Protopic

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PROTOPIC (PROTOPIC®)

Composition:

active substance: tacrolimus;

1 g of ointment contains tacrolimus (as monohydrate) 0.3 mg or 1 mg;

excipients: white soft paraffin, mineral oil, propylene carbonate, white wax, paraffin, butylhydroxytoluene (E 321), alpha-tocopherol.

Pharmaceutical form. Ointment.

Main physicochemical properties: ointment ranging from white to slightly yellowish.

Pharmacotherapeutic group. Dermatologicals. ATC code D11A H01.

Pharmacological Properties

Pharmacodynamics

By binding to a specific cytoplasmic protein, immunophilin (FKBP12), tacrolimus inhibits calcium-dependent signal transduction to T-lymphocytes, thereby preventing their activation and subsequent synthesis of IL-2, IL-3, IL-4, IL-5, and other cytokines such as GM-CSF, TNF-α, and IFN-γ.

In vitro studies have shown that in the skin of healthy individuals, tacrolimus inhibits Langerhans cell-mediated stimulation of T-lymphocytes. Tacrolimus has also been shown to prevent the release of inflammatory mediators from mast cells, basophils, and eosinophils.

In patients with atopic dermatitis, skin clearance during treatment with tacrolimus ointment was associated with reduced expression of the Fc receptor on Langerhans cells and inhibition of their stimulatory effect on T-lymphocytes.

Tacrolimus in the ointment formulation does not affect collagen synthesis and therefore does not cause skin atrophy.

Pharmacokinetics

Absorption. Data obtained from healthy volunteers indicate that systemic exposure to tacrolimus after single or repeated topical application of tacrolimus ointment is absent or minimal.

The minimum therapeutic concentrations required for systemic immunosuppression following oral administration of tacrolimus range from 5–20 ng/mL in post-transplant patients.

In most patients with atopic dermatitis (adults and children) who applied tacrolimus ointment (0.03–0.1%) once or repeatedly, blood concentrations of tacrolimus were < 1 ng/mL. When blood concentrations exceeded 1 ng/mL, this was transient. Systemic exposure increased with larger affected skin areas. However, the rate and extent of local absorption of tacrolimus decreased as the skin healed. In adults and children treated over approximately 50% of body surface area, systemic exposure (i.e., AUC) to tacrolimus as the active ingredient in Protopic ointment was approximately 30 times lower than systemic exposure to immunosuppressants following their oral administration in patients with transplanted kidney or liver. The lowest blood concentration of tacrolimus at which systemic effects occur is unknown.

No drug accumulation was observed with long-term use (up to 1 year) in children and adults.

Distribution. Because systemic absorption of tacrolimus ointment is low, the high plasma protein binding capacity (> 98.8%) is considered clinically insignificant. After topical application, tacrolimus acts locally and is characterized by minimal absorption into the systemic circulation.

Metabolism. Tacrolimus is not metabolized in the skin. When it enters the systemic circulation, it is extensively metabolized in the liver via CYP3A4.

Elimination. Following intravenous administration, tacrolimus exhibits low clearance. The mean total clearance is approximately 2.25 L/h. Hepatic clearance of the drug absorbed into systemic circulation may be reduced in patients with severe hepatic impairment or when co-administered with CYP3A4 inhibitors.

After repeated topical application of tacrolimus ointment, the elimination half-life is 75 hours in adults and 65 hours in children.

Children

The pharmacokinetic properties of tacrolimus after topical application are similar to those observed in adults, including minimal systemic exposure and absence of accumulation (see above).

Clinical characteristics.

Indications.

Treatment of atopic dermatitis in children from 2 years of age – Protopic ointment 0.03%, in adults and adolescents from 16 years of age – Protopic ointment 0.03% and 0.1%.

Treatment of flares

Adults and adolescents (aged 16 years and older)

Treatment of moderate to severe atopic dermatitis in adults and adolescents (aged 16 years and older) who respond inadequately or are unresponsive to conventional therapies, including treatment with topical corticosteroids.

Children (aged 2 to 16 years)

Treatment of moderate to severe atopic dermatitis in children aged 2 to 16 years who respond inadequately to conventional therapies, including topical corticosteroids.

Prevention of flare-ups

Prophylactic treatment of moderate to severe atopic dermatitis to prevent sudden disease exacerbations and prolong the duration of flare-free periods in patients with a high frequency of recurrences (4 or more times per year) who have shown an initial response to a maximum 6-week course of ointment treatment (twice daily) – complete, almost complete, or partial healing of lesions.

Contraindications.

Hypersensitivity to tacrolimus, macrolides, or excipients.

Interaction with other medicinal products and other forms of interaction.

Formal interaction studies of the topical ointment formulation of tacrolimus have not been conducted.

Tacrolimus is not metabolized in human skin, which practically excludes the possibility of interactions with other drugs in the skin that could affect tacrolimus metabolism.

Systemically available tacrolimus is metabolized by hepatic cytochrome P450 3A4 (CYP3A4). The level of systemic exposure following topical application of tacrolimus ointment is low (< 1 ng/mL) and is unlikely to be significantly altered by concomitant administration of known CYP3A4 inhibitors. However, the possibility of interaction cannot be entirely excluded; therefore, concomitant systemic use of known CYP3A4 inhibitors (such as erythromycin, itraconazole, ketoconazole, diltiazem) in patients with large affected skin areas and/or erythroderma should be performed with caution.

Children.

A drug interaction study with protein-conjugated meningococcal group C vaccine was conducted in children aged 2–11 years. No impact on vaccination, immune memory formation, or humoral or cellular immunity was observed.

Special precautions for use.

Protopic ointment must not be used in patients with congenital or acquired immunodeficiency or in patients receiving immunosuppressive agents.

The effect of Protopic ointment on the immune system in children under 2 years of age has not been established (see section "Indications").

During treatment with the ointment, exposure of the skin to sunlight should be minimized. Avoid ultraviolet irradiation in solariums and phototherapy with UV-B and PUVA therapy (combination of psoralen and UV-A). The physician should advise patients on appropriate sun protection measures, such as minimizing time spent in the sun, using sunscreen products, and covering the skin with appropriate clothing. Protopic ointment should not be applied to lesions considered potentially malignant or premalignant.

For 2 hours after application of Protopic ointment, emollients should not be applied to the same skin areas. Concomitant use of other topical agents, as well as systemic steroids or immunosuppressants, has not been studied.

The efficacy and safety of Protopic ointment in the treatment of infected atopic dermatitis have not been evaluated. Any infection at the treatment site should be resolved prior to initiating Protopic ointment. Patients with atopic dermatitis are prone to developing superficial skin infections. Treatment with Protopic ointment may be associated with an increased risk of folliculitis and herpesvirus infections (herpes simplex virus [herpetic eczema], herpes simplex [herpes gladiatorum], or Kaposi's varicelliform eruption) (see section "Adverse reactions"). In the presence of such infections, the benefit-risk ratio of Protopic use should be carefully assessed.

Protopic contains tacrolimus as the active ingredient, a calcineurin inhibitor. In transplant patients, long-term systemic exposure to potent immunosuppressants and systemic use of calcineurin inhibitors has been associated with an increased risk of lymphoma and skin malignancies. In patients with atopic dermatitis treated with Protopic, significant systemic levels of tacrolimus have not been observed, and the role of local immunosuppression is unknown. Based on long-term studies and clinical experience, a causal link between Protopic ointment treatment and the development of malignancies has not been confirmed, but definitive conclusions cannot be drawn. It is recommended to use tacrolimus ointment at the lowest concentration and with the lowest frequency for the shortest necessary duration, as determined by the physician based on clinical assessment (see section "Dosage and administration").

During clinical trials, rare cases of lymphadenopathy (0.8%) were reported. Most of these cases were associated with infections (skin, respiratory tract, dental) and resolved with appropriate antibiotic treatment. Lymphadenopathy at the start of treatment requires appropriate laboratory investigations and ongoing monitoring. Persistent lymphadenopathy requires evaluation of its etiology. Protopic should be discontinued if no clear etiology for lymphadenopathy is identified or if acute infectious mononucleosis is present.

Patients who develop lymphadenopathy during treatment should remain under medical supervision to confirm resolution of lymphadenopathy.

Avoid contact of the ointment with eyes and mucous membranes. In case of accidental contact, the ointment should be thoroughly wiped off and/or washed with water.

The use of Protopic ointment under occlusive dressings has not been studied and is therefore not recommended.

As with other topical agents, patients should wash their hands after application unless the hands are being treated.

Tacrolimus is extensively metabolized in the liver, and although blood concentrations following topical application are very low, patients with hepatic impairment should use the ointment with caution.

Protopic is not recommended for use in patients with epidermal barrier defects such as Netherton's syndrome, lamellar ichthyosis, erythroderma, or graft-versus-host disease (GVHD) skin reactions. These skin conditions may increase systemic absorption of tacrolimus. Post-marketing reports have described cases of elevated tacrolimus levels in patients with these conditions.

Protopic should be used with caution in patients with extensive skin involvement over a prolonged period, especially in children (see section "Dosage and administration").

Any new skin lesions appearing at the site of application, other than atopic dermatitis itself, should be evaluated by a physician.

If symptoms of atopic dermatitis do not improve, the treatment should be re-evaluated.

PROTOPIC ointment contains butylated hydroxytoluene (E 321), which may cause local skin reactions (e.g., contact dermatitis) or irritation of the eyes and mucous membranes.

Use during pregnancy or breastfeeding.

There are no data on the use of tacrolimus ointment in pregnant women. Animal studies have shown that systemic administration leads to reproductive toxicity. The potential risk to humans is unknown.

Protopic ointment should not be used during pregnancy except in life-threatening or extremely urgent situations.

Breastfeeding

Clinical data demonstrate that following systemic administration, tacrolimus is excreted into breast milk. Although clinical data indicate that systemic exposure from topical tacrolimus ointment is low, breastfeeding should be discontinued during treatment with Protopic ointment.

Fertility

Data on fertility are lacking.

Ability to affect reaction rate while driving or operating machinery.

The product is applied topically and has no effect or negligible effect on the ability to drive or operate machinery.

Method of Administration and Dosage

Apply Protopic ointment in a thin layer to affected areas or areas of skin most commonly involved. The ointment may be applied to any part of the body (including face, neck, etc.), including flexural surfaces. Avoid contact of the ointment with mucous membranes. Do not apply the ointment under occlusive dressings, as this method of administration has not been studied (see section "Special Warnings and Precautions for Use").

Treatment of Flares

Protopic may be used either short-term or over a prolonged period, in repeated treatment courses. Prolonged treatment should not be continuous.

Treatment with Protopic should be initiated at the first sign of symptoms and continued until complete, almost complete, or marked resolution of skin lesions. Each affected skin area should be treated with the ointment. After this, patients may be transitioned to maintenance therapy (see below). If early signs of recurrence appear, treatment should be resumed.

Children aged 2 to 16 years

Use the lower-concentration ointment (Protopic 0.03%). Treatment course: twice daily for three weeks. Thereafter, reduce the frequency of application to once daily until complete resolution of skin lesions (see section "Special Warnings and Precautions for Use").

Adults and adolescents (aged 16 years and older)

Begin treatment with Protopic 0.1% twice daily and continue until complete resolution of skin lesions. If symptoms recur, treatment should be restarted. If the clinical condition allows, consider reducing the frequency of application or switching to the lower-concentration ointment (Protopic 0.03%).

Improvement is usually observed within the first week of treatment. If no signs of improvement are seen within two weeks of ointment use, alternative treatment options should be considered.

Elderly Patients

Specific studies in elderly patients have not been conducted. However, clinical experience in this age group indicates that dosage adjustment is not required.

Prevention of Flare-ups

Patients may be transitioned to maintenance therapy after a 6-week treatment course with twice-daily ointment application (until complete, almost complete, or marked resolution of skin lesions).

Children aged 2 to 16 years

Use the lower-concentration ointment (Protopic 0.03%). Apply the ointment once daily, twice weekly (e.g., on Mondays and Thursdays) to areas of skin most commonly affected by atopic dermatitis, to prevent flare-ups. Between applications, allow a 2–3 day interval.

After 12 months of ointment use, treatment should be temporarily discontinued in a child to assess the need for continued maintenance therapy and to evaluate disease course.

Adults and adolescents (aged 16 years and older)

Use Protopic 0.1% ointment. Apply once daily, twice weekly (e.g., on Mondays and Thursdays) to areas of skin most commonly affected by atopic dermatitis, to prevent flare-ups. Between applications, allow a 2–3 day interval.

After 12 months of treatment, the physician should evaluate the patient's condition and decide on continuing preventive therapy, as data on preventive treatment beyond 12 months are lacking.

If signs of flare-up occur, resume treatment with the ointment twice daily.

Elderly Patients

Specific studies in elderly patients have not been conducted.

Children

Protopic ointment is indicated for use in children aged 2 years and older.

Overdose

Overdose is unlikely with topical application.

In case of accidental ingestion, standard supportive measures should be taken, including monitoring of vital functions and general condition. Induction of vomiting or gastric lavage is not recommended due to the nature of the ointment's excipients.

Adverse reactions

During clinical studies, approximately 50% of patients experienced an adverse reaction in the form of skin irritation at the application site. Burning sensation and pruritus were frequently reported, usually mild or moderate in intensity, which mostly resolved after the first week of treatment. Erythema was a commonly observed adverse reaction. Sensation of warmth, pain, paresthesia, and rash were also frequently observed. Alcohol intolerance (facial flushing or skin irritation after ingestion of alcoholic beverages) was frequently reported. During the post-marketing period, reactions at the application site and dermatitis were observed.

Patients may have an increased risk of developing folliculitis, acne, and herpes viral infections.

Listed below are adverse reactions associated with the use of the medicinal product. The frequency of adverse reactions is classified as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), and not known (frequency cannot be estimated from the available data).

Adverse effects within each group are listed in order of decreasing severity.

Table 1

* The adverse reaction was reported during the post-marketing period.

Prevention of flare-ups

In a preventive treatment study (using the ointment twice weekly) involving adults and children with moderate to severe atopic dermatitis, the following adverse reactions occurred more frequently than in the control group: impetigo at the application site (7.7% of children) and infections at the application site (6.4% of children and 6.3% of adults).

Children

The frequency, type, and severity of adverse reactions in children were similar to those in adults.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after medicinal product authorization is of great importance. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in a place inaccessible to children.

Do not use the medicinal product after the expiry date stated on the packaging.

Packaging.

0.03% or 0.1% ointment, 10 g, 30 g, or 60 g in a plastic tube; 1 tube per cardboard box.

Prescription category. Prescription only.

Manufacturer.

LEO Laboratories Limited

Manufacturer's location and address of the place of business.

285 Cashel Road, Crumlin, Dublin 12, D12 E923, Ireland / 285 Cashel Road, Crumlin, Dublin 12, D12 E923, Ireland.

Marketing Authorization Holder.

LEO Pharma A/S

Location of the Marketing Authorization Holder.

Industriparken 55, DK-2750 Ballerup, Denmark / Industriparken 55, DK-2750 Ballerup, Denmark.