Regulatory Decision Summary for ENSTILAR

Benefits and Uncertainties

Both calcipotriol and betamethasone dipropionate are known to have an anti-inflammatory activity. The combination of calcipotriol 50 mcg/g and betamethasone dipropionate 0.5 mg/g has been internationally marketed for the topical treatment of psoriasis vulgaris since 2001.

In a pooled analysis of the Intent To Treat (ITT) population, Enstilar achieved treatment success according to Investigators Global Assessment (IGA) at week 4 in 51.4% of subjects. It also showed slightly greater treatment success than its active comparators and substantially greater success than vehicle in all clinical trials. These results were supported by improvements in the secondary endpoints: IGA by week 1; modified Psoriasis Area and Severity Index (m-PASI) at week 1 and 4; percentage of subjects with ≥75% reduction in m-PASI from baseline to week 4; Patients Global Assessment of disease severity (PaGa) at week 4; decrease in itch severity at week 1 and 4; and quality of life.

Apart from the propellants, Enstilar is identical to Dovobet ointment and has benefitted from the extensive non-clinical study program that was conducted for Dovobet. However, both in vitro and clinical studies support Enstilar as having enhanced penetration of calcipotriol and betamethasone dipropionate over Dovobet ointment, translating into a slight but significant increase in potency.

Enstilar showed similar efficacy and safety in all age groups from 18 years and above, including elderly subjects. It was tested in men and women of diverse ethnic backgrounds and with different levels of disease severity. Enstilar was not tested on palmoplantar and nail psoriasis. The safety and efficacy of Enstilar in children below 18 years have not been established. Children may have greater susceptibility to corticosteroid-related systemic effects. Therefore use in children is not recommended.

Harms and Uncertainties

Betamethasone dipropionate is a potent corticosteroid and topical use may be associated with local and systemic side effects (local: skin atrophy, telangiectasia, striae, folliculitis, hypertrichosis, perioral dermatitis, allergic contact dermatitis, and depigmentation; systemic: adrenocortical suppression, cataract, infections, impaired glycaemic control of diabetes mellitus, and increase of intra-ocular pressure).

Calcipotriol is a synthetic analog of Vitamin D3 and topical use may be associated with local and systemic side effects (local: pruritus, skin irritation, burning and stinging sensation, dry skin, erythema, rash, dermatitis, psoriasis aggravated, photosensitivity and hypersensitivity reactions including very rare cases of angioedema; systemic: hypercalcaemia, hypercalciuria and bone calcium mobilization).

Animal studies showed oral calcipotriol to have some carcinogenic and photo(co)carcinogenic potential in rats and mice, respectively. Concerns of photo(co)carcinogencity have led to a label statement advising to limit exposure to light when using Enstilar. In large oral doses, betamethasone dipropionate is fetotoxic and teratogenic in mice. Therefore, the label statement advises to use Enstilar during pregnancy only when potential benefit justifies the risk.

Clinical trials conducted with Enstilar recorded few adverse reactions as very little drug substance is absorbed into the systemic circulation. Most reactions were limited to the application site and included pruritus, irritation, pain, rebound effect, folliculitis, hypersensitivity and skin hypopigmentation.

The safety and efficacy of Enstilar was tested for a maximum of 4 weeks in clinical trials. Therefore Enstilars indication was limited to 4 weeks.

Conclusion

In non-clinical and clinical studies, Enstilar demonstrated a favourable Harm-Benefits-Uncertainty profile.