Calcipotriol

(BAN, rINN)
Calcipotriol Chemical formula
Synonyms: Calcipotriene Kalsipotriol; Kalsipotrioli; MC-903. (5Z,7E,22E,24S)-24-Cyclopropyl-9,10-secochola5,7,10(19),22-tetraene-1
Cyrillic synonym: Кальципотриол.

💊 Chemical information

Chemical formula: C27H40O3 = 412.6.
CAS — 112828-00-9; 112965-21-6.
ATC — D05AX02.
ATC Vet — QD05AX02.

Pharmacopoeias.

In Eur., which also includes the monohydrate.

Ph. Eur. 6.2 (Calcipotriol, Anhydrous; Calcipotriolum Anhydricum). A white or almost white, crystalline powder. It is sensitive to heat and light. A reversible isomerisation to pre-calcipotriol takes place in solution, depending on temperature and time. The activity is due to both compounds. Practically insoluble in water; freely soluble in alcohol; slightly soluble in dichloromethane. Store in airtight containers at a temperature of −20° or below. Protect from light.

Ph. Eur. 6.2 (Calcipotriol Monohydrate; Calcipotriolum Monohydricum). A white or almost white, crystalline powder. It is sensitive to light. A reversible isomerisation to pre-calcipotriol takes place in solution, depending on temperature and time. The activity is due to both compounds. Practically insoluble in water; freely soluble in alcohol; slightly soluble in dichloromethane. Store in airtight containers. Protect from light.

💊 Adverse Effects and Precautions

The most frequent adverse effect associated with calcipotriol is skin irritation and it should not therefore be applied to the facial area. Symptoms may include burning, itching, erythema, and dry skin, but stopping therapy is seldom necessary. Aggravation of psoriasis may occur. Hypercalcaemia has occurred during treatment with calcipotriol and although rapidly reversible on withdrawal, it should not be used in patients with disorders of calcium metabolism. Other rare adverse effects may include skin atrophy, hyperpigmentation, and photosensitivity. Patients should limit or avoid excessive exposure to both natural and artificial sunlight, because animal studies have suggested that topical calcipotriol may enhance the effect of UV radiation to induce skin tumours.

Effects on calcium homoeostasis.

Calcipotriol is a vitamin D derivative and therefore has the potential to cause hypercalcaemia and hypercalciuria. Up to December 1993, when about 150 000 patients in the UK had been treated with calcipotriol, the UK CSM had received 6 reports of hypercalcaemia and 2 of hypercalciuria.1 Three of the patients with hypercalcaemia either had used doses in excess of the recommended maximum (see Uses and Administration, below) or had pustular or exfoliative psoriasis. Hypercalcaemia and hypercalciuria were reversible on withdrawal of calcipotriol. A study2 investigating the effect of calcipotriol on urine calcium excretion found that use of the maximum recommended dose for 4 weeks produced increased urine calcium excretion, and the authors suggested that patients requiring the maximum dose of calcipotriol should be monitored for hypercalciuria before and during treatment. A review3 of the effects of vitamin D analogues on calcium homoeostasis concluded that patients with unstable psoriasis are at particular risk of toxicity from calcipotriol and that measurement of urine calcium excretion is a more sensitive indicator of toxicity than serum-calcium concentrations.
1. Committee on Safety of Medicines/Medicines Control Agency. Dovonex ointment (calcipotriol). Current Problems 1994; 20: 3. Also available at: http://www.mhra.gov.uk/home/ idcplg?IdcService=GET_FILE&dDocName=CON2024457& RevisionSelectionMethod=LatestReleased (accessed 27/09/07
2. Berth-Jones J, et al. Urine calcium excretion during treatment of psoriasis with topical calcipotriol. Br J Dermatol 1993; 129: 411–14
3. Bourke JF, et al. Vitamin D analogues in psoriasis: effects on systemic calcium homeostasis. Br J Dermatol 1996; 135: 347–54.

Hyperpigmentation.

Hyperpigmentation occurred at the site of calcipotriol application in 2 patients after use with PUVA-bath therapy (a topical psoralen with UVA irradiation) for psoriasis.1The effect persisted for at least 4 months in these patients. Hyperpigmentation of psoriatic plaques was also reported in a patient treated with topical calcipotriol and UVB phototherapy.2 Abnormal lentiginous pigmentation of psoriatic plaques occurred in a patient treated with topical calcipotriol for psoriasis, which had worsened during chemotherapy for melanoma, and was still present 2 years after stopping chemotherapy and calcipotriol.3The authors also noted that melanoma can cause pigment changes and may have played a role in this case. There has been some interest in the hyperpigmentary effects of calcipotriol for the possible treatment of vitiligo (see Skin Disorders, below).
1. Gläser R, et al. Hyperpigmentation due to topical calcipotriol and photochemotherapy in two psoriatic patients. Br J Dermatol 1998; 139: 148–51
2. Rütter A, Schwarz T. Ausgeprägte Hyperpigmentierung in psoriatischen Plaques als Folge einer Kombinationsbehandlung mit UVB-311 nm und Calcipotriol. Hautarzt 2000; 51: 431–3
3. Oláh J, et al. Pigment anomaly caused by calcipotriol in a subject with melanoma. J Eur Acad Dermatol Venereol 2004; 18: 113–15.

💊 Uses and Administration

Calcipotriol is a vitamin D 3 derivative. In vitro it appears to induce differentiation and to suppress proliferation of keratinocytes. Calcipotriol is used in a cream or ointment for the management of plaque psoriasis and as a solution in the management of scalp psoriasis; the concentration of calcipotriol used is 0.005%. Applications should be made once or twice daily. No more than 100 g of cream or ointment, or 60 mL of scalp solution, should be applied in one week. If both are used, the limit is 60 g of cream or ointment with 30 mL of scalp solution, or 30 g of cream or ointment with 60 mL of scalp solution. For the use of calcipotriol in children, see below.

Administration in children.

Topical calcipotriol may be used in the management of plaque psoriasis in children. In the UK, the cream or ointment (0.005%) may be applied twice daily. The maximum applied in one week should be 50 g in children aged 6 to 12 years, and 75 g in children more than 12 years of age. The BNFC also suggests that under specialist supervision the scalp solution (0.005%) may be applied twice daily to children aged 6 years and over for the treatment of scalp psoriasis; no more than 30 mL of the solution should be applied in one week to those aged 6 to 12 years, with older children receiving a maximum of 45 mL in one week. When preparations are used together, the BNFC recommends a maximum total calcipotriol dose of 2.5 mg in any one week for children aged 6 to 12 years (e.g. 20 mL of the scalp solution with 30 g of the cream or ointment); in older children, the maximum is 3.75 mg in any one week (e.g. 30 mL of the scalp solution with 45 g of the cream or ointment). In the UK, the scalp solution is not licensed for use in children and the cream and ointment are not licensed for use in children under 6 years; however, safety and efficacy have been reported in small 8-week studies that have included children as young as 2 years old.1-3 There are also a few case reports of topical calcipotriol use in infants with psoriasis, aged 3 months4 and 6 months.5
1. Darley CR, et al. Safety and efficacy of calcipotriol ointment (Dovonex ) in treating children with psoriasis vulgaris. Br J Dermatol 1996; 135: 390–3
2. Oranje AP, et al. Topical calcipotriol in childhood psoriasis. J Am Acad Dermatol 1997; 36: 203–8
3. Patrizi A, et al. Topical calcipotriol in childhood psoriasis. Acta Derm Venereol 1999; 79: 477
4. Travis LB, Silverberg NB. Psoriasis in infancy: therapy with calcipotriene ointment. Cutis 2001; 68: 341–4
5. Choi YJ, et al. Infantile psoriasis: successful treatment with topical calcipotriol. Pediatr Dermatol 2000; 17: 242–4.

Skin disorders.

Topical drugs are the treatment of first choice for chronic plaque psoriasis. Calcipotriol, dithranol, and coal tar are commonly used for mild to moderate forms of the disorder. Calcipotriol inhibits cell proliferation and increases cell differentiation by binding to vitamin D receptors, thus inhibiting epidermal growth and returning some normality to the skin’s structure. It is also possible that calcipotriol affects immunological and inflammatory processes in the skin.1 Topical calcipotriol has been shown to be effective in mild to moderate chronic plaque psoriasis; it is at least as effective as dithranol, coal tar, and corticosteroids, and has been reported to be superior in a number of studies.1,2 Calcipotriol is also more cosmetically acceptable than dithranol, which can stain, and coal tar, which can have an unpleasant smell. Benefits have been maintained with long-term use, and repeat courses are effective for the management of relapse. Although there are fewer studies in children, calcipotriol has been reported to be safe and effective in studies including children aged 2 to 15 years1 (see also Administration in Children, above). Calcipotriol, applied as a topical solution, is also effective for scalp psoriasis.3 When solutions of calcipotriol and betamethasone were compared for mild to moderate scalp psoriasis,4 calcipotriol produced a satisfactory response, but betamethasone was more effective and was associated with less irritation of the scalp and face. Similar results were reported in a study comparing calcipotriol with clobetasol propionate in moderate to severe scalp psoriasis.5 In a study of patients with nail psoriasis about half received benefit from calcipotriol ointment over a 3 to 5 month treatment period.6 This result was similar to that found for patients treated with betamethasone and salicylic acid ointment. Use of calcipotriol with other antipsoriatic drugs may be beneficial. The combination of calcipotriol with a topical corticosteroid is more effective than monotherapy with either of these.1,7,8Treatment for up to 4 weeks is usually effective and may be followed by maintenance calcipotriol monotherapy.9 Topical calcipotriol with systemic therapies has also been tried. There is evidence that the response to oral ciclosporin or acitretin can be improved,1 as can the response to phototherapy (UVB) or photochemotherapy (PUVA).1,10 Combination therapy may also reduce the cumulative dose of acitretin, UVB, or PUVA required to achieve clearance or marked improvement of psoriasis, potentially reducing the risk of long-term adverse effects from these treatments.1,10,11 However, because of the potential for the vehicle of topical calcipotriol preparations to block UV irradiation, they should be applied at least 2 hours before irradiation.12 Despite promising reports from combination therapy using topical calcipotriol with systemic treatment, phototherapy, or photochemotherapy, a systematic review13 found that although there can be a measurable additive effect, it may not be clinically significant in patients’ own assessments. A 2-week course of high-dose calcipotriol (up to 360 g of 0.005% ointment weekly) has been used for inpatient treatment of extensive psoriasis, followed by the usual recommended dose (up to 100 g weekly) for residual psoriasis.14 Asymptomatic hypercalcaemia and hypercalciuria occurred in some patients, and the authors suggested that the monitoring of calcium homoeostasis is mandatory with this regimen (see also Effects on Calcium Homoeostasis, above). Relapse occurred in most patients within one year. Beneficial results with calcipotriol have also been reported in small numbers of patients with various skin disorders15 including acrodermatitis continua of Hallopeau, confluent and reticulated papillomatosis, congenital ichthyosis, inflammatory linear verrucous epidermal nevus, lichen amyloidosis, morphea or linear scleroderma, pityriasis rubra pilaris, prurigo nodularis, and seborrhoeic dermatitis. A small open study16 has indicated that topical calcipotriol may be effective in the treatment of oral leucoplakia. It has also been tried, alone or with UVA or UVB, or a topical corticosteroid, in the treatment of vitiligo17-21, but results have been mixed.
1. Scott LJ, et al. Calcipotriol ointment: a review of its use in the management of psoriasis. Am J Clin Dermatol 2001; 2: 95–120
2. Ashcroft DM, et al. Systematic review of comparative efficacy and tolerability of calcipotriol in treating chronic plaque psoriasis. BMJ 2000; 320: 963–7
3. Thaçi D, et al. Calcipotriol solution for the treatment of scalp psoriasis: evaluation of efficacy, safety and acceptance in 3,396 patients. Dermatology 2001; 203: 153–6
4. Klaber MR, et al. Comparative effects of calcipotriol solution (50 micrograms/mL) and betamethasone 17-valerate solution (1 mg/mL) in the treatment of scalp psoriasis. Br J Dermatol 1994; 131: 678–83
5. Reygagne P, et al. Clobetasol propionate shampoo 0.05% and calcipotriol solution 0.005%: a randomized comparison of efficacy and safety in subjects with scalp psoriasis. J Dermatol Treat 2005; 16: 31–6
6. Tosti A, et al. Calcipotriol ointment in nail psoriasis: a controlled double-blind comparison with betamethasone dipropionate and salicylic acid. Br J Dermatol 1998; 139: 655–9
7. Fenton C, Plosker GL. Calcipotriol/betamethasone dipropionate: a review of its use in the treatment of psoriasis vulgaris. Am J Clin Dermatol 2004; 5: 463–78
8. Kragballe K, van de Kerkhof PCM. 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. J Eur Acad Dermatol Venereol 2006; 20: 39–44
9. White S, et al. Use of calcipotriene cream (Dovonex cream) following acute treatment of psoriasis vulgaris with the calcipotriene/betamethasone dipropionate two-compound product (Taclonex ): a randomized, parallel-group clinical trial. Am J Clin Dermatol 2006; 7: 177–84
10. Torras H, et al. A combination therapy of calcipotriol cream and PUVA reduces the UVA dose and improves the response of psoriasis vulgaris. J Dermatol Treat 2004; 15: 98–103
11. Woo WK, McKenna KE. Combination TL01 ultraviolet B phototherapy and topical calcipotriol for psoriasis: a prospective randomized placebo-controlled clinical trial. Br J Dermatol 2003; 149: 146–50
12. De Rie MA, et al. Calcipotriol ointment and cream or their vehicles applied immediately before irradiation inhibit ultraviolet B-induced erythema. Br J Dermatol 2000; 142: 1160–5
13. Ashcroft DM, et al. Combination regimens of topical calcipotriene in chronic plaque psoriasis: systematic review of efficacy and tolerability. Arch Dermatol 2000; 136: 1536–43
14. Bleiker TO, et al. Long-term outcome of severe chronic plaque psoriasis following treatment with high-dose topical calcipotriol. Br J Dermatol 1998; 139: 285–6
15. Holm EA, Jemec GBE. The therapeutic potential of calcipotriol in diseases other than psoriasis. Int J Dermatol 2002; 41: 38–43
16. Femiano F, et al. Oral leukoplakia: open trial of topical therapy with calcipotriol compared with tretinoin. Int J Oral Maxillofac Surg 2001; 30: 402–6
17. Ameen M, et al. Topical calcipotriol as monotherapy and in combination with psoralen plus ultraviolet A in the treatment of vitiligo. Br J Dermatol 2001; 145: 476–9
18. Chiaverini C, et al. Treatment of vitiligo by topical calcipotriol. J Eur Acad Dermatol Venereol 2002; 16: 137–8
19. Kumaran MS, et al. Effect of topical calcipotriol, betamethasone dipropionate and their combination in the treatment of localized vitiligo. J Eur Acad Dermatol Venereol 2006; 20: 269–73
20. Goktas E, et al. Combination of narrow band UVB and topical calcipotriol for the treatment of vitiligo. J Eur Acad Dermatol Venereol 2006; 20: 553–7
21. Arca E, et al. Narrow-band ultraviolet B as monotherapy and in combination with topical calcipotriol in the treatment of vitiligo. J Dermatol 2006; 33: 338–43.

💊 Preparations

Proprietary Preparations

Arg.: Daivonex; Dermocal†; Austral.: Daivonex; Austria: Psorcutan; Belg.: Daivonex; Braz.: Daivonex; Canad.: Dovonex; Chile: Daivonex; Cz.: Daivonex; Psorcutan†; Denm.: Daivonex; Fin.: Daivonex; Fr.: Daivonex; Ger.: Daivonex; Psorcutan; Gr.: Cipocal; Dovonex; F-Psorin; Psoraffect; Hong Kong: Daivonex; Hung.: Daivonex; India: Daivonex; Indon.: Daivonex; Irl.: Dovonex; Israel: Daivonex; Ital.: Daivonex; Psorcutan; Jpn: Dovonex; Malaysia: Daivobet; Daivonex; Mex.: Daivonex; Eukadar; Neth.: Daivonex; Norw.: Daivonex; NZ: Daivonex; Philipp.: Daivonex; Pol.: Daivonex; Port.: Daivonex; Rus.: Daivonex (Дайвонекс); S.Afr.: Dovonex; Singapore: Daivonex; Spain: Daivonex; Swed.: Daivonex; Switz.: Daivonex; Thai.: Daivonex; Turk.: Psorcutan; UK: Dovonex; USA: Dovonex; Venez.: Daivonex†. Multi-ingredient: Austral.: Daivobet; Austria: Psorcutan Beta; Belg.: Dovobet; Braz.: Daivobet; Canad.: Dovobet; Cz.: Daivobet; Denm.: Daivobet; Fin.: Daivobet; Fr.: Daivobet; Ger.: Daivobet; Psorcutan Beta; Gr.: Dovobet; Hong Kong: Daivobet; Hung.: Daivobet; Indon.: Daivobet; Irl.: Dovobet; Israel: Daivobet; Ital.: Dovobet; Token; Mex.: Daivobet; Neth.: Dovobet; Norw.: Daivobet; NZ: Daivobet; Philipp.: Daivobet; Pol.: Daivobet; Port.: Daivobet; Rus.: Daivobet (Дайвобет); Singapore: Daivobet; Spain: Daivobet; Swed.: Daivobet; Switz.: Daivobet; Thai.: Daivobet; UK: Dovobet; USA: Taclonex.
Published November 16, 2018.