Daivobet Mechanism of Action

Pharmacology: Pharmacodynamics: 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.
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.
Ointment: A safety study in 634 psoriasis patients has investigated repeated courses of Calcipotriol hydrate and betamethasone dipropionate (Daivobet) 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 Calcipotriol hydrate and betamethasone dipropionate (Daivobet) 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.
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 treatment-related increase in urinary calcium.
Gel: The efficacy of once daily use of Daivobet 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 Daivobet Gel was statistically significantly more effective than the comparators. Results for speed of onset based on similar data at week 2 also showed Daivobet Gel to be statistically significantly more effective than the comparators. (See Table 1.)

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The efficacy of once daily use of Daivobet 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. (See Tables 2 and 3.)

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Another randomised, investigator-blinded clinical study including 312 patients with scalp psoriasis of at least moderate severity according to the IGA investigated use of Daivobet 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 Daivobet Gel was statistically significantly more effective than Daivonex Scalp solution. (See Table 4.)

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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 Daivobet 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 Daivobet Gel group and 3.0 % in the calcipotriol group; P=0.73). No cases of skin atrophy were reported.
Paediatric population: 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 Daivobet 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.
Pharmacokinetics: Ointment: The human transdermal absorption of calcipotriol and betamethasone respectively has been shown to be less than 1% of the administered dose for both substances. The systemic absorption under normal conditions of use is not expected to have any influence on systemic parameters.
The pharmacokinetic behaviour of the two active constituents is not influenced by the presence of each other.
Gel: The systemic exposure to calcipotriol and betamethasone dipropionate from topically applied Daivobet Gel is comparable to Daivobet Ointment in rats and minipigs. Clinical studies with radio-labelled 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 cm2) for 12 hours. Application to psoriasis plaques and under occlusive dressings may increase the absorption of topical corticosteroids. Following systemic exposure, both active ingredients - calcipotriol and betamethasone dipropionate - are rapidly and extensively metabolised. The main route of excretion of calcipotriol is via faeces (rats and minipigs) and for betamethasone dipropionate it is via urine (rats and mice). 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.
Toxicology: Preclinical Safety Data: 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 was detected. Moreover, reduction in offspring survival, body weight and body weight gain were observed. There was no impairment of fertility. The relevance for humans in 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 hazard risk of betamethasone dipropionate to humans. No photocarcinogenicity study has been performed with betamethasone dipropionate.
Gel: In local tolerability studies in rabbits, Daivobet gel caused mild to moderate skin irritation and a slight transient irritation of the eye.