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Calcipotriol/betamethasone dipropionate foam

Author: Anoma Ranaweera, Medical Writer, Auckland, New Zealand. DermNet Editor in Chief: Adjunct A/Prof Dr Amanda Oakley, Dermatologist, Hamilton, New Zealand. Copy edited by Gus Mitchell. October 2019.


What is psoriasis?

Psoriasis is an autoimmune skin disorder characterised by circumscribed, red, scaly plaques.

Chronic plaque psoriasis

What is calcipotriol/betamethasone dipropionate foam?

Calcipotriol/betamethasone dipropionate foam (trade name Enstilar®) is a topical prescription medicine for psoriasis in adults 18 years and older. Enstilar is an alcohol-free foam formulation of the two drugs in a pressurised spray; this permits application across large areas [1,2].

The United States, the European Union, Canada, and Australia have approved Enstilar foam (calcipotriol/betamethasone dipropionate 50µg/gm/0.5µg/g) for the treatment of plaque psoriasis. It is not yet approved in New Zealand as of October 2019. Calcipotriol is known as calcipotriene in the USA.

The combination of calcipotriol and betamethasone dipropionate is also available as a gel, an ointment and a cream (trade name Daivobet®, Dovobet®, and others).

How does calcipotriol/betamethasone dipropionate work?

The mechanism of action of the ingredients have been studied independently as well as in combination [1,3].

Calcipotriol

Calcipotriol hydrate is a synthetic vitamin D analogue.

  • In psoriasis, vitamin D and its analogues act mainly to inhibit keratinocyte proliferation and induce keratinocyte differentiation.
  • Calcipotriol works by reducing the number of new skin cells that are produced and making the new cells mature more quickly.
  • The underlying antiproliferative mechanism of vitamin D in keratinocytes involves the induction of the growth inhibitory factor transforming growth factor-β and of cyclin-dependent kinase inhibitors, with subsequent growth arrest in the G1 phase of the cell cycle.
  • Vitamin D also has an immunomodulatory effect, suppressing activation and differentiation of Th17/Th1 cells and inducing a Th2 response.

Betamethasone dipropionate

Betamethasone dipropionate is a potent synthetic topical corticosteroid.

  • In psoriasis, corticosteroids suppress the immune system, particularly pro-inflammatory cytokines and chemokines, thereby inhibiting T-cell activation.
  • Betamethasone dipropionate works in psoriasis by reducing inflammation to relieve skin symptoms such as burning, pain, itching, and swelling.

The combination of calcipotriol and betamethasone dipropionate

Enstilar foam combines the pharmacological effects of calcipotriol and betamethasone dipropionate [2].

  • The combination treatment flattens psoriasis plaques, removing scaling, and reducing discomfort.
  • In combination, calcipotriol and betamethasone dipropionate promote greater anti-inflammatory and anti-proliferative effects than either component alone.

How is calcipotriol/betamethasone dipropionate administered?

Each gram of Enstilar foam contains 52.2 mcg calcipotriene hydrate (equivalent to 50 mcg of calcipotriene) and 0.643 mg of betamethasone dipropionate (equivalent to 0.5 mg of betamethasone) [1,4].

  • Enstilar foam is applied once daily to affected areas for up to 4 weeks.
  • The medication is applied by holding the can at least 3 cm from the skin and spraying onto the affected area and gently rubbing in.
  • The foam can be sprayed by holding the can in any orientation except horizontally.
  • Hands should be washed thoroughly after applying Enstilar foam on any part of the body unless the hands are being treated.
  • Do not use an increased dose of the foam to make up for any forgotten dose.
  • Patients should stop using the foam when control over the psoriasis is achieved.

Caution

No more than 60 g of Enstilar foam should be used in every four days.

  • It should not be used with occlusive dressings unless directed by a physician.
  • The foam is not for oral, ophthalmic, or intravaginal use.
  • Avoid use on the face, groin, or axillae, or if skin atrophy is present at the treatment site.
  • The treated skin areas should be protected from sunlight and ultraviolet (UV) rays, for example, by wearing sun-protective clothing.
  • Additional topical corticosteroids should not be used in areas treated with Enstilar foam.

What are the contraindications for use of calcipotriol/betamethasone dipropionate foam?

Calcipotriol/betamethasone dipropionate foam is indicated for plaque psoriasis. The main contraindication to calcipotriol/betamethasone dipropionate foam is hypersensitivity to the active substance or to any of the excipients [1,5].

It should not be used for acute types of psoriasis such as generalised pustular psoriasis or erythrodermic psoriasis.

Calcipotriol/betamethasone dipropionate foam should also not be used for skin affected with:

Before using Enstilar foam, patients should inform treating physicians in the following circumstances:

  • If they have a calcium metabolism disorder
  • If they are having phototherapy
  • If they are pregnant or plan to become pregnant
  • If they are breastfeeding or plan to breastfeed.

What are the warnings and precautions for use of calcipotriol/betamethasone dipropionate foam?

Flammability

The propellants in calcipotriol/betamethasone dipropionate foam are flammable. Patients are instructed to avoid fire, flame, and smoking during and immediately following application. Keep the foam in a cool dry place, store below 25°C, and store away from sunlight. Do not expose the container to temperatures above 50°C as it is pressurised and extremely flammable [1,3].

Hypercalcaemia and hypercalciuria

Hypercalcemia and hypercalciuria have been observed with the use of calcipotriol/betamethasone dipropionate foam and is more likely if recommended doses are exceeded [1].

If hypercalcaemia or hypercalciuria develops, treatment should be discontinued until parameters of calcium metabolism have normalised.

The incidence of hypercalcemia and hypercalciuria following calcipotriol/betamethasone dipropionate foam treatment of more than 4 weeks has not been evaluated.

Effects on the endocrine system

Systemic absorption of topical corticosteroids, such as betamethasone dipropionate, can rarely produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for clinical glucocorticosteroid insufficiency during treatment or upon withdrawal of the topical corticosteroid. Factors that predispose a patient to HPA axis suppression include treatment to large surface areas, prolonged use of occlusive dressings, altered skin barrier, liver failure, and young age [1].

Systemic effects of topical corticosteroids may also include Cushing syndrome, hyperglycaemia, and glucosuria.

Local side effects from topical corticosteroids include:

Misdiagnosis of fungal infection can lead to tinea incognita.

Allergic contact dermatitis

Allergy to topical corticosteroids may rarely result in allergic contact dermatitis, which has also been reported to occur with topical calcipotriol [1].

Use of calcipotriol/betamethasone dipropionate foam in specific populations

Older people

In clinical trials, no overall differences in Enstilar foam exposure, safety or effectiveness have been observed between older and younger subjects. In these trials, however, the number of subjects aged 65 years and older was not sufficient to determine whether they responded differently from younger subjects [1,3].

Children

The safety and efficacy of Enstilar foam in paediatric patients less than 18 years of age have not yet been established.

Because of a higher ratio of skin surface area to body mass, children under the age of 12 years are at particular risk of systemic adverse effects when they are treated with topical corticosteroids, including growth retardation [1,3].

Pregnant women

There are no adequate and well-controlled studies in pregnant women. Pregnant women were excluded from the clinical studies conducted with Enstilar foam.

Enstilar foam should only be used during pregnancy if the potential benefit to the patient justifies the potential risk to the fetus.

Animal reproduction studies have not been conducted with Enstilar foam. However, calcipotriol has been shown to be fetotoxic and betamethasone dipropionate has been shown to be teratogenic in animals when given systemically [1,3].

Nursing mothers

It is not known whether topically administered calcipotriol or corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk.

Because many drugs are excreted in human milk, caution should be exercised when Enstilar foam is administered to a nursing woman.

The patient should be instructed not to use the foam on the breast when nursing [1,3].

What are the potential drug interactions of calcipotriol/betamethasone dipropionate foam?

No interaction studies have been performed [1].

Enstilar foam should not be used concomitantly with the following medications, as they may occasionally cause excessive blood calcium levels:

  • Colecalciferol
  • Calcium citrate
  • Calcium acetate
  • Chlorothiazide
  • Calcium gluconate
  • Chlorthalidone
  • Calcitriol.

What are the possible side effects of calcipotriol/betamethasone dipropionate foam?

Adverse effects in < 1% of recipients associated with the use of Enstilar in clinical trials included [6,7]:

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

New Zealand approved datasheets are the official source of information for these prescription medicines, including approved uses and risk information. Check the individual New Zealand datasheet on the Medsafe website.

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References

  1. Enstilar foam — US FDA prescribing information PDF. Available from: www.accessdata.fda.gov/drugsatfda_docs/label/2015/207589s000lbl.pdf [accessed August 2019]
  2. Kuehl B, Shear NH. The Evolution of Topical Formulations in Psoriasis. Skin Therapy Lett 2018; 23: 5–9. PubMed
  3. Enstilar foam — Medscape drug information. Available from: reference.medscape.com/drug/taclonex-enstilar-calcipotriene-betamethasone-999451 [accessed September 2019]
  4. Frieder J, Kivelevitch D, Menter A. Calcipotriene betamethasone dipropionate aerosol foam in the treatment of plaque psoriasis: a review of the literature. Ther Deliv 2017; 8: 737–46. PubMed
  5. Enstilar foam — European pharmaceutical review. Available from: mri.cts-mrp.eu/human/downloads/DK_H_2478_001_PAR.pdf [accessed September 2019]
  6. Menter A, Gold LS, Koo J, Villumsen J, Rosén M, Lebwohl M. Fixed-Combination Calcipotriene Plus Betamethasone Dipropionate Aerosol Foam Is Well Tolerated in Patients with Psoriasis Vulgaris: Pooled Data from Three Randomized Controlled Studies. Skinmed. 2017; 15: 119–24. PubMed
  7. Stein Gold LF. Topical Therapies for Psoriasis: Improving Management Strategies and Patient Adherence. Semin Cutan Med Surg 2016; 35: S36–44. PubMed

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