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Calcipotriol and Betamethasone Dipropionate (Dovobet*, Daivobet®): A New Formulation for the Treatment of Psoriasis

Y. Poulin, MD, FRCPC
Department of Dermatology, Centre Hospitalier Universitaire de Quebec, Canada

ABSTRACT

A new compound product containing calcipotriol 50μg/gm and betamethasone dipropionate 0.5mg/gm (Dovobet*, LEO Pharma) in an ointment base was recently introduced in Canada for the treatment of psoriasis. Known as Daivobet® in Europe, it was introduced to the Danish market in 2001, and approved for marketing by the European Union. This compound has been shown to be more active than either agent used alone. The efficacy of once daily application was not shown to be different from that of twice daily use.

Key Words: psoriasis, calcipotriol, betamethasone dipropionate

Calcipotriol

Calcipotriol is safe and efficacious for the treatment of psoriasis when used alone, but has a slow onset of action,1,2 which works mainly by favoring keratinocyte differentiation.3-5 Skin irritation occurs in 10% to 15% of patients.6 Calcipotriol does not influence calcium homeostasis at dosages of 100gm per week or less.7

Corticosteroids

Topical corticosteroids are efficacious in the treatment of psoriasis, working by inhibition of inflammatory processes.8 However, the risk of side-effects from corticosteroids increases with the potency of the steroid molecule and the duration of use.

The corticosteroid and the calcipotriol molecules work via different pathways in the treatment of psoriasis, and the anti-inflammatory properties of the corticosteroid reduce the potential skin irritation from calcipotriol.9,10 Using both of them simultaneously is a rational approach in the control of psoriasis.

Combining Calcipotriol and Corticosteroids

Using a combination of calcipotriol and a corticosteroid has been reported previously.9-14 In these trials, calcipotriol and the steroid were applied at different times of the day, in alternate weeks or in alternate days. All these trials demonstrated a higher speed of psoriasis improvement with the dual regimen. Most of them also showed a higher success rate and a better side-effect profile for the combination regimens.

Extemporaneous compounding of calcipotriol with a corticosteroid is tempting. However this may rapidly lead to deleterious alterations of the active molecules.15 Calcipotriol needs a basic pH, whereas betamethasone dipropionate requires an acidic one. Satisfactory, stable mixing of these components that were previously considered unmixable was obtained by creating an entirely new vehicle. In this new vehicle, betamethasone dipropionate remains unchanged, as does the calcipotriol molecule,16 and demonstrates full antipsoriatic activity.17 At room temperature, the shelf life of this compound is 2 years.

Clinical Trials

A series of prospective, randomized, double-blind parallel group clinical trials involving about 6,000 psoriatic subjects was done to evaluate the comparative efficacy of the new product versus its individual components.18 All these trials clearly showed that the new combination product was significantly more active than either agent used alone. Moreover, the results of once daily dosing were very similar to those seen with twice daily application.

In a trial by Douglas, et al,19 1,106 patients were randomized to twice daily double-blind treatment with the combination (Dovobet*), betamethasone dipropionate and calcipotriol for 4 weeks. The mean decrease in PASI from baseline to the end of the double-blind phase was 74.4% for the Dovobet* group compared to 61.3% in the betamethasone group and 55.3% in the calcipotriol group. Patients then received twice daily calcipotriol, unblinded, for a further 4 weeks. Ninety two percent of the randomized patients entered the maintenance phase of the study. Although this phase was open, investigators and patients were still blinded to what treatment had been used before. At the end of the double-blind phase, the mean PASI in the combination to calcipotriol group was 2.5 and 3.6 at the end of the maintenance phase. The corresponding figures for the betamethasone to calcipotriol group were 3.9 and 4.1, and for the calcipotriol to calcipotriol group 4.4 and 3.7. Psoriasis was maintained under control following transfer to calcipotriol without any signs of rebound flare.19

The results of three randomized, double-blind trials involving a total of 2,964 patients (including Douglas, et al’s19) were recently presented.19-21 Table 1 summarizes the main data from these trials. After one month of treatment, the mean percentage reduction in the Psoriasis Area and Severity Index (PASI) was 68.6% for the once daily application of the product and 73.2-74.4% for the twice-daily use. In comparison, the decrease in the PASI score for betamethasone dipropionate used alone twice daily was 61.3- 63.1%. The mean decrease in PASI score for calcipotriol used alone twice daily was 48.8-58.8%. As per the investigators’ assessments, 68-76.1% of patients achieved a 75-100% overall improvement for the twice daily application of the new compound. In comparison, 46.6-55.8% of the betamethasone dipropionate group, and 33.4-50.7% of the calcipotriol group achieved a 75-100% overall improvement.

Moreover, all trials showed a faster response in reducing the PASI score for the new product; major improvement was seen after only 1 week of treatment. For example, the results of a trial where the compound product was applied only once daily showed a mean reduction in PASI of 48.1% after only 1 week of treatment with the combination ointment, vs. 41.4% with betamethasone dipropionate applied twice daily, and 28.4% with calcipotriol applied twice daily.

Douglas19

Papp20

Guenther21

Number of randomized subjects

1106

1040

818

Mean % reduction in PASI after 1 week:

  • Dovobet* b.i.d.
  • Dovobet* once daily
  • Betamethasone dipropionate b.i.d.
  • Calcipotriol b.i.d.
  • Vehicle b.i.d.


47.4%
— —
39.8%
31%
— —


48.1%
— —
41.4%
28.4%
21.5%


47.6%
45.5%
— —
33.6%
20%

Mean % decrease in PASI after 4 weeks:

  • Dovobet* b.i.d.
  • Dovobet* once daily
  • Betamethasone dipropionate b.i.d.
  • Calcipotriol b.i.d.
  • Vehicle b.i.d.


74.4%
— —
61.3%
55.3%
— —


73.2%
— —
63.1%
48.8%
28.8%


73.8%
68.6%
— —
58.8%
26.6%

% of subjects who achieved 75-100% of improvement
(investigators’ assessment)

  • Dovobet* b.i.d.
  • Dovobet* once daily
  • Betamethasone dipropionate b.i.d.
  • Calcipotriol b.i.d.
  • Vehicle



68%
— —
46.6%
38.9%
— —



76.1%
— —
55.8%
33.4%
7.5%



73.5%
63.3%
— —
50.7%
9.2%.

Adverse Effects

All trials demonstrated that the side-effects were lower in the groups receiving the new compound, compared with those receiving calcipotriol alone. All trials restricted the amount of ointment to be used to less than 100g/wk, and serum calcium was measured with no changes reported.18

Skin irritation was reduced by combining betamethasone dipropionate with calcipotriol. Transfering patients to calcipotriol treatment was found to be safe and maintained the clinical control of the psoriasis.20,21

Conclusion

The new formulation containing both calcipotriol and betamethasone dipropionate in an optimal vehicle leads to fast, effective results, and has less side-effects than calcipotriol used alone.
* registered trademark of LEO Pharmaceutical Products used under the licence by LEO Pharma Inc., Thornhill, Ontario, Canada.

Acknowledgement

We wish to thank J.E. Swan for her contribution to this manuscript.

References

  1. Ashcroft DM, Po AL, Williams HC, Griffiths CE. Systematic review of comparative efficacy and tolerability of calcipotriol in treating chronic plaque psoriasis. BMJ 320(7240):963-7 (2000 Apr).
  2. Ashcroft DM, Li Wan Po A, Williams HC, Griffiths CE. Combination regimens of topical calcipotriene in chronic plaque psoriasis: systematic review of efficacy and tolerability. Arch Dermatol 136(12):1536-43 (2000 Dec).
  3. Reichrath J, Muller SM, Kerber A, Baum HP, Bahmer FA. Biologic effects of topical calcipotriol (MC 903) treatment in psoriatic skin. J Am Acad Dermatol 36(1):19-28 (1997 Jan).
  4. Kragballe K, Iversen L. Calcipotriol. A new topical antipsoriatic. Dermatol Clin 11(1):137-141 (1993 Jan).
  5. Kragballe K. Treatment of psoriasis with calcipotriol and other vitamin D analogues. J Am Acad Dermatol 27(6 Pt 1):1001-8 (1992 Dec).
  6. Cullen SI. Long-term effectiveness and safety of topical calcipotriene for psoriasis. Calcipotriene Study Group. South Med J 89(11):1053-6 (1996 Nov).
  7. Guzzo C, Lazarus G, Goffe BS, Katz HI, Lowe NJ, Pincus SH. Topical calcipotriene has no short-term effect on calcium and bone metabolism of patients with psoriasis. J Am Acad Dermatol 34(3):429-33 (1996 Mar).
  8. Lange K, Kleuser B, Gysler A, et al. Cutaneous inflammation and proliferation in vitro: differential effects and mode of action of topical glucocorticoids. Skin Pharmacol Appl Skin Physiol 13(2):93-103 (2000 Mar-Apr).
  9. Kragballe K, Barnes L, Hamberg KJ, et al. Calcipotriol cream with or without concurrent topical corticosteroid in psoriasis: tolerability and efficacy. Br J Dermatol 139(4):649-54 (1998 Oct).
  10. Singh S, Reddy DC, Pandey SS. Topical therapy for psoriasis with the use of augmented betamethasone and calcipotriene on alternate weeks. J Am Acad Dermatol 43(1 Pt 1):61-5 (2000 Jul).
  11. Lebwohl M, Yoles A, Lombardi K, Lou W. Calcipotriene ointment and halobetasol ointment in the long-term treatment of psoriasis: effects on the duration of improvement. J Am Acad Dermatol 39(3):447-50 (1998 Sep).
  12. Lebwohl M, Siskin SB, Epinette W, et al. A multicenter trial of calcipotriene ointment and halobetasol ointment compared with either agent alone for the treatment of psoriasis. J Am Acad Dermatol 35(2 Pt 1):268-9 (1996 Aug).
  13. Ortonne JP. Psoriasis: New therapeutic modality by calcipotriol and betamethasone dipropionate. Nouv Dermatol 14:746-51 (1995).
  14. Salmhofer W, Maier H, Soyer HP, Honigsmann H, Hodl S. Double-blind, placebo-controlled, randomized, right-left study comparing calcipotriol monotherapy with a combined treatment of calcipotriol and diflucortolone valerate in chronic plaque psoriasis. Acta Derm Venereol Suppl (Stockh) (211):5-8 (2000).
  15. Patel B, Siskin S, Krazmien R, Lebwohl M. Compatibility of calcipotriene with other topical medications. J Am Acad Dermatol 38(6 Pt 1):1010-1 (1998 Jun).
  16. Traulsen J, Parneix-Spake A. The bioavailability of betamethasone dipropionate in an ointment combination with calcipotriol (Daivobet Ointment) is equal to that of betamethasone alone in Diprosone ointment. J Eur Acad Dermatol Venereol 15(Suppl 2):250 (2001 Nov). Poster P 24-51 presented at the 10th Congress of the EADV (2001 Oct), Munich, Germany.
  17. Van Rossum MM, van Erp PE, van de Kerkhof PC. Treatment of psoriasis with a new combination of calcipotriol and betamethasone dipropionate: a flow cytometric study. Dermatology 203(2):148-52 (2001).
  18. Data on file, LEO Pharma.
  19. Douglas WS, Poulin Y, Decroix J, et al. A new calcipotriol/betamethasone formulation with rapid onset of action was superior to monotherapy with betamethasone dipropionate for calcipotriol in psoriasis vulgaris. Acta Derm Venereol 82:131-35 (2002).
  20. Papp K, Talbot DJ and the study group. Rapid onset of action and superior efficacy in psoriasis vulgaris with a new combination product containing calcipotriol and betamethasone dipropionate in a new vehicle. J Eur Acad Dermatol Venereol 15(Suppl 2):245 (2001 Nov). Poster P 24-36 presented at the 10th Congress of the EADV (2001 Oct), Munich, Germany.
  21. Guenther L, Springborg J and the study group. Daivobet ointment-A new fixed combination of Calcipotriol and Betamethasone Dipropionate is effective used once daily in Psoriasis Vulgaris. J Eur Acad Dermatol Venereol 15(Suppl 2):237 (2001 Nov). Poster P 24-2 presented at the 10th Congress of the EADV (2001 Oct), Munich, Germany.

In this issue:

  1. Calcipotriol and Betamethasone Dipropionate (Dovobet*, Daivobet®): A New Formulation for the Treatment of Psoriasis
  2. The Utility of Patch Testing Children with Atopic Dermatitis
  3. Update on Drugs and Drug News - June 2002