Treatment of patients 3 months of age and older with mild or moderate atopic dermatitis

where treatment with topical corticosteroids is either inadvisable or not possible. This may include:

· Intolerance to topical corticosteroids

· Lack of effect of topical corticosteroids

· Use on the face and neck where prolonged intermittent treatment with topical corticosteroids may be

Inappropriate

Treatment with Elidel should be initiated by physicians with experience in the diagnosis and treatment of atopic dermatitis.

Elidel can be used in the short term for the treatment of the signs and symptoms of atopic eczema and

intermittently in the long term for the prevention of progression to flares.

Elidel treatment should begin at the first appearance of signs and symptoms of atopic dermatitis. Elidel

should only be applied to areas affected with atopic dermatitis. Pimecrolimus should be used for as

short period as possible during flares of disease. The patient or caregiver should stop using pimecrolimus when signs and symptoms resolve. Treatment should be intermittent, short-term and not continuous.

If no improvement occurs after 6 weeks, or in case of disease exacerbation, treatment should be

stopped. The diagnosis of atopic dermatitis should be re-evaluated and further therapeutic options

considered.

Adults

Apply a thin layer of Elidel to the affected skin twice daily and rub in gently and completely. Each affected region of the skin should be treated with pimecrolimus until clearance occurs and then treatment

should be discontinued.

Elidel may be used on all skin areas, including the head and face, neck and intertriginous areas, except on

mucous membranes. Elidel should not be applied under occlusion (see section 4.4).

In the long-term management of atopic dermatitis (eczema), Elidel treatment should begin at first appearance of signs and symptoms of atopic dermatitis to prevent flares of the disease. Elidel should be used twice daily.

Emollients can be applied immediately after using Elidel.

Paediatric population

For infants (3-23 months), children (2-11 years) and adolescents (12-17 years) the posology and method of administration are the same as for adults.

Elderly patients

Atopic dermatitis (eczema) is rarely observed in patients aged 65 and over. Clinical studies with Elidel did not include a sufficient number of patients in this age range to determine whether they respond differently from younger patients.

Method of administration

Elidel should be applied thinly to the affected areas twice daily.

Pimecrolimus cream should not be used in patients with congenital or acquired immunodeficiencies or

in patients on therapy that causes immunosuppression.

Long-term effect on the local skin immune response and on the incidence of skin malignancies is unknown.

Pimecrolimus should not be applied to potentially malignant or pre-malignant skin lesions.

Pimecrolimus should not be applied to areas affected by acute cutaneous viral infections (herpes

simplex, chicken pox).

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 superficial skin infections including eczema

herpeticum (Kaposi's varicelliform eruption), treatment with pimecrolimus may be associated with an

increased risk of skin herpes simplex virus infection, or eczema herpeticum (manifesting as rapid spread of vesicular and erosive lesions). In the presence of herpes simplex skin infection, pimecrolimus

treatment at the site of infection should be discontinued until the viral infection has cleared.

Patients with severe atopic dermatitis may have an increased risk of skin bacterial infections (impetigo)

during treatment with pimecrolimus.

Use of Elidel may cause mild and transient reactions at the site of application, such as a feeling of warmth

and/or burning sensation (see section 4.8). If the application site reaction is severe, the risk-benefit of

treatment should be re-evaluated.

Care should be taken to avoid contact with eyes and mucous membranes. If accidentally applied to these

areas, the cream should be thoroughly wiped off and/or rinsed off with water.

Physicians should advise patients on appropriate sun protection measures, such as minimisation of the time in the sun, use of sunscreen product and covering the skin with appropriate clothing (see section 4.5).

Elidel contains the active substance pimecrolimus, a calcineurin inhibitor. In transplant patients, prolonged systemic exposure to intense immunosuppression following systemic administration of calcineurin inhibitors has been associated with an increased risk of developing lymphomas and skin malignancies.

Cases of malignancies, including cutaneous and other types of lymphoma, and skin cancers have been

reported in patients using pimecrolimus cream (see section 4.8). However, patients with atopic dermatitis

treated with Elidel have not been found to have significant systemic pimecrolimus levels.

In clinical studies, 14/1,544 (0.9%) cases of lymphadenopathy were reported while using Elidel (see section 4.8). These cases of lymphadenopathy were usually related to infections and noted to resolve upon appropriate antibiotic therapy. Of these 14 cases, the majority had either a clear etiology or were known to resolve. Patients who receive Elidel and who develop lymphadenopathy

should have the etiology of their lymphadenopathy investigated. In the absence of a clear etiology for the

lymphadenopathy, or in the presence of acute infectious mononucleosis, treatment with pimecrolimus

 should be discontinued. Patients who develop lymphadenopathy should be monitored to

ensure that the lymphadenopathy resolves.

Populations with potentially higher risk of systemic exposure.

Elidel has not been studied in patients with Netherton’s syndrome. Due to the potential for increased systemic absorption of pimecrolimus, Elidel is not recommended in patients with Netherton's syndrome.

As the safety of pimecrolimus has not been established in erythrodermic patients, the use of Elidel in this patient population cannot be recommended.

The use of Elidel under occlusion has not been studied in patients. Occlusive dressings are not recommended.

In patients with severely inflamed and/or damaged skin, the systemic concentrations may be higher.

Elidel contains cetyl alcohol and stearyl alcohol which may cause local skin reactions (e.g. contact

dermatitis). As well as benzyl alcohol which may cause allergic reactions and mild local irritation, and propylene glycol (E 1520) which may cause skin irritation.

Potential interactions between pimecrolimus and other medicinal products have not been

systematically evaluated. Pimecrolimus is exclusively metabolised by CYP 450 3A4. Based on its minimal

extent of absorption, interactions of pimecrolimus with systemically administered medicinal products

are unlikely to occur (see section 5.2).

The present data indicate that pimecrolimus can be used simultaneously with antibiotics,

antihistamines and corticosteroids (oral/nasal/inhaled).

Based on the minimal extent of absorption of Elidel, a potential systemic interaction with vaccination

is unlikely to occur In patients with extensive disease, it is recommended to administer vaccinations during treatment-free intervals. In a 5-year study in infants 3 months to less than 12 months of age at enrolment with mild to moderate atopic dermatitis patients who were treated with Elidel cream or topical corticosteroids displayed normal immune response maturation and developed effective immunisation against vaccine antigens (see section 5.1).

Application of pimecrolimus to vaccination sites, as long as local reactions persist, was not studied and is

therefore not recommended.

There is no experience with concomitant use of immunosuppressive therapies given for atopic eczema such as UVB, UVA, PUVA, azathioprine and cyclosporin A.

Pimecrolimus has no photocarcinogenic potential in animals (see section 5.3.). However, since the

relevance to man is unknown excessive exposure of the skin to ultraviolet light including light from a

solarium, or therapy with PUVA, UVA or UVB should be avoided during treatment with

pimecrolimus.

Rare cases of flushing, rash, exanthema, burning, itching or swelling have been observed shortly after the intake of alcohol in patients using pimecrolimus cream (see section 4.8).

Pregnancy

There are no adequate data from the use of pimecrolimus in pregnant women. Animal studies using dermal application do not indicate direct or indirect harmful effects with respect to embryonal/fetal

development. Studies in animals after oral application have shown reproductive toxicity (see section 5.3).

Based on the minimal extent of pimecrolimus absorption after topical application of pimecrolimus (see

section 5.2), the potential risk for humans is considered limited. However, pimecrolimus should not be

used during pregnancy.

Lactation

Animal studies on milk excretion after topical application were not conducted and the use of Elidel in

breastfeeding women has not been studied. It is not known whether pimecrolimus is excreted in the milk

after topical application.

However, based on the minimal extent of pimecrolimus absorption after topical application of

pimecrolimus, (see section 5.2), the potential risk for humans is considered limited. Caution should be

exercised when pimecrolimus is administered to breastfeeding women.

Breastfeeding mothers may use Elidel but should not apply Elidel to the breast in order to avoid

unintentional oral uptake by the newborn.

Fertility

There are no clinical data on the effects of pimecrolimus on male or female fertility (see section 5.3

Preclinical safety data).

Elide! has no or just an insignificant effect on the ability to drive and use machines.

The most common adverse events were application site reactions which were reported by approximately

19% of the patients treated with Elidel and 16% of patients in the control groups. These reactions generally occurred early in treatment, were mild/moderate and were of short duration.

The following undesirable effects have been observed with the frequencies indicated below during clinical trials using pimecrolimus cream 10mg/g and post marketing.

Frequencies are defined as: very common (³1/10); common (³1/100, <1/10); uncommon (³1/1,000, <1/100); rare (³1/10,000, <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Post marketing: Cases of malignancy, including cutaneous and other types of lymphoma, and skin cancers, have been reported in patients using pimecrolimus cream (see section 4.4).

Cases of lymphadenopathy have been reported in post-marketing use and in clinical trials, however a causal relationship with the pimecrolimus treatment has not been established (see section 4.4).

Paediatric population

The clinical safety database of children aged 3 months and older treated with pimcrolimus 10mg/g cream is extensive with long-term safety data available for up to 5 years. The safety profiles in infants, children and adolescent were comparable in nature and frequency of the adverse events observed. The most common observed adverse reactions were application site reactions.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It

allows continued monitoring of the benefit/risk balance of the medicinal product: Health care

professionals are asked to report any suspected adverse reactions via the Bundesmstitut fur

arzneimittel und Medizinprodukte Abt. Pharmakovigilanz, Kurt-Georg-Kiesinger-Allee 3

D-53175 Bonn (Germany), Website: www.bfarm.de.

.

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 (ACD), 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 (2 3 months), children, adolescents, and adults enrolled in phase II and III studies. Over 1,500

of these patients were treated with Elide! and over 500 were treated with control treatment i.e. either

Elide) 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:

* 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 (Cocheran/Mantel/Haenszel test) test stratified by centre

2Improvement=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:

Elide! 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,

treatment 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 pimecrolimus10mg/g cream treatment; treatment with pimecrolimus 10mg/g cream showed better efficacy in all secondary assessments (Eczema Area Severity Index, Investigators Global Assessment, subject assessment); pruritus was controlled within a week with pimecrolimus 10mg/g cream. More patients treated with pimecrolimus 10mg/g 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 10mg/g cream did not use corticosteroids in 12 months [children (57% Elidel vs 32% control), infants (64% Elidel vs 35% control)]. The efficacy of pimecrolimus 10mg/g cream was maintained over time.

A 6-month randomized, 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 10mg/g cream did not experience any flare compared with 24.0% of the patients randomized 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 10mg/g 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 10mg/g 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, randomized, active-controlled study was conducted in 2,418 infants 3

months to 11 months of age at enrollment with mild to moderate atopic dermatitis (AD). The

primary objective was to compare safety by assessing adverse events, and the effects of treatments on

the developing immune system and growth velocity

Infants were randomized to Elidel (n = 1,205; with short-term topical corticosteroids (TCSs) for disease flares) or low/mid potency TCS  (n = 1,213).

Elidel was well tolerated in subjects with mild to moderate AD who were 3 to 11 months of age at the start of the study. The profile and frequency of adverse events was similar in the tow treatment groups. No impairment of systemic immune assessments was seen, and subjects with AD who were treated with pimecrolimus 10mg/g 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 Elidel and vehicle, which did not induce a reduction of skin thickness.

Paediatric population

Results of relevant studies in infants, children and adults are detailed above in section 5.1.

Data in humans

Absorption in adults

Systemic exposure to pimecrolimus was investigated in 12 adults with atopic dermatitis who were

treated with Elidel twice daily for 3 weeks. The affected body surface area (BSA) ranged from

15-59 %. 77.5 % of pimecrolimus blood concentrations were below 0.5 ng/ml and 99.8% of the

total sample were below 1 ng/ml. The highest pimecrolimus blood concentration was 1.4 ng/ml

in one patient.

In 40 adult patients treated for up to 1 year with Elide], having 14-62% of their BSA affected at

baseline, 98 % of pimecrolimus blood concentrations were below 0.5 ng/ml. 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

8 adult atopic dermatitis patient , in which AUC levels could be quantified the AUC(0-12h) values

ranged from 2.5 to 11.4 ng h/ml.

Absorption in infants, children and adolescents

Systemic exposure to pimecrolimus was investigated in 58 paediatric patients aged 3 months to 14 years, of those 41 were below 2 years of age. The affected BSA ranged from 10-92%. These children were treated with Elidel twice daily for 3 weeks. Five (8.6 %) of the 58 patients were treated for up to

1 year on a “as needed” basis with 2 patients being aged ≥3 to ≤6 months and 3 patients being aged > 6 to ≤ 12 months.

Pimecrolimus blood concentrations 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.

Around 67% of pimecrolimus blood concentrations were below 0.5 ng/ml and 93% of all samples were below 2 ng/ml in infants (aged 3 to 23 months).

In the age group ≥3 to ≤6 months, 31% of the blood samples had pimecrolimus concentrations below 0.5

ng/ml and 90% below 2.0 ng/ml with the highest blood concentration of 4.14 ng/ml measured in one patient sample which was suspected to be contaminated during venipuncture.

-In the age group > 6 to ≤ 12 months, 66% of the blood samples had pimecrolimus concentrations below 0.5ng/ml and 90% below 2.0 ng/ml with the highest blood concentration of 2.6 ng/ml measured in one patient sample.

-In infant aged > 12 to < 24 months, 80% of the blood samples had pimecrolimus concentrations below 0.5ng/ml and 97% below 2.0 ng/ml. The maximum pimecrolimus concentration in this age group was 2.0 ng/ml in one sample.

In the 5 children treated for 1 year with 2 of them aged ≥3 to ≤6 months and 3 aged > 6 to ≤ 12 months, blood concentrations were consistently low, with a maximum blood concentration was of 1.94 ng/ml in one sample of a1 patient aged ≥3 to ≤6 months. There was no increase in blood concentration over time in any patient during the 12 months of treatment.

In children and adolescents (2 to 14 years) 68% of pimecrolimus blood concentrations were below 0.5 ng/ml and 99% of all samples were below 2 ng/ml., The highest blood concentrations measured in one patient was 2.0 ng/ml.

In 8 paediatric patients aged 2-14 years, AUC (0-12h) ranged from 5.4 to 18.8 ng h/ml. AUC ranges observed in patients with <40% body surface area (BSA) affected at baseline were comparable to those in patients with ≥40% BSA.

The maximum body surface area treated was 92% in clinical pharmacology studies and up to 100% in Phase III trials.

Distribution

Consistent with its skin selectivity, after topical application, pimecrolimus blood levels are very

low. Therefore, pimecrolimus metabolism could not be determined after topical administration.

In vitro plasma protein binding studies have shown that 99.6 % of pimecrolimus in plasma is bound

to proteins. The major fraction of pimecrolimus in plasma is bound to different lipoproteins.

Biotransformation

After single oral administration of radio-labelled pimecrolimus in healthy subjects, unchanged

pimecrolimus was the major active substance-related component in blood and there were numerous

minor metabolites of moderate polarity that appeared to be products of O-demethylations and

oxygenation.

No metabolism of pimecrolimus was observed in human skin in vitro.

Elimination

After oral administration, active substance-related radioactivity was excreted principally via the faeces

(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 faeces was accounted for by unchanged pimecrolimus

Conventional studies of repeated dose toxicity, reproductive toxicity and carcinogenicity using oral

administration produced effects at exposures sufficiently in excess of those in man to be of negligible clinical significance. Pimecrolimus had no genotoxic, antigenic, phototoxic, photoallergenic or photocarcinogenic potential. Dermal application in embryo/fetal developmental studies in rats and rabbits and in carcinogenicity studies in mice and rats were negative.

The bioavailability of pimecrolimus in mini-pigs following a single dermal dose (applied for 22h under semiocclusion) was 0.03%. The amount of active substance-related material in the skin at the application site (almost exclusively unchanged pimecrolimus) remained practically constant for 10 days.

Effects on reproductive organs and altered sex hormone functions were seen in male and female

rats in repeated dose toxicity studies after oral administration of 10 or 40 mg/kg/day(= 20 to

60 times the maximum human exposure after dermal application). This is reflected by the

findings from the fertility study. The No Observed Adverse Effect Level (NOAEL) for female

fertility was 10 mg/kg/day(= 20 times the maximum human exposure after dermal application).

In the oral embryotoxicity study in rabbits, a higher resorption rate associated with maternal

toxicity was observed at 20 mg/kg/day(= 7 times the maximum human exposure after dermal

application); the mean number of live fetuses was not affected.

Dose-dependent increases in the incidence of lymphomas were observed at all doses in a 39 week

monkey oral toxicity study. Signs ofrecovery and/or at least partial reversibility of the effects

were noted upon cessation of dosages in a few animals. Failure to derive a NOAEL precludes an

assessment of the margin of safety between a non-carcinogenic concentration in the monkey and

exposures in patients. The systemic exposure at the LOAEL of l 5mg/kg/day was 3 l times the

highest maximum exposure observed in a human (paediatric patient). The risk for humans cannot

be completely ruled out as the potential for local immunosuppression with the long-term use of

pimecrolimus cream is unknown.

6.1 List of excipients

Medium chain triglycerides

Oleyl alcohol (Ph. Eur.)

Propylene glycol (E 1520)

Stearyl alcohol (Ph. Eur.)

Cetyl alcohol (Hexadecan-1--ol)

Esters of mono- and di-glycerides of edible fatty acids Sodium cetostearyl sulphate (Ph. Eur.)

Benzyl alcohol

Citric acid

Sodium hydroxide

Purified water

Not applicable

Store below 30 °C. Do not freeze.

Aluminium tube with a phenol-epoxy protective inner lacquer and polypropylene screw cap.

Tubes of 5 g, 15 g, 30 g, 60 g and 100 g. Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.