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Calcipotriol/betamethasone for the treatment of psoriasis: efficacy, safety, and patient acceptability

Authors Rogalski C

Received 12 March 2015

Accepted for publication 28 April 2015

Published 8 June 2015 Volume 2015:5 Pages 97—107

DOI https://doi.org/10.2147/PTT.S63127

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 6

Editor who approved publication: Prof. Dr. Uwe Wollina



Christina Rogalski

Medical Business Development, edia.con gemeinnützige GmbH, Leipzig, Saxony, Germany

Background: One of the advances in the treatment of plaque-type psoriasis is combined local therapy with calcipotriol and betamethasone. To provide both ingredients in a two-compound product, efforts have been made to unite calcipotriol and betamethasone because they are usually inactivated when present in the same formulation. This aspect was resolved when carefully designed vehicle components were invented (gel and ointment). This article reviews the efficacy, safety, and patient acceptability of calcipotriol/betamethasone dipropionate.
Methods: A literature search of all articles published until February 2015 was performed, including the largest medical databases. The search strategy for evaluating the main topics of this review – efficacy, safety, and patient acceptability – was defined before checking the publications.
Results: Seventy references were found and checked for relevance. For efficacy, the proportion of patients whose psoriasis improved was always significantly higher in the two-compound group compared to the group treated with the individual substances. In the context of safety, the fixed combination was generally associated with a lower risk of adverse events. In terms of patient acceptability, the fixed combination led to a significant improvement in quality of life. The two-compound product was more convenient to handle and time saving compared to former treatments.
Conclusion: Calcipotriol/betamethasone dipropionate in a fixed combination is an effective and well-tolerated medication in mild-to-moderate psoriasis of body and scalp and, in addition, is an evidence-based treatment modality.

Keywords: psoriasis, calcipotriol/betamethasone, safety, efficacy, fixed combination, two-compound medication

Introduction

The treatment of psoriasis has been well studied. Especially, topical corticosteroids and vitamin D analogs are effective agents in mild-to-moderate plaque-type psoriasis.

Their mode of action, the pathophysiological rationale for the treatment of psoriasis, as well as their described adverse effects lead to the idea of combining calcipotriol and betamethasone as a promising treatment modality. Concerning both medications, the past decade was characterized by various clinical trials to evaluate efficacy and safety in the topical treatment of psoriasis.

Concerning the side effects, potent steroids such as betamethasone are associated with cutaneous atrophy, formation of telangiectasia, striae, perioral dermatitis, and rebound effects. Systemic effects can occasionally result in a suppression of the hypothalamic–pituitary–adrenal axis (in case of excessive amounts or if applied under occlusion). Calcipotriol does not produce any of the side effects of betamethasone. The only known local adverse reaction is skin irritation (common in application to the face and intertriginous areas).1

This spectrum of side effects is partly canceled when calcipotriol and betamethasone are combined. Their different mechanisms of action are the reason for this phenomenon. Calcipotriol acts on vitamin D receptors as an analog to correct epidermal proliferation, abnormal keratinization, and angiogenesis. In contrast to calcipotriol, corticosteroids stimulate or inhibit genes, interfering with inflammatory pathways (inhibition of cytokine production and reduction of inflammatory mediators such as prostaglandins and leukotrienes).2 The other reason for a combination of both substances is their influence on the disease pattern: Psoriasis is characterized by a chronic inflammatory skin condition, accompanied by hyperproliferation and abnormal differentiation of the keratinocytes. Both calcipotriol and betamethasone exert their action on these pathological features. The combined medical therapy with different mechanisms of action and safety profiles enhances efficacy.2

To provide both ingredients in a two-compound product, efforts have been made to unite calcipotriol and betamethasone because they are usually inactivated in the same formulation. This aspect was resolved when carefully designed vehicle components were invented. Since 2008 (approval for use on the scalp in Canada and the USA) and 2004 (approval for use on the remainder of the skin surface), fixed combinations of calcipotriol/betamethasone dipropionate have been approved for the treatment of psoriasis (gel and ointment).

This article reviews the efficacy, safety, and patient acceptability of calcipotriol/betamethasone dipropionate.

Methods

A literature search of all articles published until February 2015 was performed, including the largest medical databases (eg, MEDLINE and EMBASE). The search strategy for evaluating the main topics of this review – efficacy, safety, and patient acceptability – was defined before checking the publications. Search terms were as follows: “betamethasone calcipotriol” and either “two-compound” or “fixed combination”. Seventy references were found and checked for relevance.

Articles included in the analysis had to meet the following criteria: review of randomized controlled trials or meta-analyses or original randomized controlled clinical trials; evaluation of the two-compound calcipotriol/betamethasone dipropionate; and published in English, French, Spanish, or German (Figure 1).

Figure 1 Flowchart of the publication selection process.

This article is a narrative review. Therefore, a meta-analysis is not carried out and no restriction on data abstraction is necessary.

The articles on clinical trials (Table 1) and (systematic) reviews (Table 2) have been searched for information on safety, efficacy, and patient acceptability.

Table 1 Publications of clinical trials on calcipotriol/betamethasone dipropionate in a fixed-dose combination
Abbreviations: DESIRE, Daivobet®/Dovobet® Experience Study In Regions of Europe; PRO-long, Patient Reported Outcomes in a long-term study.

Table 2 Reviews and meta-analyses on the two-compound calcipotriol/betamethasone dipropionate formulation
Abbreviations: NA, not applicable; PASI, Psoriasis Area and Severity Index.

Efficacy

The Cochrane Review of topical treatments for chronic plaque psoriasis3 analyzed the results of 2,058 patients from among five parallel-group studies to find proof of the efficacy of the two-compound product versus placebo in reduction of Psoriasis Area and Severity Index (PASI) score.

Calcipotriol/betamethasone products were also compared to corticosteroids. Four between-patient trials reported Investigator’s Assessment of Overall Global Improvement (IAGI) data for 1,991 participants. As these treatment comparisons were very different, only subtotals were pooled. In all but one trial,4 combination treatment was significantly more effective than corticosteroid administration alone.

The severity of psoriasis or the age of the patient has no impact on the observed response.5 To summarize the study results, the cochrane review on topical treatments for plaque type psoriasis performed a meta-analysis to compare vitamin D combination products to placebo. Four clinical trials were included in the analysis, applying a combination of calcipotriol/betamethasone once daily.4,68 The standardized mean difference [SMD] was –1.14; 95% confidence interval [CI]: –1.57; –0.70. The twice daily application12,23 was also effective (SMD: –1.41; CI: –1.86; –0.97). Since application twice daily is not more effective than once a day (SMD: –1.24; CI: –1,53; –0.95),50 the latter is the regimen of choice.9

The treatment of scalp psoriasis is characterized by clinical management with guidelines and clear evidence-based recommendations. Therefore, Bottomley et al10 performed a systematic review to assist physicians with prescribing choices. The two-compound formulation was more effective than other commonly used therapies (potent steroids, calcipotriol alone, Polytar, or Capasal) in terms of achieving a response to the Investigator’s Global Assessment (IGA) scale and local skin signs (Total Sign Score [TSS]).10 Although there is evidence from one clinical trial that it may not be as effective as clobetasol, combined treatment with calcipotriol and betamethasone dipropionate was found to be significantly less effective than clobetasol propionate spray alone (0.45 standardized mean difference [SMD]; 95% confidence interval [CI]: 0.09–0.81).3

Safety

Moreover, short- and long-term tolerability of the two-compound preparation was stated in a systematic review of >11,000 patients treated in clinical trials.11 Only 0.8% withdrew because of adverse events. The most common adverse reactions were local cutaneous events (ie, pruritus), which occurred less frequently than with other products because of the presence of a potent steroid. To address the possibility of cushingoid untoward effects, two long-term clinical trials observed safety parameters in 1,503 patients treated up to 12 months.12,13 The fixed-combination therapy turned out to be the best tolerated compared to calcipotriol alone or alternated with calcipotriol in 4-week cycles. Side effects of long-term corticosteroid treatments were reported in 22 patients. Adverse drug reactions with incidence >1% were as follows: skin atrophy (n=7) and folliculitis (n=4).12 In the clinical trial performed by Luger et al,13 pruritus was the most common adverse effect, and in one patient, rosacea occurred. Tachyphylaxis phenomenon was not mentioned in any of these trials.

In summary, the fixed-dose combination is associated with 75% less cutaneous reactions compared with tacalcitol and 50% less than with calcipotriene, but nearly the same as the rate after treatment with betamethasone alone.14

The systematic review on the effectiveness of the two-compound formulation calcipotriol and betamethasone dipropionate gel in the treatment of moderately severe scalp psoriasis also revealed data on safety.10 The two-compound gel had significantly lower all adverse event rates than calcipotriol, placebo, and Polytar, though the adverse event rates for the skin were nonsignificantly lower. The systematic review of Guenther14 reports no changes in serum calcium, skin atrophy, or striae in any of the six reviewed trials (n=4,494 patients with psoriasis of the scalp).

A large-scale analysis includes data from 2,700 patients.15 Pooled 8-week safety data from nine clinical trials evaluating once-daily calcipotriol/betamethasone treatment of psoriasis of the body, including the scalp, showed the reduced risk of adverse events when using the combined formulation and stated a favorable safety profile for it. The fixed-combination gel does not provoke any clinically relevant hypercalcemia as vitamin D analogs alone do. The low incidence of pruritus was attributed to the combination with betamethasone. Furthermore, there is evidence from pharmacovigilance data that this treatment modality is also well tolerated in the practical use of the physicians.15

Long-term safety of the two-compound calcipotriol/betamethasone (<100 g/week) has been evaluated in clinical trials for up to 52 weeks. The ointment was well tolerated in patients with psoriasis on the trunk/limbs.12 The most common adverse events were exacerbation of psoriasis, skin burning, pruritus, and erythema.16 With long-term use, there is an increased risk of local and systemic corticosteroid adverse reactions. The treatment should be discontinued in case of adverse reactions related to long-term use of corticosteroid.

Patient acceptability

In chronic diseases such as psoriasis vulgaris, adherence is one of the critical factors of efficacy of a treatment.8 Only 50%–60% of the psoriatic patients are adherent to therapies.17

Pruritus is one distressing symptom in psoriasis, which can lead to discomfort and loss of sleep and finally result in negative effects on daily activity and productivity. As shown in several studies, the fixed-combination therapy resulted in fewer side effects, especially pruritus. The low incidence of pruritus was attributed to the combination with betamethasone.15

For example, the patient information of the calcipotriol/betamethasone in a gel formulation (Xamiol®) states in the patient information that the bottle should be shaken, the hair should be parted to expose the affected area of the skin, the gel should be applied on dry skin and rubbed gently in; and hands should be washed after applying. To remove any excess gel vehicle from the hair, a mild unmedicated shampoo should be applied to dry hair and left on for a few minutes. A second shampooing may be required.18 Several studies examined the quality of life of the patients or patients’ satisfaction during treatment with calcipotriol/betamethasone two-compound products.1923 Clareus et al19 evaluated patient satisfaction after a 4-week course and repeated courses for up to 6 months in 1,224 patients. In approximately 75% of these, satisfaction with treatment was high to very high after one course and remained high with more treatment courses; 60% of the patients were willing to provide copayments for the two-compound product. The quality of life was assessed in the 36-item Short Form Health Survey by Ortonne et al20 and the Disability Index and EuroQoL 5D questionnaire by van de Kerkhof.23 The two-compound scalp formulation was superior to calcipotriol solution alone in terms of the improvement in quality of life in the patients of both trials, whereas Saraceno et al24 did not find a significant difference in improvement of quality of life in their two treatment arms. The practicability of the combined treatment with calcipotriol/betamethasone gel (Daivobet® Gel) was the subject of a quality-of-life study performed by Sticherling et al.22 The fixed combination led to a significant improvement in quality of life. The two-compound product was more convenient to handle and time saving compared to former treatments.

In addition, other reasons for patients’ acceptability of the gel formulation are the once-daily application and the presence of a unique formulation suitable for both the scalp and the body.

The acceptability of a local treatment regimen is determined by several factors: late-onset efficacy, unfavorable galenic or cosmetic features, user-unfriendly application modes, or the occurrence of side effects.13 PASI50 achieved on the 1st week of treatment is a good motivation to trigger adherence to the therapy.3

Discussion

The efficacy of the two-compound formulation calcipotriol/betamethasone has been proven in numerous clinical trials (Table 3). Augustin et al25 compared the results of the clinical trials with their daily current practice use in Germany to make a recommendation. These include statements on efficacy, safety, and acceptability (Table 3) and an algorithm of use: In mild to moderate psoriasis the application of a compound product (once daily/4 weeks) is recommended. In case of clearance, the therapy can be stopped. With noticeable or slight improvement or no change of the skin lesions, the use of another four weeks/once daily is advised. A second line therapy, for example UVB (Ultraviolet B), can be added in cases where the psoriatic lesions worsened.26

Table 3 Combination of evidence and clinical experience
Notes: Data from Augustin et al.25 A2, randomized double-blind comparative clinical trials of good quality (eg, sample size calculation, flow chart, intention-to-treat analysis, sufficient size); B, randomized clinical trials of moderate (weak) quality or other comparative trials (nonrandomized, cohort studies; patient–control studies); C, noncomparative trials.

Because of the quick response, some authors recommend the use of the fixed-dose combination of calcipotriol and betamethasone to complement treatment with biologic response modifiers (such as etanercept, efalizumab, or adalimumab) to improve the patient’s quality of life during the interval before the biologic agent shows its maximum effect (Evidence Level III, opinions of respected authorities).2729 The adjunctive use of a topical calcipotriene (0.005%) and betamethasone dipropionate (0.064%) combination ointment was shown to be effective in sustaining the original efficacy of etanercept by augmenting response to the 50 mg/week subcutaneous dose, thus stabilizing the disease.30

As combination therapy is a common approach to psoriasis to minimize the risk of adverse events and to improve the effect, the fixed-dose combination calcipotriol/betamethasone has been combined with systemic low-dose cyclosporine aimed at a synergistic effect (greater PASI 75 rate at Week 8 and more patients achieved PASI 90 after Week 8). The data of this open-label trial indicate an enhanced clinical response and an optimized risk–benefit ratio.31

Some Chinese medicine therapies have shown therapeutic effect on psoriasis vulgaris.3234 Wen et al35 are going to perform a pilot study to evaluate Chinese medicine (YXBCM01, most common granule used in Guangdong Provincial Hospital) in combination with calcipotriol/betamethasone ointment.

The combination of vitamin D3 analogs with potent corticosteroids accelerates clinical response and increases efficacy. There is evidence for both short- and long-term efficacy and safety. The synergistic effects and the complementary mechanisms of action lead to an increased tolerability and eventually to a better adherence of the patients.

In conclusion, calcipotriol/betamethasone dipropionate in a fixed combination is an effective and well-tolerated medication in mild-to-moderate psoriasis of body and scalp and, in addition, an evidence-based treatment modality.

Disclosure

The author reports no conflicts of interest in this work.


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