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Pharmacology: Pharmacodynamics: In humans, the natural supply of vitamin D depends mainly on exposure to the ultraviolet rays of the sun for conversion of 7-dehydrocholesterol to vitamin D3 (cholecalciferol) in the skin. Calcipotriol is a synthetic analog of vitamin D3. Clinical studies with radiolabelled ointment indicate that approximately 6% (± 3%, SD) of the applied dose of Calcipotriol is absorbed systemically when the ointment is applied topically to psoriasis plaques or 5% (± 2.6%, SD) when applied to normal skin, and much of the absorbed active is converted to inactive metabolites within 24 hours of application. Vitamin D and its metabolites are transported in the blood, bound to specific plasma proteins. The active form of the vitamin, 1, 25-dihydroxy vitamin D3 (calcitriol), is known to be recycled via the liver and excreted in the bile. Calcipotriol metabolism following systemic uptake is rapid, and occurs via a similar pathway to the natural hormone. The primary metabolites are much less potent than the parent compound. There is evidence that material 1, 25-dihydroxy vitamin D3 (calcitriol) may enter the fetal circulation, but it is not known whether it is excreted in human milk. The systemic disposition of Calcipotriol is expected to be similar to that of the naturally occurring vitamin.
Clinical Studies: Adequate and well-controlled trials of patients treated with Calcipotriol Ointment have demonstrated improvement usually beginning after two weeks of therapy. This improvement continued in patients using Calcipotriol Ointment once daily and twice daily. After 8 weeks of once daily Calcipotriol Ointment, 56.7% of patients showed at least marked improvements (6.4% showed complete clearing). After 8 weeks of twice daily Calcipotriol Ointment 70.0% of patients showed at least marked improvement (11.3% showed complete clearing). Subtracting percentages of patients using placebo (vehicle only) from percentages of patients using Calcipotriol Ointment who had at least marked improvements after 8 weeks yields 39.9% for once daily and 49.6% for twice daily. This adjustment for placebo effect indicates that what might appear to be differences between once and twice daily use may reflect differences in the studies independent from the frequency of dosing. Although there was a numerical difference in comparison across studies, twice daily dosing has not been shown to be superior in efficacy to once daily dosing. Over 400 patients have been treated in open label clinical studies of Calcipotriol Ointment for periods of up to one year. In half of these studies, patients who previously had not responded well to Calcipotriol Ointment were excluded. The adverse events in these extended studies included skin irritation in approximately 25% of patients and worsening of psoriasis in approximately 10% of patients. In one of these open label studies, half of the patients no longer required Calcipotriol Ointment by 16 weeks of treatment, because of satisfactory therapeutic results.
Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: When Calcipotriol was applied topically to mice for up to 24 months at dosages of 3, 10 and 30 μg/kg/day (corresponding to 9, 30 and 90 μg/m2/day, and no significant changes in tumor incidence were observed when compared to control. In a study in which albino hairless mice were exposed to both UVR and topically applied Calcipotriol, a reduction in the time required for UVR to induce the formation of skin tumors was observed (statistically significant in males only), suggesting that Calcipotriol may enhance the effect of UVR to induce skin tumors. Patients that apply Calcipotriol Ointment to exposed portions of the body should avoid excessive exposure to either natural or artificial sunlight (including tanning booths, sun lamps, etc.). Physicians may wish to avoid use of phototherapy in patients that use Calcipotriol Ointment. Calcipotriol did not elicit any mutagenic effects in an Ames mutagenicity assay, a mouse lymphoma TK locus assay, a human lymphocyte chromosome aberration assay, or in a micronucleus assay conducted in mice. Studies in rates at doses up to 54 μg/kg/day (324 μg/m2/day) of Calcipotriol indicated no impairment of fertility or general reproductive performance.
