Clinical trials of calcipotriene foam did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
Topically applied calcipotriene can be absorbed in sufficient amounts to produce systemic effects. Elevated serum calcium has been observed with use of topical calcipotriene [See Warnings and Precautions ( 5.2)] .
Calcipotriene foam contains the compound calcipotriene, a synthetic vitamin D3 analog, in an aqueous-based emulsion foam vehicle for topical dermatologic use.
Chemically, calcipotriene is (5Z,7E,22E,24S)-24-cyclopropyl-9,10-secochola-5,7,10(19), 22-tetraene- 1α,3β,24-triol. The structural formula is represented below:
Molecular Formula: C27H40O3 Molecular Weight: 412.6 Calcipotriene is a white or off-white crystalline substance. Calcipotriene foam contains calcipotriene 50 mcg/g in an aqueous-based emulsion foam vehicle consisting of cetyl alcohol, dibasic sodium phosphate, dl-α-tocopherol, edetate disodium, isopropyl myristate, light mineral oil, polyoxyl 20 cetostearyl ether, propylene glycol, purified water, stearyl alcohol, and white petrolatum. calcipotriene foam is dispensed from an aluminum can pressurized with a hydrocarbon (propane/n-butane/isobutane) propellant.
Calcipotriene is a synthetic vitamin D3 analog that has a similar receptor binding affinity as natural vitamin D3. However, the exact mechanism of action contributing to the clinical efficacy in the treatment of psoriasis is unknown.
Effects on Calcium Metabolism
In 19 subjects with psoriasis aged 12 to less than 17 years treated with calcipotriene foam two times a day for 15 days, there was no significant effect on indices of calcium metabolism including serum albumin adjusted calcium, urine calcium/creatinine ratio, iPTH, alkaline phosphatase, magnesium and phosphorus.
The effects of calcipotriene foam, 0.005%, on calcium metabolism were evaluated in 18 pediatric subjects 5 to 11 years of age receiving calcipotriene foam administered twice daily for a minimum of 14 days (mean: 56 days, range: 14 to 69 days). These subjects had plaque psoriasis involving an average of 10% of the body surface area (BSA) (range: 0.5%-36.5%). There was no relationship between urinary calcium/creatinine ratio (comparing Week 2 to Baseline) and % BSA treated.
The systemic absorption of calcipotriene in subjects with psoriasis of the body was evaluated at steady state following application of either calcipotriene foam or calcipotriene ointment to a body surface area of 5% to 10%. In the calcipotriene foam treatment group, 15 out of 16 subjects had calcipotriene plasma concentrations below the limit of quantitation (10 pg/mL), while in the calcipotriene ointment treated group, 5 out of 16 subjects had measurable calcipotriene plasma concentrations at various time points. All measurable plasma calcipotriene concentrations were below 25 pg/mL.
The pharmacokinetics of calcipotriene foam, 0.005% was investigated when applied topically for 15 days to 17 subjects aged 12 to less than 17 years with moderate plaque psoriasis involving a mean BSA of 24%, excluding face and scalp, and a mean scalp involvement of 43%. Systemic concentration of calcipotriene were not quantifiable in any of the subjects (limit of quantification = 10 pg/mL).
In 11 pediatric subjects 7 to 11 years of age with plaque psoriasis involving a mean BSA of 10%, plasma concentration of calcipotriene was measured following 2 weeks of twice daily administration of calcipotriene foam. No subject had quantifiable calcipotriene plasma concentration (limit of quantification = 10 pg/mL).
The systemic disposition of calcipotriene is expected to be similar to that of the naturally occurring vitamin D. Absorbed calcipotriene is known to be converted to inactive metabolites within 24 hours of application and the metabolism occurs via a similar pathway to the natural hormone.
Calcipotriene topically administered to mice for up to 24 months at dose levels of 3, 10, or 30 mcg/kg/day (corresponding to 9, 30, or 90 mcg /m 2 /day) showed no significant changes in tumor incidence when compared with controls.
The genotoxic potential of calcipotriene was evaluated in an Ames assay, a mouse lymphoma TK locus assay, a human lymphocyte chromosome aberration assay, and a mouse micronucleus assay. All assay results were negative.
Studies in rats at oral doses up to 54 mcg /kg/day (318 mcg /m 2 /day) of calcipotriene indicated no impairment of fertility or general reproductive performance.
In two multi-center, randomized, double-blind, vehicle-controlled clinical trials a total of 659 subjects with psoriasis were randomized 2:1 to calcipotriene foam or vehicle; subjects applied the assigned treatment twice daily for 8 weeks. Baseline disease severity was graded using a 5-point Investigator Static Global Assessment scale (ISGA), on which subjects scored either “mild” or “moderate” as shown in Table 1.
|Clear||0||No evidence of scaling, erythema, or plaque thickness|
|Almost clear||1||Occasional fine scale, faint erythema, and barely perceptible plaque thickness|
|Mild||2||Fine scale with light coloration and mild plaque elevation|
|Moderate||3||Coarse scale with moderate red coloration and moderate plaque thickness|
|Severe||4||Thick tenacious scale with deep coloration and severe plaque thickness|
Efficacy evaluation was carried out at Week 8 with treatment success being defined as a score of “clear” (grade 0) or “almost clear” (grade 1) and at least 2 grade improvement from the baseline score. Approximately 30% of enrolled subjects were graded as “mild” on the ISGA scale. The study population ranged in age from 12 to 89 years with 10 subjects less than 18 years of age at baseline. The subjects were 54% male and 88% Caucasian. Table 2 presents the efficacy results for each trial.
|Trial 1||Trial 2|
|Calcipotriene foam N = 223||Vehicle Foam N = 113||Calcipotriene foam N = 214||Vehicle Foam N = 109|
|Number (%) of Subjects with Treatment Success||31 (14%)||8 (7%)||58 (27%)||17 (16%)|
In one trial, subjects graded as “mild” at baseline showed a greater response to vehicle than calcipotriene foam.
Table 3 presents the success rates by disease severity at baseline for each trial.
|ISGA Scores at Baseline||Trial 1||Trial 2|
|Calcipotriene foam (N = 223)||Vehicle Foam (N = 113)||Calcipotriene foam (N = 214)||Vehicle Foam (N = 109)|
|Mild||2/73 (2.7%)||3/34 (8.8%)||8/56 (14.3%)||4/31 (12.9%)|
|Moderate||29/150 (19.3%)||5/79 (6.3%)||50/158 (31.6%)||13/78 (16.7%)|
In another multi-center, randomized, double-blind, vehicle-controlled clinical trial, a total of 363 subjects with moderate plaque psoriasis of the scalp and body were randomized 1:1 to calcipotriene foam or vehicle. Subjects applied the assigned treatment to the affected areas twice daily for 8 weeks.
Baseline disease severity of the scalp was graded using a 6-point ISGA; a score of “moderate” corresponded to grade 3.
The primary efficacy evaluation for scalp involvement was carried out at Week 8 with treatment success being defined as a score of “clear” (grade 0) or “almost clear” (grade 1). The study population ranged in age from 12 to 97 years with 11 subjects less than 18 years of age at baseline. The subjects were 60% male and 87% Caucasian. Table 4 presents the efficacy results for the trial.
|Calcipotriene foam N = 181||Vehicle Foam N = 182|
|Number (%) of Subjects with Treatment Success||74 (41%)||44 (24%)|
The contribution to efficacy of individual components of the vehicle has not been established.
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