DAIVOBET 50 µg/0,5 mg/g Pom T/60g

Calcipotriol.............................................................................................................50,000 micrograms

As calcipotriol monohydrate................................................................52,200 micrograms

Betamethasone..........................................................................................................................0,500 mg

As betamethasone dipropionate.........................................................................0,643 mg

For 1 g of ointment.

Excipient with known effect: 1 g of ointment contains 50 micrograms of butylhydroxytoluene (E321).

Topical treatment of plaque psoriasis (psoriasis vulgaris), suitable for topical treatment in adults.

Dosage

Daivobet ointment must be applied once daily to the lesions. The recommended duration of treatment is 4 weeks. Data exist on the use of repeated courses of Daivobet up to 52 weeks. If it is necessary to continue or resume treatment after 4 weeks, treatment should be continued after medical advice and under regular medical supervision.

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

Special populations

Renal and hepatic impairment

The safety and efficacy of Daivobet ointment in patients with severe renal impairment or severe hepatic disorders have not been evaluated.

Paediatric population

The safety and efficacy of Daivobet ointment in children under 18 years of age have not been established. The data currently available in children aged 12 to 17 years are described in sections Adverse effects and Pharmacodynamics but no dosage recommendation can be made.

Method of administration

Daivobet ointment must be applied to the lesions. For optimal effect, it is not recommended to shower or bathe immediately after application of Daivobet ointment.

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

Daivobet is contraindicated in erythrodermic, exfoliative and pustular psoriasis.

Due to the presence of calcipotriol, Daivobet is contraindicated in patients with a history of calcium metabolism disorders (see section Warnings and precautions).

Due to the presence of corticosteroids, Daivobet is contraindicated in the following cases: skin lesions of viral origin (for example herpes or chickenpox), infections of fungal or bacterial origin, parasitic infections, skin involvement related to tuberculosis, perioral dermatitis, skin atrophy, striae, fragility of the cutaneous venous network, ichthyosis, acne vulgaris, acne rosacea, rosacea, ulcers and wounds (see section Warnings and precautions).

Effect on the endocrine system

Daivobet ointment contains a class III strong-group corticosteroid and the simultaneous use of other corticosteroids should be avoided. The adverse effects observed with systemic corticosteroid treatment, such as suppression of the hypothalamic-pituitary axis or the effect on metabolic control of diabetes mellitus, may also occur during topical corticosteroid treatment due to passage into the general circulation.

Application under occlusive dressing should be avoided as it increases systemic absorption of corticosteroids. Application over large areas of damaged skin, on mucous membranes or in skin folds should be avoided as it increases systemic absorption of corticosteroids (see section Adverse effects).

In a study of patients with psoriasis extending to both the scalp and the body, using high doses of Daivobet gel in combination (application to the scalp) and high doses of Daivobet ointment (application to the body), 5 patients out of 32 showed a borderline decrease in their cortisol level in response to stimulation by corticotropin (ACTH) after 4 weeks of treatment (see section Pharmacodynamics).

Visual disorders

Visual disturbances may occur with systemic or local corticosteroid therapy. In case of blurred vision or the appearance of any other visual symptom during corticosteroid therapy, an ophthalmological examination is required to look for cataract, glaucoma, or rarer lesions such as central serous chorioretinopathy, as described with systemic or local administration of corticosteroids.

Effects on calcium metabolism

Due to the presence of calcipotriol, hypercalcaemia may occur if the maximum daily dose (15 g) is exceeded. Calcaemia normalises upon discontinuation of treatment. The risk of hypercalcaemia is minimal when the recommendations regarding calcipotriol are followed.

Treatment of more than 30 % of the body surface area should be avoided (see section Dosage and administration).

Local adverse effects

Daivobet ointment contains a class III strong-group corticosteroid and the simultaneous use of other corticosteroids should be avoided.

The skin of the face and the genital region is very sensitive to corticosteroids. The product should not be used on these areas. The patient should be trained in the correct use of the product in order to avoid accidental application and transfer to the face, mouth and eyes. Wash hands after each application in order to avoid accidental transfer to these areas.

Concomitant skin infections

When lesions become superinfected, they must be treated with antimicrobial therapy.

However, if the infection worsens, corticosteroid treatment should be discontinued (see section Contraindications).

Discontinuation of treatment

Treatment of psoriasis with topical corticosteroids carries a risk of generalised pustular psoriasis or rebound effect upon discontinuation. Medical monitoring should therefore be continued after treatment is stopped.

Long-term treatment

With long-term treatment the risk of local or systemic corticosteroid adverse effects is increased. Treatment should be discontinued in the event of adverse effects related to long-term corticosteroid use (see section Adverse effects).

Use not evaluated

There is no data on the use of Daivobet in guttate psoriasis.

Concomitant treatment and UV exposure

There is only limited experience with the use of this product on the scalp. Daivobet ointment for psoriatic lesions of the body has been used in combination with Daivobet gel for psoriatic lesions of the scalp, but experience is limited regarding the combination of Daivobet with other topical anti-psoriatic products applied to the same areas, with other systemically administered anti-psoriatic products, or with phototherapy.

During treatment with Daivobet, the physician is advised to counsel patients to limit or avoid excessive exposure to natural or artificial light. Topically applied calcipotriol should be combined with UV only if the physician and the patient consider that the potential benefits outweigh the potential risks (see section Preclinical safety).

Adverse effects related to excipients

Daivobet ointment contains butylhydroxytoluene (E321) and may cause local skin reactions (for example: eczema), or irritation of the eyes and mucous membranes.

No interaction studies have been performed with Daivobet.

Pregnancy

There are no relevant data on the use of Daivobet in pregnant women. Studies in animals with glucocorticoids have shown reproductive toxicity (see section Preclinical safety) however a number of epidemiological studies (fewer than 300 pregnancies carried to term) have not shown congenital abnormalities in children born to mothers treated with corticosteroids during pregnancy. The potential risk for humans is not known with certainty. Consequently, Daivobet should only be used during pregnancy when the potential benefit justifies the potential risk.

Breast-feeding

Betamethasone passes into breast milk but the risk of an adverse effect in the infant appears unlikely at therapeutic doses. There are no data on the excretion of calcipotriol into breast milk. Caution is required when prescribing Daivobet to a breast-feeding woman. Do not use Daivobet on the breasts in breast-feeding women.

Fertility

Studies in rats after oral administration of calcipotriol or betamethasone dipropionate have demonstrated no impairment of fertility in males or females (see section Preclinical safety).

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

The estimate of the frequency of adverse reactions is based on a pooled analysis of data from clinical studies, including post-marketing tolerability studies and spontaneous reports.

The adverse reactions most frequently reported during treatment are various skin reactions such as pruritus and skin exfoliation.

Cases of pustular psoriasis and hypercalcaemia have been reported.

Adverse reactions are presented by MedDRA system organ class (SOC), and individual adverse reactions are presented within each SOC in order of decreasing frequency. Within each frequency category, adverse reactions are presented in order of decreasing seriousness.

* Reported skin infections include skin infections of bacterial, fungal and viral origin.

** Various types of skin eruptions have been reported, such as exfoliative, papular and pustular eruptions.

*** Burning at the application site is included in pain at the application site.

**** See section Warnings and precautions.

Paediatric population

In an uncontrolled open study, 33 adolescents aged 12 to 17 years with plaque psoriasis were treated with Daivobet ointment for 4 weeks with a maximum dose of 56 g per week. No new adverse events were observed and no concerning data regarding the systemic effect of corticosteroids were identified. However, the size of the study does not allow firm conclusions regarding the tolerability profile of Daivobet ointment in children and adolescents.

The following adverse effects, considered to be related to the pharmacological class of calcipotriol and betamethasone, are respectively:

Calcipotriol

Adverse effects include application site reactions, pruritus, skin irritation, burning and stinging sensation, dry skin, erythema, skin eruptions, dermatitis, eczema, worsening of psoriasis, photosensitivity and hypersensitivity reactions including very rare cases of angioedema and facial oedema.

Systemic effects following topical application may very rarely occur and cause hypercalcaemia or hypercalciuria (see section Warnings and precautions).

Betamethasone (as dipropionate)

Local reactions may occur after topical use, especially with long-term use, including skin atrophy, telangiectasia, striae, folliculitis, hypertrichosis, perioral dermatitis, allergic contact dermatitis, depigmentation and colloid milium.

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

Systemic effects after topical application of corticosteroids are rare in adults but can be severe. Suppression of the hypothalamic-pituitary-adrenal axis, cataract, infections, an impact on metabolic control of diabetes mellitus and an increase in intraocular pressure may occur, especially after prolonged treatment. Systemic effects occur more frequently with application under occlusion (plastic, skin folds), application over large surface areas and long-term treatment (see section Warnings and precautions).

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 via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Pharmacovigilance Centres - Website: https://signalement.social-sante.gouv.fr/.

Use of doses above the recommended dose may lead to an increase in serum calcium, an effect that is reversible on discontinuation of treatment. Symptoms of hypercalcaemia include polyuria, constipation, muscle weakness, confusion and coma.

Excessive and prolonged use of topical corticosteroids may lead to suppression of the hypothalamic-pituitary axis, resulting in secondary adrenal insufficiency that is usually reversible. In such cases, symptomatic treatment is indicated.

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

One case of misuse has been reported in a patient treated for extensive erythrodermic psoriasis with 240 g of Daivobet ointment per week (corresponding to a daily dose of approximately 34 g) for 5 months (maximum recommended dose 15 g per day); during treatment the patient developed Cushing's syndrome and then pustular psoriasis after abrupt discontinuation of treatment.

Pharmacotherapeutic class: Antipsoriatics. Other anti-psoriatics for topical use, Calcipotriol, combinations, ATC code: D05AX52.

Calcipotriol is an analogue of vitamin D. Data in vitro suggest that calcipotriol induces differentiation and inhibits proliferation of keratinocytes. This is the proposed mechanism to explain its effects in psoriasis.

Like other topical corticosteroids, betamethasone dipropionate has anti-inflammatory, anti-pruritic, vasoconstrictive, and immunosuppressive properties, without demonstrated curative action. Treatment under occlusion may increase the effect due to greater penetration into the stratum corneum. The incidence of adverse effects will therefore be increased. The mechanism of action of the anti-inflammatory activity of topical corticosteroids is not fully established.

A safety study in 634 psoriasis patients investigated the effects of repeated courses of Daivobet ointment used once daily as needed, either alone or alternating with Daivonex, for up to 52 weeks compared with Daivonex used alone for 48 weeks after initial treatment with Daivobet ointment. Adverse effects were reported by 21,7 % of patients in the Daivobet ointment group, 29,6 % in the Daivobet ointment/Daivonex alternating group and 37,9 % in the Daivonex group. The adverse effects reported by more than 2 % of patients in the Daivobet ointment group are pruritus (5,8 %) and psoriasis (5,3 %). Adverse effects that could be related to long-term corticosteroid treatment (for example skin atrophy, folliculitis, depigmentation, furuncle and purpura) were reported by 4,8 % of patients in the Daivobet ointment group, 2,8 % in the Daivobet ointment/Daivonex alternating group and 2,9 % in the Daivonex group.

The adrenal response to ACTH was determined by measuring cortisol levels in patients with both extensive scalp and body psoriasis using up to 106 g per week of Daivobet gel combined with Daivobet ointment. A borderline decrease in cortisol level, 30 minutes after ACTH administration, was observed in 5 of 32 patients (15,6%) after 4 weeks of treatment and in 2 of 11 patients (18,2%) who continued treatment for up to 8 weeks. In all cases, cortisol levels were at a normal level 60 minutes after ACTH administration. No change in calcium metabolism was observed in these patients. Regarding hypothalamic-pituitary suppression, this study shows that at very high doses Daivobet gel and ointment may have a weak effect on the hypothalamic-pituitary axis.

Paediatric population

The adrenal response to ACTH administration was measured in an uncontrolled study of 4 weeks in 33 adolescents aged 12 to 17 years with body psoriasis who used up to 56 g per week of Daivobet ointment. No cases of hypothalamic-pituitary-axis suppression were reported. No hypercalcaemia was reported, but one patient had an increase in urinary calcium possibly related to treatment.

Clinical studies with a labelled ointment showed that the systemic absorption of calcipotriol and betamethasone from Daivobet ointment is less than 1 % of the dose (2,5 g) when applied to healthy skin (625 cm²) for 12 hours. Application to psoriatic plaques and under occlusive dressing may increase the absorption of topical corticosteroids. Absorption through damaged skin is approximately 24 %.

After systemic exposure, both active substances - calcipotriol and betamethasone dipropionate - are rapidly and extensively metabolised. Protein binding is approximately 64 %. The plasma elimination half-life after intravenous administration is 5-6 hours. Due to the formation of a depot in the skin, elimination after cutaneous application is on the order of a few days. Betamethasone is metabolised mainly by the liver, but also by the kidneys into glucuronides and sulphate esters. Calcipotriol is excreted via the faeces (rats and guinea pigs) and betamethasone dipropionate via the urine (rats and mice). In rats, tissue distribution studies of radiolabelled calcipotriol and betamethasone dipropionate showed that the kidney and liver had, respectively, the highest levels of radioactivity.

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

Studies performed with corticosteroids in animals have shown embryotoxicity (cleft palate, skeletal malformations). In reproduction studies performed in rats after long-term oral administration, prolonged gestation and prolonged, difficult labour were observed. In addition, decreased survival, body weight and weight gain of the offspring were observed. There was no impairment of fertility. The relevance of these data to humans is not known.

A dermal carcinogenicity study in mice and an oral carcinogenicity study in rats did not reveal any particular risks of calcipotriol applicable to humans.

Photo(co)carcinogenicity studies in mice suggest that calcipotriol may increase the skin tumour-inducing effect of UV radiation.

A dermal carcinogenicity study in mice and an oral carcinogenicity study in rats did not show any particular risks of betamethasone dipropionate applicable to humans. No photocarcinogenicity study has been performed with betamethasone dipropionate.

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

2 years.

After first opening: 1 year.

Store at a temperature not exceeding 25 °C.

No special requirements.