Elidel 1 %

Potential interactions between ELIDEL and other drugs, including immunizations, have not been systematically evaluated. Although very low blood levels of pimecrolimus are detected in a minority of patients after topical application, the concomitant administration of known CYP3A inhibitors in patients with wide spread and/or erythrodermic diseases should be done with caution.

Some examples of these drugs are: erythromycin, itraconazole, ketoconazole, fluconazole, calcium channel blocker and cimetidine.

Apply a thin layer of ELIDEL (pimecrolimus) Cream, 1% to sufficiently cover the affected skin area twice daily. ELIDEL may be used on all skin surfaces, including the head, neck, and intertriginous areas.

ELIDEL Cream should be used for short or long intermittent periods of treatment. Therapy should be stopped upon clearance of the signs and symptoms of atopic dermatitis (e.g. pruritus, inflammation and erythema). Treatment should be discontinued if resolution of disease occurs. If no improvement occurs after 3 weeks of treatment, or in case of disease exacerbation, ELIDEL therapy should be discontinued and patients should consult their physicians.

The use of ELIDEL under occlusion has not been studied, therefore occlusive dressings are not recommended.

In human dermal safety studies, ELIDEL did not induce contact sensitization, phototoxicity, or photoallergy, nor did it show any cumulative irritation. ELIDEL did not elicit skin atrophy compared to topical corticosteroid use.

In a one year safety study in pediatric patients age 2-17 years old involving sequential use of ELIDEL Cream and a topical corticosteroid, 43% of ELIDEL patients and 68% of vehicle patients used corticosteroids during the study. Corticosteroids were used for more than 7 days by 34% of ELIDEL patients and 54% of vehicle patients. An increased incidence of impetigo, skin infection, superinfection (infected atopic dermatitis), rhinitis, and urticaria were found in the patients that had used ELIDEL Cream and topical corticosteroid sequentially as compared to ELIDEL Cream alone.

In 3 randomized, double-blind vehicle-controlled pediatric studies and one active controlled adult study, 843 and 328 patients respectively, were treated with ELIDEL Cream 1%. In these clinical trials, 48 (4%) of the 1171 ELIDEL patients and 13 (3%) of 408 vehicle-treated patients discontinued therapy due to adverse events. Discontinuations for AEs were primarily due to application site reactions, and cutaneous infections. The most common application site reaction was application site burning, which occurred in 8-26% of patients treated with ELIDEL Cream.

The following adverse reactions have been reported in patients also having used ELIDEL Cream. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Isolated cases of malignant neoplasms were reported from post-marketing surveillance for patients also having used ELIDEL Cream 1%. The malignancies included T- and B-cell type lymphomas, skin neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma), and malignancies of various organs. A causal relationship between the use of ELIDEL Cream 1% and the reported cases has not been established. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Alcohol intolerance has been rarely (<1 out of 1000) reported in patients treated with ELIDEL 1% Cream. In most cases, flushing, rash, burning, itching or swelling occurred shortly after the intake of alcohol.

Allergic reactions (e.g. rash, urticaria, angioedema) and skin discoloration (e.g. hypopigmentation, hyperpigmentation) have been rarely reported in patients treated with ELIDEL. Very rarely, anaphylactic reactions, including erythroderma and anaphylactic shock have been reported.

A clinical study showed that the incidence of overall viral skin infections were significantly increased in the ELIDEL treated group compared to the vehicle control group (12.4% vs. 6.3%, p=0.038).

In clinical trials, there were two cases of cancer (squamous cell carcinoma of the skin and colon carcinoma) out of 19 000 patients on ELIDEL, and 5 cases of cancer (gastric cancer, melanoma, malignant histiocytosis, leukemia, and thyroid cancer) out of 4000 patients given the control, 4 out of 5 of which were on topical corticosteroids. Clinical studies show no evidence of an increased risk of cancer.

Clinical studies of ELIDEL did not include sufficient numbers of subjects aged 65 and older to establish efficacy and safety of the drug in geriatric patients.

There are no data to support use of ELIDEL in immunocompromised patients.

In clinical studies, cases of skin papilloma or warts (1%) were observed in pediatric patients treated with ELIDEL. In cases where patients have worsening of skin papillomas or do not respond to conventional therapy, discontinuation of ELIDEL should be considered until complete resolution of the warts is achieved.

Animal photocarcinogenicity study: Despite the absence of observed phototoxicity in humans, ELIDEL Cream and its vehicle shortened the time to skin papilloma formation. It is prudent for patients to minimize or avoid exposure to natural or artificial sunlight. The enhancement of ultraviolet carcinogenicity is not necessarily dependent on phototoxic mechanisms.

Animal studies of monkey and mice using pimecrolimus administered at high and sustained doses were associated with lymphoma formation. Chronic topical dosing of ELIDEL Cream 1% or vehicle alone in hairless mice with concurrent exposure to UV radiation decreased the median time to onset of skin tumor formation.

ELIDEL (pimecrolimus) Cream, 1% should not be applied to areas of active cutaneous viral infections.

ELIDEL has not been evaluated for its efficacy and safety in the treatment of clinically infected atopic dermatitis. Before commencing treatment with ELIDEL, clinical infections at treatment sites should be cleared.

While patients with atopic dermatitis are predisposed to surface infections including eczema herpeticum (Kaposi's varicelliform eruption) treatment with ELIDEL may be associated with an increased risk of varicella zoster virus infection (chickenpox or shingles), herpes simplex virus infection, or eczema herpeticum. In presence of these skin infections, ELIDEL treatment at the site of infection should be discontinued until the viral infection is cleared.

Although patients treated with ELIDEL experienced overall a lower incidence of bacterial skin infections as compared to patients treated with the vehicle, patients with severe atopic dermatitis may have an increased risk of skin bacterial infections (impetigo) during treatment with ELIDEL.

Cases of lymphadenopathy (0.9%) were reported in patients treated with ELIDEL. These cases of lymphadenopathy were usually related to infections and noted to resolve upon appropriate antibiotic therapy. However, in the absence of clear etiology for the lymphadenopathy, or in the presence of acute infectious mononucleosis, discontinuation of ELIDEL should be considered. Patients who developed lymphadenopathy should be monitored to ensure that the lymphadenopathy resolves.

Patients using ELIDEL should receive the following information and instructions:

Patients should use ELIDEL as directed by the physician. ELIDEL is for external use only. Patients should wash their hands after application if hands are not an area for treatment. Care should be taken to avoid contact with nose, eyes and mouth. If accidentally applied to these areas, the cream should be thoroughly wiped off and rinsed off with water.

• Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using ELIDEL.

  
  

• Patients should not use this medication for any disorder other than that for which it was prescribed.

  
  

• Patients should report any signs of adverse reactions to their physician.

  
  

• Before applying ELIDEL after a bath or shower, be sure your skin is completely dry.

  
  

• Therapy should be discontinued after signs and symptoms of atopic dermatitis have resolved. If no improvement is seen following 3 weeks of treatment, or in case of disease exacerbation, ELIDEL therapy should be discontinued and patients should consult their physicians.

ELIDEL Cream should not be used in patients with Netherton's syndrome due to the potential for increased systemic absorption of pimecrolimus.

The use of ELIDEL may cause local symptoms such as skin burning, which are mostly mild and transient. If the application site reaction is severe, the risk-benefit of treatment with ELIDEL should be considered.

ELIDEL (pimecrolimus) Cream, 1% is not for ophthalmic use.

ELIDEL may be used in pediatric patients 2 years of age and older. ELIDEL is not recommended for use in pediatric patients below the age of 2 years. Studies have been conducted in pediatric patients below 2 years of age (3 months to 23 months). Certain adverse event incidences, including pyrexia, URI, cough, rhinitis, viral rash, and wheezing, were found to be higher in patients treated with ELIDEL in comparison with patients treated with vehicle.

The effects of ELIDEL on the developing immune system in infants are unknown.

There are no adequate and well-controlled studies in pregnant women. Studies in rats and rabbits, by dermal and oral administration gave no evidence of a teratogenic potential of pimecrolimus. Because animal reproduction studies are not always predictive of human response, this drug should be used only if clearly needed during pregnancy.

It is not known whether this drug is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from pimecrolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

The exact mechanism of action of pimecrolimus in atopic dermatitis is not known. However, it has been demonstrated that 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 and interferon gamma (Th1-type) and 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/IgE. Pimecrolimus does not affect the growth of, or IL-8 release from, keratinocyte, fibroblast, and endothelial cell lines.

In man, the fate of pimecrolimus in the body following topical application could not be determined due to low systemic absorption and low resultant blood concentrations of pimecrolimus. No drug metabolism was observed in human skin in vitro.

After single oral administration 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 less than 1% of radioactivity in feces was accounted for by unchanged pimecrolimus.

The range of blood concentrations measured in adult AD patients (≥18 years of age) was similar to that in pediatric patients. The highest blood level of pimecrolimus measured in adults was 1.4 ng/mL. In 8 adult AD patients the AUC_(0-12h) values ranged from 2.5 to 11.4 ng·h/mL.

In 40 adult patients treated for up to 1 year with ELIDEL, blood concentrations of pimecrolimus were low. A maximum blood concentration of 0.8 ng/mL was observed in only 2 patients in week 6 of treatment. There was no increase of 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 was 0.91 ng/mL.

Systemic exposure to pimecrolimus was investigated in 58 pediatric patients aged 3 months to 4 years and 8 to 14 years. For these patients, atopic dermatitis (AD) lesions involving 10-92% of the total body surface area were treated with ELIDEL (pimecrolimus) Cream, 1% twice daily for 3 weeks.

Blood concentrations measured in the youngest patients aged 3 to 23 months were consistently low, ranging from below the assay limit of quantitation (LoQ: 0.1 ng/mL) to 2.6 ng/mL. In earlier studies, blood concentrations in pediatric patients 8 months to 14 years of age were also low, ranging from below the LoQ (0.5 ng/mL) to 2.0 ng/mL. Overall, the majority of concentrations measured was below the limit of quantitation and there was no evidence of higher blood concentrations in patients even with a high proportion of their total body surface area (%TBSA) under treatment (>70% TBSA).