregnancy and lactation

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 notrevealed 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.

Breastfeeding

Betamethasone passes into breast milk, but riskof an adverse effect on the infant seems

unlikely with therapeutic doses. There are no data on the excretionof calcipotriol in breast

milk. Caution should be exercised when prescribing Xamiol gel to women who breast-feed.

The patient should be instructed not to use Xamiol on the breast when breast-feeding.

Fertility

Studies in rats with oral doses of calcipotriol or betamethasonedipropionate demonstrated

no impairment of male and female fertility.

4.7 Effects on abilityto drive and use machines

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

4.8 Undesirable effects

The clinical trial programme for Xamiolgel has so far included more than 4,700

patients of whom more than 2,100 were treated with Xamiol gel. Approximately 8% of

patients treated with Xamiol gel experienced a non-serious adverse drug reaction.

These reactions are usually mild and cover mainly various skin reactions with pruritus

being the most common.

Based on data from clinical trials and postmarket use the following adverse reactions

are listed for Xamiol gel.

The adverse reactions are listed by MedDRA System Organ Class, and the individual

adverse reactions are listed starting with the most frequently reported. Within each

frequency grouping, the adverse reactionsare listed in order of decreasing

seriousness.

The following terminologies have been used in order to classify the frequencies of

adverse reactions:

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

Very rare <1/10,000

Not known (cannot be estimated from the available data)

Eye disorders

Uncommon:Eye irritation

Skin and subcutaneous tissue disorders

Common:Pruritus

Uncommon: Exacerbation of psoriasis

Burning sensation of skin

Skin pain or irritation

Folliculitis

Dermatitis

Erythema

Acne

Dry skin

Rash

Pustular rash

The following adverse reactions are considered to be related to the pharmacological

classes of calcipotriol and betamethasone, respectively:

Calcipotriol

Adverse 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 ofgeneralised pustular psoriasis.

Systemic effects due to topical use of corticosteroids are rare in adults, however,they

can be severe. Adrenocortical suppression, cataract, infections, impact on the

metabolic control of diabetes mellitus and increase of intra-ocular pressure can occur,

especially after long-term treatment. Systemicreactions occur more frequently when

applied under occlusion (plastic, skin folds), when applied on large areas and during

long-term treatment (see section 4.4).

4.9 Overdose

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 Daivobet ointment weekly (corresponding to a daily dose of

approximately 34 g) for 5 months (maximum recommended dose 15 g daily) developed

Cushing's syndrome and pustular psoriasis after abruptly stopping treatment.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antipsoriatics.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. Theincidence 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 Daivobet 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. With regard

to HPA suppression, therefore, this study shows some evidence that very high doses of

Xamiol gel and ointment may have a weak effect on the HPA axis.

The efficacy of once daily use of Xamiol gelwas investigated in two randomised, double-

blind, 8-week clinical studies including atotal 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 werebetamethasone dipropionate in the gel vehicle,

calcipotriol in the gel vehicle and (in one of thestudies) 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 ofonset based on similar data at week 2 also

showed Xamiol gel to be statistically significantly more effective than the comparators.

% of patients

with absent or

very mild

disease Xamiol gel

(n=1,108) Beta-

methasone

dipropionate

(n=1,118) Calcipotriol

(n=558) Gel vehicle

(n=136)

week 2 53.2% 42.8% 1 17.2% 1 11.8% 1

week 8 69.8% 62.5% 1 40.1% 1 22.8% 1

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

The efficacy of once daily use of Xamiol gel on non-scalp regions of the body was

investigated in a randomised, double-blind, 8-week clinical study including 296 patients

with psoriasis vulgaris of mild or moderate severity according to the IGA. Comparators

were betamethasone dipropionate in the gel vehicle, calcipotriol in the gel vehicle and the

gel vehicle alone, all used once daily. Primaryresponse criteria were controlled disease

according to the IGA at week 4 and week 8.Controlled disease was defined as 'clear' or

'minimal disease' for patients with moderate disease at baseline or 'clear' for patients with

mild disease at baseline. The percentage change in Psoriasis Severity and Area index

(PASI) from baseline to week 4 and week8 were secondary response criteria.

% of patients

with controlled

disease Xamiol gel

(n=126) Beta-

methasone

dipropionate

(n=68) Calcipotriol

(n=67) Gel vehicle

(n=35)

week 4 20.6% 10.3% 1 4.5% 1 2.9% 1

week 8 31.7% 19.1% 1 13.4% 1 0.0% 1

Statistically significantly less effective than Xamiol gel (P<0.05)

Mean

precentage

reduction in

PASI (SD) Xamiol gel

(n=126) Beta-

methasone

dipropionate

(n=68) Calcipotriol

(n=67) Gel vehicle

(n=35)

week 4 50.2 (32.7) 40.8 (33.3) 1 32.1 (23.6) 1 17.0 (31.8) 1

week 8 58.8 (32.4) 51.8 (35.0) 40.8 (31.9) 1 11.1 (29.5) 1

Statistically significantly less effective than Xamiol gel (P<0.05)

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 Daivonex 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 Daivonex

Scalp solution.

% of patients with absent or

very mild disease Xamiol gel

(n=207) Daivonex Scalp solution

(n=105)

week 8 68.6% 31.4% 1

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

A randomised, double-blind long-term clinicalstudy 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 gelvehicle. Both treatments were applied once

daily, intermittently as required, for up to52 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 thetreatment 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.

5.2 Pharmacokinetic properties

The systemic exposure to calcipotrioland betamethasone dipropionate from topically

applied Xamiol gel is comparable to Daivobetointment in rats and minipigs. Clinical

studies with radiolabelled ointment indicate thatthe systemic absorption of calcipotriol and

betamethasone from Daivobet ointment formulation is less than 1% of the dose (2.5 g)

when applied to normal skin (625 cm 2 ) for 12 hours. Application to psoriasis plaques and

under occlusive dressings may increase theabsorption of topical corticosteroids.

Absorption through damaged skin is approx. 24%.

Following systemic exposure, both activeingredients – calcipotriol and betamethasone

dipropionate – are rapidly and extensively metabolised. Protein binding is approx. 64%.

Plasma elimination half-life after intravenous application is 5-6 hours. Due to the formation

of a depot in the skin elimination afterdermal application is in order of days.

Betamethasone is metabolised especially in theliver, but also in the kidneys to glucuronide

and sulphate esters. The main route of excretion of calcipotriol is via faeces (rats and

minipigs) and for betamethasone dipropionate it isvia urine (rats and mice). In rats, tissue

distribution studies with radiolabelled calcipotriol and betamethasone dipropionate,

respectively, showed that the kidney and liverhad 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 or8 weeks with both Xamiol gel and Daivobet

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.

5.3 Preclinical safetydata

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 impairmentof fertility. The relevance for humans is unknown.

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

humans.

Photo(co)carcinogenicity study in mice suggestthat calcipotriol may enhance the effect of

UVR to induce skin tumours.

No carcinogenicity or photocarcinogenicity studies have been performed with

betamethasone dipropionate.

In local tolerability studies in rabbits, Xamiolgel caused mild to moderate skin irritation and

a slight transient irritation of the eye.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients:

Paraffin,liquid

Polyoxypropylene-15 stearyl ether

Castor oil, hydrogenated

Butylhydroxytoluene (E321)

All-rac-α-tocopherol

6.2 Incompatibilities

In the absence of compatibility studies, thismedicinal product must not be mixed with other

medicinal products.

6.3 Shelf life

2 years.

After first opening: 3 months.

6.4 Special precautions for storage

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

6.5 Nature and contents of container

High-density polyethylene bottles with low-density polyethylene nozzle and a high-density

polyethylene screw cap. The bottles are placed in cartons.

Pack sizes: 4, 15, 30, 60 g.

Not all pack sizes may be marketed.

Manufacturer

LEO Pharmaceutical Products Ltd.,

Industriparken 55, DK-2750 Ballerup, Denmark.

Importer

Dexxon Ltd.,

1 Dexcel St., Or-Akiva 30600, Israel.

The format of this leaflet was determined bythe ministry of health (MOH) and its content

was checked and approved by the MOH on January 2012.