There has been no experience of overdose with Elidel 1% cream. No incidents of accidental ingestion have been reported.

 

Use in pregnancy: There are no adequate data from the use of Elidel in pregnant women. Dermal application on animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development.
Caution should be exercised when prescribing Elidel to pregnant women. However, based on the minimal extent of pimecrolimus absorption after topical application of Elidel, the potential risk for humans is considered limited.
Use in lactation: Pimecrolimus has not been administered to lactating women.
Animal studies on milk excretion after topical application were not conducted. It is not known whether pimecrolimus is excreted in the milk after topical application. Because many drugs are excreted in human milk, caution should be exercised when Elidel is administered to a nursing woman. However, based on the minimal extent of pimecrolimus absorption after topical application of Elidel, the potential risk for humans is considered limited.
Nursing mothers should not apply Elidel to the breast.

 

Instructions for Use and Handling: Any unsused product should be disposed of in accordance with local requirements.
Once opened, the contents of the tube should be used within 12 weeks.

 

Do not store above 30°C. Do not freeze.

 

Pharmacology: Pharmacodynamics: Nonclinical Pharmacology: Pimecrolimus is an anti-inflammatory ascomycin macrolactam derivative and a selective inhibitor of the production and release of pro-inflammatory cytokines and mediators in T cells and mast cells.
Pimecrolimus binds with high affinity to macrophilin-12 and inhibits the calcium-dependent phosphatase calcineurin. As a consequence, it inhibits T-cell activation by blocking the transcription of early cytokines. In particular, pimecrolimus inhibits at nanomolar concentrations interleukin-2, interferon-γ (Th1-type), interleukin-4 and interleukin-10 (Th2-type) cytokine synthesis in human T cells. In addition, pimecrolimus prevents the release of cytokines and pro-inflammatory mediators from mast cells in vitro after stimulation by antigen/immunoglobulin E (IgE). Pimecrolimus does not affect the growth of keratinocyte, fibroblast or endothelial cell lines.
Pimecrolimus exhibits high anti-inflammatory activity in animal models of skin inflammation after topical and systemic application. Pimecrolimus is as effective as the high potency corticosteroids clobetasol-17-propionate and fluticasone after topical application in the pig model of allergic contact dermatitis (ACD). Unlike clobetasol-17-propionate, pimecrolimus does not cause skin atrophy in pigs. Unlike clobetasol-17-propionate and fluticasone, pimecrolimus does not cause blanching and changes in skin texture in pigs. Pimecrolimus also inhibits the inflammatory response to irritants, as shown in murine models of irritant contact dermatitis. Furthermore, topical and oral pimecrolimus effectively reduces skin inflammation and pruritus and normalizes histopathological changes in hypomagnesemic hairless rats, a model that mimics acute aspects of atopic dermatitis. In comparison with tacrolimus (FK 506), topical pimecrolimus penetrates similarly into rat and pig skin. However, due to its higher lipophilicity, the extent of permeation through skin is lower by a factor of 10 as compared to tacrolimus. It does, therefore, selectively target the skin. In rats, oral pimecrolimus is superior to cyclosporine A by a factor of 4 and superior to tacrolimus by a factor of >2 in inhibiting ACD.
In contrast to its efficacy in skin inflammation models, the potential of pimecrolimus for affecting systemic immune responses is low. In the rat, after SC administration, the potency of pimecrolimus in inhibiting the formation of antibodies to sheep red blood cells is 48-fold lower than with tacrolimus. In contrast to cyclosporine A and tacrolimus, oral treatment of mice with pimecrolimus neither impairs the primary immune response nor decreases lymph node weight and cellularity in ACD. Overall, pimecrolimus has unique pharmacological properties: It combines high skin-selective anti-inflammatory activity with a low potential for affecting systemic immune responses.
In animal studies, single oral doses of pimecrolimus had no effect on basal lung and cardiovascular functions. Central nervous system and endocrine parameters [eg, growth hormone (GH), prolactin, luteinizing hormone (LH), testosterone and corticosterone] were also unaffected. Based on its mechanism of action, pimecrolimus is not expected to have any effect on the hypothalamic-pituitary-adrenal (HPA) axis.
Clinical Data: Short-Term (Acute) Treatment in Pediatric Patients: Children and Adolescents: Two 6-week, vehicle-controlled trials were conducted including a total of 403 pediatric patients aged 2-17 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 were as follows: (See table.)

A significant improvement in pruritus was observed within the 1st week of treatment in 44% of children and adolescents and in 70% of infants.
Long-Term Treatment in Pediatric Patients: In 2 double-blind studies of long-term management of atopic dermatitis in 713 children and adolescents (2-17 years) and 251 infants (3-23 months), Elidel was evaluated as foundation therapy.
In addition to emollients, the Elidel group received Elidel 1% cream used at 1st signs of itching and redness to prevent progression to flares of atopic dermatitis. Only in case of flare not controlled by Elidel, treatment with medium potency topical corticosteroids was initiated.
The control group received a standard treatment consisting of emollient plus medium potency topical corticosteroids to treat flares. Elidel vehicle was used instead of Elidel 1% cream in order to maintain the studies blind.
Both studies showed a reduction in the incidence of flares (p<0.001) in favor of Elidel treatment; Elidel treatment showed better efficacy in all secondary assessments (eczema area severity index, IGA, subject assessment); pruritus was controlled within a week with Elidel. Significantly, more patients on Elidel completed 6 months [children (61% Elidel vs 34% control); infants (70% Elidel vs 33% control)] and 12 months [children (51% Elidel vs 28% control)] infants (57% Elidel vs 28% control)] with no flare. Significantly, more patients treated with Elidel did not use corticosteroids in the first 6 months (children: 65% Elidel vs 37% control; infants: 70% Elidel vs 39% control) or 12 months (children: 57% Elidel 1% cream vs 32% control). The efficacy of Elidel was maintained over time with the ability to prevent disease progression to severe flares.
A 6-month randomized, double-blind, parallel group, vehicle-controlled study of similar design was performed in 192 adults with moderate to severe AD (DE-01). 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% of the patients treated with Elidel did not experience any flare compared with 24% of the patients randomized to the control group.
Special Studies: Tolerability studies demonstrated that Elidel is devoid of any contact sensitizing, phototoxic or photosensitizing potential nor did it show 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 16 healthy volunteers treated for 4 weeks. Both topical corticosteroids induced a significant reduction in skin thickness measured by echography, as compared to Elidel 1% cream and vehicle, which did not induce a reduction of skin thickness.
Pharmacokinetics: Data In Animals: Pimecrolimus is lipophilic. When applied topically, its permeation through skin is very low. In minipigs, the total drug-related material systemically absorbed following a single 22-hr application of Elidel under semi-occlusion was at most 1% of the dose; the bioavailability of unchanged pimecrolimus was estimated to be about 0.03%. The amount of radiolabeled drug-related material in the skin at the application site remained essentially constant in the time interval 0-10 days after a 22-hr application; at 5 days post-dose, it represented almost exclusively unchanged pimecrolimus. The major fraction of the absorbed topical dose was completely metabolized and excreted slowly via the bile into the feces.
Data in Humans: Absorption in Adults: Systemic exposure to pimecrolimus was investigated in 12 adult patients treated with Elidel twice daily for 3 weeks. These patients have atopic dermatitis (eczema) lesions affecting 15-59% of their body surface area (BSA). 77.5% of pimecrolimus blood concentrations were <0.5 ng/mL, the assay limit of quantitation (LoQ), and 99.8% of the total samples were <1 ng/mL. The highest blood concentration of pimecrolimus measured in one patient was 1.4 ng/mL.
In 40 adult patients treated for up to 1 year with Elidel, having 14-62% of their BSA affected at baseline, 98% of pimecrolimus blood concentrations were consistently low, mostly below the LoQ. A maximum blood concentration of 0.8 ng/mL was measured in only 2 patients in week 6 of treatment. There was no increase in blood concentration over time in any patient during the 12 months of treatment. In 13 adult patients with hand dermatitis treated with Elidel twice daily for 3 weeks (palmar and dorsal surfaces of hands treated, overnight occlusion), the maximum blood concentration of pimecrolimus measured was 0.91 ng/mL.
Given the high proportion of pimecrolimus blood levels below the LoQ after topical application, the AUC could only be calculated from a few individuals. In 8 adult AD patients presenting with at least 3 quantifiable blood levels per visit day, the AUC_{(0-12 hrs)} values ranged from 2.5-11.4 ng·hr/mL.
Absorption in Children: Systemic exposure to pimecrolimus was investigated in 58 pediatric patients aged 3 months to 14 years, who had atopic dermatitis (eczema) lesions involving 10-92% of the total BSA. These children were treated with Elidel 1% cream twice daily for 3 weeks and 5 out of them were treated for up to 1 year on "as needed" basis.
The blood concentrations measured in these pediatric patients were consistently low regardless of the extent of lesions treated or duration of therapy. They were in a range similar to that measured in adult patients treated under the same dosing regimen. Sixty percent (60%) of pimecrolimus blood concentrations were <0.5 ng/mL (LoQ) and 97% of all samples were <2 ng/mL. The highest blood concentrations measured in 2 pediatric patients aged 8 months to 14 years were 2 ng/mL.
In the youngest patients (aged 3-23 months), the highest blood concentration measured in 1 patient was 2.6 ng/mL. In the 5 children treated for 1 year, blood concentrations were consistently low and the maximum blood concentration measured was 1.94 ng/mL (1 patient). In these 5 patients, there was no increase in blood concentration over time in any patient during the 12 months of treatment.
In 8 pediatric patients aged 2-14 years presenting at least 3 measurable blood concentrations per visit day, AUC_{(0-12 hrs)} ranged from 5.4-18.8 ng·hr/mL. Area under the concentration-time curve (AUC) ranges observed in patients with <40% BSA affected at baseline were comparable to those in patients with ≥40% BSA.
Comparison to Oral Pharmacokinetic Data: In psoriatic patients treated with oral pimecrolimus doses ranging from 5 mg once daily to 30 mg twice daily for 4 weeks, pimecrolimus was well-tolerated at all doses including the highest dose. No significant adverse events were reported and no significant change was observed in physical examination, vital signs and laboratory (including renal) safety parameters. The highest dose was associated with an AUC_{(0-12 hrs)} of 294.9 ng·hr/mL. This exposure is approximately 26 and 16 times higher, respectively, than the highest systemic exposure observed in adult and pediatric atopic dermatitis (eczema) patients treated topically with Elidel twice daily for 3 weeks [AUC_{(0-12 hrs)} of 11.4 ng·hr/mL and 18.8 ng·hr/mL, respectively].
Distribution, Metabolism and Excretion: Consistent with its skin selectivity, after topical application, pimecrolimus blood levels are very low. Therefore, pimecrolimus metabolism could not be determined after topical administration.
After single oral administration of radiolabeled pimecrolimus in healthy subjects, unchanged pimecrolimus was the major drug-related component in blood and there were numerous minor metabolites of moderate polarity that appeared to be products of O-demethylations and oxygenation. Drug-related radioactivity was excreted principally via the feces (78.4%) and only a small fraction (2.5%) was recovered in urine. Total mean recovery of radioactivity was 80.9%. Parent compound was not detected in urine and <1% of radioactivity in feces was accounted for by unchanged pimecrolimus.
No drug metabolism was observed in human skin in vitro.
Toxicology: Preclinical Safety Data: Toxicology Studies After Dermal Application: A variety of preclinical safety studies were conducted with the pimecrolimus cream formulations in several animal species. There was no evidence of irritation, sensitization or local or systemic toxicity.
In a 2-year dermal carcinogenicity study in rats using Elidel, no cutaneous or systemic carcinogenic effects were observed up to the highest practicable dose of 10 mg/kg/day or 110 mg/m²/day represented by a mean AUC_{(0-24 hrs)} of 125 ng·hr/mL (equivalent to 3.3 times the maximum exposure observed in pediatric patients in clinical trials). In a mouse dermal carcinogenicity study using pimecrolimus in an ethanolic solution, no increase in incidence of neoplasms was observed in the skin or other organs up to the highest dose of 4 mg/kg/day or 12 mg/m²/day, corresponding to a mean AUC_{(0-24 hrs)} value of 1040 ng·hr/mL (equivalent to 27 times the maximum exposure observed in pediatric patients in clinical trials).
In a dermal photocarcinogenicity study in hairless mice using Elidel, no photocarcinogenic effect versus vehicle-treated animals was noted up to the highest dose of 10 mg/kg/day or 30 mg/m²/day, corresponding to a mean AUC_{(0-24 hrs)} value of 2100 ng·hr/mL (equivalent to 55 times the maximum exposure observed in pediatric patients in clinical trials).
In dermal reproduction studies, no maternal or fetal toxicity was observed up to the highest practicable doses tested, 10 mg/kg/day or 110 mg/m²/day in rats and 10 mg/kg/day or 36 mg/m²/day in rabbits. In rabbits, the corresponding mean AUC_{(0-24 hrs)} was 24.8 ng·hr/mL. AUC could not be calculated in rats.
Toxicology Studies After Oral Administration: Adverse reactions not observed in clinical studies but seen in animals at exposures considered sufficiently in excess of the maximum human exposure, indicating little emollients can be applied together with Elidel.