XAMIOL

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Xamiol

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One gram of gel contains: 50 microgram of calcipotriol (as hydrate) and 0.5 mg of

betamethasone (as dipropionate).

Excipient with known effect:

Butylhydroxytoluene (E321) 160 microgram/g gel.

For the 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 on the scalp and topical treatment of mild to

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

4.2 Posology and 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

medicinal products, the maximum daily dose should

not exceed 15 g. The body surface area treated with calcipotriol containing medicinal

products should not exceed 30% (see section 4.4).

If used on the scalp

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 (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. Currently available data in children aged 12 to 17 years are described in

section 4.8 and 5.1, but no recommendation on a posology can be made.

Method of administration

Xamiol gel should not be applied directly to the face or eyes. In order to achieve optimal

effect, it is not recommended to take a shower or bath, or to wash the hair in case of

scalp application, immediately after application of Xamiol gel. Xamiol gel should remain

on the skin during the night or during the day.

When using the Applicator

Prior to the first use of the Applicator the cartridge and the applicator head must be

assembled. After priming, each full actuation delivers 0.05 g of Xamiol gel. Xamiol gel is

applied to the affected area by using the Applicator. The hands should be washed after

use if Xamiol gel gets on the fingers. Xamiol gel Applicator is accompanied by the

package leaflet with detailed instructions for use.

When using the bottle

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

The hands should be washed after use.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Xamiol is contraindicated in erythrodermic, exfoliative and pustular psoriasis.

Due to the content of calcipotriol, Xamiol gel is contraindicated in patients with known

disorders of calcium metabolism (see section 4.4).

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, perioral

dermatitis, atrophic skin, striae atrophicae, fragility of skin veins, ichthyosis, acne

vulgaris, acne rosacea, rosacea, ulcers and wounds (see section 4.4).

4.4 Special warnings and precautions for use

Effects on endocrine system

Xamiol gel contains a potent group III steroid and concurrent treatment with other

steroids must be avoided. Adverse reactions 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. 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 extensive scalp 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).

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 a 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.

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 normalised when treatment is discontinued. The

risk of hypercalcaemia is minimal when the recommendations relevant to calcipotriol are

followed.

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

Local adverse reactions

Xamiol gel contains a potent group III-steroid and concurrent treatment with other

steroids on the same treatment area must be avoided.

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

should not be used in these areas. The patient must be instructed 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, they should be treated with

antimicrobiological therapy. However, if infection worsens, treatment with corticosteroids

should be stopped (see section 4.3).

Discontinuation of treatment

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.

Long-term use

With long-term use there is an increased risk of local and systemic corticosteroid

adverse reactions. The treatment should be discontinued in case of adverse reactions

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

Unevaluated use

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

Concurrent treatment and UV exposure

Daivobet ointment for body psoriasis lesions has been used in combination with Xamiol

gel for scalp psoriasis lesions, but there is limited experience of combination of Xamiol

with other topical anti-psoriatic products at the same treatment area, other anti-psoriatic

medicinal 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).

Adverse reactions to excipients

Xamiol gel contains butylhydroxytoluene (E321) as an excipient, which may cause local

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

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed with Xamiol.

4.6 Fertility, 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 (less than 300 pregnancy outcomes) 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.

Breast-feeding

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. 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 betamethasone dipropionate

demonstrated no impairment of male and female fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

The estimation of the frequency of adverse reactions is based on a pooled analysis

of data from clinical studies including post-authorisation safety studies and

spontaneous reporting.

The most frequently reported adverse reaction during treatment is pruritus.

Adverse reactions are listed by MedDRA SOC and the individual adverse reactions

are listed starting with the most frequently reported. Within each frequency

grouping, adverse reactions are presented in the order of decreasing seriousness.

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)

Not known (cannot be estimated from the available data)

Infections and infestations

Uncommon ≥1/1,000 to <1/100

Skin infection*

Folliculitis

Immune system disorders

Rare ≥1/10,000 to <1/1,000

Hypersensitivity

Eye disorders

Uncommon ≥1/1,000 to <1/100

Eye irritation

Not known

Vision, blurred**

Skin and subcutaneous tissue disorders

Common ≥1/100 to < 1/10

Pruritus

Uncommon ≥1/1,000 to <1/100

Exacerbation of psoriasis

Dermatitis

Erythema

Rash***

Acne

Skin burning sensation

Skin irritation

Dry skin

Rare ≥1/10,000 to <1/1,000

Skin striae

Skin exfoliation

Not known

Hair colour changes****

General disorders and administration site conditions

Uncommon ≥1/1,000 to <1/100

Application site pain*****

Rare ≥1/10,000 to <1/1,000

Rebound effect

*Skin infections including bacterial, fungal and viral skin infections have been

reported.

**See section 4.4.

***Various types of rash reactions such as rash erythematous and rash pustular

have been reported.

****Transient discolouration of the hair at scalp application site, to a yellowish

colour in white or gray hair, has been reported.

*****Application site burning is included in application site pain.

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 with topical corticosteroids, there may be a risk of

generalised pustular psoriasis.

Systemic reactions 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. Systemic reactions occur more

frequently when applied under occlusion (plastic, skin folds), when applied on large

areas and during long-term treatment (see section 4.4).

Paediatric population

No clinically relevant differences between the safety profiles in adult and adolescent

populations have been observed.

A total of 216 adolescent subjects were treated in three open label clinical trials.

See section 5.1 for further details regarding the trials.

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.

Any suspected adverse events should be reported to the Ministry of Health according to

the National Regulation by using an online form

https://sideeffects.health.gov.il

4.9 Overdose

Use above the recommended dose may cause elevated serum calcium which subsides

when treatment is discontinued. The symptoms of hypercalcemia include polyuria,

constipation, muscle weakness, confusion and coma.

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 during treatment and then 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 immunosuppressive 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 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 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.

% of patients

with absent or

very mild

disease

Xamiol gel

(n=1,108)

Betamethasone

dipropionate

(n=1,118)

Calcipotriol

(n=558)

Gel vehicle

(n=136)

week 2

53.2%

42.8%

17.2%

11.8%

week 8

69.8%

62.5%

40.1%

22.8%

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. Primary response 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 week 8 were secondary response

criteria.

% of patients

with controlled

disease

Xamiol gel

(n=126)

Betamethasone

dipropionate

(n=68)

Calcipotriol

(n=67)

Gel vehicle

(n=35)

week 4

20.6%

10.3%

4.5%

2.9%

week 8

31.7%

19.1%

13.4%

0.0%

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

Mean

percentage

reduction in

PASI (SD)

Xamiol gel

(n=126)

Betamethasone

dipropionate

(n=68)

Calcipotriol

(n=67)

Gel vehicle

(n=35)

week 4

50.2 (32.7)

40.8 (33.3)

32.1 (23.6)

17.0 (31.8)

week 8

58.8 (32.4)

51.8 (35.0)

40.8 (31.9)

11.1 (29.5)

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%

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.

Paediatric population

Scalp

Effects on calcium metabolism were investigated in two uncontrolled open 8-week

studies including in total 109 adolescents aged 12-17 years with scalp psoriasis who

used up to 69 g per week of Xamiol gel. No cases of hypercalcaemia and no clinically

relevant changes in urinary calcium were reported. The adrenal response to ACTH

challenge was measured in 30 patients; one patient showed a decrease in cortisol

response to ACTH challenge after 4 weeks of treatment, which was mild, without clinical

manifestations, and reversible.

Scalp and body

Effects on calcium metabolism were investigated in one uncontrolled open 8-week trial

in 107 adolescents aged 12-17 years with scalp and body psoriasis who used up to

114.2 g per week of Xamiol gel. No cases of hypercalcaemia and no clinically relevant

changes in urinary calcium were reported. The adrenal response to ACTH challenge

was measured in 31 patients; five patients showed a decrease in cortisol response to

ACTH challenge where 2 of the 5 patients showed only borderline decreases. Four of

the patients showed decrease after 4 weeks of treatment and 2 showed decrease after

8 weeks including 1 patient showing a decrease at both periods. These events were

mild, without clinical manifestations, and reversible.

5.2 Pharmacokinetic properties

The systemic exposure to calcipotriol and betamethasone dipropionate from topically

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

studies with radiolabelled ointment indicate that the 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

) for 12 hours. Application to psoriasis

plaques and under occlusive dressings may increase the absorption of topical

corticosteroids. Absorption through damaged skin is approx. 24%.

Following systemic exposure, both active ingredients – 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 after dermal application is in order of days.

Betamethasone is metabolised especially in the liver, but also in the kidneys to

glucuronide and sulfate esters. 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