Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark
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 Dovobet gel and Dovobet 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 Dovobet gel and ointment may have a weak effect on the HPA axis.
The efficacy of once daily use of Dovobet 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 Dovobet gel was statistically significantly more effective than the comparators. Results for speed of onset based on similar data at week 2 also showed Dovobet gel to be statistically significantly more effective than the comparators.
| % of patients with absent or very mild disease | Dovobet gel (n=1,108) | Betamethasone dipropionate (n=1,118) | Calcipotriol (n=558) | Gel vehicle (n=136) |
|---|---|---|---|---|
| week 2 | 53.2% | 42.8%1 | 17.2%1 | 11.8%1 |
| week 8 | 69.8% | 62.5%1 | 40.1%1 | 22.8%1 |
1 Statistically significantly less effective than Dovobet gel (P<0.001)
The efficacy of once daily use of Dovobet 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 | Dovobet gel (n=126) | Betamethasone dipropionate (n=68) | Calcipotriol (n=67) | Gel vehicle (n=35) |
|---|---|---|---|---|
| week 4 | 20.6% | 10.3%1 | 4.5%1 | 2.9%1 |
| week 8 | 31.7% | 19.1%1 | 13.4%1 | 0.0%1 |
1 Statistically significantly less effective than Dovobet gel (P<0.05)
| Mean percentage reduction in PASI (SD) | Dovobet gel (n=126) | Betamethasone dipropionate (n=68) | Calcipotriol (n=67) | Gel vehicle (n=35) |
|---|---|---|---|---|
| week 4 | 50.2 (32.7) | 40.8 (33.3)1 | 32.1 (23.6)1 | 17.0 (31.8)1 |
| week 8 | 58.8 (32.4) | 51.8 (35.0) | 40.8 (31.9)1 | 11.1 (29.5)1 |
1 Statistically significantly less effective than Dovobet 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 Dovobet gel once daily compared with Dovonex 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 Dovobet gel was statistically significantly more effective than Dovonex Scalp solution.
| % of patients with absent or very mild disease | Dovobet gel (n=207) | Dovonex Scalp solution (n=105) |
|---|---|---|
| week 8 | 68.6% | 31.4%1 |
1 Statistically significantly less effective than Dovobet 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 Dovobet 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 Dovobet gel group and 3.0 % in the calcipotriol group; P=0.73). No cases of skin atrophy were reported.
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 Dovobet 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.
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 Dovobet 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.
The systemic exposure to calcipotriol and betamethasone dipropionate from topically applied Dovobet gel is comparable to Dovobet ointment in rats and minipigs. Clinical studies with radiolabelled ointment indicate that the systemic absorption of calcipotriol and betamethasone from Dovobet 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. 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 Dovobet gel and Dovobet 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.
In local tolerability studies in rabbits, Dovobet gel caused mild to moderate skin irritation and a slight transient irritation of the eye.
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