Протопик®

General characteristics. Structure:

In 100 g of ointment 0,03 g or 0,1 g of a takrolimus contain (in the form of a takrolimus of monohydrate);
excipients: paraffin white soft, liquid paraffin, propilencarbonate, white beeswax, hard paraffin.

Description: Ointment of a homogeneous consistence from white till slightly yellowish color.

Pharmacological properties:

Pharmacodynamics. Takrolimus treats group of inhibitors of a kaltsinevrin. It contacts specific cytoplasmatic protein an immunoeagle owl (FKBP12) which is a cytosolic receptor for a kaltsinevrin (FK506). As a result of it the complex including такролимус, FKBP12, calcium, a calmodulin and кальциневрин that leads to inhibition of fosfatazny activity of a kaltsinevrin forms. It makes impossible dephosphorylation and a translocation of a nuclear factor of the activated T-cells (NFAT) necessary for initiation of a transcription of genes, cytokines, coding products key for the T-cellular immune response (SILT-2 and interferon - gamma). Besides, такролимус inhibits a transcription of the genes coding products of such cytokines as IL-3, IL-4, IL-5, a granulotsitarno-macrophagic colony stimulating factor (GMKSF) and a factor of a necrosis of a tumor (FNO-) which take part in the initial stages of activation of T lymphocytes. In addition, under the influence of a takrolimus there is an inhibition of release of mediators of an inflammation from mast cells, basophiles and eosinophils, and also decrease in an expression of FcεRI (a high-affine superficial receptor for immunoglobulin E) on Langergans's cells that leads to decrease in their activity and a prezentirovaniye  of antigen T lymphocytes.
Ointment of a takrolimus does not influence synthesis of collagen and, thus, does not cause    a skin atrophy.

Pharmacokinetics.
Absorption. Absorption of a takrolimus in a system blood stream at topical administration is minimum. At most of patients with atopic dermatitis (at adults and children) both at single drawing, and at repeated use of 0,03 and 0,1% of ointment of a takrolimus concentration it in a blood plasma made <1,0 ng/ml. System absorption depends on the area of defeat and decreases in process of disappearance of clinical displays of atopic dermatitis. Cumulation of drug at prolonged use (till 1 year) at children and adults was not noted.
Distribution in an organism. Because system absorption of ointment of a takrolimus low, high ability to contact proteins of plasma (more than 98,8%) is considered as clinically not significant.
Metabolism. Takrolimus is not metabolized in skin. At hit in a system blood stream такролимус it is substantially metabolized in a liver by means of CYP3A4.
Removal. At repeated topical administration of ointment of a takrolimus the elimination half-life makes 75 h at adults and children have 65 h.

Indications to use:

Protopik® ointment is applied in a dosage of 0,03% and 0,1% at adults and only children from 2 to 16 years have 0,03% for treatment of atopic dermatitis (moderate severity and severe forms) in case of its resistance to other means of outside therapy or existence of contraindications to those.

Route of administration and doses:

To adults and children 2 years are more senior apply Protopik® ointment a thin layer on affected areas of skin. Drug can be used on any body parts, including a face and   a neck, in the field of skin folds. It is not necessary to apply drug on mucous membranes and under occlusive bandages.

Use for children (2 years are also more senior) and teenagers up to 16 years
Treatment it is necessary to begin with drawing 0,03% of Protopik® ointment two times a day. Treatment duration according to this scheme should not exceed three weeks. Further the frequency of use decreases to once a day, treatment continues before full clarification of the centers of defeat.
Use for adults and teenagers of 16 years is also more senior
Treatment it is necessary to begin with use 0,1% of Protopik® ointment two times a day and to continue before full clarification of the centers of defeat. In process of improvement it is possible to reduce the frequency of drawing 0,1% of ointment or to switch to 0,03% of Protopik® ointment. In case of repeated emergence of symptoms of a disease it is necessary to resume treatment of 0,1% Protopik® ointment twice a day. If the clinical picture allows, it is necessary to make an attempt to reduce drug use frequency, or to use a smaller dosage – 0,03% Protopik® ointment. Use for people of advanced age (65 years are also more senior). Features of use for people of advanced age are absent.

Usually improvement is observed within one week from the moment of the beginning of therapy.
If improvement signs against the background of therapy are absent within two weeks, it is necessary to consider a question of change of therapeutic tactics.
Treatment of aggravations
Protopik® ointment can be used is short-term or long in the form of periodically repeating therapy courses. Treatment of affected areas of skin is carried out before total disappearance of clinical displays of atopic dermatitis. As a rule, improvement is observed within the first week of treatment. If signs of improvement are not observed within two weeks from the moment of the beginning of use   of ointment, it is necessary to consider other options of further treatment. Treatment should be resumed at emergence of the first signs of an exacerbation of atopic dermatitis.
Prevention of aggravations
For the prevention of aggravations and increase in duration of remission at patients with frequent (more than 4 times a year) exacerbations of a disease in the anamnesis recommend a maintenance therapy by Protopik® ointment. Expediency of purpose of a maintenance therapy is determined by efficiency of the previous treatment by the standard scheme (2 times a day) for no more than 6 weeks.
At a maintenance therapy Protopik® ointment should be applied 2 times a week (for example, on Monday and Thursday) on the sites of skin which are usually struck at aggravations.
The period between putting drug has to make not less than 2-3 days. Adults and teenagers have 16 years and are more senior 0,1% Protopik® ointment, at children (2 years and are more senior) – 0,03% Protopik® ointment are used. At manifestation of signs of an aggravation it is necessary to pass to the usual mode of therapy with Protopik® ointment (see the section "Treatment of Aggravations").
In 12 months of a maintenance therapy it is necessary to estimate clinical dynamics and to resolve an issue of expediency of continuation of preventive use   of Protopik® ointment. At children for assessment of clinical dynamics it is necessary to cancel temporarily drug and then to consider a question of need of continuation of a maintenance therapy.

Features of use:

Protopik® ointment cannot be used at patients with the inborn or acquired immunodeficiencies or at patients who accept immunosuppressive drugs.
During use of Protopik® ointment it is necessary to minimize hit on skin of sunshine, visits of a sunbed, therapy by UV rays of B or And in a combination with Psoralenum (PUVA therapy).
Protopik® ointment should not be applied to treatment of sites of defeat which are considered as potentially malignant or premalignant.
During 2 h on sites of skin on which Protopik® ointment was applied it is impossible to use emollients.
Efficiency and safety of use of Protopik® ointment in treatment of the infected atopic dermatitis was not estimated. In the presence of infection signs before purpose of Protopik® ointment performing the corresponding therapy is necessary. Use of Protopik® ointment can be connected with the increased risk of development of a herpes infection. In the presence of signs of a herpes infection it is necessary to estimate individually a ratio of advantage and risk of use of Protopik.
In the presence of a lymphadenopathy it is necessary to inspect the patient prior to therapy and to watch him during ointment use. In the absence of the obvious reason of a lymphadenopathy or in the presence of symptoms of an acute infectious mononucleosis it is necessary to stop Protopik® ointment uses.
It is necessary to avoid hit of ointment in eyes and on mucous membranes (in cases of accidental hit ointment needs to be removed and/or washed out carefully water).
It is not recommended to carry Protopik® ointment under occlusive bandages and to wear dense air-tight clothes.
The same as when using any other local medicine, patients have to wash hands after putting ointment, except those cases when ointment to be applied on area of hands with the medical purpose.

Side effects:

The most frequent undesirable reactions are symptoms of irritation of skin (a burning sensation and an itch, reddening, pain, paresthesias and rash) in a site of application. As a rule, they are expressed moderately or slightly and pass within the first week after an initiation of treatment.
Often the intolerance of alcohol meets (face reddening or symptoms of irritation of skin after the use of alcoholic drinks).
At the patients applying Protopik® ointment the increased risk of development of a folliculitis, an acne and a herpes infection is noted.
Undesirable reactions are divided by occurrence frequency on very frequent (> 1/10), frequent (> 1/100, <1/10) and rare (> 1/1,000, <1/100). Within each group undesirable reactions are presented in decreasing order of the importance.

General frustration and local reactions
Very frequent: burning and an itch in the place of use.
Frequent: a caumesthesia, reddening, pain, irritation, rash in the place of use

Infections
Frequent: herpes infection (herpes simplex of the person and lips, varitselliformny rash of Kaposha).

Skin and hypodermic cellulose
Frequent: folliculitis, itch.
Infrequent: acne.

Nervous system
Frequent: paresthesias, hyperesthesia.

Metabolism and feeding habits
Frequent: intolerance of alcohol (a hyperemia of the person or symptoms of irritation of skin after the use of alcoholic drinks).

For the entire period of observation of drug isolated cases of a rozatse, malignancy were registered (skin and other types of lymphoma, a carcinoma cutaneum).

Interaction with other medicines:

Takrolimus is not metabolized in skin that excludes risk of medicinal interactions in skin which can influence his metabolism.  
As system absorption of a takrolimus when using in the form of ointment is minimum, interaction with CYP3A4 inhibitors (erythromycin, итраконазол, кетоконазол, diltiazem, etc.) at simultaneous uses with Protopik® ointment it is improbable, however cannot be completely excluded at patients with extensive sites of defeat and/or an erythrosis.
Influence of Protopik® ointment on efficiency of vaccination was not studied. However, because of potential risk of decrease in efficiency, vaccination needs to be carried out prior to use of ointment or 14 days later after the last use of Protopik® ointment. In case of use of a live attenuirovanny vaccine, this period has to be increased up to 28 days, otherwise it is necessary to consider the possibility of use of alternative vaccines.
The possibility of combined use of Protopik® ointment with other outside drugs, system glucocorticosteroids and immunodepressants was not studied.

Contraindications:

Hypersensitivity to a takrolimus, to excipients, to macroleads.
Pregnancy and breastfeeding.
It is not necessary to apply Protopik® at patients with genetic defects of an epidermal barrier, such as Neterton's syndrome, and also at a generalized erythrosis in connection with risk of the progressing increase in system absorption of a takrolimus.
Use of Protopik® ointment in a dosage of 0,1% is contraindicated at children and teenagers 16 years are younger, in a dosage of 0,03% - at children 2 years are younger.

With care
Протопик® it is substantially metabolized in a liver, and though its concentration in blood at external use very low, at patients with a dekompensirovanny liver failure ointment is used with care.
It is necessary to be careful when using Protopik® ointment at patients with extensive damage of skin, especially long courses, and at children.

Overdose:

At topical administration of cases of overdose it was not noted.
At hit inside it is necessary to take the standard measures which include control of the vital functions of an organism and observation of the general state. Stimulation of vomiting or a gastric lavage are not recommended.

Storage conditions:

To store at a temperature not above 25 °C. To store in the place, unavailable to children.
Period of validity 3 years. Not to use drug after the termination of date of the period of validity specified on packaging!

Issue conditions:

According to the recipe

Packaging:

Ointment for external use of 0,03% and 0,1%.
On 10, 30 or 60 grams of ointment for external use in plastic tubas.
On 1 tuba together with the application instruction in a cardboard pack.