Topical treatment of stable plaque psoriasis vulgaris amenable to topical therapy in adults.

Posology
Daivobet ointment should be applied to the affected area once daily. The recommended treatment period is 4
weeks. There is experience with repeated courses of Daivobet up to 52 weeks. If it is necessary to continue
or restart treatment after 4 weeks, 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).
Special populations
Renal and hepatic impairment
The safety and efficacy of Daivobet ointment in patients with severe renal insufficiency or severe hepatic
disorders have not been evaluated.
Paediatric population
The safety and efficacy of Daivobet ointment 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
Daivobet ointment should be applied to the affected area. In order to achieve optimal effect, it is not
recommended to take a shower or bath immediately after application of Daivobet ointment.

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. Daivobet is contraindicated in erythrodermic, exfoliative and pustular psoriasis. Due to the content of calcipotriol, Daivobet is contraindicated in patients with known disorders of calcium metabolism (see section 4.4). Due to the content of corticosteroid Daivobet 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).

Effects on endocrine system
Daivobet ointment 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 Daivobet 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
Daivobet 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 posttreatment
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 Daivobet in guttate psoriasis.
Concurrent treatment and UV exposure
There is limited experience for the use of this medicinal product on the scalp. Daivobet ointment for body
psoriasis lesions has been used in combination with Daivobet gel for scalp psoriasis lesions, but there is
limited experience of combination of Daivobet with other topical anti-psoriatic products at the same
treatment area, other anti-psoriatic medicinal products administered systemically or with phototherapy.
During Daivobet 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
Daivobet ointment contains butylhydroxytoluene (E321) as an excipient, which may cause local skin
reactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes.

No interaction studies have been performed with Daivobet.

Pregnancy
There are no adequate data from the use of Daivobet 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, Daivobet 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 Daivobet to women who breast-feed. The patient should be instructed not to use
Daivobet 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).

Daivobet has no or negligible influence on the ability to drive and use machines

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 reactions during treatment are various skin reactions, like pruritus, and
skin exfoliation.
Pustular psoriasis and hypercalcaemia have been reported.
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)

Paediatric population
In an uncontrolled open study, 33 adolescents aged 12-17 years with psoriasis vulgaris were treated with
Daivobet ointment for 4 weeks to a maximum of 56 g per week. No new adverse events were observed and
no concerns regarding systemic corticosteroid effect were identified. The size of this study does however not
allow firm conclusions regarding the safety profile of Daivobet ointment in children and adolescents.
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).
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. Healthcare professionals are asked
to report any suspected adverse reactions
To reports any side effect(s):
Saudi Arabia:

Use above the recommended dose may cause elevated serum calcium which subsides when treatment is
discontinued. The symptoms of hypercalcaemia 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.

Pharmacotherapeutic group: Antipsoriatics. Other antipsoriatics for topical use, Calcipotriol, combinations.
ATC Code: DO5AX52
Calcipotriol is a vitamin D analogue. In vitro data suggests 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. The mechanism of the anti-inflammatory activity
of the topical steroids, in general, is unclear.
A safety study in 634 psoriasis patients has investigated repeated courses of Daivobet ointment used once
daily as required, either alone or alternating with Daivonex, for up to 52 weeks, compared with Daivonex
used alone for 48 weeks after an initial course of Daivobet ointment. Adverse drug reactions were reported
by 21.7 % of the patients in the Daivobet ointment group, 29.6 % in the Daivobet ointment/Daivonex
alternating group and 37.9 % in the Daivonex group. The adverse drug reactions that were reported by more
than 2 % of the patients in the Daivobet ointment group were pruritus (5.8 %) and psoriasis (5.3 %). Adverse
events of concern possibly related to long-term corticosteroid use (e.g. skin atrophy, folliculitis,
depigmentation, furuncle and purpura) were reported by 4.8 % of the patients in the Daivobet ointment
group, 2.8 % in the Daivobet ointment/Daivonex alternating group and 2.9 % in the Daivonex group.

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 Daivobet 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 Daivobet gel and ointment may have a
weak effect on the HPA axis.
Paediatric population
The adrenal response to ACTH challenge was measured in an uncontrolled 4-week study in 33 adolescents
aged 12-17 years with body psoriasis who used up to 56 g per week of Daivobet ointment. No cases of HPA
axis suppression were reported. No hypercalcaemia was reported but one patient had a possible treatmentrelated
increase in urinary calcium.

Clinical studies with radiolabelled ointment indicate that the systemic absorption of calcipotriol and
betamethasone from Daivobet ointment 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. 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 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 Daivobet 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.

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 and an oral carcinogenicity study in rats revealed no
special risk to humans.
Photo(co)carcinogenicity studies in mice suggest that calcipotriol may enhance the effect of UVR to induce
skin tumours.

A dermal carcinogenicity study in mice and an oral carcinogenicity study in rats revealed no special risk of
betamethasone dipropionate to humans. No photocarcinogenicity study has been performed with
betamethasone dipropionate.

Liquid paraffin
Polyoxypropylene stearyl ether
All-rac-α-tocopherol
White soft paraffin
Butylhydroxytoluene (E321)

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

2 years After first opening: 1 year

Do not store above 30°C.

Aluminium/epoxyphenol tubes with polyethylene screw cap.
Tube sizes: 3 (sample), 15, 30, 60, 100 and 120 g.
Not all pack sizes may be marketed.

No special requirements.