SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT
ELIDEL 1%

2. QUALITATIVE AND QUANTITATIVE
A g pimecrolimus cream contains 10 mg.
For excipients, see section 6.1.

3. PHARMACEUTICAL FORM
Cream.
whitish and homogeneous.

4. CLINICAL

therapeutic indications 4.1
Elidel 1% is indicated for the treatment of short-term and long-term control of signs and symptoms of dermatitis atopice mild-moderate (eczema) in adults and children over 2 years.

4.2 Posology and method of administration
Elidel must be prescribed by physicians experienced in the treatment of the topic dermatitis atopice.
Data from clinical studies support that treatment with Elidel 1% can be intermittently until 12 months.
If there is no improvement after 6 weeks, or if the disease exacerbation, Elidel 1% should be discontinued and will be considered other treatment options.

Adults

Apply a thin layer of Elidel 1% on the affected skin twice daily, then maseaza easy to complete penetration in the skin.

Elidel 1% can be used on all skin surfaces, including the head and face, neck and intertriginoase areas. Not applicable to mucous membranes. Elidel 1% should not be applied under occlusion (see section 4.4 warnings and precautions ).

In

control long-term atopice dermatitis, treatment with Elidel 1% should be initiated at the first signs and symptoms of the disease to prevent its overheating. Elidel 1% must be applied twice daily, persist as long as signs and symptoms of disease. If stopped, treatment should be resumed at the first signs and symptoms to prevent overheating disease.
Lenitive substances can be applied immediately after use of Elidel 1% .
Due to low systemic absorption, there is no restriction on total daily dose, total body surface area or during treatment.

Children
For children (2-11 years) and adolescents (12-17 years) dose is the same as for adults.

Using

Elidel 1% in patients aged under 2 years is not recommended until new data become available.

Dermatita atopica (eczema) is rarely seen in patients older than 65 years. Clinical trials with Elidel 1% did not include a sufficiently large number of patients in this age group to determine whether they respond differently to the drug, compared with younger patients.

Contraindications

4.3
Hypersensitivity to pimecrolimus, other macrolactami or any of the excipients.

4.4 warnings and precautions

Elidel 1% should not be applied to skin areas affected by acute viral infection (herpes simplex, chicken pox).

Elidel 1% has not been evaluated in terms of efficacy and safety in treatment dermatitelor atopice infected. Before starting treatment with Elidel 1% , clinical infections at the treatment must be healed.

Since

patients with dermatitis atopica are likely to superficial skin infections including eczema herpetic (variceliforma Kaposi rash), treatment with Elidel 1% may be associated with an increased risk of viral infection with skin herpes simplex or eczema herpetic (manifestându is through a rapid expansion veziculelor erosion and damage). In the presence of skin infection with herpes simplex, treatment with Elidel 1% site infection will be interrupted until the viral infection is cured.

Although

patients treated with Elidel 1% showed a totally low incidence of bacterial skin infections compared with patients treated with vehicle-excipients patients with severe dermatitis atopica may have an increased risk of skin infections bacterial (impetigo) during treatment with Elidel 1% .

Using

Elidel 1% may produce mild and transient reactions at the application, such as sensation of heat and / or local burning. If the reaction at the application is recommended severe revaluation the benefit / risk.

attention is needed to avoid contact with eyes and mucous membranes. If accidentally applied to these areas, the cream should be removed entirely and / or cleaned with water.

Using

Elidel 1% as dressing plosive not yet been studied in patients. Not recommended clothing mute.

Since

safety Elidel 1% has not yet been established in patients with erythrodermia, use this group of patients can not be recommended.

Elidel 1% has not been studied in patients with Netherton syndrome. In patients with Netherton syndrome, due to increased potential for systemic absorption pimecrolimusului, Elidel 1% is not recommended.

Doctors should warn patients about the appropriate sunscreen, such as minimizing the time of exposure to the sun, use of sunscreen and cover skin with clothing appropriate (see section 4.5 Interaction with other medicinal products, other interactions ).

Elidel 1% has not been studied in patients with compromised immunity and in patients with malignant skin lesions and no data to support its use in these patients.

long-term effect on the immune response at local level and the incidence of cutaneous malignant skin lesions is unknown.

Elidel 1% contains alcohol and alcohol Cetyl stearilic which can cause local reactions at the skin. Elidel 1% also contains propilenglicol, which can cause skin irritation

4.5 Interaction with other medicinal products, other interactions
Potential interactions between Elidel 1% and other products have not been systematically evaluated. Pimecrolimusul is exclusively metabolized by CYP 450 3A4. Due to its minimal absorption is unlikely to occur interaction Elidel 1% with medicines administered systemically (see section 5.2 Pharmacokinetic Properties ).

present data indicate that Elidel 1% can be used simultaneously with antibiotics, steroids and antihistaminice (oral / nasal / inhaler).

Because absorption

minimum possible interaction with systemic vaccination is unlikely to occur. However, this interaction has not been studied. Therefore, patients with extensive disease is recommended that vaccination should be made during periods without treatment.

concomitant use of other topical anti-inflammatory preparations, including glucocorticoid has not been investigated, so Elidel 1% should not be used with glucocorticoid topic and other topical anti-inflammatory products. There is experience with the simultaneous use of immunosuppressive therapies admnistrate for eczema atopica like UVB, UVA, PUVA, azatioprina and cyclosporine A.

Elidel 1% has the potential fotocarcinogen animals (see section 5.3 Preclinical data safe ). However, the relevance to humans is unknown, excessive exposure to ultraviolet light skin, including light from solar or PUVA therapy, UVA and UVB should be avoided during treatment with Elidel 1% .

4.6 Pregnancy and lactation
Pregnancy
No data are available about the appropriate use of Elidel 1% in pregnant women. Studies in animals by applying skin product did not reveal adverse effects on the direct or indirect embryonal / fetal. Studies in animals after oral administration have shown reproductive toxicity (see section 5.3. Preclinical safety data ).
Due to the absorption minimum pimecrolimusului after application topic of Elidel 1% (see section 5.2. Famacocinetice Properties ), the potential risk to humans is considered limited.
However, Elidel 1% should not be used during pregnancy.

Lactation

No studies have been conducted on the animal excretion in milk after applying the medicine topic. It is not known whether pimecrolimusul is excreted in milk after administration topic.

However, due to the absorption minimum pimecrolimusului after application topic of Elidel 1% (see section 5.2. famacocinetice Properties ), the potential risk to humans is considered limited .
Caution is needed when Elidel 1% is given to women who are breastfeeding.

nursing mothers can use Elidel 1% but should not apply Elidel 1% on the breast to avoid oral ingestion neintentionta the newborn.

4.7 Effects on ability to drive and use machines
Elidel 1% has no known effects on the ability to drive or use machines.

4.8 side effects
The most common side effects were application site reactions have been reported in about 19% of patients treated with Elidel 1% and 16% of patients in the control group. These reactions generally occurred in the initial stages of treatment were mild / moderate and short term.

frequency estimate: very common (= 1 / 10); common (= 1 / 100 to <1 / 10); uncommon (= 1 / 1000 to <1 / 100); rare (= 1 / 10000 to <1 / 1000); very rare (<1 / 10000, including isolated reports).

Very common

: burning sensation at the site of application.

Common

: application site reactions (irritation, itching and redness), skin infections (foliculita).

Uncommon : furuncule, impetigo, herpes simplex, shingles, shingles with dermatitis (eczema herpetic), molluscum contagiosum, papilom skin, application site reactions such as rash, pain, paraesthesia, descuamare, dryness, edema and worsening pre-existing condition.

4.9 Overdose
There is experience with the overdose with Elidel 1% .
There were no reported cases of accidental ingestion.

5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group : other dermatological preparations.
ATC code: D11A X15

Non-Clinical Pharmacology
Pimecrolimusul is a derivative of ascomicina macrolactam, anti, lipofilic and selective inhibitor of the production and release pro-inflammatory citokinelor.
Pimecrolimusul binds with high affinity for-12 and macrofilina inhibit calcium-dependent phosphatase of calcineurinei. As a result, inhibits the synthesis of anti-inflammatory cells citokinelor T.
Pimecrolimusul present antiinflamatorie intense activity in the skin inflammation in animal models after applying the topic and systemic. In swine models with allergic contact dermatitis, pimecrolimusul topic is as effective as corticosterioizii. Unlike steroids, pimecrolimusul produce pig skin atrophy and does not affect Langerhans cells in skin murinelor.

Pimecrolimusul has only a low potential for impaired systemic immune responses, as observed in standard models of systemic immunosuppression. Moreover, pimecrolimusul do not affect the primary immune response and do not affect lymph ganglionii if allergic contact dermatitis in murine. Pimecrolimusul given topic penetrate similar but less penetrate through human skin than Corticosteroids indicating such a potentially very low pimecrolimusului systemic absorption.
In conclusion, pimecrolimusul pharmacological profile is different from selective cutaneous corticosteroids. It combines high activity antiinflamatorie skin with a low potential for impaired immune response locally and systemically.

clinical data
Efficacy and safety profile Elidel 1% has been estimated at more than 2000 patients who were small children (= 3 months), children, adolescents and adults enrolled in studies phase II and III. Over 1500 of these patients were treated with Elidel 1% and over 500 have received treatment or control, or vehicle-excipients of Elidel < em> 1% and / or glucocorticoid topic.

Treatment Short-term (acute)

Children and adolescents: have been made two controlled clinical trials with excipients-vehicle, each with a duration of 6 weeks, including a total of 403 pediatric patients aged 2 and 17 years. Patients were treated with Elidel 1% twice a day. Data from both studies were cumulative.

small children : it was conducted a study similar to the duration of 6 weeks, which included 186 patients aged between 3 and 23 months.

Upon completion of these three studies lasting 6 weeks, the efficacy results were as follows:

		colspan="2" Children and adolescents		colspan="2" children
Objective	Criteria	Elidel 1%	Excipient	Val.p	Elidel 1%	Excipient	Val.p
		(N = 267)	(N = 136)		(N = 123)	(N = 63)
IgA *	Vindecare1	34.80%	18.40%	<0001	54.50%	23.80%	<0001
IgA *	Ameliorare2	59.90%	33%	not done	68%	40%	not done
pruritus	Absent or easy	56.60%	33.80%	<0001	72.40%	33.30%	<0001
EASI °	Global (average percentage change) 3	-43.6	-0.7	<0001	-61.8	7.35	<0001
EASI °	head / neck (average percentage change) 3	-61.1	+0.6	<0001	-74.0	31.48	<0001

*

investigators Global Assessment (Global Assesment investigators)
° Severity Index of the Area with eczema (eczema Area Severity Index): The average percentage change in clinical signs (erythema, infiltration, escoratie, lichenificare) and body surface area involved
1 p value based on CMH test properly Medical Center
2 = Improving IgA levels reduced from the initial
3 p value based on ANCOVA model of EASI for the day 43, in which factors are the medical center and treatment, and baseline (day 1) of EASI is covariabila

pruritului significant improvement was observed in the first week of treatment in 44% of children and adolescents and 70% of young children.

Adults: Elidel 1% was less effective than 0.1% betametazona-17-Valera to treat short-term (3 weeks) in adults with dermatitis atopica moderate to severe.

long-term treatment:
In two double-blind studies carried out to control long-term atopice dermatitis, in which they were enrolled 713 children and adolescents (2-17 years) and 251 infants (3-23 months), Elidel 1% has been evaluated as first line therapy.

Elidel 1% has been used at the first signs of redness and itching to prevent progression to overheating of dermatitis atopice. Only in cases of severe overheating of the disease who have not pututu be controlled Elidel 1% , was established treatment with topical glucocorticoid with an average potency. When was initiated glucocorticoid therapy for the treatment of overheating, with tratametul Elidel 1% has been discontinued. The control group received excipients in-vehicle Elidel 1% to meet the blind studies.

Both studies showed a significant reduction in the incidence of overheating (p <0001) in favor of Elidel 1% ; treatment with Elidel 1% has shown efficacy in May good ratings in all secondary (Severity Index of Area of eczema, the investigator overall assessment, the evaluation of subjects); pruritului control was achieved during the first week of treatment with Elidel 1% . More patients treated with Elidel 1% , following treatment for 6 months [children (61% in the Elidel group 1% , compared to 34% in the control group ), children (in the 70% Elidel 1% , compared to 33% in the control group) and for 12 months without appearing overheating [Children (51% in the Elidel 1 % , compared to 28% in the control group), children (57% in the Elidel 1% , compared to 28% in the control group )].

Elidel 1% has been the reduction in the use Corticosteroids topic: more patients treated with Elidel 1% are not used in glucocorticoid cele12 months [ children (57% in the Elidel 1% to 32% in the control group), children (64% in the Elidel 1% , compared to 35% in group control)]. Efficacy of Elidel 1% was maintained over time.

A study lasting 6 months randomized, double-blind, parallel groups, excipients-controlled vehicle with a similar model, was conducted in 192 adults with moderate dermatitis atopica to severe. Topic with glucocorticoid medication was used in 14.2% ± 24.2 days in a period of 24 weeks of treatment in the Elidel 1% and 37.2 ± 34.6% of days the control group (p <0001). A total of 50% of patients treated with Elidel 1% have had no overheating compared with 24% of patients randomized in the control group.

He made a double-blind study, lasting one year dermatitis in adults with moderate to severe atopica to compare Elidel 1% with triamcinolon acetonid 0.1% cream (for trunk and extremities) plus hydrocortisone acetate 1% cream (for face, neck and areas intertriginoase). Both Elidel 1% and Glucocorticoids topic were used without restrictions. Half of patients in the control group received glucocorticoid topic for more than 95% of study days. Elidel 1% was less effective against triamcinolon acetonid 0.1% cream (for the trunk and extremities) plus hydrocortisone acetate 1% cream (for face, neck and areas intertriginoase) in the treatment of long-term (52 weeks) dermatitis in adults with moderate to severe atopica.

Clinical trials

long time had as 1 year. There is no clinical data for treatment periods of more than 1 year.

A

applied more often than twice a day has not yet been studied.

Special Education:
Studies have shown that tolerance Elidel 1% has the potential to generate awareness contact fototoxicitate, fotosensibilizare and irritation by accumulation.

potential to cause atrophy in humans has been tested, compared with glucocorticoid topic with medium and high potency (betametazona-17-Valera 0.1% cream, triamcinolon acetonid 0.1% cream) and vehicle-excipients on 16 volunteers treated for 4 weeks. Both glucocorticoid induced topic have a significant reduction in skin thickness measured ultrasound compared with Elidel 1% and excipients-vehicle, which induced a reduction in skin thickness.

5.2 Pharmacokinetic properties
Data from animals
Bioavailability pimecrolimusului the small pigs in the application of a single dose dermal (applied for 22 hours under semi-occlusion) was 0.03%. The amount of radioactive medicine marked skin at the site of application has remained virtually constant for 10 days (pimecrolimus almost exclusively as unchanged).

data in humans
absorption in adults
Systemic exposure to pimecrolimus was investigated in 12 adult patients with dermatitis atopica who were treated with Elidel 1% twice daily for 3 weeks. Body surface (SC) affected varies from 15-59%. 77.5% of the plasma concentrations of pimecrolimus were below 0.5 ng / ml and 99.8% of total values were below 1 ng / ml. The highest concentration of plasma pimecrolimus in a patient was 1.4 ng / ml.

in 40 adult patients treated for up to 1 year Elidel 1% , which had injuries that affect the initial 14-62% of SC, 98% of the plasma concentrations of pimecrolimus have was below 0.5 ng / ml. A maximum plasma concentration of 0.8 ng / ml was measured at only 2 patients in a 6-weeks of treatment. There was no increase in plasma concentration over time to a patient during the 12 months of treatment. 8 adult patients with dermatitis atopica, which were the ASC, the ASC (0-12h) ranged between 2.5 and 11.4 ng h / ml.

absorption in children
Systemic exposure to pimecrolimus was investigated in 58 pediatric patients aged 3 months and 14 years. Body surface affected (SC) varied between 10-92%. These children were treated with Elidel 1%, twice daily for 3 weeks and five of them were treated by 1 year, as "in need".

plasma concentrations of pimecrolimus were consistently lower, regardless of the extension of lesions treated or duration of treatment. These values have been included in a measure similar to that in adult patients. Around 60% of plasma concentrations of pimecrolimus were below 0.5 ng / ml and 97% of the total values were below 2 ng / ml. The highest plasma concentrations measured at 2 pediatric patients aged 8 months and 14 years were 2.0 ng / ml.

At

small children (aged 3 to 23 months), the largest plasma concentrations measured in a patient was 2.6 ng / ml. 5 children treated for 1 year, plasma concentrations were consistently low (maximum plasma concentration was 1.94 ng / ml in 1 patient). There was an increase in serum in time to a patient during the 12 months of treatment.

On 8

pediatric patients aged 2-14 years, ASC (0-12h) ranged from 5.4 to 18.8 ng h / ml. The range of variation of ASC in patients with <40% of SC was affected initially comparable to that observed in patients with = 40% of the SC affected.

In clinical pharmacology studies, the body was treated maximum of 92% in phase III studies, up to 100%.

distribution, metabolism and excretion
As a result of selectivity skin after application topic, plasma concentrations of pimecrolimus are very low. Thus, metabolism pimecrolimusului could not be determined after topic.
After a single oral administration of pimecrolimus marked radioactive in healthy subjects, unchanged pimecrolimusul main component was determined in the blood along with numerous minor metabolites with moderate polarity that appear to be made of the O-demetilare and oxygenation.

radioactivity associated with the drug was mainly excreted in stool (78.4%) and only a small percentage (2.5%) was eliminated in the urine. Average total radioactivity was eliminated by 80.9%. It was detected in the urine unchanged pimecrolimus and less than 1% of faecal radioactivity was due to pimecrolimusului unchanged.

In vitro has not been seen in the metabolism pimecrolimusului tegument human.

5.3 Preclinical safety data
Conventional studies of toxicity after repeated doses, toxicity on reproductive function and carcinogenicity using oral administration resulted in exposure effects considered large enough to man, to have clinical significance. Pimecrolimusul had no genotoxic potential, antigens, fototoxic, fotoalergenic or fotocarcinogenic. Dermal application in studies on the development Embryo / fetal rats and the rabbits and carcinogenicity studies in mice and rats were negative.

In toxicity after repeated doses after oral administration of 10 or 40 mg / kg / day (= 20 to 60 times the maximum exposure in humans after dermal application) in male and female rats were observed effects on the reproductive and sexual alter hormonal functions. This shows data from studies of fertility. The level at which reatii no observed effects (NOAEL) on female fertility was 10 mg / kg / day (= 20 times the maximum human exposure after dermal application). In studies of oral embriotoxicitate in rabbits, a higher rate of resorption associated with maternal toxicity was observed at dose of 20 mg / kg / day (= 7 times the maximum human exposure after dermal application), the average number of live births fetilor not been affected.

6. PHARMACEUTICAL
6.1 List of excipients
Medium chain triglycerides, oleic alcohol, propilenglicol alcohol stearilic, Cetyl alcohol, mono-and digliceride, cetostearyl sodium sulphate, benzyl alcohol, anhydrous citric acid, sodium hydroxide, purified water.

6.2 Incompatibilities
Not applicable.

6.3 period
2 years.
12 months - after opening the tube.

6.4 Special precautions for storage
A store below 25 ° C.
Do not freeze.