Calcipotriol and Betamethasone Dipropionate for the Treatment of Psoriasis: A 52-Week Study

J. W. P. Toole, BSc, MD, FRCPC
Section of Dermatology, University of Manitoba, Winnipeg, MB, Canada

ABSTRACT

Psoriasis is a common skin disease affecting 1%-3% of the world’s population with significant impacts on quality of life. There is a great need for therapies that are efficacious and safe, not only for the short-term, but also for long-term management. Dovobet^®/ Daivobet^®/ Taclonex^® is a product combining two molecules, calcipotriol and betamethasone dipropionate, that may offer psoriatic patients with an option for maintenance therapy. The efficacy and safety of this combined formulation when used over a 4-week period is well documented. A recent publication in the British Journal of Dermatology discusses the safety of this product when used for 52 weeks.1

Key Words: Calcipotriol, Betamethasone Dipropionate, Psoriasis

Dovobet^®(Leo Pharma)/ Daivobet^®(Leo Pharma)/ Taclonex^®(Warner Chilcott) is a two-compound ointment containing calcipotriol 50ìg/gm and betamethasone dipropionate 0.5mg/gm. Hereafter, this ointment will be referred to as either “Dovobet^®” or “combination product” in this article.

Calcipotriol

Calcipotriol is a Vitamin D analog with a broad range of pharmacologic activities. Like vitamin D, calcipotriol inhibits keratinocyte proliferation, promotes epidermal differentiation and has a significant impact on cytokines and T-cells in the skin. Calcipotriol, however, has much less effect on calcium levels as compared to vitamin D. Topical calcipotriol 50ìg/gm has been used worldwide for over 15 years for the treatment of psoriasis vulgaris. A plethora of randomized controlled double-blind studies have confirmed its efficacy.^2,3

Topical calcipotriol has a good long-term safety profile and again there are many studies documenting this.^3,4 Most adverse reactions relate to initial application, irritation to or aggravation of existing psoriatic lesions. There have been isolated case reports of hypercalcemia,⁵ however this is uncommon when application is limited to <100gm/week in adults.

Corticosteroids

Topical corticosteroids have been the cornerstone of psoriasis therapy for many years. A recent study demonstrated that a super-potent steroid was used by 44% of psoriasis patients.⁶ Their efficacy and limitations are well known. Apart from concerns relating to systemic absorption, the major concern relating to long-term topical steroid use is cutaneous atrophy and its various clinical presentations.

Betamethasone dipropionate has been categorized by the World Health Organization as a group III (mid-high) potency steroid. It has been shown to be safe and effective in treating psoriasis vulgaris.

Combined Formulation

Initially, combining betamethasone dipropionate and calcipotriol in a vehicle proved difficult as these two substances are incompatible in aqueous and alcoholic media. In Dovobet^®, these molecules are combined in a water free vehicle, ensuring maximum stability and efficacy. It is also formulated to achieve optimal skin permeability.⁷

A recent study documented the effects of the molecules, in isolation and in combination, when used on psoriatic skin.⁸ Calcipotriol alone had a major effect on the proliferation marker Ki-67 and differentiation marker keratin-10 (K-10) while reducing T-cell subsets CD 45RO (+) and CD8 (+). Betamethasone dipropionate produced a highly significant increase of the K-10 positive epidermal surface without an effect on Ki-67 positive nuclei, and the effect on T-cell subsets was a reduction of natural cell to cell receptors CD94 and CD161 in the epidermis. Therapy involving both molecules showed no added effect in relationship to proliferation marker Ki-67 and keratinization marker keratin-10, but when amalgamated, they had a profound effect on all T-cell subsets. This suggested a different mode of action of the two molecules on psoriatic plaques at the molecular level and points to evidence that supports a synergistic effect when they are combined.

Dovobet^® has been proven to be highly effective in treating psoriasis vulgaris.⁹ A recent study suggested PASI 50 and PASI 75 response in greater than 80% and 50% of patients respectively, regardless of initial disease severity. The report combined data from six phase III studies involving more than 6500 patients.^10,11

Many recent reports have noted the profound effect that psoriasis has on the quality of life of patients. When applied once daily, Dovobet^® has been shown to be superior to calcipotriol applied twice daily in improving the quality of life of patients with psoriasis vulgaris.¹²

The majority of studies documenting the efficacy and safety of Dovobet^® have been limited to four-week periods of observation. As such, due to the chronic nature of psoriasis, detailed documentation to track long-term safety and efficacy is required by regulatory authorities.

Study Results

Recently, results of a 52-week randomized study of Dovobet^® in the treatment of psoriasis vulgaris were published in the British Journal of Dermatology.¹ The primary objective of this study was to investigate the safety of two treatment regimens involving the “as needed” use of Dovobet^® over 52 weeks. In particular, side-effects relating to the long-term use of a topical steroid were assessed by an adjudication panel consisting of three dermatologists not otherwise involved in the study.

Patients were randomized to one of the three double-blinded treatment groups:

• 52-weeks of combination product;
• 52-weeks of alternating 4-week periods of the combination product and calcipotriol ointment (alternating group); and
• 4-weeks of the combination product followed by 48 weeks of calcipotriol ointment (calcipotriol [non-steroidal control] group).

Treatment was limited to once daily application as required, and usage was limited to a maximum of 100gm/week per patient. Patients were seen every 4 weeks for assessment of adverse effects. A subset of 19 patients had adrenal function tests at baseline and after 4, 12, and 62 weeks.

The study was conducted from August 2002 to April 2004 and 634 patients were enrolled in 67 European centers and 10 Canadian centers. The treatment groups were similar with respect to age, sex, ethnic origin, duration of psoriasis, duration of previous topical steroid use and disease severity.

There were 21.7% of patients that developed adverse drug reactions in the Dovobet^® group, 29.6% in the alternating group, and 37.9% in the calcipotriol group. In addition to the aggravation of existing psoriatic lesions, the most common adverse reaction was application-related irritation. The most common adverse reactions with calcipotriol treatment are known to be irritation and pruritus, as was reflected in the calcipotriol group. This study indicates that the steroid molecule reduces the irritative effect of calcipotriol in the Dovobet^® group. The incidence of initial flare-ups of psoriatic lesions was similar in all groups.

There was one systemic event in the subset of 19 patients undergoing adrenal function testing. This one patient, who demonstrated adrenal insufficiency, was in the calcipotriol treatment group. Consequently, the event was considered unrelated to the therapy.

Skin atrophy was identified by the adjudication panel in 1.9% of the Dovobet^® group, 0.5% of the alternating group, and 1.0% in the calcipotriol group. The four patients identified in the Dovobet^® group demonstrated atrophy at 10–33 weeks of therapy and the condition resolved in three of the four patients. The fourth patient had used topical corticosteroids continuously for the previous 10 years prior to the study and continued to use Dovobet^® every other day, as needed, in the remaining 40 weeks of the study following identification of the atrophy. In addition, he was prescribed Dovobet^® once the study was completed. Folliculitis was noted by the adjudication panel in three patients in the Dovobet^® group and in one patient in the alternating group, however all cases were mild. One patient in the calcipotriol group developed cellulitis. There were two cases of depigmentation in the Dovobet^® group, one of which had resolved during the period of observation.

The study concluded that Dovobet®, when used for up to 52 weeks, was safe and well tolerated whether used as monotherapy, or alternating every 4 weeks with calcipotriol treatment.

Conclusion

The combination of calcipotriol and betamethasone dipropionate has been proven to be a very effective option for the topical treatment of psoriasis vulgaris.8-12 Recently published findings indicate its safety and tolerability for continuous use as needed for up to 52 weeks.¹

References

1. Kragballe K, Austad J, Barnes L, et al. A 52-week randomized safety study of a calcipotriol/betamethasone dipropionate two-compound product (Dovobet/Daivobet/Taclonex) in the treatment of psoriasis vulgaris. Br J Dermatol 154(6):1155-60 (2006 Jun).
2. Ramsay CA, Berth-Jones J, Brundin G, et al. Long-term use of topical calcipotriol in chronic plaque psoriasis. Dermatology 189(3):260-4 (1994 Jan).
3. Aaronson DS, Lebwohl M. Review of therapy of psoriasis: the prebiologic armamentarium. Dermatol Clin 22(4):379-88 (2004 Oct).
4. Cullen SI. Long-term effectiveness and safety of topical calcipotriene for psoriasis. Calcipotriene Study Group. South Med J 89(11):1053-6 (1996 Nov).
5. Georgiou S, Tsambaos D. Hypercalcaemia and hypercalciuria after topical treatment of psoriasis with excessive amounts of calcipotriol. Acta Derm Venereol 79(1):86 (1999 Jan).
6. Pearce DJ, Spencer L, Hu J, et al. Class I topical corticosteroid use by psoriasis patients in an academic practice. J Dermatolog Treat 15(4):235-8 (2004 Jul).
7. Simonsen L, Hoy G, Didriksen E, et al. Development of a new formulation combining calcipotriol and betamethasone dipropionate in an ointment vehicle. Drug Dev Ind Pharm 30(10):1095-102 (2004 Jan).
8. Vissers WH, Berends M, Muys L, et al. The effect of the combination of calcipotriol and betamethasone dipropionate versus both monotherapies on epidermal proliferation, keratinization and T-cell subsets in chronic plaque psoriasis. Exp Dermatol 13(2):106-12 (2004 Feb).
9. Papp KA, Guenther L, Boyden B, et al. Early onset of action and efficacy of a combination of calcipotriene and betamethasone dipropionate in the treatment of psoriasis. J Am Acad Dermatol 48(1):48-54 (2003 Jan).
10. Anstey AV, Kragballe K. Retrospective assessment of PASI 50 and PASI 75 attainment with a calcipotriol/betamethasone dipropionate ointment. Int J Dermatol 45(8):970-5 (2006 Aug).
11. Kragballe K, van de Kerkhof PC. Consistency of data in six phase III clinical studies of a two-compound product containing calcipotriol and betamethasone dipropionate ointment for the treatment of psoriasis. J Eur Acad Dermatol Venereol 20(1):39-44 (2006 Jan).
12. van de Kerkhof PC. The impact of a two-compound product containing calcipotriol and betamethasone dipropionate (Daivobet/Dovobet) on the quality of life in patients with psoriasis vulgaris: a randomized controlled trial. Br J Dermatol 151(3):663-8 (2004 Sep).

1. Calcipotriol and Betamethasone Dipropionate for the Treatment of Psoriasis: A 52-Week Study
2. Drug Treatments for Skin Disease Introduced in 2006
3. Update on Drugs and Drug News - May 2007