Daivobet

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DAIVOBET® (DAIVOBET)

Composition:

Active substances: betamethasone; calcipotriol;

1 g of ointment contains 0.643 mg of betamethasone dipropionate, equivalent to 0.5 mg of betamethasone, and 52.2 µg of calcipotriol monohydrate, equivalent to 50 µg of calcipotriol;

Excipients: mineral oil, stearyl alcohol polyoxyl ether, alpha-tocopherol, white soft paraffin, butylated hydroxytoluene (E 321).

Pharmaceutical form. Ointment.

Main physicochemical characteristics: ointment of white to yellow color.

Pharmacotherapeutic group. Antipsoriatic agents for topical use. Other antipsoriatic agents for topical use. Calcipotriol combinations.

ATC code D05AX52.

Pharmacological properties.

Pharmacodynamics.

Calcipotriol is a vitamin D analogue. In vitro studies indicate that calcipotriol inhibits keratinocyte proliferation and promotes their morphological differentiation. This is the proposed mechanism of its effect in psoriasis.

Like other topical corticosteroids, betamethasone dipropionate exerts anti-inflammatory, antipruritic, vasoconstrictive, and immunosuppressive effects, but does not eliminate the underlying cause of the disease. The use of occlusive dressings enhances the therapeutic effect by increasing penetration into the stratum corneum of the epidermis. However, this may also increase the frequency of adverse reactions. The exact mechanism of the anti-inflammatory activity of topical corticosteroids has not been fully elucidated.

In a safety study involving 634 patients with psoriasis, repeated treatment courses with Daivobet ointment applied once daily as needed, either as monotherapy or alternated with the medicinal product Dovonex, were evaluated over a period of up to 52 weeks, compared to Dovonex monotherapy for 48 weeks following an initial course of Daivobet ointment. Adverse drug reactions were reported in 21.7% of patients in the Daivobet ointment treatment group, in 29.6% of patients in the Daivobet ointment/alternating Dovonex treatment group, and in 37.9% of patients in the Dovonex treatment group. Adverse drug reactions reported in more than 2% of patients in the Daivobet ointment group were pruritus (5.8%) and psoriasis (5.3%). Adverse drug reactions of interest, possibly related to long-term corticosteroid use (e.g., skin atrophy, folliculitis, depigmentation, boils, and purpura), were observed in 4.8% of patients in the Daivobet ointment group, 2.8% in the alternating Daivobet/Dovonex group, and 2.9% in the Dovonex group.

Adrenal response to adrenocorticotropic hormone (ACTH) was assessed by measuring serum cortisol levels in patients with extensive psoriasis affecting both the scalp and other body areas, using up to 106 g of a combination of Daivobet gel and Daivobet ointment per week. A borderline reduction in cortisol excretion in response to ACTH stimulation was observed at 30 minutes in 5 out of 32 patients (15.6%) after 4 weeks of treatment, and also in 2 out of 11 patients (18.2%) who continued treatment for 8 weeks. In all cases, serum cortisol levels were within normal limits at 60 minutes after ACTH stimulation. No signs of altered calcium metabolism were observed in these patients. Thus, with regard to suppression of the hypothalamic-pituitary-adrenal (HPA) axis function, this study provided some evidence that very high doses of Daivobet gel and ointment may have a slight effect on HPA axis function.

Paediatric patients

Adrenal response to ACTH stimulation was evaluated in an uncontrolled 4-week study in 33 adolescents aged 12–17 years with body psoriasis who used up to 56 g of Daivobet ointment per week. No cases of hypothalamic-pituitary-adrenal (HPA) axis suppression were reported. No cases of hypercalcaemia were observed, but one patient showed increased urinary calcium levels, possibly treatment-related.

Pharmacokinetics.

Results from clinical studies using radiolabelled ointment indicate that systemic absorption of calcipotriol and betamethasone after application of Daivobet ointment is less than 1% of the applied dose (2.5 g) when applied to healthy skin (625 cm²) for 12 hours. Application to psoriatic plaques or under occlusive dressings may increase absorption of topically applied corticosteroids. Absorption through damaged skin is approximately 24%.

Following systemic exposure, both active ingredients—calcipotriol and betamethasone dipropionate—are rapidly and extensively metabolized. The drug is approximately 64% protein-bound. The elimination half-life of the drug from plasma after intravenous administration is 5–6 hours. Due to depot formation in the skin, elimination of the drug from the skin after topical application occurs over several days. Betamethasone is primarily metabolized in the liver, but also in the kidneys, forming glucuronides and sulfonates. The main excretion pathway for calcipotriol is fecal (in rats and miniature pigs), while for betamethasone dipropionate it is urinary (in rats and mice). Tissue distribution studies in rats using radiolabelled calcipotriol and betamethasone dipropionate demonstrated that the kidneys and liver had the highest levels of radioactivity.

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

Clinical characteristics.

Indications.

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

Contraindications.

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

The use of the medicinal product Daivobet is contraindicated in patients with psoriatic erythroderma, exfoliative or pustular psoriasis.

Due to the presence of calcipotriol, Daivobet is contraindicated in patients with known disorders of calcium metabolism (see section "Special precautions for use").

Due to the presence of corticosteroid, Daivobet is contraindicated in the following conditions: viral skin infections (e.g., herpes or varicella), fungal, bacterial, and parasitic skin infections, cutaneous manifestations of tuberculosis, perioral dermatitis, skin atrophy, atrophic striae, increased vascular fragility, ichthyosis, common acne, rosacea, rosacea-like dermatitis, ulcers, and wounds (see section "Special precautions for use").

Interaction with other medicinal products and other forms of interaction.

No interaction studies with Daivobet have been conducted.

Special precautions for use.

Effect on the endocrine system

Dovobet ointment contains a potent group III steroid. Concomitant treatment with other steroids should be avoided. Adverse reactions associated with systemic corticosteroid therapy, such as suppression of adrenal cortex function or effects on metabolic control in diabetes mellitus, may also occur during treatment with topically applied corticosteroids due to systemic absorption.

Application of the medicinal product under occlusive dressings should be avoided, as this increases systemic absorption of corticosteroids. Application to large areas of damaged skin, mucous membranes, or skin folds should be avoided, since this increases systemic absorption of corticosteroids (see section "Undesirable effects").

In a study involving patients with either widespread scalp psoriasis or widespread psoriasis of other body areas who used a combination of Dovobet gel in high doses (application to the scalp) and Dovobet ointment in high doses (application to other body areas), borderline reduction in cortisol excretion in response to ACTH stimulation was observed in 5 out of 32 patients after 4 weeks of treatment (see section "Pharmacodynamics").

Effect on calcium metabolism

Due to the presence of calcipotriol, hypercalcemia may develop if the maximum daily dose (15 g) is exceeded. Serum calcium levels return to normal upon discontinuation of treatment. The risk of hypercalcemia is minimal when recommendations regarding calcipotriol are followed. The medicinal product should not be applied to skin areas exceeding 30% of the body surface (see section "Dosage and administration").

Local adverse reactions

Dovobet contains a potent group III steroid. Concomitant treatment with other steroids on the same area should be avoided. Facial and genital skin is highly sensitive to corticosteroids. The medicinal product should not be applied to these areas. Patients should be informed about proper use of the medicinal product to prevent accidental application or contact with the face, mouth, and eyes. Hands should be washed after each application to prevent accidental transfer to these body areas.

Concomitant skin infections

If lesions become secondarily infected, antibacterial therapy should be initiated. However, if an infection worsens, corticosteroid treatment should be discontinued (see section "Contraindications").

Withdrawal of therapy

When treating psoriasis with topical corticosteroids, there is a risk of generalized pustular psoriasis or rebound phenomena upon discontinuation of the medicinal product. Therefore, continued medical supervision after stopping treatment is necessary.

Long-term use of the medicinal product

Long-term use of corticosteroids increases the risk of local or systemic adverse reactions. Treatment with the medicinal product should be discontinued if adverse reactions associated with prolonged corticosteroid use occur (see section "Undesirable effects").

Uses not evaluated

There is no experience with the use of Dovobet medicinal product in patients with guttate psoriasis.

Concomitant therapy and UV irradiation

To date, data on the use of this medicinal product on the scalp are limited. Dovobet ointment for treatment of psoriatic lesions on the body has been used in combination with Dovobet gel for treatment of psoriatic lesions on the scalp; however, experience with combining Dovobet medicinal product with other topical anti-psoriatic agents applied to the same area, with other systemic anti-psoriatic agents, or with phototherapy is limited.

During treatment with Dovobet, patients are advised to limit or avoid excessive exposure to natural or artificial light. Topical calcipotriol should not be used in combination with UV radiation, except when the physician and patient consider that the expected benefit outweighs the potential risk.

Adverse reactions to excipients

Dovobet ointment contains butylhydroxytoluene (E 321) as an excipient, which may cause local skin reactions (e.g., contact dermatitis) or irritation of the eyes and mucous membranes.

Use during pregnancy or breastfeeding.

Pregnancy

There are currently insufficient data on the use of Dovobet medicinal product in pregnant women. Animal studies with glucocorticosteroids have shown reproductive toxicity; however, epidemiological studies (fewer than 300 pregnancy outcomes) have not shown congenital anomalies in infants whose mothers used corticosteroids during pregnancy. The potential risk in humans has not yet been established. Therefore, Dovobet should be used during pregnancy only if the expected benefit outweighs the potential risk.

Breastfeeding

Betamethasone passes into breast milk, but adverse effects in the infant are unlikely when the medicinal product is used at therapeutic doses. There are no clinical data on the excretion of calcipotriol into breast milk. Dovobet should be prescribed with caution to women who are breastfeeding. Patients should not apply Dovobet to the breasts while nursing an infant.

Fertility

Studies in rats with oral administration of calcipotriol or betamethasone dipropionate showed no reduction in fertility in males or females.

Ability to affect reaction speed when driving or operating machinery.

The effect of the medicinal product Dovobet on the ability to drive vehicles or operate machinery is absent or negligible.

Dosage and Administration

Apply Daivobet ointment to affected skin areas once daily. The recommended treatment duration is 4 weeks. There is experience with repeated treatment courses of Daivobet ointment for up to 52 weeks. If treatment with the medicinal product needs to be continued or resumed after 4 weeks, the use of the medicinal product should be continued only after consultation with a physician and under regular medical supervision.

When using medicinal products containing calcipotriol, the maximum daily dose should not exceed 15 g. The application area of medicinal products containing calcipotriol should not exceed 30% of the body surface area (see section "Special Warnings and Precautions for Use").

Special Patient Groups

Patients with Renal and Hepatic Impairment

The safety and efficacy of Daivobet ointment in patients with severe renal insufficiency or severe hepatic diseases have not been established.

Administration Method

Daivobet ointment should be applied to affected skin areas. It is not recommended to take a shower or bath immediately after application of Daivobet ointment to achieve optimal effect.

Children

Pediatric Patients

The safety and efficacy of Daivobet ointment in children (under 18 years of age) have not been established. Current data on the use of the medicinal product in children aged 12 to 17 years are described in sections "Pharmacodynamics" and "Adverse Reactions", but no dosage recommendations can be provided.

Overdose

Administration of the medicinal product in doses exceeding the recommended dose may lead to elevated serum calcium levels, which resolve upon discontinuation of treatment. Symptoms of hypercalcemia include polyuria, constipation, muscle weakness, confusion, and coma.

Prolonged excessive use of topical corticosteroids may suppress the hypothalamic-pituitary-adrenal (HPA) axis, leading to secondary adrenal insufficiency, which is usually reversible. In such cases, symptomatic treatment is indicated.

In cases of chronic toxicity, a gradual withdrawal of corticosteroids should be performed.

Cases of improper use have been reported: in one patient with widespread erythrodermic psoriasis who received treatment with 240 g of Daivobet ointment weekly (corresponding to a daily dose of approximately 34 g) for 5 months (the maximum recommended daily dose is 15 g), Cushing's syndrome developed during treatment, followed by pustular psoriasis after abrupt discontinuation of therapy.

Adverse reactions.

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

The most commonly reported adverse reactions during treatment are various skin-related reactions, such as pruritus and skin desquamation.

Cases of pustular psoriasis and hypercalcemia have been reported.

Adverse reactions are listed by MedDRA system organ class (SOC) and by frequency. Within each frequency grouping, adverse reactions are presented in order of decreasing severity.

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)

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

**Various types of rashes have been reported, such as exfoliative rash, papular rash, and pustular rash.

***Burning sensation at the application site is included under pain at the application site.

Paediatric population

In an uncontrolled open-label study, 33 adolescents aged 12–17 years with plaque psoriasis were treated with Daivobet ointment for 4 weeks up to a maximum dose of 56 g per week. No new adverse reactions or systemic corticosteroid effects were identified. However, the size of this study does not allow definitive conclusions regarding the safety profile of Daivobet ointment when used in children.

The adverse reactions listed below are considered to be related to the pharmacological classes of calcipotriol and betamethasone, respectively.

Calcipotriol

Adverse effects include application site reactions, pruritus, skin irritation, burning and stinging sensations, skin dryness, erythema, rash, dermatitis, eczema, exacerbation of psoriasis, photosensitivity, and hypersensitivity reactions, which in very rare cases may include angioedema and facial swelling.

Very rarely, systemic reactions may occur following topical application, leading to hypercalcaemia or hypercalciuria (see section "Special precautions for use").

Betamethasone (as dipropionate)

Local application may lead to application site reactions, especially during prolonged use, including skin atrophy, telangiectasia, striae, folliculitis, hypertrichosis, perioral dermatitis, allergic contact dermatitis, depigmentation, and cutaneous collagenous degeneration. When treating psoriasis with topical corticosteroids, there may be a risk of developing generalized pustular psoriasis.

Systemic reactions associated with topical corticosteroids are rare in adults but may be severe. These include adrenal suppression, cataract formation, infections, impaired metabolic control of diabetes mellitus, and increased intraocular pressure, particularly after prolonged treatment. Systemic reactions are more likely to occur when occlusive dressings (plastic, skin folds) are used, when the product is applied over large areas, or during long-term treatment (see section "Special precautions for use").

Shelf life. 2 years.

After first opening – 1 year.

Storage conditions. Store at temperatures not exceeding 25 °C. Keep out of the reach of children.

Packaging. 15 g or 30 g ointment in a tube. One tube per cardboard box.

Prescription status. Over-the-counter.

Manufacturer.

LEO Laboratories Limited.

Manufacturer's address and place of business.

285 Cashel Road, Crumlin, Dublin 12, Ireland.