Elidel cream for external use 1% tube 15 g

Instructions Elidel cream for external use 1% tube 15 g

Composition

active ingredient: pimecrolimus;

1 g of cream contains 10 mg of pimecrolimus;

Excipients: sodium hydroxide, anhydrous citric acid, benzyl alcohol, sodium cetostearyl sulfate, mono- and diglycerides, cetyl alcohol, stearyl alcohol, propylene glycol, oleyl alcohol, medium chain triglycerides, purified water.

Dosage form

Cream for external use.

Main physicochemical properties: whitish homogeneous cream.

Pharmacotherapeutic group

Dermatological agents. Agents used for atopic dermatitis, excluding corticosteroids.

ATX code D11A H02.

Pharmacological properties

Pharmacodynamics.

Mechanism of action

Pimecrolimus is a lipophilic derivative of the anti-inflammatory macrolactam ascomycin and a selective inhibitor of the formation and release of cytokines, which are mediators of inflammation.

Pimecrolimus binds to macrophilin-12 with high specificity and inhibits the calcium-dependent phosphatase calcineurin. As a result, it blocks the synthesis of inflammatory cytokines in T lymphocytes.

Pharmacodynamic action

Pimecrolimus has been shown to have high anti-inflammatory activity in animal models of skin inflammation when applied topically and systemically. In a model of allergic contact dermatitis in pigs, pimecrolimus was as effective as potent corticosteroids when applied topically. Unlike corticosteroids, pimecrolimus does not cause skin atrophy in pigs and does not affect Langerhans cells in mouse skin.

Pimecrolimus does not reduce the primary immune response and does not affect lymph nodes when used in allergic contact dermatitis in mice. When applied topically, it also penetrates human skin, although much less deeply than corticosteroids, indicating that pimecrolimus has a very low capacity for systemic absorption.

Therefore, the pharmacological action of pimecrolimus is skin-selective and distinct from that of corticosteroids.

Clinical efficacy and safety

The efficacy and safety profile of Elidel® has been evaluated in over 2000 patients, including children aged ≥3 months and adults, who participated in phase II and III studies. Over 1500 of these patients received Elidel® and over 500 received the control drug, i.e. either Elidel® base and/or topical corticosteroids.

Short-term therapy

Children aged 2-17 years: Two six-week placebo-controlled studies were conducted, which included a total of 403 patients aged 2-17 years. Patients applied Elidel® twice daily. The data from both studies were pooled.

Children aged 3–23 months: A similar study was conducted with 186 patients aged 3–23 months.

The efficacy evaluation results in these three six-week studies and endpoints are shown in the table below.

A significant reduction in itching intensity was observed during the first week of therapy in 44% of children aged 2–17 years and in 70% of children aged 3–23 months.

Adults: Elidel® was less effective than 0.1% betamethasone-17-valerate in short-term treatment (3 weeks) of adults with moderate to severe atopic dermatitis.

Long-term therapy

Elidel® was started at the first sign of itching and redness to prevent progression to atopic dermatitis flare. Only in the event of a severe flare not controlled by Elidel® was treatment with a medium-potency topical corticosteroid initiated. After initiation of corticosteroid treatment due to an exacerbation, further use of Elidel® was discontinued. Control patients used Elidel® base to ensure data masking.

Both studies demonstrated a significant reduction in exacerbation rates (p < 0.001) with 1% pimecrolimus cream; treatment with 1% pimecrolimus cream was superior on all secondary endpoints (eczema area and severity index, investigator global assessment, patient assessment); and control of pruritus was achieved within one week with 1% pimecrolimus cream. More patients receiving 1% pimecrolimus cream were free of exacerbations at 6 months (children aged 2–11 years [61% in the Elidel® group compared to 34% in the control group], children aged 3–23 months [70% in the Elidel® group compared to 33% in the control group]) and 12 months (children aged 2–11 years [51% in the Elidel® group compared to 28% in the control group], children aged 3–23 months [57% in the Elidel® group compared to 28% in the control group]).

Elidel® reduces the need for topical corticosteroids: more patients treated with 1% pimecrolimus cream did not require corticosteroids over 12 months (children aged 2–11 years [57% in the Elidel® group compared to 32% in the control group], children aged 3–23 months [64% in the Elidel® group compared to 35% in the control group]). The efficacy of 1% pimecrolimus cream did not change over time.

A 6-month, randomized, double-blind, parallel-group, placebo-controlled study of the same design was conducted in 192 adults with moderate to severe atopic dermatitis. Topical corticosteroids were required on 14.2 ± 24.2% of days during the 24-week treatment period in the Elidel® group and on 37.2 ± 34.6% of days in the control group (p < 0.001). Overall, 50.0% of patients treated with 1% pimecrolimus cream experienced no exacerbations compared with 24.0% of patients randomized to the control group.

A one-year, double-blind study in adults with moderate to severe atopic dermatitis was conducted to compare the effects of Elidel® and 0.1% triamcinolone acetonide cream (for the trunk and extremities) plus 1% hydrocortisone acetate cream (for the face, neck, and skin contact areas). Both 1% pimecrolimus cream and topical corticosteroids were used without restriction. Half of the patients in the control group used topical corticosteroids on more than 95% of the study days. The efficacy of 1% pimecrolimus cream was inferior to the efficacy of 0.1% triamcinolone acetonide cream (for the trunk and extremities) plus 1% hydrocortisone acetate cream (for the face, neck, and skin contact areas) in long-term treatment (52 weeks) of adults with moderate to severe atopic dermatitis.

Safety in long-term use

A 5-year, open-label, randomized, active-controlled study was conducted in 2418 children aged 3 to <12 months at baseline with mild to moderate atopic dermatitis (AD). The primary objective was to compare safety as assessed by adverse events (AEs) and the effects of therapy on immune development and growth velocity. Children aged 3–23 months were randomized to Elidel® (n = 1,205; short-term topical corticosteroids (TCs) for flare-ups) or low/intermediate-potency topical corticosteroids (TCs; n = 1,213).

Elidel® was well tolerated in patients with mild to moderate AD aged 3 to 12 months at baseline. The adverse event profile and incidence were similar in both treatment groups. No deterioration in systemic immune assessments was observed in AD patients treated with 1% pimecrolimus cream or ICS, normal immune response development was observed, and vaccination with vaccine antigens was effective in them. There was no apparent difference in growth rate.

Specialized research

The atrophic potential of Elidel® in therapeutic use was tested in comparison with medium- and potent topical steroids (betamethasone-17-valerate, 0.1% cream, triamcinolone acetonide, 0.1% cream) and cream vehicle in a four-week study in 16 healthy volunteers. Both topical corticosteroids caused a significant reduction in skin thickness, as measured by ultrasound, compared with pimecrolimus 1% cream and cream vehicle, which did not cause a reduction in skin thickness.

Children

The results of relevant studies conducted in children aged 3–23 months and 2–17 years are described in detail above in the Pharmacodynamics section.

Pharmacokinetics.

Data obtained for humans

Absorption when used by adults

The systemic absorption of pimecrolimus was studied in 12 adults with atopic dermatitis who applied Elidel® twice daily for three weeks. The body surface area (BSA) affected by the disease ranged from 15% to 59%. In 77.5% of the samples, the blood concentration of pimecrolimus was below 0.5 ng/mL, and in 99.8% of all samples, it was below 1 ng/mL. The highest blood concentration of pimecrolimus was 1.4 ng/mL in one patient.

In 40 adult patients treated with Elidel® for one year with 14–62% of the BPH, 98% of the samples had pimecrolimus blood levels below 0.5 ng/ml at baseline. The maximum blood level, 0.8 ng/ml, was only observed in two patients after six weeks of treatment. No patients showed an increase in blood levels during 12 months of treatment. In eight adult patients with atopic dermatitis for whom AUC could be quantified, AUC(0–12 h) values ranged from 2.5 to 11.4 ng h/ml.

Absorption when used in pediatric therapy

Systemic exposure to pimecrolimus was investigated in 58 children aged 3 months to 14 years, of whom 41 patients were <2 years of age. The affected PPT ranged from 10% to 92%. Elidel® was administered twice daily for three weeks in these children. Five (8.6%) of the 58 patients received treatment for up to one year on an as-needed basis, two of these patients were ≥3 to ≤6 months of age and three were >6 to ≤2 months of age.

Pimecrolimus blood concentrations were consistently low regardless of the area of the lesion or the duration of therapy, and were within the range established for adult patients.

In approximately 67% of samples, the concentration of pimecrolimus in the blood was below 0.5 ng/mL and in 93% of all samples obtained from children aged 3 to 23 months, it was below 2 ng/mL.

In children aged ≥ 3–≤ 6 months, 31% of blood samples had pimecrolimus concentrations below 0.5 ng/mL and 90% of samples had concentrations below 2.0 ng/mL, with the highest blood concentration being 4.14 ng/mL in one sample, but contamination during venipuncture is suspected.

In children aged > 6 – ≤ 12 months, pimecrolimus concentrations were below 0.5 ng/mL in 66% of blood samples and below 2.0 ng/mL in 90% of samples, with the highest blood concentration being 2.6 ng/mL in one sample.

In children in the age group > 12 - < 24 months, pimecrolimus concentrations were below 0.5 ng/ml in 80% of blood samples and below 2.0 ng/ml in 97% of samples, with the highest pimecrolimus concentration in the blood of patients in this age group being 2.0 ng/ml in one sample.

In five children treated for one year, two of whom were ≥ 3 to ≤ 6 months of age and three of whom were > 6 to ≤ 12 months of age, blood concentrations were consistently low, with a maximum blood concentration of 1.94 ng/mL in one sample obtained from a child ≥ 3 to ≤ 6 months of age. There was no increase in blood concentrations over time in all patients during the 12 months of therapy.

In children aged 2 to 14 years, 68% of samples had pimecrolimus blood concentrations below 0.5 ng/mL and 99% of all samples had pimecrolimus blood concentrations below 2.0 ng/mL, with the highest blood concentration determined in one patient being 2.0 ng/mL.

In eight children aged 2–14 years, AUC(0-12h) values ranged from 5.4–18.8 ng h/mL. AUC values in patients with < 40% TBI at baseline were comparable to those in patients with ≥ 40% TBI.

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

Distribution

Due to the selective skin action of topical pimecrolimus, the blood levels of pimecrolimus are very low. Therefore, the metabolic transformation of pimecrolimus during topical application cannot be assessed.

In vitro plasma protein binding studies indicate that 99.6% of pimecrolimus in plasma is protein bound. The majority of pimecrolimus in plasma is bound to various lipoproteins.

Biotransformation

Following a single oral dose of radiolabeled pimecrolimus to adult patients, unchanged pimecrolimus was the major active substance-related component in the blood, and numerous minor metabolites of moderate polarity were also detected, which are assumed to be products of O-dimethylation and oxygenation. No metabolic transformation of pimecrolimus was observed in human skin in vitro.

Following oral administration, the active substance-related radioactivity was excreted primarily in the feces (78.4%) and only a minor fraction (2.5%) in the urine. The overall mean recovery of radioactivity was 80.9%. No parent compound was detected in the urine, and less than 1% of the radioactivity in the feces was due to unchanged pimecrolimus.

Indication

Treatment of patients aged 3 months and over with mild to moderate atopic dermatitis when treatment with topical corticosteroids is undesirable or not possible. This may be the case for:

intolerance to local corticosteroids;

insufficient effect of local corticosteroids;

the need for use on the face and neck, where long-term intermittent use of corticosteroids may be inappropriate.

Contraindication

Hypersensitivity to pimecrolimus, other macrolactams or other components of the drug.

Interaction with other medicinal products and other types of interactions

The potential for interactions of pimecrolimus with other medicinal products has not been systematically evaluated. Pimecrolimus is metabolised exclusively by CYP4503A4. Given the minimal absorption of Elidel®, interactions with systemically administered medicinal products are unlikely.

These data indicate that pimecrolimus can be used concomitantly with antibiotics, antihistamines, and corticosteroids (oral, nasal, or inhaled).

Given the minimal absorption of Elidel®, its systemic interaction with vaccination is unlikely. In patients with widespread or disseminated forms of the disease, vaccination is recommended during periods when drug treatment is not used.

The use of pimecrolimus at the vaccination site while local reactions persisted has not been studied and is therefore not recommended. A 5-year study was conducted in children with mild to moderate atopic dermatitis, aged 3 months to less than 12 months at study entry. Patients with atopic dermatitis who received Elidel® cream or topical corticosteroids had normal immune responses and developed effective immunization against vaccine antigens.

There are no data on the concomitant use of immunosuppressive agents prescribed for atopic eczema, such as ultraviolet B and A radiation, PUVA therapy (psoralen and ultraviolet A radiation), azathioprine, and cyclosporine A.

Pimecrolimus has not shown photocarcinogenic potential in animals. However, as the effects in humans are unknown, excessive exposure of the skin to ultraviolet light (including tanning beds, ultraviolet B and A therapy, and PUVA therapy) should be avoided during treatment with pimecrolimus.

Rare cases of redness, rash, burning sensation, itching or swelling have been observed immediately after drinking alcohol in patients using pimecrolimus cream (see section “Adverse reactions”).

Application features

Pimecrolimus cream is not recommended for use in patients with hereditary or acquired immunodeficiency or in patients receiving treatment with immunosuppressive agents.

The long-term effects on the local immune response of the skin and the incidence of skin malignancies are unknown. Pimecrolimus should not be applied to potentially malignant lesions or areas of skin affected by premalignant diseases.

Pimecrolimus should not be applied to skin areas affected by acute viral infections (herpes simplex, chickenpox).

The efficacy and safety of Elidel® have not been evaluated in the treatment of clinically infected atopic dermatitis. Infected areas should be cleared before starting treatment with Elidel®.

Since patients with atopic dermatitis are prone to superficial skin infections, including eczema herpeticum (eczema herpetiformis of Kaposi), treatment with pimecrolimus may increase the risk of infection with herpes simplex virus or the development of eczema herpeticum. In such cases, treatment with Elidel® should be discontinued until the viral infection has resolved.

Patients with acute atopic dermatitis are at increased risk of developing bacterial skin infections (impetigo) during treatment with pimecrolimus.

Elidel® may cause minor, transient reactions at the application site, such as a feeling of warmth and/or burning (see section 4.8). Patients should inform their doctor if the reactions at the application site are severe.

Contact with eyes and mucous membranes should be avoided. If the product accidentally gets on these areas, it should be wiped off thoroughly and/or rinsed with water.

Elidel® contains the active substance pimecrolimus, a calcineurin inhibitor. In patients after transplantation and after long-term systemic use of immunosuppressants, systemic use of calcineurin inhibitors is associated with an increased risk of lymphomas and skin malignancies.

Malignancies, including cutaneous and other forms of lymphoma and skin malignancies, have also been reported in patients using pimecrolimus cream (see section 4.8). However, no significant systemic exposure to pimecrolimus was observed in patients with atopic dermatitis treated with Elidel®.

In clinical trials, 14/1544 (0.9%) cases of lymphadenopathy were reported with Elidel® cream, 10 mg/g (see section “Adverse reactions”). These cases of lymphadenopathy were usually associated with infections and were noted to resolve after appropriate antibiotic therapy. In the majority of these 14 cases, the lymphadenopathy had a clear etiology and resolved as described above. In patients receiving Elidel® cream, 10 mg/g, who develop lymphadenopathy, the etiology of the lymphadenopathy should be investigated. In the absence of a clear etiology for the lymphadenopathy or in the presence of acute infectious mononucleosis, pimecrolimus treatment should be discontinued. Patients who develop lymphadenopathy should be monitored to ensure that the lymphadenopathy resolves.

Patient groups with a potentially higher risk of systemic exposure. Elidel® has not been studied in patients with Netherton's syndrome. Due to the potential for higher systemic absorption of pimecrolimus, the use of Elidel® in patients with Netherton's syndrome is not recommended.

Since the safety of pimecrolimus in patients with erythroderma has not been evaluated, the use of Elidel® in this group of patients is not recommended.

The use of Elidel® under occlusive dressings has not been studied. It is not recommended to use the medicinal product under occlusive dressings.

In patients with acute inflammatory processes of the skin and/or its damage, systemic concentration may be higher.

Elidel® contains cetyl and stearyl alcohols, which may cause local skin reactions (e.g. contact dermatitis). Elidel® also contains 10 mg of benzyl alcohol per 1 g of cream, which may cause allergic reactions and mild local irritation. Elidel® also contains 50 mg of propylene glycol (E 1520) per 1 g of cream, which may cause skin irritation.

Use during pregnancy or breastfeeding

There are no adequate data from the use of pimecrolimus in pregnant women. Animal studies with dermal application of pimecrolimus do not indicate direct or indirect harmful effects with respect to embryonal/intrauterine development. Animal studies with oral administration of pimecrolimus have shown reproductive toxicity.

Given the minimal absorption of pimecrolimus after topical application, the potential risk to humans is considered negligible. However, pimecrolimus should not be used during pregnancy.

Animal studies with dermal application have not been conducted, and the use of pimecrolimus in lactating women has not been studied. It is not known whether pimecrolimus is excreted in breast milk when applied topically. However, given the minimal absorption of pimecrolimus after topical application, the potential risk to humans is considered to be negligible.

Elidel® should be administered with caution to women who are breastfeeding.

Breastfeeding women can use Elidel®, but should not apply it to the breast area to avoid inadvertent ingestion of the drug into the oral cavity of newborn infants.

There are no clinical data on the effect of Elidel® cream on female or male fertility.

Ability to influence reaction speed when driving vehicles or other mechanisms

The effect of Elidel® on the ability to drive and use machines has not been established.

Method of administration and doses

Treatment with Elidel® should be initiated under the supervision of a physician experienced in the diagnosis and treatment of atopic dermatitis.

Elidel® can be used short-term to treat the signs and symptoms of atopic eczema and intermittently over a long period of time to prevent flare-ups.

Treatment should be initiated at the first signs and symptoms of atopic dermatitis. Elidel® should be applied only to areas affected by atopic dermatitis. Pimecrolimus should be used for the shortest possible period during an exacerbation. The patient or caregiver should discontinue pimecrolimus when signs or symptoms resolve. Treatment should be intermittent and short-term.

If no improvement is observed after 6 weeks or the patient's condition worsens, treatment should be discontinued. The diagnosis of atopic dermatitis should be re-evaluated and further therapeutic measures considered.

Elidel® can be used on all skin areas, including the head, face, neck and intertriginous areas (inguinal folds and genitals), except mucous membranes. Elidel® should not be used under occlusive dressings (see section "Interaction with other medicinal products and other forms of interaction").

In the long-term treatment of atopic dermatitis (eczema), treatment with Elidel® should be initiated at the first signs and symptoms of atopic dermatitis to prevent the spread and further exacerbation of the disease. Elidel® should be applied twice daily. Emollients should be applied immediately after application of Elidel®.

Children: For children aged 3–23 months and 2–17 years, the dosage and method of administration are the same as for adults.

Elderly patients: Cases of atopic dermatitis (eczema) have been reported rarely in patients aged 65 years and older. Clinical studies with Elidel® did not include sufficient numbers of patients in this age group to determine whether their response to treatment differs from that of younger patients.

Children

Use for children aged 3 months and over.

Overdose

There are no reports of cases of overdose with Elidel®.

Side effects

The most common adverse reactions were application site reactions, reported by approximately 19% of patients treated with Elidel® and 16% of patients in the control groups. These reactions generally occurred early in treatment, were mild/moderate in duration, and were transient.

Adverse reactions were observed during clinical trials with pimecrolimus cream 1% and are known from spontaneous reports.

Adverse reactions are classified by frequency in descending order: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000); not known (cannot be estimated from available data).

Postmarketing experience: Cases of malignancies, including cutaneous and other types of lymphoma, and skin cancer, have been reported in patients using pimecrolimus cream (see section 4.4).

During post-marketing use and in clinical trials, cases of lymphadenopathy have been reported, but a causal relationship to pimecrolimus treatment has not been established (see section 4.4).

Children

The clinical safety database for children aged 3 months and older treated with pimecrolimus 1% cream is extensive and includes long-term safety data for 5 years. The safety profiles in children aged 3–23 months and 2–17 years were comparable in terms of the nature and frequency of adverse events observed. The most common adverse reactions observed were application site reactions.

Reporting adverse reactions after the registration of a medicinal product is important. This allows monitoring of the benefit/risk ratio when using this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the link: https://aisf.dec.gov.ua

Expiration date

2 years.

Storage conditions

Store out of the reach of children at a temperature not exceeding 25 ° C, do not freeze. After opening the tube, the drug should be used within 12 months.

Packaging

15, 30, 60 or 100 g of cream for external use 1% in a tube, 1 tube together with instructions for medical use of the medicinal product in a cardboard box.

Vacation category

According to the recipe.

Producer

MEDA Manufacturing / MEDA Manufacturing.

Address

Avenue JF Kennedy, 33700 Merignac, France.