Instructions Protopic ointment 0.1% tube 10 g
Composition
active ingredient: 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.
Dosage form
Ointment.
Main physicochemical properties: ointment from white to slightly yellowish color.
Pharmacotherapeutic group
Dermatological products. ATX code D11A H01.
Pharmacological properties
Pharmacodynamics.
By binding to a specific cytoplasmic protein immunophilin (FKBP12), tacrolimus inhibits calcium-dependent signaling to T lymphocytes, 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 in healthy human skin showed that tacrolimus inhibited Langerhans cell-mediated stimulation of T lymphocytes. Tacrolimus was also shown to inhibit the release of inflammatory mediators from mast cells, basophils and eosinophils.
In patients with atopic dermatitis, skin clearing during treatment with tacrolimus in the form of an ointment was accompanied by a decrease in Fc receptor expression on Langerhans cells and inhibition of their stimulatory effect on T lymphocytes.
Tacrolimus in the ointment dosage form does not affect collagen synthesis, thus, does not cause skin atrophy.
Pharmacokinetics.
Absorption: Data from healthy volunteers have shown that there is no or minimal systemic exposure to tacrolimus following single or multiple topical applications of tacrolimus ointment.
The minimum therapeutic concentrations for systemic immunosuppression with oral tacrolimus are 5–20 ng/mL in transplant patients.
In most patients with atopic dermatitis (adults and children) who received single or repeated applications of tacrolimus ointment (0.03-0.1%), blood concentrations of tacrolimus were < 1 ng/ml. If blood concentrations exceeded 1 ng/ml, this was transient. The level of systemic exposure increased with increasing area of the affected area. However, the rate and extent of local absorption of tacrolimus decreased with healing of the skin. In adults and children who received an average of 50% of their body surface area, the level of systemic exposure (i.e. AUC) to tacrolimus as the active ingredient of Protopic ointment was approximately 30 times lower than the level of systemic exposure to immunosuppressants after oral administration to kidney or liver transplant patients. The lowest blood concentration of tacrolimus at which systemic effects are observed is unknown.
Cumulation of the drug with long-term use (up to 1 year) in children and adults was not observed.
Distribution in the body. Due to the low systemic absorption of tacrolimus ointment, its high plasma protein binding (> 98.8%) is considered to be of no clinical significance. When tacrolimus ointment is used, the drug acts locally and is characterized by minimal absorption into the systemic circulation.
Metabolism: Tacrolimus is not metabolized in the skin. Once in the systemic circulation, tacrolimus is extensively metabolized in the liver by CYP3A4.
Elimination: Tacrolimus has a low clearance following intravenous administration. The mean total clearance is approximately 2.25 l/h. The hepatic clearance of the drug absorbed into the systemic circulation may be reduced in patients with severe hepatic impairment or when concomitantly administered with CYP3A4 inhibitors.
With repeated topical application of tacrolimus ointment, the half-life is 75 hours in adults and 65 hours in children.
Children.
The pharmacokinetic properties of tacrolimus after topical administration are similar to those reported in adults, including minimal systemic exposure and lack of accumulation (see above).
Indication
Treatment of atopic dermatitis in children aged 2 years and older – Protopic ointment 0.03%, in adults and adolescents aged 16 years and older – Protopic ointment 0.03% and 0.1%.
Treatment of exacerbations
Adults and adolescents (aged 16 and over)
Treatment of moderate to severe atopic dermatitis in adults and adolescents (aged 16 years and over) who have responded inadequately to or are insensitive to conventional treatments, including topical corticosteroids.
Children (ages 2 to 16)
Treatment of moderate to severe atopic dermatitis in children aged 2 to 16 years who have responded inadequately to conventional treatments, including topical corticosteroids.
Prevention of exacerbations
Prophylactic treatment of moderate to severe atopic dermatitis to prevent sudden exacerbations of the disease and prolong the duration of exacerbation-free periods in patients with a high frequency of relapses (4 or more times a year) who have had an initial response to a maximum of 6 weeks of ointment treatment (twice a day) - complete, almost complete or minor healing of the lesions.
Contraindication
Hypersensitivity to tacrolimus, macrolides or excipients.
Interaction with other medicinal products and other types of interactions
Tacrolimus is not metabolized in human skin, which virtually eliminates the possibility of interactions with other drugs in the skin that could affect the metabolism of tacrolimus.
Systemically available tacrolimus is metabolised by hepatic cytochrome P450 3A4 (CYP3A4). The systemic exposure to topical tacrolimus ointment is low (< 1 ng/ml) and is unlikely to be altered by concomitant use of known CYP3A4 inhibitors. However, the possibility of an interaction cannot be excluded and therefore concomitant systemic use of known CYP3A4 inhibitors (such as erythromycin, itraconazole, ketoconazole, diltiazem) in patients with extensive lesions and/or erythroderma should be undertaken with caution.
Children.
A drug interaction study was conducted with a meningococcal group C protein conjugate vaccine in children aged 2 to 11 years. No effect on vaccination, immune memory, or humoral or cellular immunity was observed.
Application features
Protopic ointment should not be used in patients with congenital or acquired immunodeficiency or in patients taking immunosuppressive drugs.
The effect of Protopic ointment on the immune system of children under 2 years of age has not been established (see section “Indications”).
During the use of the ointment, it is necessary to minimize exposure to sunlight, avoid ultraviolet radiation in a solarium, therapy with UV-B and UV-A rays in combination with psoralen (PUVA therapy). The doctor should advise patients on appropriate sun protection, for example: minimizing time spent in the sun, using sunscreen and covering the skin with appropriate clothing. Protopic ointment should not be applied to affected areas that are considered potentially malignant or precancerous.
Emollients should not be applied to skin areas treated with Protopic ointment for 2 hours. Concomitant use of other topical medications, 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. Infection in the treatment areas should be eliminated before administering 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 herpetic viral infections (herpes virus (eczema herpeticum), herpes simplex (herpetic fever), Kaposi's varicella pustulosis) (see section "Adverse reactions"). In the presence of these infections, the risk-benefit ratio of Protopic should be assessed.
Protopic contains the active substance tacrolimus, a calcineurin inhibitor. In transplant patients, prolonged systemic exposure to potent immunosuppressants and systemic administration of calcineurin inhibitors may be associated with an increased risk of developing lymphomas and skin malignancies. In patients with atopic dermatitis treated with Protopic, no significant systemic levels of tacrolimus were detected and the role of local immunosuppression is unknown. Based on the results of long-term studies and experience, an association between treatment with Protopic ointment and the development of malignancies has not been confirmed, but definitive conclusions cannot be drawn. It is recommended to use tacrolimus ointment in the lowest concentration and with the lowest frequency for the shortest necessary period, determined by the physician based on the assessment of the clinical condition (see section "Method of administration and dosage").
During clinical trials, rare cases of lymphadenopathy (0.8%) were reported. Most of these cases were associated with infections (skin, respiratory tract, dental) that were treated with appropriate antibiotics. If lymphadenopathy is present, appropriate laboratory tests and ongoing monitoring are required at the start of treatment. In the case of persistent lymphadenopathy, its etiology should be determined. In the absence of a clear etiology for lymphadenopathy or in the presence of acute infectious mononucleosis, Protopic should be discontinued.
Patients who develop lymphadenopathy during treatment should be monitored to confirm that the lymphadenopathy resolves.
Avoid contact with eyes and mucous membranes. If the ointment accidentally gets on these areas, wipe it off thoroughly and/or rinse with water.
The use of Protopic ointment under occlusive dressings has not been studied and is therefore not recommended.
As with other topical medications, patients should wash their hands after application unless treatment of the skin on the hands is required.
Tacrolimus is extensively metabolized in the liver, and although its blood concentration is very low when applied topically, patients with liver failure should use the ointment with caution.
Protopic should be used with caution in patients with extensive skin lesions over a long period of time, especially in children (see section “Method of administration and dosage”).
Any new formations, other than atopic dermatitis itself, on the areas of skin where the ointment was applied should be examined by a doctor.
If the symptoms of atopic dermatitis do not improve, treatment should be reviewed.
PROTOPIC ointment contains butylhydroxytoluene (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 reproductive toxicity when administered systemically. The potential risk to humans is unknown.
Protopic ointment should not be used during pregnancy, except in cases of extreme urgency.
Breast-feeding
Clinical data show that tacrolimus is excreted in breast milk after systemic administration. Although clinical data have shown that systemic exposure to tacrolimus ointment is low, breast-feeding should be discontinued during treatment with Protopic ointment.
Fertility
There are no data on fertility.
Ability to influence reaction speed when driving vehicles or other mechanisms
The drug is applied topically and has no or negligible influence on the ability to drive and use machines.
Method of administration and doses
Protopic ointment should be applied in a thin layer to the affected or most frequently affected areas of the skin. The ointment can be applied to any part of the body (face, neck, etc.), including flexural surfaces. It is necessary to avoid contact of the ointment with mucous membranes. The ointment should not be applied under occlusive dressings, as this method of application has not been studied (see section "Peculiarities of use").
Treatment of exacerbations
Protopic can be used for short-term or long-term treatment, as repeated courses of therapy. Long-term treatment should not be continuous.
Treatment with Protopic should be initiated at the first appearance of symptoms and continued until complete, nearly complete or significant clearance of skin lesions. Each affected area should be treated with the ointment. Patients may then be transferred to prophylactic treatment (see below). Treatment should be resumed at the first sign of recurrence of symptoms.
Children aged 2 to 16 years
It is necessary to use a lower concentration ointment (Protopic 0.03%). The course of treatment is twice a day for three weeks. In the future, the frequency of application should be reduced to once a day until the skin lesions disappear completely (see the section "Peculiarities of use").
Adults and adolescents (aged 16 years and over)
Treatment should be initiated with Protopic 0.1% twice daily and continued until the skin lesions have completely disappeared. If symptoms recur, treatment should be restarted. If the clinical condition permits, it is necessary to try to reduce the frequency of application of the drug or use a lower concentration of ointment (Protopic 0.03%).
Typically, improvement can be seen within the first week of treatment. If signs of improvement are not seen within two weeks of using the ointment, other treatment options should be considered.
Elderly patients
No specific studies have been conducted in elderly patients. However, clinical experience with patients in this age group suggests that no dosage adjustment is necessary.
Prevention of exacerbations
Patients can be transferred to preventive treatment after a 6-week course of ointment treatment with the drug applied twice a day (until complete, almost complete, or significant disappearance of skin lesions).
Children aged 2 to 16 years
A lower concentration ointment (Protopic 0.03%) should be used. The ointment should be applied once a day twice a week (for example, on Monday and Thursday) to the areas of skin most affected by atopic dermatitis to prevent flare-ups. There should be a 2-3 day break between applications of the ointment.
After 12 months of using the ointment, the child should temporarily suspend treatment to determine the need to continue the course of preventive therapy and to assess the course of the disease.
Adults and adolescents (aged 16 years and over)
Protopic 0.1% ointment should be used. The ointment should be applied once a day twice a week (for example, on Monday and Thursday) to the areas of skin most affected by atopic dermatitis to prevent flare-ups. There should be a 2-3 day break between applications of the ointment.
After 12 months of treatment, the physician should assess the patient's condition and decide on further preventive treatment, as data regarding preventive treatment lasting longer than 12 months are lacking.
If signs of exacerbation occur, it is necessary to return to using the drug twice a day.
Elderly patients
Separate studies involving elderly patients have not been conducted.
Children.
Protopic ointment is used for children aged 2 years and older.
Overdose
In case of ingestion, it is necessary to take standard measures, which include monitoring of vital functions of the body and general condition. Induction of vomiting or gastric lavage is not recommended due to the characteristics of the excipients contained in the ointment.
Side effects
During clinical trials, approximately 50% of patients experienced an adverse reaction in the form of skin irritation at the site of application of the ointment. Burning and itching were common, usually mild to moderate, and generally resolved after the first week of treatment. The most common adverse reaction was erythema. Warmth, pain, paresthesia, and rash were also common. Alcohol intolerance (facial flushing or skin irritation after drinking alcoholic beverages) was common. In the post-marketing period, application site reactions, dermatitis, were observed.
Patients may be at increased risk of folliculitis, acne, and herpes virus infections.
The following are the adverse reactions associated with the use of the drug. The frequency of adverse reactions is classified as: very common (≥1/10), common (≥1/100 to <1/10), rare (≥1/1000 to <1/100) and unknown frequency.
Within each group, adverse reactions are presented in order of decreasing seriousness.
Table 1
| Organ system class | Very common ≥1/10 | Frequent ≥1/100, <1/10 | Liquid ≥1/1000, <1/100 | Unknown frequency (frequency cannot be estimated from the available data) |
| Infectious and parasitic diseases | | Local skin infection, regardless of etiology, including but not limited to infections such as: eczema herpetiformis, folliculitis, herpes simplex, herpes virus infection, Kaposi's varicelliform pustulosis* | | Herpetic eye infection* |
| Metabolic and digestive disorders | | Alcohol intolerance (facial flushing or skin irritation after drinking alcoholic beverages) | | |
| Nervous system disorders | | Paresthesia and dysesthesia (hyperesthesia, burning sensation) | | |
| Skin and subcutaneous tissue disorders | | Itch | Acne* | Rosacea* Lentigo* |
| General disorders and administration site conditions | Burning sensation and itching at the application site | Feeling of warmth, erythema, pain, irritation, paresthesia and rash at the application site | | Swelling at the application site* |
| Laboratory and instrumental data | | | | Increased blood levels of the drug* (see section "Special warnings and precautions for use") |
* Adverse reaction reported in the post-marketing period.
Prevention of exacerbations
In a study of prophylactic treatment (using the ointment twice a week) involving adults and children with moderate to severe atopic dermatitis, the following adverse reactions were noted to occur more frequently than in the control group: impetigo at the application site (7.7% of children) and infection 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 possible adverse 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
3 years.
Storage conditions
Store at a temperature not exceeding 25 °C out of the reach of children.
Do not use the drug after the expiration date indicated on the package.
Packaging
0.03% or 0.1% ointment 10 g, 30 g or 60 g in a plastic tube; 1 tube in a cardboard box.
Vacation category
According to the recipe.
Producer
LEO Laboratories Limited
Location of the manufacturer and its business address.
285 Cashel Road, Crumlin, Dublin 12, D12 E923, Ireland / 285 Cashel Road, Crumlin, Dublin 12, D12 E923, Ireland.
Applicant
LEO Pharma A/S / LEO Pharma A/S.
Location of the applicant.
Industriparken, 55, DK-2750 Ballerup, Denmark / Industriparken, 55, DK-2750 Ballerup, Denmark.
