Israel - English - Ministry of Health
עעבקנהזןולעטמרופ " רשואוקדבנונכותותואירבהדרשמי
1. NAME OF THE MEDICINAL PRODUCT
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
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
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).
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.
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.
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.
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).
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
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.
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.
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
The following terminologies have been used in order to classify the frequencies of
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)
Skin and subcutaneous tissue disorders
Uncommon: Exacerbation of psoriasis
Burning sensation of skin
Skin pain or irritation
The following adverse reactions are considered to be related to the pharmacological
classes of calcipotriol and betamethasone, respectively:
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).
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,
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
disease Xamiol gel
(n=558) Gel vehicle
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
disease Xamiol gel
(n=67) Gel vehicle
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)
PASI (SD) Xamiol gel
(n=67) Gel vehicle
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
% of patients with absent or
very mild disease Xamiol gel
(n=207) Daivonex Scalp solution
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
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
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:
Polyoxypropylene-15 stearyl ether
Castor oil, hydrogenated
In the absence of compatibility studies, thismedicinal product must not be mixed with other
6.3 Shelf life
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.
LEO Pharmaceutical Products Ltd.,
Industriparken 55, DK-2750 Ballerup, Denmark.
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.