Pooled safety analysis of calcipotriol plus betamethasone dipropionate gel for the treatment of psoriasis on the body and scalp

Transcription

1 DOI: /jdv JEADV ORIGINAL ARTICLE Pooled safety analysis of calcipotriol plus betamethasone dipropionate gel for the treatment of psoriasis on the body and scalp K. Kragballe 1 *, P. van de Kerkhof 2 1 Department of Dermatology, Arhus University Hospital, Arhus, Denmark 2 Department of Dermatology, Radboud University Medical Centre, Nijmegen, The Netherlands *Correspondence: K. Kragballe. kkragballe@dadlnet.dk Abstract The fixed combination calcipotriol plus betamethasone dipropionate gel is a first-line treatment for psoriasis vulgaris. The objective was to perform a large-scale assessment of tolerability of fixed combination gel (Cal/BD). Analysis was performed on pooled 8-week safety data from nine clinical trials evaluating once-daily Cal/BD treatment of scalp (n = 6) and body (n = 3) psoriasis. Pharmacovigilance data were also assessed. Patients were treated with Cal/BD [n = 1953 (scalp), n = 824 (body)], betamethasone dipropionate gel (BD; n = 1214, n = 562), calcipotriol gel (Cal; n = 979, n = 175), gel vehicle (VEH; n = 173, n = 226), calcipotriol scalp solution [n = 104 (scalp only)] and tacalcitol ointment [TAC; n = 184 (body only)]. Most adverse events (AEs) were mild moderate severity. The proportion of scalp psoriasis patients with 1 AE was lowest with Cal/BD (35% versus 38 57%). A similar proportion was found with Cal/BD for body psoriasis (32%), however, lower proportions were reported with BD (24%) and Cal (29%). The most common AEs with Cal/BD included nasopharyngitis, pruritus and upper respiratory tract infection (2 5% of patients). Overall, only 5% of patients treated with Cal/BD reported 1 lesional/perilesional AEs: the lowest incidence versus scalp comparators (6 19%) and second lowest to BD (3%) for body psoriasis. Similarly, Cal/BD treatment resulted in the lowest incidence of 1 adverse drug reactions (ADRs) in scalp psoriasis patients (8% versus 9 27%) and second lowest to BD (6% versus 4%) for body psoriasis. Overall, incidence of serious AEs (SAEs) was low (0 1%). Data received postmarketing through spontaneous reporting revealed that SAEs reported more than once with Cal/BD treatment were psoriasis (n = 5); and alopecia, erythrodermic psoriasis, pruritus, skin atrophy and urticaria (n = 2 each). In this large subset of patients treated with Cal/BD, incidence of AEs and ADRs is consistently low. This analysis provides further evidence of the good tolerability of the fixed combination gel as treatment for psoriasis vulgaris. Received: 21 January 2014; Accepted: 6 February 2014 Conflicts of interest Dr Kragballe has received consultancy fees from LEO Pharma and acted as an advisor/investigator/speaker for Abbott, Janssen, Amgen, Almirall, LEO Pharma, MSD and Pfizer. Professor van de Kerkhof has received consultancy fees and grant support from LEO Pharma. Funding source Medical writing support was provided by Tamara Hirsch, PhD, from Mudskipper Business Ltd, which was funded by LEO Pharma. Previous presentation Primary publications for each study included in this analysis have previously been published. Introduction Psoriasis is one of the most common chronic inflammatory skin conditions, with a prevalence of 2 3% in Western countries, 1 and is associated with serious comorbidities, such as cardiovascular disease, depression and psoriatic arthritis. 2,3 It can have a profound impact on the patient s physical, psychological and social wellbeing, 4,5 significantly compromising their quality of life to a degree comparable with that of other major diseases including cancer and heart disease. 6 Topical therapy remains the mainstay in the treatment of psoriasis, with more than 80% of patients managing their psoriasis with topicals alone Current guidelines for the first-line

2 Pooled safety analysis for fixed combination gel 11 treatment of mild-to-moderate psoriasis recommend the topical use of vitamin D analogues and corticosteroids. 9 Safety concerns typically associated with these monotherapies include skin irritation and hypercalcaemia for vitamin D analogues, skin atrophy and adrenal suppression with long-term use for corticosteroids. As such, a fixed combination topical preparation containing the vitamin D analogue calcipotriol and the corticosteroid betamethasone dipropionate was developed and shown to be well tolerated with superior efficacy versus the individual components for treatment of psoriasis vulgaris Therapeutic benefit is achieved with the fixed combination, promoting greater antiinflammatory and antiproliferative effects than for either active ingredient alone, coupled with a faster response and potentially fewer safety concerns 17,18 compared with monotherapies. This is due to the steroid component of the fixed combination gel depressing the incidence of skin irritation sometimes experienced with use of vitamin D analogues, and calcipotriol potentially reducing steroid-induced skin atrophy. 19 Treatment adherence, particularly where long-term management is required, is a challenge. The issue of non-adherence is complex but, in terms of topical treatment, is exacerbated by the necessity of application, which can be cumbersome and time consuming, and poor acceptability by the patient of certain treatment vehicles, such as ointments, that are often perceived to be messy. 20,21 A lipophilic, alcohol-free gel formulation of the fixed combination preparation (Daivobet â / Dovobet â gel/taclonex â topical suspension [LEO Pharma, Ballerup, Denmark]) was developed to offer minimal impact on the patient s daily routine and thereby promote patient adherence. In Europe, it has been approved for the once-daily treatment of mild-to-moderate psoriasis vulgaris of the body and all severities of psoriasis vulgaris of the scalp, and has been on the market for over 5 years. We wished to perform a large-scale assessment of the tolerability of the fixed combination gel for the treatment of psoriasis of the scalp or body. Analysis on pooled 8-week safety data from nine clinical trials evaluating once-daily fixed combination gel treatment was performed. In addition, postmarketing data from spontaneous reporting have also been collated to provide an overview of the safety profile in the real-world setting. Materials and methods Patients Eligible patients were aged 18 years or above with a diagnosis of psoriasis vulgaris affecting 10% of the scalp or body. Patients were required to have a minimum disease severity rating of mild according to the investigator s global assessment (IGA) and needed to be amenable to topical treatment with a maximum of 100 g of medication per week. Exclusion criteria included any other topical treatment of the body or scalp (except for medicated shampoos in scalp studies and emollients), or ultraviolet B therapy, all within 2 weeks of randomization. Patients were also excluded if they had received biological therapies with a possible effect on psoriasis vulgaris within 1 6 months prior to randomization, and other systemic antipsoriatic therapies, psoralen + UVA or Grenz ray therapy within 4 weeks prior to randomization. All patients provided written, informed consent before entering the study, and the protocol was approved by each centre s institutional review board or ethics committee. Studies Eight-week safety data from nine randomized, double-blind, vehicle-controlled studies were included in these pooled analyses. Data from six trials on patients with scalp psoriasis were included: LEO identifier, MBL 0405 [NCT ], MBL 0406 [NCT ], MBL 0503 [NCT ], MBL 0401 [initiated prior to formalized registration requirements], MBL 0407 [NCT ] and MBL 0502 [NCT ] Three trials on patients with psoriasis of the body were also included: MBL 0202 [NCT ], LEO80185-G23 [NCT ] and LEO80185-G21 [NCT ] (see Fig. 1). 16,18,28 Treatment groups within these studies included once-daily application of the fixed combination calcipotriol plus betamethasone dipropionate gel versus monotherapies in a gel formulation (betamethasone dipropionate gel and calcipotriol gel) plus additional comparator treatments (tacalcitol ointment or twice-daily calcipotriol scalp solution). Each study was approved by the responsible ethics committees at the associated study site and was conducted according to the principles of the Declaration of Helsinki and Good Clinical Practice. The primary objective of these analyses was to establish the safety of the fixed combination gel for the treatment of psoriasis of the scalp and body, by performing a large-scale assessment of the known safety data. This was fulfilled by assessment of clinical trial data and real-world usage (using pharmacovigilance data). Assessments Information about adverse events (AEs) was obtained by means of non-leading questioning of the patients and by recording changes observed by the investigator. For each AE, the nature of the event, intensity, duration and causal relationship according to the investigator s clinical judgement, in addition to the outcome of the event, were recorded. AEs were monitored throughout each study and graded according to the Medical Dictionary for Regulatory Activities (v13.0). Cutaneous events were classified as lesional/perilesional (defined as AEs located 2 cm from the lesional border of the areas treated with the investigational product) or distant from the treated lesions. An additional safety assessment included within these pooled analyses was the level of albumin-corrected serum calcium for which data were included from three scalp studies (NCT , NCT and NCT ) and one body study (NCT ).

3 12 Kragballe and van de Kerkhof Figure 1 Summary of clinical trials assessing safety of fixed combination gel. Pharmacovigilance Postmarketing data on spontaneously reported AEs or adverse drug reactions (ADRs) in patients administered the fixed combination gel in daily practice was extracted from the LEO Pharma global pharmacovigilance safety database (access date: 31 October 2013). Statistical analysis Safety findings from the pooled clinical trial data are reported separately for indication (psoriasis of the scalp and body). In addition, assessment of safety by patient subgroups (according to age, gender, race and baseline disease severity) was also performed. All patients who applied study medication and for whom the presence or confirmed absence of AEs was available were included in these analyses. No formal statistical analyses were performed on the safety data reported here and data are presented descriptively by treatment. Results Patients For the studies included within these analyses, randomized treatment occurred between February 2004 and March Safety data for the fixed combination gel were available for 1953 scalp psoriasis patients and 824 body psoriasis patients. The median age and the mean duration of disease were comparable between the two patient populations, and the majority of patients had psoriasis of moderate severity (according to the IGA) at baseline (Table 1). In the scalp psoriasis studies, most patients completed their randomized 8-week treatment period (81 92%; Table 2). The incidence of withdrawals was lowest with the fixed combination gel and betamethasone dipropionate gel (8% and 9% respectively) compared with other active comparators (16 18%; Table 2). A similar pattern was observed in the body psoriasis studies: 75 93% patients completed treatment, with the lowest incidence of withdrawal with the fixed combination gel (7%) versus the other active treatment groups (11 12%). The mean duration of exposure to the fixed combination gel was slightly higher than its comparators in both pooled analysis sets: 7.3 versus weeks, respectively, in the scalp psoriasis studies and 7.7 versus weeks, respectively, in the body psoriasis studies. The mean doses of the fixed combination gel applied to the scalp and body was 18.6 g and 29.0 g per week, respectively. Safety and tolerability Overall, most AEs that were reported within both analysis sets were of mild-to-moderate severity. The proportion of patients within the scalp psoriasis studies with 1 AE was lowest with fixed combination gel (35%) versus the comparator groups (38 57%). A similar proportion of patients reported 1 AE with fixed combination gel treatment for body psoriasis (32%); however, lower incidences were reported with betamethasone dipropionate gel (24%) and calcipotriol gel (29%; versus 35% for gel vehicle and 45% with tacalcitol ointment). The AE profiles for the fixed combination gel were similar for scalp and body psoriasis with the most common AEs including nasopharyngitis, pruritus and upper respiratory tract infection (reported in 2 5% of patients; Table 3). In patients who were considered to be using a large amount of fixed combination gel (40 g per week), the most commonly reported AE was nasopharyngitis (4 5%) across both pooled analysis sets (Table 4). The proportion of scalp psoriasis patients with 1 lesional/ perilesional AE was lowest with fixed combination gel (5%) compared with the comparator treatments (6 19%; Table 5).

4 Pooled safety analysis for fixed combination gel 13 Table 1 Patient demographics and baseline characteristics Scalp psoriasis Fixed combination gel (n = 1953) Betamethasone gel (n = 1214) Calcipotriol gel (n = 979) Gel vehicle (n = 173) Calcipotriol scalp solution (n = 104) Median age, years (range) 49.0 (17 92) 50.0 (18 91) 49.0 (17 91) 50.0 (18 97) 49.0 (24 85) Sex, Male 894 (46) 537 (44) 444 (45) 87 (50) 44 (42) Mean duration of psoriasis, years (range) 16.0 (0 66) 16.8 (0 71) 16.8 (0 72) 15.3 (1 60) 19.0 (1 70) Mean investigator assessed extent of psoriasis, No involvement 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) <10% 0 (0) 3 (0) 0 (0) 0 (0) 0 (0) 10 29% 757 (39) 400 (33) 352 (36) 67 (39) 45 (43) 30 49% 474 (24) 314 (26) 265 (27) 46 (27) 19 (18) 50 69% 291 (15) 190 (16) 146 (15) 24 (14) 14 (14) 70 89% 243 (12) 172 (14) 115 (12) 19 (11) 12 (12) % 188 (10) 135 (11) 101 (10) 17 (10) 14 (14) IGA, Mild 117 (6) 83 (7) 50 (5) 10 (6) 0 (0) Moderate 1117 (57) 666 (55) 534 (55) 97 (56) 64 (62) Severe 607 (31) 406 (33) 343 (35) 58 (34) 33 (32) Very severe 112 (6) 59 (5) 52 (5) 8 (5) 7 (7) Body psoriasis Fixed combination gel (n = 824) Betamethasone gel (n = 562) Calcipotriol gel (n = 175) Gel vehicle (n = 226) Tacalcitol ointment (n = 184) Median age, years (range) 49.5 (18 84) 48.9 (19 88) 50.1 (18 82) 51.1 (18 82) 51.7 (18 82) Sex, Male 492 (60) 334 (59) 108 (62) 138 (61) 115 (63) Mean duration of psoriasis, years (range) 18.7 (1 80) 16.2 (1 63) 17.5 (1 64) 18.3 (0 70) 19.1 (0 60) Mean investigator assessed extent of psoriasis,*% (range) Total body surface area 11 (2 90) 12 (2 84) 13 (1 60) 10 (2 41) 10 (3 84) IGA, Mild 138 (17) 130 (23) 37 (21) 30 (13) 0 (0) Moderate 597 (73) 417 (74) 126 (72) 164 (73) 119 (65) Severe 84 (10) 14 (3) 12 (7) 32 (14) 58 (32) Very severe 5 (1) 1 (0) 0 (0) 0 (0) 7 (4) *Excludes NCT in which extent of affected body surface area was not recorded. IGA, investigator s global assessment The proportion of patients with psoriasis of the body who reported 1 lesional/perilesional AE with the fixed combination gel was also low (5%), although the lowest incidence occurred with betamethasone dipropionate gel treatment (3%, compared with 7 17% for the other comparators). The incidence of serious AEs (SAEs) was low across both pooled analysis sets (0 1%). For treatment with the fixed combination gel, all reported SAEs were singular occurrences: 13 (0.7%) scalp psoriasis patients experienced a total of 17 SAEs, and 2 SAEs were reported in two (0.2%) patients with psoriasis of the body. Across both pooled analysis sets, no SAEs were considered related to treatment with the fixed combination gel. Two SAEs were considered possibly related to comparator treatment: moderate sinus tachycardia (calcipotriol gel) and nephrolithiasis (betamethasone dipropionate gel). Treatment with the fixed combination gel was discontinued in 12 scalp psoriasis patients (1%; due to 14 AEs) and five patients with psoriasis of the body (1%; due to 7 AEs); all AEs considered possibly related to the fixed combination gel resolved following treatment discontinuation. The proportion of scalp psoriasis patients who experienced 1 ADR was lowest with fixed combination gel treatment (8%) compared with the comparators (9 27%) (Table 6). For treat-

5 14 Kragballe and van de Kerkhof Table 2 Patient disposition Scalp psoriasis Fixed combination gel, Betamethasone gel, Calcipotriol gel, Gel vehicle, Calcipotriol scalp solution, Total number of patients completing treatment period 1795 (92) 1107 (91) 818 (84) 140 (81) 85 (82) Total number of withdrawn patients 158 (8) 107 (9) 161 (16) 33 (19) 19 (18) Unacceptable treatment efficacy 17 (1) 20 (2) 44 (5) 16 (9) 5 (5) Unacceptable AE(s) 19 (1) 15 (1) 55 (6) 7 (4) 9 (9) Exclusion criteria emerging during study 7 (0) 9 (1) 10 (1) 3 (2) 0 (0) Lost to follow-up 44 (2) 22 (2) 21 (2) 2 (1) 0 (0) Death 1 (0) 0 (0) 2 (0) 0 (0) 0 (0) Voluntary 25 (1) 11 (1) 12 (1) 2 (1) 2 (2) Other reason(s) 52 (3) 38 (3) 44 (5) 9 (5) 5 (5) Body psoriasis Fixed combination gel, Betamethasone gel, Calcipotriol gel, Gel vehicle, Tacalcitol ointment Total number of patients completing treatment period 764 (93) 495 (88) 155 (89) 169 (75) 163 (89) Total number of withdrawn patients 60 (7) 67 (12) 20 (11) 57 (25) 21 (11) Unacceptable treatment efficacy 10 (1) 5 (1) 6 (3) 16 (9) 5 (5) Unacceptable AE(s) 8 (1) 3 (1) 7 (4) 6 (3) 4 (2) Exclusion criteria emerging during study 8 (1) 3 (1) 2 (1) 0 (0) 0 (0) Lost to follow-up 20 (2) 31 (6) 4 (2) 11 (5) 3 (2) Death 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Voluntary 7 (1) 18 (3) 2 (1) 6 (3) 2 (1) Other reason(s) 10 (1) 8 (1) 1 (1) 3 (1) 0 (0)

6 Pooled safety analysis for fixed combination gel 15 Table 3 All adverse events by system organ class (SOC) Number of patients (%)* Fixed combination gel (n = 1953) Betamethasone gel (n = 1214) Calcipotriol gel (n = 979) Gel vehicle (n = 173) Calcipotriol scalp solution (n = 104) Scalp psoriasis Infections and infestations 259 (13) 215 (18) 122 (13) 21 (12) 18 (17) Skin and subcutaneous tissue disorders 177 (9) 116 (10) 202 (21) 27 (16) 27 (26) Nervous system disorders 112 (6) 67 (6) 70 (7) 9 (5) 5 (5) Musculoskeletal and connective tissue disorders 82 (4) 51 (4) 32 (3) 6 (4) 5 (5) Gastrointestinal disorders 64 (3) 37 (3) 38 (4) 6 (4) 2 (2) Injury, poisoning and procedural complications General disorders and administration site conditions Respiratory, thoracic and mediastinal disorders 38 (2) 26 (2) 18 (2) 3 (2) 7 (7) 37 (2) 29 (2) 36 (4) 3 (2) 9 (9) 33 (2) 31 (3) 21 (2) 8 (5) 2 (2) Eye disorders 18 (0.9) 10 (0.8) 19 (2) 5 (3) 0 Vascular disorders 18 (0.9) 7 (0.6) 8 (0.8) 1 (0.6) 2 (2) Psychiatric disorders 14 (0.7) 10 (0.8) 5 (0.5) 1 (0.6) 3 (3) Reproductive system and breast disorders 14 (0.7) 3 (0.2) 5 (0.5) 0 0 Investigations 11 (0.6) 4 (0.3) 4 (0.4) 0 1 (1) Metabolism and nutrition disorders 12 (0.6) 4 (0.3) 8 (0.8) 0 0 Neoplasms, benign, malignant and unspecified 10 (0.5) 5 (0.4) 3 (0.3) 0 0 Immune system disorders 7 (0.4) 3 (0.2) 6 (0.6) 1 (0.6) 0 Ear and labyrinth disorders 6 (0.3) 7 (0.6) 4 (0.4) 2 (1) 1 (1) Surgical and medical procedures 6 (0.3) 6 (0.5) 6 (0.6) 0 2 (2) Blood and lymphatic system disorders 3 (0.2) 0 1 (0.1) 0 0 Cardiac disorders 2 (0.1) 3 (0.2) 4 (0.4) 0 0 Renal and urinary disorders 2 (0.1) 3 (0.2) 2 (0.2) 1 (0.6) 0 Endocrine disorders 2 (0.1) 0 3 (0.3) 0 0 Social circumstances 0 2 (0.2) Number of patients (%)* Fixed combination gel (n = 824) Betamethasone gel (n = 562) Calcipotriol gel (n = 175) Gel vehicle (n = 226) Tacalcitol ointment (n = 184) Body psoriasis Infections and infestations 134 (16) 63 (11) 23 (13) 31 (14) 32 (17) Skin and subcutaneous tissue disorders 40 (5) 22 (4) 15 (9) 22 (10) 28 (15) Nervous system disorders 21 (3) 11 (2) 4 (2) 8 (4) 6 (3)

7 16 Kragballe and van de Kerkhof Table 3 Continued Number of patients (%)* Fixed combination gel (n = 824) Betamethasone gel (n = 562) Calcipotriol gel (n = 175) Gel vehicle (n = 226) Tacalcitol ointment (n = 184) Musculoskeletal and connective tissue disorders Respiratory, thoracic and mediastinal disorders Injury, poisoning and procedural complications 19 (2) 10 (2) 3 (2) 4 (2) 7 (4) 18 (2) 12 (2) 4 (2) 6 (3) 2 (1) 17 (2) 14 (3) 1 (0.6) 5 (2) 10 (5) Gastrointestinal disorders 17 (2) 10 (2) 2 (1) 8 (4) 10 (5) Investigations 17 (2) 10 (2) 0 2 (0.9) 0 General disorders and administration site conditions 15 (2) 4 (0.7) 3 (2) 5 (2) 5 (3) Metabolism and nutrition disorders 9 (1) 7 (1) Vascular disorders 8 (1) 5 (0.9) 0 1 (0.4) 2 (1) Immune system disorders 3 (0.4) 1 (0.2) Psychiatric disorders 3 (0.4) 1 (0.2) Ear and labyrinth disorders 3 (0.4) (0.9) 1 (0.5) Surgical and medical procedures 2 (0.2) 4 (0.7) 0 2 (0.9) 2 (1) Reproductive system and breast disorders 2 (0.2) 2 (0.4) (2) Eye disorders 2 (0.2) 0 1 (0.6) 1 (0.4) 0 Renal and urinary disorders 1 (0.1) 2 (0.4) Cardiac disorders 1 (0.1) 1 (0.2) 1 (0.6) 2 (0.9) 1 (0.5) Neoplasms, benign, malignant and unspecified 1 (0.1) (1) Endocrine disorders 0 2 (0.4) Blood and lymphatic system disorders 0 1 (0.2) 0 2 (0.9) 0 Hepatobiliary disorders 0 1 (0.2) *A single patient can be listed in more than category.

8 Pooled safety analysis for fixed combination gel 17 Table 4 Adverse events occurring in patients using > 40 g of fixed combination gel per week, in 1% of the treatment population by system organ class (SOC) and preferred term Scalp psoriasis Fixed combination gel, Infections and infestations Nasopharyngitis 9 (5) Influenza 6 (3) Folliculitis 3 (2) Sinusitis 3 (2) Bladder infection 2 (1) Nervous system disorders Headache 6 (3) Skin and subcutaneous tissue disorders Pruritus 4 (2) Psoriasis 3 (2) Acne 3 (2) Skin irritation 2 (1) Musculoskeletal and connective tissue disorders Arthralgia 3 (2) Back pain 2 (1) Respiratory, thoracic and mediastinal disorders Cough 2 (1) Gastrointestinal disorders Diarrhoea 2 (1) Toothache 2 (1) Body psoriasis Fixed combination gel, Infections and infestations Nasopharyngitis 8 (4) Influenza 6 (3) Upper respiratory tract infection 4 (2) Sinusitis 4 (2) Bronchitis 2 (1) Investigations Blood parathyroid hormone increased 3 (2) Respiratory, thoracic and mediastinal disorders Nasal congestion 2 (1) Gastrointestinal disorders Diarrhoea 2 (1) Nervous system disorders Headache 1 (1) ment of psoriasis of the body, the incidence of ADRs was also low with the fixed combination gel (6%) although lower incidence was reported with the betamethasone dipropionate gel (4%, versus 8 16% for all other comparators). Pruritus was the most commonly reported ADR across all treatments assessed, except for betamethasone dipropionate gel where an increase in parathyroid hormone levels was most common. No clinically relevant changes in biochemistry parameters were found. The mean change in albumin-corrected serum calcium levels from baseline was 0.02 mmol/l for both pooled analysis sets. Subgroup analysis of AE incidence according to age, gender, race and baseline disease severity showed little effect, although the incidence of AEs in female patients treating their scalp psoriasis tended to be higher than males across all treatment groups except for treatment with calcipotriol scalp solution. Pharmacovigilance Since launch (until 31 October 2013), a total of bottles of the fixed combination gel have been sold worldwide. Within this time period, the most common spontaneously reported non-serious skin-related AEs with the fixed combination gel were psoriasis (n = 58; reflecting worsening of psoriasis), pruritus (n = 55) and alopecia (n = 46; Table 7). For skin-related SAEs, those that have been reported more than once were psoriasis (n = 5); and alopecia, erythrodermic psoriasis, pruritus, skin atrophy and urticaria (n = 2 each). Discussion This large-scale analysis includes safety data from over 2700 patients who have used the fixed combination gel to treat their psoriasis. Comparable baseline characteristics allowed for pooling of clinical trial data to consider overall safety implications for the fixed combination gel compared with its constituent components and calcipotriol scalp solution/tacalcitol ointment, and for which a favourable safety profile was demonstrated for the fixed combination gel as a treatment for psoriasis of the scalp and body. Treatment with the fixed combination gel reduces the risk of AEs associated with monotherapy treatment with vitamin D analogues and potent steroids. 16,19 High doses of topical vitamin D analogues, such as calcipotriol, have been associated with hypercalcaemia, 29 however, these pooled analyses indicate that normal treatment with the fixed combination gel does not cause any such clinically relevant events. In addition, no spontaneous events of hypercalcaemia were reported according to pharmacovigilance data. Skin irritation, another side effect typically associated with vitamin D analogues, 30 was less frequent with the fixed combination gel versus the calcipotriol monotherapy comparators, and it is thought that the anti-inflammatory action of the corticosteroid in the fixed combination treatment alleviates these reactions. The low incidence of pruritus in patients treated with the fixed combination gel is likely also to be attributable to the presence of the corticosteroid, with incidence rates comparable with betamethasone dipropionate monotherapy. Pruritus is a common distressing aspect of psoriasis. 31 It can cause pronounced discomfort often associated with loss of sleep which can consequently lead to negative effects on daily activities and productivity. 32 Minimizing the risk of pruritus can therefore afford significant improvement to a patient s quality of life.

9 18 Kragballe and van de Kerkhof Table 5 Lesional/perilesional AEs occurring in 1% of the treatment population by system organ class (SOC) and preferred term Scalp psoriasis Fixed combination gel, Betamethasone gel, Calcipotriol gel, Gel vehicle, Calcipotriol scalp solution, Skin and subcutaneous tissue disorders Pruritus 39 (2) 20 (2) 64 (7) 9 (5) 5 (5) Skin irritation 7 (0) 2 (0) 22 (2) 3 (2) 4 (4) Alopecia 3 (0) 6 (1) 3 (0) 2 (1) 0 (0) Skin burning sensation 2 (0) 3 (0) 4 (0) 0 (0) 2 (2) Dermatitis contact 2 (0) 0 (0) 1 (0) 1 (1) 1 (1) Nervous system disorders Burning sensation 6 (0) 5 (0) 16 (2) 0 (0) 1 (1) General disorders and administration site conditions Pain 4 (0) 1 (0) 4 (0) 3 (2) 0 (0) Application site burning 2 (0) 1 (0) 3 (0) 0 (0) 1 (1) Application site warmth 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) Injury, poisoning and procedural complications Skin laceration 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) Body psoriasis Fixed combination gel, Betamethasone gel, Calcipotriol gel, Gel vehicle, Tacalcitol ointment, Skin and subcutaneous tissue disorders Pruritus 9 (1) 2 (0) 4 (2) 15 (7) 12 (7) Psoriasis 3 (0) 3 (1) 1 (1) 3 (1) 1 (1) Erythema 1 (0) 1 (0) 2 (1) 0 (0) 1 (1) Skin burning sensation 0 (0) 0 (0) 2 (1) 2 (1) 1 (1) General disorders and administration site conditions Application site pain 3 (0) 1 (0) 0 (0) 3 (1) 2 (1) Pain 2 (0) 1 (0) 2 (1) 0 (0) 0 (0) Nervous system disorders Burning sensation 2 (0) 0 (0) 0 (0) 4 (2) 2 (1)

10 Pooled safety analysis for fixed combination gel 19 Table 6 Adverse drug reactions occurring in 1% of the treatment population by system organ class (SOC) and preferred term Scalp psoriasis Fixed combination gel, Betamethasone gel, Calcipotriol gel, Gel vehicle, Calcipotriol scalp solution, Skin and subcutaneous tissue disorders Pruritus 36 (2) 21 (2) 72 (7) 7 (4) 6 (6) Skin irritation 9 (1) 6 (1) 31 (3) 4 (2) 5 (5) Erythema 9 (1) 4 (0) 26 (3) 1 (1) 6 (6) Alopecia 5 (0) 6 (1) 3 (0) 2 (1) 0 (0) Skin burning sensation 3 (0) 3 (0) 8 (1) 0 (0) 2 (2) Dry skin 16 (4) 3 (0) 9 (1) 0 (0) 1 (1) Eczema 3 (0) 0 (0) 7 (1) 0 (0) 1 (1) Dermatitis 4 (0) 0 (0) 3 (0) 1 (1) 1 (1) Dermatitis contact 2 (0) 0 (0) 4 (0) 1 (1) 2 (2) Nervous system disorders Burning sensation 8 (0) 6 (1) 19 (2) 0 (0) 1 (1) Headache 10 (1) 13 (1) 2 (0) 2 (1) 0 (0) Infections and infestations Folliculitis 10 (1) 12 (1) 3 (0) 0 (0) 0 (0) General disorders and administration site conditions Pain 6 (0) 1 (0) 6 (1) 3 (2) 0 (0) Application site burning 2 (0) 1 (0) 3 (0) 0 (0) 5 (5) Oedema 0 (0) 0 (0) 1 (0) 0 (0) 1 (1) Application site warmth 1 (0) 0 (0) 0 (0) 0 (0) 1 (1) Body psoriasis Fixed combination gel, Betamethasone gel, Calcipotriol gel, Gel vehicle, Tacalcitol ointment, Skin and subcutaneous tissue disorders Pruritus 12 (2) 2 (0) 5 (3) 15 (7) 11 (6) Skin burning sensation 0 (0) 0 (0) 2 (1) 2 (1) 1 (1) Erythema 1 (0) 0 (0) 2 (1) 0 (0) 1 (1) Investigations Blood parathyroid hormone increased 7 (1) 6 (1) 0 (0) 1 (0) 0 (0) General disorders and administration site conditions Application site pain 3 (0) 1 (0) 0 (0) 3 (1) 2 (1) Pain 2 (0) 1 (0) 2 (1) 0 (0) 0 (0) Nervous system disorders Burning sensation 2 (0) 0 (0) 0 (0) 5 (2) 2 (1)

11 20 Kragballe and van de Kerkhof Table 7 Spontaneously reported non-serious skin-related adverse events ( 5 events); categorized by system organ class (SOC) and preferred term Adverse event Numbers reported Skin and subcutaneous tissue disorders Psoriasis 58 Pruritus 55 Alopecia 46 Erythema 34 Skin irritation 20 Dry skin 18 Skin exfoliation 18 Hair colour changes 12 Pain of skin 12 Rash 11 Skin burning sensation 9 Skin atrophy 8 Rebound psoriasis 5 Skin discoloration 5 Skin reaction 5 Administration site conditions Application site pain 20 Application site erythema 15 Application site pruritus 12 Application site irritation 9 Application site burn 6 Application site discoloration 6 A good tolerability profile with a low risk of AEs can have a significant positive impact upon patient quality of life, thereby potentially leading to improved treatment adherence. 33 Here, the favourable tolerability profile for the fixed combination gel determined from clinical trial data has translated to a comparable profile in real-life daily practice, as indicated by the pharmacovigilance data. The real-life effectiveness of a product has been defined as a function of clinical efficacy, adherence and safety, 34 and the combination of the good tolerability profile of the fixed combination gel and its ease-of-use has the potential to improve patient adherence to treatment, thereby increasing effectiveness and patient quality of life in the real-life setting. A limitation of the current analysis is that only short-term safety and tolerability of the fixed combination treatment (up to 8 weeks) was assessed. Assessment of long-term treatment would provide a more accurate reflection of the tolerability profile that patients can expect with prolonged use. Of particular interest is the safety profile associated with long-term use of high potency steroids, which has been associated with adrenal suppression. 35 Within the current 8-week pooled analyses, no cases of adrenal suppression were reported, although serum cortisol levels were not specifically measured. However, adrenal suppression was recently assessed in 43 patients with extensive psoriasis who were treated with the fixed combination gel for 8 weeks. 36 Two (4.7%) patients showed signs of adrenal suppression at Week 4; both were withdrawn from treatment and had normal serum cortisol values at follow-up 4 weeks later. 36 There were no instances of adrenal suppression logged as part of the pharmacovigilance monitoring. Of note, a 52-week clinical trial has assessed the long-term safety of the fixed combination gel, used as needed, for the treatment of scalp psoriasis. 26 Of the 429 patients who were treated with the fixed combination gel, 11 (2.6%) were judged to present with AEs possibly associated with long-term use of corticosteroids, versus 13 patients (3.0%) with calcipotriol, demonstrating that there was no increased risk of steroid-associated AEs with year-long use of the fixed combination gel. 26 It is thought that the addition of calcipotriol in the fixed combination gel offers steroid-sparing benefits by reducing the quantity of betamethasone dipropionate used, thereby potentially reducing the risk of any steroid-associated AEs. 9 In conclusion, in these pooled analyses of safety data from a large subset of psoriasis patients treated with fixed combination gel, the incidence of AEs and ADRs is consistently low, providing further evidence of the good tolerability of the fixed combination gel as treatment for psoriasis of the scalp and body. 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