Tacrolimus 0.03% ointment for external use 15 g

The drug Takropic® is used in dosages of 0.03% and 0.1% for adults and adolescents over 16 years of age, and only 0.03% for children aged 2 to 16 years for the treatment of atopic dermatitis (moderate and severe forms) in cases of resistance to other topical therapies or the presence of contraindications to such therapies.

For adults and children over 2 years old, Takropic® should be applied in a thin layer to the affected areas of the skin. The product can be used on any part of the body, including the face and neck, in skin fold areas. It should not be applied to mucous membranes or under occlusive dressings.

Use in children (2 years and older) and adolescents up to 16 years old
Treatment should begin with the application of 0.03% Takropic® ointment twice daily. The duration of treatment with this regimen should not exceed three weeks. Subsequently, the frequency of application is reduced to once daily, and treatment continues until the lesions are completely cleared.

Use in adults and adolescents 16 years and older
Treatment should begin with the application of 0.1% Takropic® ointment twice daily and continue until the lesions are completely cleared. As improvement occurs, the frequency of application of the 0.1% ointment can be reduced or switched to the use of 0.03% Takropic® ointment. In case of recurrence of disease symptoms, treatment should be resumed with 0.1% Takropic® ointment twice daily. If clinically appropriate, an attempt should be made to reduce the frequency of application or to use a lower dosage - 0.03% Takropic® ointment.

Use in elderly patients (65 years and older)
There are no special considerations for use in elderly patients. Improvement is usually observed within one week of starting therapy. If signs of improvement are not present within two weeks, a change in therapeutic strategy should be considered.

Treatment of exacerbations
Takropic® can be used short-term or long-term in the form of periodically repeated courses of therapy. Treatment of the affected skin areas is conducted until the clinical manifestations of atopic dermatitis completely disappear. Improvement is generally observed within the first week of treatment. If signs of improvement are not observed within two weeks of starting the ointment, other treatment options should be considered. Treatment should be resumed at the first signs of exacerbation of atopic dermatitis.

Prevention of exacerbations
To prevent exacerbations and increase the duration of remission in patients with frequent (more than 4 times a year) exacerbations in their history, maintenance therapy with Takropic® is recommended. The appropriateness of prescribing maintenance therapy is determined by the effectiveness of the preceding treatment according to the standard regimen (twice daily) for no more than 6 weeks.

In maintenance therapy, Takropic® ointment should be applied twice a week (for example, on Monday and Thursday) to the areas of skin that are usually affected during exacerbations. The interval between applications should be at least 2-3 days. For adults and adolescents 16 years and older, 0.1% Takropic® ointment is used; for children (2 years and older), 0.03% Takropic® ointment is used. Upon the manifestation of signs of exacerbation, the usual treatment regimen with Takropic® ointment should be resumed (see the section "Treatment of exacerbations").

After 12 months of maintenance therapy, clinical dynamics should be assessed, and the appropriateness of continuing preventive use of Takropic® should be determined. In children, to assess clinical dynamics, the medication should be temporarily discontinued, and then the need for continuing maintenance therapy should be considered.

100 g of ointment (0.03%) contains:
active ingredient: tacrolimus, calculated as 100% substance - 0.03 g;
excipients: macrogol-400, liquid paraffin, soft white vaseline, emulsifying wax, disodium edetate, preservative Euxyl PE 9010 (phenoxyethanol 90%, ethylhexylglycerin 10%), purified water.

Homogeneous ointment of white or almost white color. A slight specific odor is permissible.

Hypersensitivity to tacrolimus, excipients of the preparation, macrolides.
Pregnancy and breastfeeding.
Tacropic® should not be used in patients with severe epidermal barrier disorders, particularly Netherton syndrome, lamellar ichthyosis, skin manifestations of graft-versus-host disease, as well as in generalized erythroderma due to the risk of increased systemic absorption of tacrolimus. The use of Tacropic® at a dosage of 0.1% is contraindicated in children and adolescents under 16 years of age, and at a dosage of 0.03% in children under 2 years of age.
With caution:
Tacrolimus is significantly metabolized in the liver, and although its blood concentration is very low with topical application, the ointment should be used with caution in patients with uncompensated liver failure.
Caution should be exercised when using Tacropic® ointment in patients with extensive skin lesions, during prolonged courses, especially in children.

The drug Tacropic® should not be used in patients with congenital or acquired immunodeficiencies or in patients taking immunosuppressive medications.
During the use of Tacropic® ointment, exposure to sunlight, visits to solariums, and ultraviolet therapy B or A in combination with psoralen (PUVA therapy) should be avoided.
Tacropic® should not be used to treat lesions considered potentially malignant or precancerous.
For 2 hours after applying Tacropic® to the skin, emollients should not be used on the treated areas.
The efficacy and safety of Tacropic® in the treatment of infected atopic dermatitis have not been evaluated. If signs of infection are present before prescribing Tacropic®, appropriate therapy must be conducted. The use of Tacropic® may be associated with an increased risk of developing herpes infection. If signs of herpes infection are present, the benefit-risk ratio of using Tacropic® should be individually assessed. In the presence of lymphadenopathy, the patient must be examined before starting therapy and monitored during the use of the drug. If there is no obvious cause for lymphadenopathy or if symptoms of acute infectious mononucleosis are present, the use of Tacropic® should be discontinued.
Contact with the eyes and mucous membranes should be avoided (in case of accidental contact with the ointment, it should be thoroughly removed and/or rinsed with water).
It is not recommended to apply Tacropic® ointment under occlusive dressings or to wear tight, impermeable clothing.
As with any other topical medication, patients should wash their hands after applying the ointment, except when the ointment is applied to the hands for therapeutic purposes.
It has been shown that in children aged 2 to 11 years, treatment with 0.03% tacrolimus ointment during vaccination with the conjugated vaccine against Neisseria meningitidis serotype C does not affect the primary response to vaccination, the induction of T-cell immune response, and the formation of immune memory.
Effect on the ability to drive vehicles and operate machinery
Studies on the effect of the drug on the ability to drive a car and on reaction speed when working with complex machinery requiring increased attention have not been conducted. Tacropic® is applied externally, and there is no reason to believe that it may affect the ability to drive a car or operate machinery.

The most common adverse reactions are symptoms of skin irritation (burning and itching sensations, redness, pain, paresthesia, and rash) at the application site.
Typically, they are moderate in severity and resolve within the first week after treatment initiation.
Alcohol intolerance is frequently observed (facial flushing or symptoms of skin irritation after consuming alcoholic beverages).
Patients using Takropic® have an increased risk of developing folliculitis, acne, and herpes infections.
The frequency of adverse reactions is distributed as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000); frequency unknown (insufficient data to assess frequency). Within each group, adverse reactions are listed in descending order of significance. Infectious diseases: common - local skin infections regardless of etiology (in particular, but not limited to, herpes eczema of Kaposi, folliculitis, infection caused by the Herpes simplex virus, other infections caused by viruses of the Herpesviridae family). Metabolism and nutrition disorders: common - alcohol intolerance (facial hyperemia or symptoms of skin irritation after consuming alcoholic beverages). Nervous system disorders: common - paresthesia, hyperesthesia. Skin and subcutaneous tissue disorders: common - folliculitis, itching; uncommon - acne. General disorders and administration site conditions: very common - burning and itching at the application site; common - warmth, redness, pain, irritation, rash at the application site; frequency unknown - swelling at the application site. Throughout the observation period of the drug, isolated cases of rosacea and malignancies (skin and other types of lymphomas, skin cancer) have been reported.In cases of local application, no instances of overdose have been reported. If ingested, standard measures should be taken, which include monitoring vital signs and observing the overall condition. Inducing vomiting or gastric lavage is not recommended.Tacrolimus is not metabolized in the skin, which eliminates the risk of drug interactions in the skin that may affect its metabolism. Since the systemic absorption of tacrolimus when used in the form of an ointment is minimal, interaction with CYP3A4 enzyme inhibitors (including erythromycin, itraconazole, ketoconazole, diltiazem) when used concurrently with Tacropic® is unlikely; however, it cannot be completely excluded in patients with extensive lesions and/or erythroderma. The effect of Tacropic® on vaccination efficacy has not been studied. However, due to the potential risk of reduced efficacy, vaccination should be performed before starting the ointment or 14 days after the last use of Tacropic®. In the case of using a live attenuated vaccine, this period should be extended to 28 days; otherwise, the possibility of using alternative vaccines should be considered. Concurrent use of tacrolimus with the conjugated vaccine against Neisseria meningitidis serotype C in children aged 2 to 11 years does not affect the primary response to vaccination, the formation of immune memory, as well as the humoral and cellular immune response. The possibility of concurrent use of Tacropic with other topical medications, systemic glucocorticosteroids, and immunosuppressants has not been studied.

Tacrolimus belongs to the group of calcineurin inhibitors. It binds to a specific cytoplasmic protein, immunophilin (FKBP12), which is a cytosolic receptor for calcineurin (FK506). As a result, a complex is formed that includes tacrolimus, FKBP12, calcium, calmodulin, and calcineurin, leading to the inhibition of calcineurin's phosphatase activity. This makes it impossible for the dephosphorylation and translocation of the nuclear factor of activated T-cells (NFAT), which is necessary for the initiation of transcription of genes encoding the production of key cytokines for the T-cell immune response (IL-2 and interferon-gamma). Additionally, tacrolimus inhibits the transcription of genes encoding the production of cytokines such as IL-3, IL-4, IL-5, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor (TNF-α), which are involved in the early stages of T-lymphocyte activation. Furthermore, under the influence of tacrolimus, there is inhibition of the release of inflammatory mediators from mast cells, basophils, and eosinophils, as well as a decrease in the expression of FcɛRI (high-affinity surface receptor for immunoglobulin E) on Langerhans cells, leading to a reduction in their activity and antigen presentation to T-lymphocytes. Tacrolimus ointment does not affect collagen synthesis and, therefore, does not cause skin atrophy.

Absorption.
The absorption of tacrolimus into the systemic circulation with local application is minimal. In most patients with atopic dermatitis (in adults and children), both after a single application and with multiple applications of 0.03% tacrolimus ointment, its concentration in plasma was < 1.0 ng/ml. Systemic absorption depends on the area of skin affected and decreases as the clinical manifestations of atopic dermatitis resolve. No accumulation of the drug was observed with prolonged use (up to 1 year) in children and adults. Distribution. Due to the low systemic absorption of tacrolimus ointment, its high ability to bind to plasma proteins (over 98.8%) is considered clinically insignificant. Metabolism. Tacrolimus is not metabolized in the skin. Upon entering the systemic circulation, tacrolimus is significantly metabolized in the liver by the isoenzyme CYP3A4. Excretion. With multiple local applications of tacrolimus ointment, the half-life is 75 hours in adults and 65 hours in children.