Published in:
01-04-2001 | Adis Drug Evaluation
Calcipotriol Ointment
A Review of its Use in the Management of Psoriasis
Published in: American Journal of Clinical Dermatology | Issue 2/2001
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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.