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.

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

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