1Scientific Insights Consulting Group Inc., Mississauga, ON, Canada
2Sunnybrook Health Sciences Centre, Toronto, ON, Canada
3University of Toronto, Toronto, ON, Canada
Conflict of interest:
Bonnie Kuehl has consulted for and accepted consulting fees from Aralez Pharmaceuticals and LEO Pharma Canada; Neil Shear has been a consultant/speaker for AbbVie, Celgene, Valeant, Lilly, Novartis, Janssen, LEO Pharma, and Sanofi Genzyme.
Most people with mild-to-moderate psoriasis manage their disease with topical therapies. However, adherence to topical treatment remains a challenge, as the daily application creates a significant treatment burden. New topical therapeutic options need to offer higher efficacy and better patient acceptability, including easier application, to reduce treatment burden and enhance patient adherence. Topical foam vehicles are innovative alternatives to creams and ointments, addressing many patient challenges with traditional vehicles. Well-designed foam vehicles are easily spread over large areas of the skin, while importantly not leaving a greasy or oily film on the skin after application. Calcipotriol/betamethasone dipropionate aerosol foam is a new psoriasis treatment option that is rapidly effective, offers greater efficacy versus ointment and gel formulations, and has been shown to increase patient treatment satisfaction. Hence, by addressing the several crucial unmet clinical needs in patients with mild-to-moderate psoriasis, this optimized foam formulation is poised to improve treatment follow-through.
calcipotriol/betamethasone dipropionate, drug delivery, vehicle, aerosol, foam, psoriasis, topical
Psoriasis is an immune disorder that most commonly manifests itself with visible plaques on the skin, resulting in considerable morbidity for those affected. The World Health Organization characterizes psoriasis as “a chronic, non-communicable, painful, disfiguring and disabling disease for which there is no cure.”1 The majority of patients are classified as having mild-moderate disease with an estimated 20% having moderate-severe disease.2 In a multinational survey (US, Canada, France, Germany, Italy, Spain, UK), dermatologists acknowledged that psoriasis is undertreated with an ongoing unmet treatment need for patients.3 In the survey, dermatologists reported not initiating or maintaining treatment due to concerns regarding the long-term safety, tolerability and efficacy of currently available therapies.3 The MAPP survey (population-based survey of psoriasis and/or psoriatic arthritis patients in North America and Europe) revealed that the majority of psoriasis patients are undertreated; >80% of patients with ≥4 palms body surface area (BSA) were receiving no treatment or topical treatment only. Further, 57% who received oral therapy and 45% who received biologic therapy discontinued treatment, citing safety/tolerability concerns and a lack/loss of efficacy.4
As with any chronic disease, patient adherence to topical psoriasis therapy is low. The high burden of treatment and the substantial effort required to maintain ongoing therapy leads to treatment fatigue. According to published data, approximately 75% of patients3 with psoriasis vulgaris (plaque psoriasis), regardless of severity, manage their disease with topical therapies, which may lead to quicker treatment fatigue as the daily treatment regimen can be cumbersome and time consuming.2 Studies in medication adherence in psoriasis have shown that 39-73% of patients do not use their medication as prescribed.5-7 Factors influencing adherence include patient specific characteristics, disease-related characteristics, treatment satisfaction, cosmetic acceptability and complexity of treatment protocols.8 Studies also report that cosmetic acceptability is a key contributor to adherence, with adherence being reduced if treatments are perceived as messy to apply and sticky on the skin.9 There is evidence that low adherence to psoriasis therapies may be related to insufficient instruction on how to use the drug, misperceptions regarding possible adverse events (AEs) and mistaken expectations about the speed and degree of improvement.1
A challenge to the use of currently available topical therapies is that many patients fail to achieve complete or almost complete clearance of their psoriasis.10 Increasing awareness of the burden of psoriasis and the psychosocial impact of the disease have underscored the clinical need for a topical therapy that is easy to use, cosmetically appealing, rapidly efficacious with short-term use, as well as be able to induce sustained efficacy for long-term maintenance.8,10
Rationale for New Topicals in Psoriasis
Topical treatment of skin conditions is an ancient technique meant to soothe and cool the skin. This practice transitioned into a scientific technique in the 19th century with evidence demonstrating that topically applied agents could impact the skin and offer systemic benefits. A growth in the understanding of skin architecture, topical drug formulation and drug delivery resulted in the ongoing development of topical therapies to address visible skin injury and dermal delivery, ideally optimizing directed delivery of an applied drug. Traditionally, topical therapy carrier vehicles were developed empirically by combining favorite and known ingredients affecting the percutaneous absorption of the drug/active ingredient. There was little consideration of cosmetic acceptability and limited knowledge of the skin penetration/ permeation of the drug at the target site. New materials and a greater understanding of product formulation and consumer acceptability have led to the identification of criteria that constitute the “ideal” vehicle, which include properties such as easy application and removal, nonirritating/nonallergenic, chemically stable, homogenous, bacteriostatic, cosmetically acceptable, pharmacologically inert, and ability to rapidly release the drug for enhanced, controlled or targeted absorption.11,12
With the knowledge that the topical carrier vehicle can influence the performance of the drug, as well as have a direct effect on the appearance and condition of the skin barrier, new vehicle compositions have been developed. These new vehicles offer improved control of application, increased skin absorption, and the maintenance or improvement to the skin barrier.13 Beyond this, compounds of active ingredients with new agents need to offer a combination of higher efficacy and better patient acceptability compared with currently available therapies in order to enhance patient adherence.10 A simplified dosing schedule, such as once per day, and rapid onset of observed effect are key factors that can improve adherence to topical therapies.14,15
More important than the carrier or the delivery vehicle, the primary consideration is the active drug and its impact on the inflammatory process responsible for psoriasis. The immune pathogenesis of psoriasis involves dendritic cells, T-cells, keratinocytes and a diverse group of inflammatory mediators (chemokines, cytokines, antimicrobial peptides) that further amplify the inflammatory response and trigger the hyperproliferation of keratinocytes. Once activated, this inflammatory process results in the development of painful, itchy, erythematous plaques covered in silvery scales.16
Vitamin D receptor agonists (e.g., calcipotriol) and glucocorticoids (e.g., betamethasone dipropionate) have shown benefit in treating psoriasis. Glucocorticoids are known potent anti-inflammatory agents that block multiple anti-inflammatory pathways. Vitamin D receptor agonists appear to enhance the immunosuppressive activity of regulatory T-cells, driving T-cells toward a T helper 2 (Th2) profile while inhibiting Th1/Th17 cells. Calcipotriol has been shown to normalize the pro-inflammatory cytokine cascade in psoriasis, ultimately interrupting the pro-inflammatory feedback loop that drives disease pathogenesis.17,18 Recent data further supports the benefit of combining betamethasone with calcipotriol. The combination of the two agents showed additive effects, inhibiting the secretion of interleukin (IL)-17A and tumor necrosis factor (TNF)-α by dendritic cells and CD4+ and CD8+ T-cells, as well as reducing the inflammatory response of stimulated keratinocytes. This cellular data supports the enhanced clinical efficacy observed with the combination product, compared to the respective monotreatments in psoriasis patients.17
Vehicle – Getting it Right
When considering topical dermatological treatment, formulators, clinicians and consumers place extraordinary importance on the type of formulation (i.e., principle of the structural matrix – cream, ointment, solution, foam) and the individual excipients of the topical preparations. This importance has been driven by the visibility of the application site, texture and feel of the applied product on the skin, as well as ease of use. The excipients are responsible for enhancing penetration/permeation of the active ingredients, skin hydration, occlusiveness and stability of the topical preparation. The formulation type is equally important as it impacts several aspects of the topical preparation including: cosmetic acceptability (greasiness, messiness, stickiness, visibility on skin and tactile sensation); ease of use/convenience (spreadability, time required for application and drying, staining of clothes/bedding); and potency of the topical preparation. Clinically, the key question is which formulation types (creams, gels, ointments, foams or liposomes) are better at delivering a drug to the skin, promoting cutaneous absorption and potentially leading to enhanced clinical efficacy. Drug delivery is controlled by the vehicle excipients as these impact partitioning of the active ingredients into, and diffusion through, the stratum corneum (absorption and penetration).12,19 Traditionally, the choice of vehicle for a particular disease was governed by a classification of preparations and disease/patient factors (e.g., location of disease, skin type, type of disease). The evolution and development of new chemical combinations and entities have driven the need for advancements in vehicle delivery. Thus, modern formulations should be able to facilitate enhanced drug delivery to different layers of the skin as well as extend the release time/activity of delivered drugs.12
Foam vehicles were developed to address several needs beyond the effective delivery of active ingredients. The formulation also needs to spread easily on large areas of the skin; not require excessive rubbing into already damaged sensitive skin; not leave a greasy or oily film on the skin after application; and not impart a greasy feeling. Foams are an innovative and easy to apply alternative to creams and ointments. Importantly, with any topical vehicle, the excipients should support the stability and delivery of the active ingredients with the additional benefit of helping repair the skin barrier.13 Foams are unique delivery vehicles as they are essentially colloids composed of two or three distinct phases: hydrophilic liquid continuous phase with a foaming agent, throughout which a gaseous dispersion phase is distributed, and sometimes a third hydrophobic dispersed phase. Pharmaceutical aerosol foams commonly exhibit three transition states: liquid in the can, propellant/aerosol as it leaves the can and foam on the skin of the patient.20
In the treatment of psoriasis, the fixed combination of calcipotriol and betamethasone as dipropionate (Cal/BD), in either ointment or gel formulations, has shown superior efficacy and improved acceptability compared with the individual active ingredients.21,22 The rationale behind the development of the fixed dose combination of Cal and BD (as dipropionate) was to allow the delivery of small amounts (0.005% and 0.05%, respectively) of two very potent drugs within a single formulation. Betamethasone dipropionate is available as micronized particles and can be easily suspended homogeneously whereas calcipotriol, present in a much lower concentration, needs to be dissolved in a carefully selected vehicle component to ensure an even distribution.23,24 While the fixed dose combinations are established first-line therapies for plaque psoriasis, adherence to the ointment formulation remains a significant challenge as the daily treatment regimen can be cumbersome and time consuming.10
To address patient needs for an easy to apply topical vehicle offering efficacy in psoriasis – an innovative aerosol foam formulation containing calcipotriol and betamethasone in a fixed dose combination was developed. The Cal/BD aerosol foam is a pressurized formulation including an emollient vehicle base, with calcipotriol and betamethasone dissolved in a mixture of volatile propellants, butane and dimethyl ether. Dimethyl ether also acts as a solvent that enhances the solubility of the active ingredients allowing them to completely dissolve, which is in contrast to the ointment and suspension formats.25 Laboratory assays show that the propellants evaporate rapidly after being sprayed on paper, with the calcipotriol and betamethasone remaining completely dissolved in solution (i.e., crystals are absent) creating a stable, supersaturated environment. Further, studies have also demonstrated that the individual components, Cal and BD, in the Cal/BD aerosol foam had significantly greater in vitro skin penetration and increased ex vivo skin permeation (penetration through all skin layers) compared with Cal and BD in the Cal/BD ointment. This is thought to be due to the development of the stable supersaturated solution, leading to greater solubility and skin penetration of the active ingredients, expected to lead to increased skin permeation and increased absorption of actives at the site of action.25
The Cal/BD foam has been compared with established topical combination products as well as the individual active ingredients in an extensive clinical trial program. In most studies, the primary efficacy endpoint was “treatment success” as defined by the proportion of patients who were clear or almost clear of psoriasis according to the physician’s global assessment of disease severity (PGA) at week 4, with at least a two-step improvement. Phase II and III studies have demonstrated significantly greater treatment success and at least a 75% reduction in modified psoriasis area and severity index (mPASI75) of the Cal/BD aerosol foam compared to foam vehicle, calcipotriol alone and betamethasone alone, Cal/BD ointment and Cal/BD gel (Table 1) in the treatment of adult patients with psoriasis on the body. The PSO-FAST study demonstrated an early (day 3) significantly greater itch relief and improvement in itch-related sleep loss compared with vehicle in patients receiving the Cal/BD aerosol foam, which was maintained for the remainder of the study.26,27 These findings are thought provoking as they demonstrate that therapy alleviated common and distressing aspects of psoriasis, including scratching in response to itchiness that can aggravate lesions and sleep loss that can impact daily productivity.30
of Study (weeks)
three-arm, Phase II study
in patients with psoriasis
(Cal/BD foam n=100;
Cal foam n=101;
BD foam n=101)
|Phase II, multicenter,|
in patients with psoriasis
(Cal/BD foam n=141;
Cal/BD ointment n=135;
foam vehicle n=49;
ointment vehicle n=51)
|PSO-FAST: Phase III,|
study comparing Cal/BD aerosol
foam to foam vehicle in patients
with ≥ mild severity psoriasis
of the trunk/limbs26
(Cal/BD foam n=323;
Phase III, randomized study
comparing Cal/BD aerosol foam
with the Cal/BD gel in patients
with mild-to-severe psoriasis29
(Cal/BD foam n=185;
Cal/BD gel n=188;
foam vehicle n=47;
gel vehicle n=43)
|Table 1: Phase II and III data for Cal/BD aerosol foam.|
These studies also showed a significant impact on patient quality of life (QoL) with reductions in Dermatology Life-Quality Index (DLQI) scores. The use of Cal/BD aerosol foam resulted in a significantly greater improvement in DLQI at week 4 versus either the foam vehicle or the Cal/BD gel. DLQI scores of 0/1 achieved by Cal/BD aerosol foam versus Cal/BD gel were, respectively, 46% versus 32% (P=0.013) at week 4 and 61% versus 44% (P=0.03) at week 12.27,31
Phase II/III studies with the Cal/BD aerosol foam have shown that this new topical agent is efficacious and well accepted in adult patients with psoriasis vulgaris for up to a 4-week treatment period. The safety profile is in alignment with the more established Cal/BD fixed combination ointment. Safety of the Cal/BD aerosol foam versus gel for up to 12 weeks of treatment has been demonstrated in a Phase III trial. Pooled-analysis of the Phase II/III clinical studies showed that the most common AEs with the Cal/BD aerosol foam were nasopharyngitis (n=6, 1.1%) and application-site pain (n=4, 0.7%).24,26,28 Notably, the Cal/BD aerosol foam has a safety and tolerability profile similar to Cal/BD ointment and the individual active ingredients, demonstrating that the superior efficacy of the aerosol foam does not impact tolerability.10
The Phase II maximum use systemic exposure (MUSE) study in 35 patients with extensive psoriasis vulgaris (covering 15-30% BSA, with at least 30% scalp involvement), demonstrated that the Cal/BD aerosol foam had no clinically relevant impact on the hypothalamic-pituitary-adrenal (HPA) axis, calcium homeostasis or renal function, demonstrating low systemic absorption of Cal and BD.32
While long-term data for the Cal/BD aerosol foam is yet to come, 52-week data from the Cal/BD ointment demonstrated that no patients experienced HPA axis suppression and that the fixed dose combination is safe and well tolerated when used longterm.33-35
Treatment failure, poor clinical outcomes and increased healthcare utilization have been linked to non-adherence to treatment as well as physician recommendations. Adherence to topical agents is related to duration of treatment, complexity of the treatment regimen, as well as patient self-image and QoL.8,36 Demands associated with disease management can create a significant treatment burden for patients with chronic diseases. This burden combined with general life demands (e.g., job, family) comprises the overall patient workload. Treatment fatigue is common, with disengagement from recommended health behaviors when a person’s workload exceeds their capacity, a primary contributing factor to non-adherence.37 With topical dermatologic products, studies suggest that patients prefer and are more adherent to, certain topical vehicles based on convenience and cosmetic acceptability.38
When considering cost of therapy, it is important to remember both direct (e.g., prescription drug costs, physician visits, treatment in day clinics) and indirect costs (e.g., loss of time from work, loss of income, non-prescription drug costs). These costs are likely exacerbated by non-adherence to medication. In psoriasis particularly, QoL is adversely affected with people coping by avoiding social situations and covering their lesions.8 An Ontario study found that greater out-of-pocket expenses was related to a higher rate of cost-related non-adherence.39
The efficacy of a fixed-dose Cal/BD combination is well established in patients with mild-to-moderate psoriasis. With the ongoing clinical challenge of achieving optimal control and adherence to treatment, the Cal/BD aerosol foam was developed to increase the therapeutic options available. The data supports that the Cal/BD aerosol foam offers enhanced efficacy due to improved skin penetration of the active ingredients after the formation of a stable supersaturated solution on the skin. With its further favorable impact on itch and quality of life, this foam formulation has the potential to improve adherence by addressing several unmet needs in patients with psoriasis.
- World Health Organization. Global report on psoriasis. 2016. Available at: http://apps.who.int/iris/bitstream/handle/10665/204417/9789241565189_eng.pdf;jsessionid=0EEEFDBBD155A8B97A2C787D686592FD?sequence=1. Accessed May 27, 2018.
- Menter A, Gottlieb A, Feldman SR, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol. 2008 May;58(5):826-50.
- van de Kerkhof PC, Reich K, Kavanaugh A, et al. Physician perspectives in the management of psoriasis and psoriatic arthritis: results from the population based Multinational Assessment of Psoriasis and Psoriatic Arthritis survey. J Eur Acad Dermatol Venereol. 2015 Oct;29(10):2002-10.
- Lebwohl MG, Bachelez H, Barker J, et al. Patient perspectives in the management of psoriasis: results from the population-based Multinational Assessment of Psoriasis and Psoriatic Arthritis Survey. J Am Acad Dermatol. 2014 May;70(5):871-81 e1-30.
- Storm A, Andersen SE, Benfeldt E, et al. One in 3 prescriptions are never redeemed: primary nonadherence in an outpatient clinic. J Am Acad Dermatol. 2008 Jul;59(1):27-33.
- Zaghloul SS, Goodfield MJ. Objective assessment of compliance with psoriasis treatment. Arch Dermatol. 2004 Apr;140(4):408-14.
- Brown KK, Rehmus WE, Kimball AB. Determining the relative importance of patient motivations for nonadherence to topical corticosteroid therapy in psoriasis. J Am Acad Dermatol. 2006 Oct;55(4):607-13.
- Bewley A, Page B. Maximizing patient adherence for optimal outcomes in psoriasis. J Eur Acad Dermatol Venereol. 2011 Jun;25 Suppl 4:9-14.
- Hol K. Patient preference for topical psoriasis formulations. Abstract P572: Poster presented at the 9th Congress of the European Academy of Dermatology and Venereology, Gothenburg, Sweden, October 6-10, 2010.
- Paul C, Bang B, Lebwohl M. Fixed combination calcipotriol plus betamethasone dipropionate aerosol foam in the treatment of psoriasis vulgaris: rationale for development and clinical profile. Expert Opin Pharmacother. 2017 Jan;18(1):115-21.
- Otto A, du Plessis J, Wiechers JW. Formulation effects of topical emulsions on transdermal and dermal delivery. Int J Cosmet Sci. 2009 Feb;31(1):1-19.
- Surber C, Smith EW. The mystical effects of dermatological vehicles. Dermatology. 2005 210(2):157-68.
- Tamarkin D. Chapter 9. Foam: a unique delivery vehicle for topically applied formulations. In: Dayan N (editor). Handbook of formulating dermal applications: a definitive practical guide. Beverly, MA: Scrivener Publishing, 2017; pp233-60.
- Zaghloul SS, Goodfield MJ. Objective assessment of compliance with psoriasis treatment. Arch Dermatol. 2004 Apr;140(4):408-14.
- Uhlenhake EE, Kurkowski D, Feldman SR. Conversations on psoriasis–what patients want and what physicians can provide: a qualitative look at patient and physician expectations. J Dermatolog Treat. 2010 Jan;21(1):6-12.
- Lynde CW, Poulin Y, Vender R, et al. Interleukin 17A: toward a new understanding of psoriasis pathogenesis. J Am Acad Dermatol. 2014 Jul;71(1):141-50.
- Lovato P, Norsgaard H, Tokura Y, et al. Calcipotriol and betamethasone dipropionate exert additive inhibitory effects on the cytokine expression of inflammatory dendritic cell-Th17 cell axis in psoriasis. J Dermatol Sci. 2016 Mar;81(3):153-64. corticosteroids in psoriasis. Psoriasis Forum. 2015 Mar;21a(1):35-41.
- Gottlieb AB. Immune modulation with combined vitamin D analogs and corticosteroids in psoriasis. Psoriasis Forum. 2015 Mar;21a(1):35-41.
- Smith EW, Surber C, Tassopoulous T, et al. Topical dermatological vehicles: a holistic approach. In: Bronaugh RL, Maibach HI (editors). Topical absorption of dermatological products. New York, NU: Dekker, 2002; pp457-63.
- Kircik LH, Bikowski JB. Vehicles matter: topical foam formulations. Practical Dermatology. 2012 Jan;(Suppl)3-18.
- Menter A, Abramovits W, Colon LE, et al. Comparing clobetasol propionate 0.05% spray to calcipotriene 0.005% betamethasone dipropionate 0.064% ointment for the treatment of moderate to severe plaque psoriasis. J Drugs Dermatol. 2009 Jan;8(1):52-7.
- Menter A, Gold LS, Bukhalo M, et al. Calcipotriene plus betamethasone dipropionate topical suspension for the treatment of mild to moderate psoriasis vulgaris on the body: a randomized, double-blind, vehicle-controlled trial. J Drugs Dermatol. 2013 Jan;12(1):92-8.
- Simonsen L, Hoy G, Didriksen E, et al. Development of a new formulation combining calcipotriol and betamethasone dipropionate in an ointment vehicle. Drug Dev Ind Pharm. 2004 30(10):1095-102.
- Koo J, Tyring S, Werschler WP, et al. Superior efficacy of calcipotriene and betamethasone dipropionate aerosol foam versus ointment in patients with psoriasis vulgaris–A randomized phase II study. J Dermatolog Treat. 2016 27(2):120-7.
- Lind M, Nielsen KT, Schefe LH, et al. Supersaturation of calcipotriene and betamethasone dipropionate in a novel aerosol foam formulation for topical treatment of psoriasis provides enhanced bioavailability of the active ingredients. Dermatol Ther (Heidelb). 2016 Sep;6(3):413-25.
- Leonardi C, Bagel J, Yamauchi P, et al. Efficacy and safety of calcipotriene plus betamethasone dipropionate aerosol foam in patients with psoriasis vulgaris–a randomized phase III study (PSO-FAST). J Drugs Dermatol. 2015 Dec;14(12):1468-77.
- Leonardi C, Bagel J, Yamauchi P, et al. The aerosol foam formulation of the fixed combination calcipotriene plus betamethasone dipropionate improves the health-related quality of life in patients with psoriasis vulgaris: results from the randomized PSO-FAST study. J Drugs Dermatol. 2016 Aug 1;15(8):981-7.
- Lebwohl M, Tyring S, Bukhalo M, et al. Fixed combination aerosol foam calcipotriene 0.005% (Cal) plus betamethasone dipropionate 0.064% (BD) is more efficacious than Cal or BD aerosol foam alone for psoriasis vulgaris: a randomized, double-blind, multicenter, three-arm, phase 2 Study. J Clin Aesthet Dermatol. 2016 Feb;9(2):34-41.
- Paul C, Stein Gold L, Cambazard F, et al. Calcipotriol plus betamethasone dipropionate aerosol foam provides superior efficacy vs. gel in patients with psoriasis vulgaris: randomized, controlled PSO-ABLE study. J Eur Acad Dermatol Venereol. 2017 Jan;31(1):119-26.
- Globe D, Bayliss MS, Harrison DJ. The impact of itch symptoms in psoriasis: results from physician interviews and patient focus groups. Health Qual Life Outcomes. 2009 Jul 6;7:62.
- Paul C, Stein Gold L, Cambazard F, et al. More rapid improvement in quality of life with fixed combination calcipotriene plus beta-methasone dipropionate aerosol foam versus topical suspension (PSO-ABLE study in patients with psoriasis vulgaris). J Am Acad Dermatol. 2016 May;74(5 Suppl 1):AB260 (abstract P3712).
- Taraska V, Tuppal R, Olesen M, et al. A novel aerosol foam formulation of calcipotriol and betamethasone has no impact on HPA axis and calcium homeostasis in patients with extensive psoriasis vulgaris. J Cutan Med Surg. 2016 Jan;20(1):44-51.
- Kragballe K, Austad J, Barnes L, et al. A 52-week randomized safety study of a calcipotriol/betamethasone dipropionate two-compound product (Dovobet/ Daivobet/Taclonex) in the treatment of psoriasis vulgaris. Br J Dermatol. 2006 Jun;154(6):1155-60.
- Kragballe K, Austad J, Barnes L, et al. Efficacy results of a 52-week, randomised, double-blind, safety study of a calcipotriol/betamethasone dipropionate two-compound product (Daivobet/Dovobet/Taclonex) in the treatment of psoriasis vulgaris. Dermatology. 2006 213(4):319-26.
- Fleming C, Ganslandt C, Leese GP. Short- and long-term safety assessment of a two-compound ointment containing calcipotriene/betamethasone dipropionate (Taclonex/Daivobet/Dovobet ointment): hypothalamic-pituitary-adrenal axis function in patients with psoriasis vulgaris. J Drugs Dermatol. 2010 Aug;9(8):969-74.
- Ahn CS, Culp L, Huang WW, et al. Adherence in dermatology. J Dermatolog Treat. 2017 Mar;28(2):94-103.
- Heckman BW, Mathew AR, Carpenter MJ. Treatment burden and treatment fatigue as barriers to health. Curr Opin Psychol. 2015 Oct 1;5:31-6.
- Augustin M, Holland B, Dartsch D, et al. Adherence in the treatment of psoriasis: a systematic review. dermatology. 2011 222(4):363-74.
- Zheng B, Poulose A, Fulford M, et al. A pilot study on cost-related medication nonadherence in Ontario. J Popul Ther Clin Pharmacol. 2012 19(2):e239-47.