A new scalp formulation of calcipotriol plus betamethasone dipropionate compared with each of its active ingredients in the same vehicle for the treatment of scalp psoriasis: a randomized, double-blind, controlled trial

Background There is a need for new treatments for scalp psoriasis, as many topical treatments are cosmetically unacceptable and difficult to apply, resulting in poor compliance. Objectives To compare the efficacy and safety of a new, once‐daily, two‐compound scalp formulation (Xamiol^®; LEO Pharma A/S, Ballerup, Denmark) containing calcipotriol 50 μg g^?1 plus betamethasone 0·5 mg g^?1 (as dipropionate), with the active ingredients as single compounds in the same vehicle. Methods This 8‐week, multicentre, double‐blind, parallel‐group study, randomized adult patients with scalp psoriasis involving > 10% of the scalp to the two‐compound scalp formulation (n = 568), betamethasone dipropionate 0·5 mg g^?1 (n = 563), or calcipotriol 50 μg g^?1 (n = 286). The primary efficacy measure was the proportion of patients with ‘absence of disease’ or ‘very mild disease’ according to investigators’ assessments at week 8. Results The proportion of patients with ‘absence of disease’ or ‘very mild disease’ at week 8 was significantly higher in the two‐compound group (68·4%) than the betamethasone dipropionate (61·0%, P = 0·0079) or calcipotriol (43·4%, P < 0·0001) groups. The proportion of patients rating their scalp psoriasis as ‘clear’ or ‘almost clear’ was significantly higher for the two‐compound scalp formulation (69·6%) than for betamethasone dipropionate (59·9%, P = 0·0006) or calcipotriol (44·7%, P < 0·0001). The incidence of lesional/perilesional adverse events was lower in the two‐compound and betamethasone dipropionate groups than the calcipotriol group. Conclusions The two‐compound scalp formulation was well tolerated and more effective in the treatment of scalp psoriasis than either of its individual components in the same vehicle.     

Significant one week efficacy of a calcipotriol plus betamethasone dipropionate scalp formulation

Background A two‐compound scalp formulation containing calcipotriol (50 μg/g) and betamethasone (0.5 mg/g; as dipropionate) (Xamiol^®, Taclonex Scalp^®) has been shown to be an effective and safe treatment for scalp psoriasis. Objective The aim of this study was to investigate the clinical efficacy of the two‐compound scalp formulation after 1 week of treatment. Methods Pooled data from two large pivotal phase III trials with 2920 patients receiving once‐daily treatment for up to 8 weeks with either the two‐compound scalp formulation (n = 1108), betamethasone dipropionate (n = 1118), calcipotriol (n = 558), or the vehicle (n = 136) were analysed. Results The percentage of patients who had ‘absent’ or ‘very mild’ disease according to Investigator’s Global Assessment after 1 week of treatment was significantly higher with the two‐compound scalp formulation (30.6%) compared to betamethasone (24.1%; P < 0.001), calcipotriol (10.0%; P < 0.001) or vehicle (6.9%; P < 0.001). Conclusion This data indicates that the two‐compound scalp formulation demonstrated significant efficacy already after 1 week, with a faster onset of effect than either of the individual components in the same vehicle, in the treatment of scalp psoriasis.     

Comparative effects of calcipotriol solution (50 μg/ml) and betamethasone 17-valerate solution (1 mg/ml) in the treatment of scalp psoriasis

The efficacy, tolerability and safety of calcipotriol solution and betamethasone 17-valerate solution were compared in a multicentre, prospective, randomized, double-blind, parallel group study. Four hundred and seventy-four patients with scalp psoriasis were recruited from six European countries and Canada. Following a 2-week washout period, either calcipotriol solution (50 μg/ml) or betamethasone 17-valerate solution (1 mg/ml) was applied twice daily for 4 weeks. After this time, patients who required no further active treatment were observed for relapse. Retreatment with calcipotriol was offered to those patients who relapsed, and who were originally in the calcipotriol-treated group. The two treatment groups were well matched at baseline. At the end of treatment, the proportion of patients who had ‘cleared’ or ‘markedly improved’ was statistically significantly greater in the betamethasone group (75%) than in the calcipotriol group (58%) (P < 0.001) (95% confidence interval of difference 25.3 → 8.6). The decrease in total sign score (sum of scores for erythema, thickness and scaliness) at the end of treatment was also statistically significantly greater in the betamethasone group (61%) than the calcipotriol group (45%) (P < 0.001) (95% confidence interval of difference 9.7 → 23.1). Adverse events were reported by 87 patients in the calcipotriol group, and 31 patients in the betamethasone group; the most common was lesional or perilesional irritation, which occurred significantly more frequently with calcipotriol (26%) than with betamethasone (8%) (P < 0.001). Fifteen patients (6%) in the calcipotriol group and four (1%) in the betamethasone group withdrew from the study because of adverse events or unacceptable treatment response (P < 0.017). There was no statistically significant change in serum total calcium in either treatment group. There was no significant difference in the rate of relapse between the two treatment groups. In the 69 calcipotriol-treated patients who relapsed, re-treatment with calcipotriol was effective and well tolerated. Calcipotriol solution was effective in treating mild to moderate scalp psoriasis. However, betamethasone solution was significantly more effective, and was associated with statistically significantly less local irritation on the scalp and face.     

Efficacy of treatment with calcipotriol/betamethasone dipropionate followed by calcipotriol alone compared with tacalcitol for the treatment of psoriasis vulgaris: a randomised, double-blind trial

BACKGROUND: A two-compound product containing calcipotriol 50 microg/g and betamethasone dipropionate 0.5 mg/g (Daivobet, Dovobet) has been demonstrated to be an effective, once daily, treatment for psoriasis vulgaris. OBJECTIVE: To compare the efficacy and safety of treatment with the two-compound product for 4 weeks followed by calcipotriol for 4 weeks, with that of tacalcitol for 8 weeks in patients with stable psoriasis vulgaris. METHODS: 501 patients were randomised to double-blind treatment with the two-compound product followed by calcipotriol 50 microg/g once daily, or to tacalcitol 4 microg/g once daily. RESULTS: Treatment with the two-compound product/calcipotriol was significantly more effective than tacalcitol in terms of mean percentage PASI reduction (65.0 vs. 33.3% at week 4 and 59.0 vs. 38.4% at week 8; p < 0.001 for both). CONCLUSION: A treatment regimen comprising calcipotriol/betamethasone ointment (Daivobet) for 4 weeks followed by calcipotriol for 4 weeks is superior to tacalcitol ointment for 8 weeks in patients with psoriasis vulgaris.     

Efficacy and safety of a new combination of calcipotriol and betamethasone dipropionate (once or twice daily) compared to calcipotriol (twice daily) in the treatment of psoriasis vulgaris: a randomized,double-blind,vehicle-controlled clinical trial

BACKGROUND: Calcipotriol and betamethasone dipropionate are both widely used, effective treatments for psoriasis. Vitamin D analogues and topical corticosteroids have different mechanisms of action in the treatment of psoriasis. A new vehicle has been developed in order to contain both calcipotriol (50 micro g g-1) and betamethasone dipropionate (0.5 mg g-1) in an ointment form. By using calcipotriol and a corticosteroid together, greater efficacy may be achieved than by using either compound alone. OBJECTIVES: The present study was conducted in order to compare the clinical efficacy and safety of the combined ointment formulation used once daily with the vehicle ointment used twice daily, calcipotriol ointment used twice daily and the combined formulation used twice daily in psoriasis vulgaris. METHODS: This was an international, multicentre, prospective, randomized, double-blind, vehicle-controlled, parallel group, 4-week study in patients with psoriasis vulgaris amenable to topical treatment. Patients were randomized to one of four treatment groups: combined formulation once daily, combined formulation twice daily, calcipotriol twice daily or vehicle twice daily. Efficacy and safety were assessed. RESULTS: There was no statistically significant difference in the mean percentage change in the Psoriasis Area and Severity Index (PASI) from baseline to end of treatment between the two combined formulation groups, but the difference in PASI reduction was significantly higher in the combined formulation groups (68.6% once daily, 73.8% twice daily) than in both the twice daily calcipotriol group (58.8%) and the vehicle group (26.6%). Safety data showed the frequency of adverse events to be less in the combined formulation groups than in both the calcipotriol group and the vehicle group. The proportion of patients with lesional/perilesional adverse reactions was less in the combined formulation groups and vehicle group than in the calcipotriol group (9.9% combined formulation once daily, 10.6% combined formulation twice daily, 19.8% calcipotriol, 12.5% vehicle). CONCLUSIONS: No statistically significant nor clinically relevant difference in efficacy was seen between the combined formulation used once daily and twice daily. When compared to vehicle ointment or calcipotriol ointment alone, the combined formulation was shown to be clearly more efficacious.     

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

BACKGROUND: Calcipotriol and betamethasone dipropionate are both proven products in the topical treatment of psoriasis. The efficacy and tolerability of a new ointment containing these two compounds has been assessed in six phase III clinical studies. OBJECTIVE: To compare the results obtained in the clinical studies of the new calcipotriol/betamethasone dipropionate ointment. METHODS: A total of 6050 patients with psoriasis took part in the six randomized, double-blind studies. The two-compound product was compared with each of the active constituents, either in the new ointment vehicle or in the marketed formulation. RESULTS: After 4 weeks of treatment the mean reduction in the Psoriasis Area and Severity Index (PASI) ranged from 65 to 74% with the two-compound product applied once or twice daily, from 46 to 59% with calcipotriol alone and from 57 to 63% with betamethasone dipropionate alone. The tolerability profile of the two-compound product was similar to betamethasone dipropionate monotherapy and better than calcipotriol alone. CONCLUSION: The new two-compound product containing calcipotriol and betamethasone dipropionate was found to consistently provide rapid, highly effective treatment of psoriasis vulgaris.     

A new calcipotriol/betamethasone formulation with rapid onset of action was superior to monotherapy with betamethasone dipropionate or calcipotriol in psoriasis vulgaris

In this study, we compared a new combination ointment containing both calcipotriol and betamethasone dipropionate with betamethasone dipropionate ointment (Diprosone) and calcipotriol ointment (Daivonex) in patients with psoriasis vulgaris; 1106 patients were randomized to twice daily double-blind treatment with combination, betamethasone dipropionate or calcipotriol for 4 weeks. Patients then received twice daily calcipotriol, unblinded, for a further 4 weeks. Mean percentage change in PASI at end of the double-blind phase was -74.4 (combination group), -61.3 (betamethasone group) and -55.3 (calcipotriol group). Mean difference (95% Cl) combination-betamethasone was -13.1 (-16.9 to -9.3, p < 0.001) and for combination-calcipotriol -19.0 (-22.8 to -15.2, p <0.001). The differences in PASI were also statistically significant after 1 week. In the double-blind phase, 8.1% of patients (combination) reported lesional/ perilesional adverse reactions compared to 4.7% (betamethasone) and 12.0% (calcipotriol). In the combination group, mean PASI at the end of the double-blind phase was 2.5, and at end of the unblinded phase 3.6, compared with 3.9 and 4.1 (betamethasone) and 4.4 and 3.7 (calcipotriol). Calcipotriol/betamethasone combination is more effective and has a more rapid onset of action than either active constituent used alone, and is well tolerated. It is safe to transfer patients from combination to calcipotriol, with maintenance of clinical effect.     

Comparative effects of calcipotriol (MC903) solution and placebo (vehicle of MC903) in the treatment of psoriasis of the scalp

The efficacy and safety of calcipotriol solution in the treatment of scalp psoriasis was compared with placebo (vehicle solution), in a multicentre double-blind, randomized, parallel-group study of 49 adult patients. Calcipotriol solution (50 μg/ml), or placebo, was applied twice daily over a 4-week period. At the end of the study period 60% of patients on calcipotriol showed clearance or marked improvement of their psoriasis compared with 17% on placebo. Overall assessment of treatment response showed that calcipotriol was superior to placebo in both investigator (P<0.001;95% confidence interval for difference 19.0–67.6) and patient (P<0.001; 95% confidence interval for difference 18.3–68.0) assessments. Total sign score for psoriasis (i.e. the sum of the scores for redness, thickness and scaliness) decreased by 48.9% in the calcipotriol group, and by 18.6% in the placebo group (P =0.005). Calcipotriol was significantly superior to placebo in reducing redness, thickness, scaliness and extent of psoriasis, and in the patients’assessment in reducing scalp flaking and itching. No statistically significant changes in blood biochemistry were detected during the study, and the solution was generally well tolerated.     

Long-term treatment of psoriasis with calcipotriol scalp solution and cream

The efficacy and safety of long-term concurrent twice-daily treatment of scalp and body psoriasis with calcipotriol scalp solution (50 mcg/ml) and calcipotriol cream (50 mcg/g) were evaluated in a prospective, multi-centre, open-label, non-controlled evaluation over 52 weeks in 202 patients. Safety and efficacy as measured by total sign score (scalp psoriasis), modified PASI (body psoriasis) and patient self-assessment were assessed at week 2, 6 and 10 and thereafter every six weeks. By week 28, mean total sign score for scalp psoriasis had reduced from 5.9 to 2.5 (p<0.001). No further reduction was seen. By week 34, mean PASI for body psoriasis had reduced from 6.8 to 2.6 (p<0.001). No further reduction was seen. At week 52, the percentage of patients assessing their psoriasis as moderate or severe had decreased from 72 to 21% for scalp psoriasis and from 62 to 19% for body psoriasis. Facial irritation was the most frequent adverse event (91/276 events) with the highest incidence occurring at week 2 and few new reports at subsequent visits. There were no significant changes in mean serum calcium, parathormone or urinary calcium/creatinine ratio. Combined treatment with calcipotriol scalp solution and cream was effective and safe for long-term treatment of scalp and body psoriasis.     

Spotlight on Calcipotriene/Betamethasone Dipropionate in Psoriasis Vulgaris of the Trunk, Limbs, and Scalp

Calcipotriene (calcipotriol)/betamethasone dipropionate (calcipotriene 50 mg/g and betamethasone 0.5 mg/g) is a fixed-dose combination of a vitamin D₃ analog and a corticosteroid indicated for the oncedaily, topical treatment of psoriasis vulgaris of the trunk, limbs, and scalp in adults. Both the ointment (Daivobet®;Dovobet®) and gel (Xamiol®; Daivobet® Gel; Dovobet® Gel) formulations of calcipotriene/betamethasone dipropionate can be used to treat psoriasis vulgaris of the trunk and/or limbs, although the gel formulation was specifically developed for the treatment of scalp psoriasis. This article reviews the efficacy and tolerability of calcipotriene/betamethasone dipropionate in patients with psoriasis vulgaris, as well as summarizing its pharmacologic properties. Calcipotriene/betamethasone dipropionate has low systemic absorption and displays local antiinflammatory and immunoregulatory properties. It reduces the hyperproliferation of keratinocytes and helps normalize keratinocyte differentiation. In large, well designed clinical trials, calcipotriene/betamethasone dipropionate, either as the ointment or the gel formulation, applied once daily for 4–8 weeks, was more effective than placebo, calcipotriene, or tacalcitol, as well as betamethasone dipropionate in most instances, for the topical, symptomatic treatment of psoriasis vulgaris of the trunk/limbs. Likewise, calcipotriene/betamethasone dipropionate gel applied once daily for 8 weeks was more effective than placebo or either component alone in the topical, symptomatic treatment of psoriasis vulgaris of the scalp. Long-term, once-daily, when required therapy with calcipotriene/betamethasone dipropionate for 52 weeks was more effective than calcipotriene alone for the treatment of scalp psoriasis, and was at least as effective as switching to calcipotriene for 48 weeks after 4 weeks of calcipotriene/betamethasone dipropionate or alternating between calcipotriene/betamethasone dipropionate and calcipotriene every 4 weeks for 52 weeks in the treatment of psoriasis vulgaris of the trunk/limbs. Calcipotriene/betamethasone dipropionate also improved health-related quality of life. Calcipotriene/betamethasone dipropionate was generally well tolerated, with most adverse drug reactions being lesional or perilesional effects of mild or moderate severity. Calcipotriene/betamethasone dipropionate was often associated with fewer lesional/perilesional adverse reactions than calcipotriene or tacalcitol and did not appear to be associated with a higher incidence of corticosteroid-related adverse events during long-term therapy. Pharmacoeconomic analyses predicted calcipotriene/betamethasone dipropionate to be more cost effective than other topical therapies. Thus, calcipotriene/betamethasone dipropionate is an important, effective, once-daily, topical therapy for the symptomatic treatment of psoriasis vulgaris of the trunk, limbs, and scalp.     

A new calcipotriol/betamethasone dipropionate formulation (Daivobet) is an effective once-daily treatment for psoriasis vulgaris

BACKGROUND: Topical corticosteroids and calcipotriol have been used separately for many years to treat psoriasis. A new combination ointment has been formulated, which contains both calcipotriol and the corticosteroid betamethasone dipropionate. OBJECTIVE: To compare the combination ointment with betamethasone dipropionate ointment, calcipotriol ointment and ointment vehicle in patients with psoriasis vulgaris. METHODS: 1,603 patients were randomised to one of the 4 double-blind treatments used once daily for 4 weeks. RESULTS: The mean percentage change in the PASI at the end of treatment was -71.3 (combination), -57.2 (betamethasone), -46.1 (calcipotriol) and -22.7 (vehicle). The mean difference of combination minus betamethasone was -14.2 (95% CI: -17.6 to -10.8, p < 0.001), of combination minus calcipotriol -25.3 (95% CI: -28.7 to -21.9, p < 0.001) and of combination minus vehicle -48.3 (95% CI: -53.2 to -43.4, p < 0.001). 6.0% of patients (combination) reported local adverse reactions compared to 4.9% (betamethasone), 11.4% (calcipotriol) and 13.6% (vehicle). CONCLUSION: Calcipotriol/betamethasone dipropionate combination ointment used once daily is well tolerated and more effective than either active constituent used alone.     

Safety and Efficacy of Calcipotriene Plus Betamethasone Dipropionate Topical Suspension in the Treatment of Extensive Scalp Psoriasis in Adolescents Ages 12 to 17 Years

The objective of this study was to assess the safety and efficacy of the fixed combination calcipotriene 0.005% plus betamethasone dipropionate 0.064% topical suspension in adolescents with extensive scalp psoriasis. In this phase II, open‐label, 8‐week study, adolescents with psoriasis (ages 12–17 years) with 20% or more of the scalp area affected (at least moderate severity according to Investigator's Global Assessment [IGA]) were assigned to once‐daily treatment with calcipotriene plus betamethasone dipropionate topical suspension. The primary endpoint was safety, focusing on calcium metabolism and hypothalamic–pituitary–adrenal axis function. Secondary efficacy endpoints were the proportion of patient's achieving treatment success (clear or almost clear disease according to the IGA and clear or very mild disease according to the Patient's Global Assessment [PaGA]) and percentage change in investigator‐assessed Total Sign Score (TSS). Pruritus was also assessed. Overall, 31 patients received treatment. Sixteen patients (52%) experienced a total of 20 adverse events; 19 were considered unrelated to study treatment, 14 were mild, and none were serious or lesional or perilesional on the scalp. One patient showed signs of mild adrenal suppression at week 4; the patient discontinued treatment and had normal test results at follow‐up 4 weeks later. No cases of hypercalcemia were reported. By treatment end, treatment success was reported for 17 patients (55%) according to the IGA and 18 (58%) according to the PGA. Mean TSS improved from 6.9 at baseline to 2.9 at treatment end (59% improvement). By week 8, 28 patients (90%) experienced mild or no itching, versus 20 (65%) at baseline. Once‐daily calcipotriene plus betamethasone dipropionate topical suspension was well tolerated and efficacious for the treatment of scalp psoriasis in adolescents.     

Effective treatment and improvement of quality of life in patients with scalp psoriasis by topical use of calcipotriol/betamethasone (Xamiol®‐gel): results

Background: Quality of life of patients with scalp psoriasis is greatly impaired due to itch and scaling. To control the disease long‐term therapy is necessary and treatment success is greatly dependent on compliance. Patients and Methods: In a prospective, non‐interventional trial in German dermatological practices 721 patients with scalp psoriasis received Xamiol^® gel (calcipotriol 50 μg/g, betamethasone 0,5 mg/g) topically for 4 weeks. Severity was assessed by physician's global assessment (PGA) and quality of life by using a scalp‐specific questionnaire at the beginning of the study and after 4 weeks of treatment. Results: The mean disease severity of scalp psoriasis (PGA) improved from 4.26 to 2.49 (–41.8 %, p < 0.0001) during 4 weeks of treatment and quality of life improved from 10.57 to 3.22 (–69.5 %, p < 0.0001). Among patients with pre‐treatment 89.5 % of patients and 87.9 % of dermatologists judged treatment response to Xamiol^® gel as better/much better compared to previous therapy. Tolerability of Xamiol^® gel was rated good/very good by 98 % of dermatologists and patients, respectively. The use of Xamiol^® gel was found easy/very easy by 90.4 % of the patients. Conclusions: Due to the major improvement of quality of life and quick onset of improvement together with the high acceptance by the patients Xamiol^® gel may be regarded as the topical treatment of choice for scalp psoriasis.     

A calcipotriene/betamethasone dipropionate two-compound scalp formulation in the treatment of scalp psoriasis in Hispanic/Latino and Black/African American patients: results of the randomized, 8-week, double-blind phase of a clinical trial

The calcipotriene/betamethasone dipropionate two-compound scalp formulation has been shown to be safe and effective in the treatment of scalp psoriasis over 8 weeks, but the patients studied were mainly White and non-Hispanic. The aim of this study was to evaluate the efficacy and safety of the two-compound scalp formulation in the treatment of scalp psoriasis in Hispanic/Latino and Black/African American patients. A total of 99 Hispanic/Latino and 78 Black/African American patients were randomized double-blind in a 3:1 ratio to 8 weeks of once daily treatment of scalp psoriasis with either the two-compound scalp formulation (n=135) or its vehicle (n=42). In the two-compound group, 71.9% of patients had cleared or minimal disease at week 8 by the investigator's global assessment compared to 40.5% in the vehicle group (odds ratio 3.30; 95% CI 1.62-6.72; P<0.001). For the five secondary efficacy response criteria, three (total sign score, thickness of scalp psoriasis, patient's global assessment) showed that two-compound scalp formulation was statistically significantly more effective than its vehicle, and the other two (redness and scaliness of scalp psoriasis) approached statistical significance in favor of the two-compound scalp formulation. There was no statistically significant difference (P=1.00) between the percentage of patients with adverse reactions in the two-compound group (7.0%) and the vehicle group (7.9%). The two-compound scalp formulation is safe and effective in the treatment of scalp psoriasis over 8 weeks in Hispanic/Latino and Black/African American patients.     

Topical treatments for scalp psoriasis: summary of a Cochrane Systematic Review

People with chronic plaque psoriasis often have lesions on the scalp that are difficult to treat. This report is a summary of a Cochrane review on the efficacy and safety of topical treatments for scalp psoriasis. For quality‐of‐evidence assessment, we used the Grading of Recommendations Assessment, Development and Evaluation Working Group approach. Only randomized controlled trials (RCTs) were eligible for inclusion. We searched the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase and LILACS; ongoing trials; indexes of included studies and screened abstracts of six psoriasis‐specific conferences up to August 2015. We included 59 RCTs, with 11 561 participants overall. Most findings were limited to short‐term treatments (< 6 months). According to the clinician and patients’ self‐assessment, a corticosteroid–vitamin D combination (e.g. betamethasone dipropionate plus calcipotriol) and corticosteroids of high and very high potency were better than vitamin D. The two‐compound combination was superior to the corticosteroid alone, but the additional benefit was small. Reporting of quality‐of‐life data was insufficient. The two‐compound combination and corticosteroids caused fewer withdrawals due to adverse events than vitamin D. There was no difference between the two‐compound combination and corticosteroid monotherapy concerning this outcome. Overall the evidence was of moderate quality. Evaluation of other topical treatments was limited. Given the comparable safety profile and only slim benefit of the two‐compound combination over the corticosteroid alone, monotherapy with generic topical corticosteroids of high and very high potency may be fully acceptable for short‐term therapy. More quality‐of‐life data and long‐term assessments are needed.     

Efficacy of once-daily treatment regimens with calcipotriol/betamethasone dipropionate ointment and calcipotriol ointment in psoriasis vulgaris

BACKGROUND: A two-compound ointment containing calcipotriol 50 micro g g-1 and betamethasone dipropionate 0.5 mg g-1 has recently been shown to be an effective treatment for psoriasis. OBJECTIVES: This study was designed to investigate efficacy and safety of different treatment regimens with the two-compound product (Daivobet/Dovobet; LEO Pharma, Ballerup, Denmark) and calcipotriol 50 micro g g-1 ointment (Daivonex/Dovonex; LEO Pharma). METHODS: In total, 972 patients with psoriasis vulgaris were randomized to one of three treatment regimens: group 1, the two-compound product once daily for 8 weeks followed by calcipotriol ointment once daily for 4 weeks; group 2, the two-compound product once daily for 4 weeks followed by 8 weeks of treatment with calcipotriol ointment once daily on weekdays and the two-compound product once daily at weekends; and group 3, calcipotriol ointment twice daily for 12 weeks. The efficacy was evaluated by Psoriasis Area and Severity Index (PASI) and investigators' global assessments of disease severity. The primary response criteria were percentage reduction in PASI and proportion of patients with absent/very mild disease according to the investigators' global assessments after 8 weeks of treatment. RESULTS: The mean reduction in PASI from baseline to the end of 8 weeks of treatment was 73.3% for group 1, 68.2% for group 2 and 64.1% for group 3. The proportion of patients with absent/very mild disease at the end of 8 weeks of treatment was 55.3% for group 1, 47.7% for group 2 and 40.7% for group 3. For both primary response criteria, group 1 was statistically superior to group 3 (P < 0.001), whereas group 2 did not differ significantly from group 3. The difference between group 1 and group 2 was statistically significant with regard to PASI but not regarding the proportion of patients with absent/very mild disease. Patients receiving initial therapy with the two-compound product achieved the fastest treatment response, and the maximum treatment effect for these patients was seen after 5 weeks. This effect was maintained with continued treatment with the two-compound product for up to 8 weeks. After 12 weeks of treatment, no significant differences were seen between the three groups with regard to reduction in PASI, whereas the proportion of patients with absent/very mild disease in group 2 was superior to that in group 3. Patients receiving therapy with the two-compound product experienced fewer lesional/perilesional adverse drug reactions than the calcipotriol-treated patients (P < 0.001): 10.9% in group 1, 11.5% in group 2 and 22.3% in group 3. CONCLUSIONS: Two different short-term treatment regimens employing a recently developed two-compound product (calcipotriol/betamethasone dipropionate) provided rapid and marked clinical efficacy and were shown to be safe therapies for psoriasis vulgaris.     

An Open Label Prospective Randomized Trial to Compare the Efficacy of Coal Tar-Salicylic Acid Ointment Versus Calcipotriol/Betamethasone Dipropionate Ointment in the Treatment of Limited Chronic Plaque Psoriasis

Background:Chronic plaque psoriasis is a common papulosquamous skin disorder, for which a number of topical agents are being used including coal tar, topical steroids and more recently topical calcipotriol/betamethasone dipropionate. There is no study comparing purified coal tar preparation with calcipotriol/betamethasone dipropionate ointment in limited chronic plaque psoriasis.Results:Mean PASI was significantly lower at week 2 (P = 0.01) and week 4 follow-up (P = 0.05) and the mean reduction in PASI was significantly higher at week 2 (P = 0.02) with calcipotriol/betamethasone than coal tar-salicylic acid, but this difference was not sustained at subsequent follow-up visits. Similarly, PGA scores at weeks 2 and 4 were significantly lower with calcipotriol/betamethasone dipropionate ointment (P = 0.003 and P = 0.007 respectively). There was no significant difference in any parameter during subsequent follow-up visits or at the end of the treatment phase (12 weeks).Conclusion:Topical nightly application of calcipotriol/betamethasone dipropionate ointment leads to an initial, more rapid reduction in disease severity, but the overall outcome parameters are comparable in the two treatment groups.     

Calcipotriol solution for the treatment of scalp psoriasis: evaluation of efficacy, safety and acceptance in 3,396 patients

BACKGROUND: Psoriasis of the scalp is a very common disease, cosmetically disturbing and therapeutically difficult to manage. OBJECTIVE: The aim of our study was to investigate the efficacy, safety and cosmetic acceptance of calcipotriol solution in a large number of patients with mild to moderate scalp psoriasis and to compare this treatment with previous therapies used. METHODS: In this multicentre prospective observational cohort study 3,396 patients were treated with calcipotriol solution (50 microg/ml) twice daily over an 8-week period either alone or in combination with other treatments. The psoriasis scalp severity index (PSSI) and investigator/patient global assessment were used for the evaluation of clinical response. RESULTS: All psoriasis severity parameters measured were reduced with a significant decrease in PSSI scores from 18.4 to 5.6 after 8 weeks of therapy (p < 0.001). About 80% of the patients showed very good or good clinical improvement. Combination of calcipotriol solution with other treatment modalities e.g. corticosteroids or salicylic acid, showed an increased treatment response. In only 2.4% of the patients side effects occurred (e.g. irritation). CONCLUSION: Calcipotriol solution is an effective, safe, well-tolerated and cosmetically acceptable treatment modality. By patients and physicians, this treatment was found to be a valuable supplement to previously available and established treatments for scalp psoriasis.     

Calcipotriol plus Betamethasondipropionat-Gel in der Behandlung der Kopfhautpsoriasis

Scalp psoriasis has a significant psychosocial impact on individuals affecting their quality of life. It occurs in 50–80% of patients with psoriasis and may be the only affected area of the body. Current topical therapies for scalp psoriasis are difficult or unpleasant to apply, resulting in decreased adherence and efficacy. A combination of calcipotriol and betamethasone dipropionate in a gel formulation has been developed and approved in Germany for the treatment of scalp psoriasis. Multiple randomized controlled clinical trials have confirmed the efficacy and safety of the new formulation. After two weeks, 60% of patients showed significant improvement; this climbed to 70%, after eight weeks. It may be safely used for up to 52 weeks. No cases of atrophy, striae, or steroid purpura were noted in two 52-week studies. Although scalp psoriasis can often be adequately treated with topical therapy, there is a need for treatment recommendations and algorithms for severe forms and for patients with extended body involvement, taking the combination of systemic and topical treatment and the presence of comorbidities into account.     

Calcipotriol Ointment

Abstract

Calcipotriol, a vitamin D₃ analog, acts not only to inhibit cell proliferation and enhance cell differentiation in the skin of patients with psoriasis, but also appears to have effects on immunologic markers that are thought to play a role in the etiology of the disease. In several well designed, short term studies in adults, calcipotriol ointment 50 μg/g twice daily provided similar or superior efficacy to several other antipsoriatic agents in adult patients with mild to moderate psoriasis. In patients with nonscalp psoriasis, the drug provided superior efficacy to twice daily placebo (vehicle ointment), twice daily fluocinonide 500 μg/g, once daily tacalcitol 4 μg/g and twice daily coal tar 5% plus allantoin 2% and hydrocortisone 0.5%. Furthermore, calcipotriol therapy generally provided superior efficacy to twice daily betamethasone valerate 1 to 1.2 mg/g or once daily dithranol 1 to 20 mg/g, and similar efficacy to twice daily betamethasone dipropionate plus salicylic acid or once daily maxacalcitol 6 to 50 μg/g. Limited data indicated that calcipotriol ointment 50 μg/g also improved overall disease severity in children. In combination with other antipsoriatic agents [acitretin, cyclosporine, betamethasone valerate, halobetasol (ulobetasol)], ultraviolet B or psoralen ultraviolet A (PUVA) phototherapy, calcipotriol ointment 50 μg/g twice daily improved the beneficial effects of these drugs on overall disease severity in adult patients with moderate to severe psoriasis. Furthermore, in separate trials, calcipotriol combination therapy reduced the dosage of acitretin required to achieve clearance of psoriasis and the duration of PUVA and dosage of UVA phototherapy, potentially improving the benefit/risk ratio for these other antipsoriatic treatments. Calcipotriol was generally well tolerated in short and long term studies in adult patients, with the majority of adverse events being mild to moderate in intensity and transient. The most common adverse events associated with calcipotriol therapy were dermatologic in nature and included lesional or perilesional irritations, face and scalp irritations, worsening of psoriasis and miscellaneous dermatologic events. Notably, there have been very few reports of patients developing hypercalcemia or hypercalciuria during calcipotriol therapy, with most occurring in patients who exceeded the recommended dosage of 100 g/week. Although data in children are limited, the drug was well tolerated with the nature and incidence of adverse effects similar to those observed in adult patients. Conclusions: Extensive clinical experience, along with several short and long term clinical trials, has shown calcipotriol ointment to be an effective and well tolerated topical agent in adult patients with psoriasis. In addition, calcipotriol ointment proved beneficial in combination with other topical, phototherapy or systemic antipsoriatic treatments, reducing the dosage and/or duration of some of these treatments and potentially improving their benefit/risk ratio. Calcipotriol ointment is valuable as a first- or second-line therapy option for the management of mild to moderate psoriasis and in combination with other antipsoriatic agents for more severe psoriasis.

Pharmacologic Properties

Calcipotriol inhibits cell proliferation and enhances cell differentiation in the skin of patients with psoriasis. These effects are mediated by binding of the drug to vitamin D receptors. Flow cytometric analysis of epidermal samples has shown significant decreases relative to placebo in numbers of proliferating basal keratinocytes in psoriatic skin treated with topical calcitriol. In addition, application of calcipotriol ointment 50 μg/g twice daily for up to 8 weeks has been shown to result in partial recovery of the stratum corneum, restoration of the stratum granulosum, and correction of intercellular spacing and number and structure of desmosomes. Application of calcipotriol ointment for 4 weeks has been associated with suppression of epidermal T cell and polymorphonuclear leucocyte accumulation in psoriatic lesions. The drug has also been shown to reduce numbers and activity of Langerhans cells, although these effects have not been shown consistently across studies and require further investigation. Other effects described include increased interleukin-10 and reduced interleukin- 8 expression, and normalization of cellular integrin distribution. Overall, application of up to 120 g/week of calcipotriol ointment 50 μg/g did not alter calcium utilization or bone turnover in pharmacodynamic studies in humans. Dosages of 100 to 300 g/week have, however, been associated with increased levels of calcium and reduced levels of parathyroid hormone (PTH) in serum, and increased urinary excretion of calcium. These effects have been attributed to increased intestinal absorption of calcium and subsequent suppression of secretion of PTH and endogenous calcitriol. Measurement of levels of radioactivity in blood, urine and feces after application of ointment containing ³H-calcipotriol has indicated systemic absorption of up to approximately 6% of applied drug in patients with psoriasis. Calcipotriol appears to be metabolized and cleared rapidly after absorption, with hepatic oxidation to 2 relatively inactive metabolites (MC1046 and MC1080) being the major route of elimination. Data obtained in rats showed elimination half-lives in blood collected up to 10 minutes after intravenous administration to be 4 and 14 minutes for calcipotriol and calcitriol, respectively. Corresponding total clearance values were 0.68 and 0.0055 L/h.

Clinical Efficacy

The short term clinical efficacy of calcipotriol ointment 50 μg/g twice daily has been evaluated in several reasonably sized (≥50 enrolled patients) comparative studies of ≤14 weeks duration in adult patients with psoriasis. In placebo (vehicle)-controlled studies, calcipotriol recipients experienced better reductions in overall disease severity (52 to 59% vs 16 to 35%), with a greater percentage of calcipotriol-treated patients achieving a ≥75% improvement in severity of psoriasis or complete clearance (responders) than placebo (59 to 74% vs 12 to 19%). Furthermore, topical calcipotriol ointment 50 μg/g twice daily provided superior efficacy to once daily tacalcitol 4 μg/g, twice daily fluocinonide 500 μg/g or twice daily coal tar 5% plus allantoin 2% and hydrocortisone 0.5% in patients with nonscalp psoriasis. In addition, calcipotriol recipients generally experienced superior beneficial effects on psoriasis severity to betamethasone valerate (1 to 1.2 mg/g twice daily) or once daily dithranol 1 to 20 mg/g recipients and similar efficacy to those receiving betamethasone dipropionate plus salicylic acid or once daily maxacalcitol 6 to 50 μg/g. Calcipotriol ointment also had significantly (p < 0.001) greater cosmetic acceptability than short-contact dithranol cream. Patient’s quality of life was significantly (p ≤ 0.02, both comparisons) improved from pretreatment levels with twice daily calcipotriol ointment 50 μg/g (assessed using Psoriasis Disease Index and Sickness Impact Profile instruments). Long term evaluations indicated that improvements in disease severity demonstrated with calcipotriol ointment therapy in the short term were maintained throughout the study period in several noncomparative trials of up to 1 year in duration in adult patients with psoriasis. At the end of the treatment period, 54 to 98% of calcipotriol recipients had shown a marked or ≥75% improvement in severity of psoriasis in these trials. Furthermore, in a randomized double-blind study, significantly (p < 0.05) more recipients of combination ‘pulse therapy’ consisting of calcipotriol ointment 50 μg/g (applied twice daily on week days) plus halobetasol ointment 500 μg/g (applied twice daily during the weekend) remained in remission throughout the 6-month study period than halobetasol recipients (using the same dosage plus placebo ointment twice daily during the week) [76 vs 40%]. Combining topical calcipotriol ointment (50 μg/g) with a topical corticosteroid, ultraviolet B (UVB) phototherapy, psoralen ultraviolet A (PUVA) phototherapy, or systemic (cyclosporine, acitretin) antipsoriatic agents improved the effects of the individual agents in reducing overall disease severity in short term studies of 2 to 12 weeks’ duration in adults. Overall psoriasis severity scores were reduced by 74 to 91% with calcipotriol-combination therapy compared with reductions of 35 to 83% in comparator agent monotherapy groups. Importantly, the addition of calcipotriol to acitretin or PUVA phototherapy reduced the dosage of these antipsoriatic therapies required and duration of UVA phototherapy. Data on the therapeutic efficacy of topical calcipotriol ointment in children are limited. After 8 weeks’ therapy, there was no significant difference in the reduction in overall disease severity between twice daily calcipotriol ointment 50 μg/g and placebo (ointment vehicle; 52 vs 37% reduction) in children aged 2 to 14 years. Nevertheless, subscale scores for erythema and scaling showed significantly (p < 0.05, both comparisons) greater reductions in calcipotriol than placebo recipients. In addition, significantly (p < 0.05) more calcipotriol recipients had shown a marked improvement or clearance of psoriasis than placebo (60 vs 44%). Topical calcipotriol ointment 50 μg/g twice daily also proved effective in reducing disease severity in a long term noncomparative study in 12 children aged 8 to 15 years. The mean overall Psoriasis Area and Severity Index score was reduced by 65% following calcipotriol treatment for a mean duration of 40 weeks.

Tolerability

In short term studies (6 to 8 weeks’ duration) the most common dermatologic adverse events associated with calcipotriol ointment 50 μg/g twice daily were lesional and perilesional irritation (12 to 20.1% of patients), face and scalp irritations (2 to 4.2%), worsening of psoriasis (2.9 to 3.9%) and miscellaneous adverse events (2.2 to 10.9%). The incidence of nondermatologic adverse events (e.g. arthralgias, bronchospasm, fatigue, flu-like symptoms, headache and nausea/vomiting) in these large trials was 1.2 to 2.9% of patients, with the overall incidence of adverse events ranging from 12 to 35.1% of patients. Symptoms were generally transient and mild to moderate in intensity. Zero to 10.2% of patients withdrew because of adverse events attributable to calcipotriol ointment treatment. The nature of adverse events occurring in long term studies was similar to those observed with short term studies, although the overall incidence of adverse events declined over time. Serious adverse events associated with calcipotriol therapy were rare. Calcipotriol ointment 50 μg/g twice daily was better tolerated than dithranol, but was associated with a significantly (p < 0.001) higher incidence of lesional and perilesional irritation than betamethasone valerate treatment. Although no significant differences in the nature and incidence of adverse events were reported between calcipotriol ointment or tacalcitol treatment in patients with nonscalp psoriasis, in those with scalp psoriasis there was a trend to a higher incidence of facial irritations with calcipotriol than tacalcitol. In general clinical practice, there have been very few reports of patients developing hypercalcemia or hypercalciuria during calcipotriol therapy, with most occurring in patients who exceeded the recommended dosage of 100 g/week. All episodes of hypercalcemia or hypercalciuria have resolved on discontinuation of treatment. Furthermore, there were no reports of any significant abnormalities in hematologic and biochemical laboratory parameters with twice daily calcipotriol ointment 50 μg/g in clinical trials. Limited data from short term studies of 8 weeks’ duration indicated that calcipotriol ointment 50 μg/g twice daily was well tolerated in 99 children aged 2 to 15 years. No serious adverse events were reported. Adverse events were similar to those observed in adults. In a short term study, adverse events possibly or probably related to calcipotriol therapy were lesional and perilesional irritations (11 to 16% of patients), irritations of the face and/or scalp (5 to 6%), various skin rashes (6%) and worsening of psoriasis (2%). In addition, there were no significant changes in hematologic or biochemical laboratory parameters, including no clinically relevant changes in liver and renal function tests or serum calcium levels. Although data are very limited, a study in 12 children (aged 8 to 15 years) indicated that calcipotriol ointment 50 μg/g twice daily (for up to 106 weeks; mean duration of therapy was 40 weeks) was well tolerated with no serious adverse effects reported.

Dosage and Administration

Calcipotriol ointment 50 μg/g is approved for the treatment of moderate plaque psoriasis. It should be applied once or twice daily to the affected area up to a maximum of 100 g/week in adult patients. In Japan, the maximum recommended adult dosage is 90 g/week. Currently, in the US there are no dosage recommendations available for the use of calcipotriol in children, whereas in the UK the maximum recommended dosage in children aged 6 to 12 years is 50 g/week increasing to 75 g/week in those over 12 years of age; no dosage recommendations are available for children less than 6 years of age. Calcipotriol should not be applied to the face or eyes, and hands should be washed to prevent this happening inadvertently. Calcipotriol is contraindicated in patients with known calcium metabolism disorders, evidence of vitamin D toxicity or hypersensitivity to calcipotriol or any other constituents of the ointment. The use of the drug during pregnancy is not recommended.