Elidel

Pharmacotherapeutic group: Other dermatological preparations. Agents for dermatitis, excluding corticosteroids., ATC code: D11AH02 Mechanism of action Pimecrolimus is a lipophilic anti-inflammatory ascomycin macrolactam derivative and a cell selective inhibitor of the production and release of pro-inflammatory cytokines. Pimecrolimus binds with high affinity to macrophilin-12 and inhibits the calcium-dependent phosphatase calcineurin. As a consequence, it blocks the synthesis of inflammatory cytokines in T cells. Pharmacodynamic effects Pimecrolimus exhibits high anti-inflammatory activity in animal models of skin inflammation after topical and systemic application. In the pig model of allergic contact dermatitis, topical pimecrolimus is as effective as potent corticosteroids. Unlike corticosteroids, pimecrolimus does not cause skin atrophy in pigs and does not affect Langerhans´cells in murine skin. Pimecrolimus neither impairs the primary immune response nor affects lymph nodes in murine allergic contact dermatitis. Topical pimecrolimus penetrates similarly into, but permeates much less through human skin than corticosteroids, indicating a very low potential of pimecrolimus for systemic absorption. In conclusion, pimecrolimus has a skin-selective pharmacological profile different from corticosteroids. Clinical efficacy and safety The efficacy and safety profile of Elidel has been evaluated in more than 2,000 patients including infants (≥3 months), children, adolescents, and adults enrolled in phase II and III studies. Over 1,500 of these patients were treated with Elidel and over 500 were treated with control treatment i.e. either Elidel vehicle and/or topical corticosteroids. Short-term (acute) treatment: Children and adolescents: Two 6-week, vehicle-controlled trials were conducted including a total of 403 paediatric patients aged 2 to 17 years. Patients were treated twice daily with Elidel. The data of both studies were pooled. Infants: A similar 6-week study was conducted in 186 patients aged 3-23 months. In these three 6-week studies, the efficacy results at endpoint were as follows: Children and adolescents Infants Endpoint Criteria Elidel 1% (N=267) Vehicle (N=136) p-value Elidel 1% (N=123) Vehicle (N=63) p-value IGA*: Clear or almost clear 1 34.8% 18.4% <0.001 54.5% 23.8% <0.001 IGA* Improvement 2 59.9% 33% not done 68% 40% Not done Pruritus: Absent or mild 56.6% 33.8% <0.001 72.4% 33.3% <0.001 EASI°: Overall (mean % change) 3 -43.6 -0.7 <0.001 -61.8 +7.35 <0.001 EASI°: Head/Neck (mean % change) 3 -61.1 +0.6 <0.001 -74.0 +31.48 <0.001 * Investigators Global Assessment ° Eczema Area Severity Index (EASI): mean % change in clinical signs (erythema, infiltration, excoriation, lichenification) and body surface area involved 1 : p-value based on CMH test stratified by centre 2 Improvement=lower IGA than at baseline 3 : p-value based on ANCOVA model of EASI at Day 43 endpoint, with centre and treatment as factors and baseline (Day 1) EASI a covariate; A significant improvement in pruritus was observed within the first week of treatment in 44% of children and adolescents and in 70% of infants. Adults: Elidel was less effective than 0.1% betamethasone-17-valerate in the short-term treatment (3 weeks) of adults with moderate to severe atopic dermatitis. Long-term treatment Two double-blind studies of long-term management of atopic dermatitis were undertaken in 713 children and adolescents (2-17 years) and 251 infants (3-23 months). Elidel was evaluated as foundation therapy. Elidel was used at first signs of itching and redness to prevent progression to flares of atopic dermatitis. Only in case of a flare of severe disease not controlled by Elidel, treatment with medium potency topical corticosteroids was initiated. When corticosteroid therapy was initiated for the treatment of flares, pimecrolimus 1% cream therapy was discontinued. The control group received Elidel vehicle in order to maintain blinding. Both studies showed a significant reduction in the incidence of flares (p<0.001) in favour of pimecrolimus 1% cream treatment; pimecrolimus 1% cream treatment showed better efficacy in all secondary assessments (Eczema Area Severity Index, Investigators Global Assessment, subject assessment); pruritus was controlled within a week with pimecrolimus 1% cream. More patients treated with pimecrolimus 1% cream completed 6 months [children (61% Elidel vs 34% control), infants (70% Elidel vs 33% control)] and 12 months with no flare [children (51% Elidel vs 28% control), infants (57% Elidel vs 28% control)]. Elidel had a sparing effect on the use of topical corticosteroids: more patients treated with pimecrolimus 1% cream did not use corticosteroids in 12 months [children (57% Elidel vs 32% control), infants (64% Elidel vs 35% control)]. The efficacy of pimecrolimus 1% cream was maintained over time. A 6-month randomised, double-blind, parallel group, vehicle-controlled study of similar design was performed in 192 adults with moderate to severe atopic dermatitis. Topical corticosteroid medication was used on 14.2 ± 24.2% of the days of the 24-week treatment period in Elidel group and on 37.2 ± 34.6% of the days in the control group (p<0.001). A total of 50.0% of the patients treated with pimecrolimus 1% cream did not experience any flare compared with 24.0% of the patients randomised to the control group. A one year double-blind study in adults with moderate to severe atopic dermatitis was conducted to compare Elidel to 0.1% triamcinolone acetonide cream (for trunk and extremities) plus 1% hydrocortisone acetate cream (for face, neck and intertriginous areas). Both pimecrolimus 1% cream and topical corticosteroids were used without restrictions. Half of the patients in the control group received topical corticosteroids for more than 95% of study days. Pimecrolimus 1% cream was less effective than 0.1% triamcinolone acetonide cream (for trunk and extremities) plus 1% hydrocortisone acetate cream (for face, neck and intertriginous areas) in the long-term treatment (52 weeks) of adults with moderate to severe atopic dermatitis. Long-term safety A 5-year, open-label, randomised, active-controlled study was conducted in 2,418 infants 3 months to less than 12 months of age at enrollment with mild to moderate atopic dermatitis (AD). The primary objective was to compare safety by assessing adverse events (AEs), and the effects of treatments on the developing immune system and growth velocity. Infants were randomised to Elidel (n = 1,205; with short-term TCSs for disease flares) or low/mid potency topical corticosteroids (TCS; n = 1,213). Elidel was well tolerated in subjects with mild to moderate AD who were 3 to 12 months of age at the start of the study. The profile and frequency of adverse events was similar in the 2 treatment groups. No impairment of systemic immune assessments was seen, and subjects with AD who were treated with pimecrolimus 1% cream or TCS displayed normal immune response maturation and developed effective immunization against vaccine antigens. There was no apparent difference in growth velocity. Special studies Tolerability studies demonstrated that Elidel has not shown contact sensitising, phototoxic or photosensitising potential, nor did they show any cumulative irritation. The atrophogenic potential of Elidel in humans was tested in comparison to medium and highly potent topical steroids (betamethasone-17-valerate 0.1% cream, triamcinolone acetonide 0.1% cream) and vehicle in sixteen healthy volunteers treated for 4 weeks. Both topical corticosteroids induced a significant reduction in skin thickness measured by echography, as compared to pimecrolimus 1% cream and vehicle, which did not induce a reduction of skin thickness. Paediatric population Results of relevant studies in infants, children and adolescents are detailed above in section 5.1.