Зенхейл®

General characteristics. Structure:

Active ingredients: 50 mkg * a mometazona of furoate, 5 mkg * a formoterola of a fumorat of a dihydrate in 1 dose.

Excipients: ethanol, oleic acid, heptafluoro-propane.

* the nominal quantity is specified, the actual quantity makes 60.5 mkg for compensation of losses when performing inhalation.
** the nominal quantity is specified, the actual quantity makes 6.1 mkg for compensation of losses when performing inhalation.

Pharmacological properties:

Pharmacodynamics. Mometazona furoate. Mometazona furoate – GKS possessing local antiinflammatory action. The antiinflammatory effect of GKS is implemented through receptors of glucocorticosteroids (GKR). After accession of GKS the GKR heterocomplex dissociates, and the part activated by a ligand passes from cytoplasm into a kernel where strengthens an expression of antiinflammatory genes, joining special sites of DNA, so-called "elements of the answer to GKS". At the same time it is considered that the main way of implementation of antiinflammatory activity is suppression of a transcription of genes. In this case the activated GKR interacts with transcription factors apolipoprotein 1 (AP1) or a nuclear factor a kappa In (YaF-kV) for reduction of an expression of genes. In addition, GKS strengthen an expression of a gene responsible for YaF-quarter inhibitor synthesis.

Mometazona furoate with high affinity contacts GKR that leads to the expressed inhibition of cells and decrease in synthesis and release of inflammatory mediators and cytokines.

Mometazona furoate considerably inhibits release of leukotrienes from leukocytes. In culture of cells of a mometazon furoate it is expressed inhibits synthesis and release of IL-1, IL-5, IL-6 and FNOα and is powerful inhibitor of products of TH2 of cytokines, SILT-4 and SILT-5 in human CD4+ T-cells. In mix of leukocytes of patients with an atopy, a mometazon furoate inhibited products of leukotrienes with bigger activity, than beclomethasone Dipropionas.

At a research on preclinical models of a mometazon furoate reduced accumulation of cells of an inflammation (including eosinophils), was implemented into walls of upper and lower respiratory tracts, and also improved function of lungs after the provocative test. Mometazona furoate reduced quantity of lymphocytes and concentration of MRNK of SILT-4 and SILT-5 cytokines.

Formoterola fumarates. Formoterol is a strong selection beta2-adrenomimetik. On average the bronkhodilatiruyushchy effect at patients with a reversible bronkhoobstruktion lasts 12 h Formoterol inhibits release of a histamine and leukotrienes in lung tissue. In preclinical trials some antiinflammatory properties, such as inhibition of edematization and accumulation of cells of an inflammation were shown.

The researches in vitro on a trachea of a Guinea pig showed that drug in the form of racemic mix or separately in a look (R, R) - or (S, S) - enantiomer represents the high-selection beta2-adrenomimetik. Activity (S, S) - the enantiomer is from 800 to 1000 times less, than at (R, R) - an enantiomer. (S, S) - the enantiomer does not interfere with influence (R, R) - an enantiomer on unstriated muscles of a trachea. Thus, lack of pharmacological justification for preferable use of one of enantiomer instead of racemic mix was shown.

Pharmacokinetics. In a cross research with single use of drug no data confirming existence of pharmacokinetic interactions between a mometazon furoate and formoteroly, being a part of the drug Zenkheyl® were received.

Absorption. Mometazona furoate. After inhalation of one or several doses of drug, a mometazon furoate (from 200 to 800 mkg) is quickly soaked up, gradually passing into a phase of the prolonged absorption. Average Tmax value makes from 0.5 to 4 h Mometazon furoate quickly is removed from plasma, average speed about 12.5 ml/min. irrespective of a dose. The effective period of T1/2 makes 25 h. Absolute bioavailability makes about 14% at healthy volunteers and from 5% to 7% at patients with bronchial asthma.

Formoterola fumarates. After administration of drug формотерол it is quickly soaked up, average value makes from 0.17 to 1.97 h. In the range of doses from 10 to 40 mkg exposure is directly proportional to a dose. Average T1/2 value in plasma makes 9.1 h.

Distribution. Mometazona furoate. Later in/in bolyusny introductions at equilibrium concentration of Vd are made by 152 l. The researches in vitro showed high linkng of a mometazon with proteins (from 98% to 99%) in the range of concentration from 5 to 500 ng/ml.

Formoterola fumarates. Linkng of a formoterol with proteins of plasma makes 61-64%, linkng with serum albumine – 34%.

Metabolism. Mometazona furoate. The main metabolites of a mometazon of furoate are not revealed. The part of drug swallowed during inhalation is soaked up in a GIT and is exposed to metabolism with formation of a large number of metabolites. In microsomes of hepatocytes drug is metabolized to a large number of metabolites, including and to 6 - beta гидроксимометазона furoate which is formed under the influence of CYP3A4 isoenzyme.

Formoterola fumarates. Drug is generally metabolized at the expense of a glyukuronization. Some other way O-demethylation with the subsequent glyukuronization is. Little significant ways of metabolism include conjugation with sulfates and a deformilirovaniye with the subsequent conjugation with sulfates. Many isoenzymes catalyze a glyukuronization (UGT1A1, 1A3, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7 and 2V15) and O-demethylation (CYP2D6, 2C19, 2C9 and 2A6) of a formoterol that allows to assume low probability of the medicinal interactions connected with inhibition of specific enzymes. In therapeutic concentration drug does not influence isoenzymes of system of P450 cytochrome.

Removal. Mometazona furoate. The marked drug administered it is inhalation, it is generally removed by intestines (74%) and to a lesser extent kidneys (8%).

Formoterola fumarates. After oral administration of 80 mkg of a marked formoterol of a fumarat it was established what during 104 h from 59% to 62% of drug is removed by kidneys, from 32% to 34% – through intestines. After inhalation administration of the drug Zenkheyl® the renal clearance of a formoterol made 217 ml/min. After single inhalation from 10 to 40 mkg of a formoterol as a part of the drug Zenkheyl® by kidneys it is removed approximately from 6.2% to 6.8% of a formoterol in not changed look.

Indications to use:

For constant use as a maintenance therapy of bronchial asthma, including for reduction of weight of exacerbations of bronchial asthma at adults and children 12 years are aged more senior:

— to patients who do not manage to control the course of a disease, applying only inhalation GKS and inhalation beta2-adrenomimetik of short action to stopping of attacks (in the mode "on requirement");

— to patients from whom disease severity demands purpose of two types of a maintenance therapy.

The drug Zenkheyl® can be also appointed to patients at whom the disease is adequately controlled by means of use of inhalation GKS and beta2-adrenomimetik of long action.

Route of administration and doses:

It is necessary to use the drug Zenkheyl® in the form of inhalation on 2 doses of 2 times/days (in the morning and in the evening).

Selection of an optimum dose of drug is based on earlier applied therapy. The basic principles by which it is necessary to be guided are given below.

The recommended drug Zenkheyl® doses:

For the patients who were earlier not receiving inhalation GKS, but weight of a state of which demands purpose of two-component therapy, the starting dose of drug depends on weight of bronchial asthma and can make 50 mkg +5 mkg / a dose, 100 mkg +5 mkg / a dose or 200 mkg +5 mkg / a dose, on 2 inhalations of 2 times/days.

For patients at the age of 12 years the maximum recommended daily dose is also more senior makes 2 inhalations of drug of 200 mkg +5 mkg / a dose of 2 times/days. At emergence of symptoms of bronchial asthma between administrations of drug, it is necessary to use inhalation beta2-adrenomimetik short action for immediate relief of symptoms.

After achievement of optimum control of bronchial asthma, it is recommended to titrate a drug dose to the minimum effective.

Recommendations about performing inhalation. Drug complete set:

1. Cylinder.

2. Actuator.

3. Counter of doses.

4. Mouthpiece and cover of the actuator.

The counter of doses shows number of the remained drug doses. The counter of doses prior to use of drug shows number "124". Every time after pressing a cylinder a dose of drug is released, and the number on the counter decreases on 1. The counter of doses will stop counting doses at achievement of number "0".

It is not necessary to take a cylinder from the actuator as at repeated installation of a cylinder in the actuator release of one dose of drug is possible, at the same time the number on the counter will decrease on 1.

The cylinder of the drug Zenkheyl® should be applied only with the corresponding actuator of drug. The actuator of drug should not be used with any other cylinders.

Cleaning of a mouthpiece. The mouthpiece should be cleaned, using dry fabric, after each 7 days of use. For this purpose delete a cover from the actuator; wipe an outside and internal surface of a mouthpiece, using dry, pure lint-free fabric; put on a cover the actuator. It is impossible to disassemble the actuator, using sharp objects. It is impossible to wash or place any parts of an inhaler in water.

Performing preliminary inhalations. Before performing inhalations it is necessary to uncover the actuator. It is necessary to check a mouthpiece for lack of foreign pollution and to be convinced that the cylinder is completely inserted into the actuator.

Before use of a new cylinder of the drug Zenkheyl® it is necessary to make 4 preliminary inhalations in air, aside from the face, every time stirring up a cylinder. After performing preliminary inhalations on the counter number "120" will be specified.

If the cylinder was not used 5 and more days in a row, it is necessary to repeat this procedure.

Performing inhalations. The drug Zenkheyl® is used only by inhalation through a mouth. Before each inhalation the cylinder should be stirred up.

Before performing inhalations it is necessary to uncover the actuator. It is necessary to check a mouthpiece for lack of foreign pollution and to be convinced that the cylinder is completely inserted into the actuator.

As it is possible exhale through a mouth more deeply and, holding the actuator a cylinder up, strong clasp a mouthpiece with lips. Begin to inhale slowly through a mouth, during a breath a finger strongly press a cylinder until it stops the movement in the actuator. Take away a finger. After the termination of a breath hold the breath as far as possible (to 10 sec.). Take out a mouthpiece from a mouth, exhale through a nose, at the same time holding a mouth closed. It is necessary to carry out the second inhalation not earlier than in 30 sec. after the first.

After each use of drug it is necessary to rinse an oral cavity water and to spit out this water, without swallowing.

After performing inhalations put on a cover the actuator.

It is necessary to throw out drug when the counter of doses shows "0" in spite of the fact that the cylinder can seem not empty and continue to work. If to continue its use, amount of the medicinal substance released at inhalation will be incorrect. It is not necessary to try to change number on the actuator or to try to remove the counter of doses.

Features of use:

Use at pregnancy and feeding by a breast. Adequate and strictly controlled drug use studies of Zenkheyl® at pregnant women were not conducted. Preclinical trials of a mometazon revealed its toxicity concerning reproductive system, similar that for all GKS group; however the potential risk for people is unknown. The drug Zenkheyl® should not be used during pregnancy unless the expected therapeutic effect for mother considerably surpasses potential risk for a fruit.

All newborns, whose mothers accepted GKS during pregnancy, have to be carefully inspected on existence of dysfunction of adrenal glands.

Formoterol, as beta2-adrenomimetik, has tokolitichesky effect (the running-down action on smooth muscles of a uterus) and can suppress patrimonial activity.

Adequate and strictly controlled drug use studies of Zenkheyl® at nursing mothers were not conducted. It is established what формотерол is allocated with milk at rats, GKS are allocated with milk at the person. Making decision on cancellation or continuation of treatment has to be accepted individually and be based on comparison of advantage of breastfeeding for the child and use of the drug Zenkheyl® for mother.

Use for children. It is contraindicated at children's age up to 12 years.

The children receiving therapy by GKS or other immunodepressants should be warned about possible danger of contact with sick some infectious diseases (for example, chicken pox or measles), and also about need of the address to the doctor if such contact will happen.

Special instructions. Stressful situations, such as injuries, operations, infectious diseases or attacks of bronchial asthma, can demand purpose of a short course of replacement therapy by system GKS which will need to be cancelled afterwards, gradually reducing their dose in process of disappearance of symptoms. Such patients are always recommended to have at themselves GKS stock in the form of tablets and information card in which it is specified that reception of GKS orally and the recommended doses is necessary for the patient in stressful situations. Also periodic control of function of bark of adrenal glands, in particular, measurement of level of cortisol in plasma is recommended to this group of patients in the morning.

Transfer of patients from system therapy of GKS on the drug Zenkheyl® can lead to manifestation of earlier existing symptoms of some allergic diseases which were hidden against the background of the previous system GKS of therapy. In such cases the symptomatic treatment is shown.

Patients have to be trained by the doctor or medical personnel in instructions for use drug.

Aggravation of a course of a disease. Against the background of use of the drug Zenkheyl® the serious side effects and complications connected with bronchial asthma can develop. Patients should not interrupt a course of treatment, however in case of lack of control of a disease or strengthening of symptoms it is necessary to see a doctor immediately.

It is not necessary to begin treatment with the drug Zenkheyl® at patients at sharp increase of symptoms of bronchial asthma, and also at zhizneugrozhayushchy aggravations. Use of the drug Zenkheyl® was not investigated at patients with promptly coming exacerbations of bronchial asthma.

The doctor has to reconsider therapy of bronchial asthma if symptoms of bronchial asthma persistirut if achievement of control of a disease requires continuous increase in a dose of drug if bronchodilators do not stop attacks of bronchial asthma any more or if the peak expiratory rate as these signs usually demonstrate deterioration in a course of bronchial asthma decreases. In above-mentioned cases it is necessary to consider the possibility of use of additional therapy of GKS.

Attacks of bronchial asthma. The drug Zenkheyl® is not drug for bystry stopping of a bronchospasm or any other manifestations of an attack of bronchial asthma. In such cases it is necessary to apply beta2-adrenomimetik of short action. In addition, the patient has to be informed on need of the immediate address to the doctor in case of deterioration in a course of bronchial asthma.

Overdose of the drug Zenkheyl® and its use with other prolonged beta2-adrenomimetika

The drug Zenkheyl® should not be used with other prolonged beta2-adrenomimetika.

For therapy of bronchial asthma the dose of the drug Zenkheyl® has to be selected individually for each patient, the dose has to be minimum for achievement of necessary therapeutic effect. The dose also should not exceed most recommended dose. The data confirming increase in efficiency of drug at increase in its dose are higher than recommended, no.

Stomatopharynx candidiasis. During conduct of clinical trials of the drug Zenkheyl® at some patients the development of candidiasis of a stomatopharynx connected with reception of GKS was noted. Such complication, as a rule, demands a special course of treatment antifungal drugs, and in certain cases and drug withdrawals. The patient should advise rinsing of a mouth after drug use.

System effect of GKS. The system effect of inhalation use of GKS can be shown, in particular, at long-term use of drug in high doses. However the probability of its emergence is much lower, than at reception of GKS orally. Distinguish suppression of function of adrenal glands, a growth inhibition at children and teenagers from potential system effects, decrease in mineral density of a bone tissue, a cataract and glaucoma. Titration of doses of the drug Zenkheyl® to a minimal effective dose is important.

Cases of development of a cataract and glaucoma against the background of reception of a mometazon of furoate are described seldom.

Suppression of function of adrenal glands. As a rule, the drug Zenkheyl® dose necessary for complete control of bronchial asthma causes smaller suppression of function гипоталамо - pituitary and adrenal system, than a peroral dose of Prednisolonum, equivalent by efficiency, is considerable.

The probability of suppression of function of adrenal glands at use of the drug Zenkheyl® exists, especially in case of use of the doses of drug exceeding recommended. Special attention to suppression of function of adrenal glands should be paid in stressful situations or before planned operations when to patients additional therapy of GKS is appointed. However during conduct of clinical trials no clinically significant influence of the drug Zenkheyl® (in a dose of a mometazon of a fumarat of 800 mkg/days) on blood plasma cortisol level was revealed.

The bronchospasm arising at inhalation. As well as for any other inhalation drug, it is necessary to consider possibilities of development of the bronchospasm caused by inhalation. In case of its development, it is necessary to cancel immediately drug and to choose an alternative method of treatment.

Hypopotassemia and hyperglycemia. Against the background of use of beta2-adrenomimetik development of a serious hypopotassemia is possible. The hypopotassemia can increase probability of development of arrhythmia.

With care it is necessary to treat patients with heavy degree of bronchial asthma as development of a hypopotassemia can be exponentiated by a hypoxia and the accompanying treatment. In such situations it is recommended to carry out continuous monitoring of level of serumal potassium.

Beta2-adrenomimetiki, including and формотерол, have hyper glycemic effect therefore additional monitoring of content of glucose in blood is recommended to patients with a diabetes mellitus.

Influence on ability to driving of motor transport and to control of mechanisms. At development of side effects from a nervous system it is necessary to refrain from driving or work with mechanisms during administration of drug.

Side effects:

Side effects which were observed during conduct of clinical trials of use of the drug Zenkheyl® for patients with bronchial asthma are given depending on the frequency of their emergence: very often (≥ 1/10); often (≥ 1/100, <1/10); infrequently (≥ 1/1000, <1/100); seldom (≥ 1/10 000, <1/1000).

* - determined as change ≥ 1 point by system of classification of a phacoscotasmus, the version III (LOCS III). Any case of development of a back subkapsulyarny cataract was not registered.

Additional side effects: uneasiness, excitement, mialgiya, dieback, distortion of flavoring feelings, peripheral hypostases, paradoxical bronchospasm, dyspepsia, increase in body weight; system side effects - oppression гипоталамо - pituitary and adrenal system, a growth inhibition at children and teenagers, demineralization of bones, steroid diabetes.

The uses given the post-registration period. During the post-registration use of the drug Zenkheyl® or inhalation drugs containing a mometazon furoate or a formoterola fumarates, the following side effects were observed: hypopotassemia, hyperglycemia, stenocardia, cardiac arrhythmias (for example, fibrillation of auricles, ventricular premature ventricular contraction, tachyarrhythmia); hypersensitivity reactions (rash, a Quincke's disease or anaphylactic reactions), deterioration in symptoms of bronchial asthma (sneezing, an asthma, the whistling rattles, a bronchospasm).

Interaction with other medicines:

Within clinical trials use of the drug Zenkheyl® together with beta2-adrenomimetika of short action and intranasal GKS did not lead to development of any undesirable interaction.

The special research of medicinal interaction of the drug Zenkheyl® was not conducted. It is supposed that the list of effects of medicinal interaction for this combined drug will represent the summary list of the effects of interaction known for each of its active ingredients.

Simultaneous use of an inhalation mometazon of furoate with powerful inhibitor of CYP3A4 enzyme, ketokonazoly, leads to significant increase in concentration of a mometazon in a blood plasma.

Simultaneous use with sympathomimetics can increase the frequency of emergence of side effects of a formoterol.

Simultaneous use with derivatives of xanthine and with nekaliysberegayushchy diuretics can strengthen gipokaliyemichesky effect of beta2-adrenomimetik.

Formoterol, as well as other beta2-adrenomimetik, the patients accepting quinidine, Disopyramidum, procaineamide, fenotiazina, терфенадин, астемизол, the macroleads, MAO inhibitors, tricyclic antidepressants or any drugs extending QT interval since the listed drugs can strengthen adrenergic effect of the drug Zenkheyl® on cardiovascular system should appoint with care. The drugs extending QT interval increase risk of development of ventricular arrhythmia.

Beta adrenoblockers can weaken effect or completely block effect of a formoterol. Therefore it is not necessary to appoint drugs of these groups (including and eye drops) at the same time, except for cases when for this purpose there are indisputable bases.

There is an increased risk of development of arrhythmias in patients at the accompanying anesthesia use halogen producing hydrocarbons.

Contraindications:

— children's age up to 12 years;

— hypersensitivity to a mometazon to furoate, a formoterola to a fumarat or other components of drug.

With care. Immunosuppression. The drug Zenkheyl® should be used with care at patients with tuberculosis or a latent tuberculosis infection, and also at patients with not treated fungus, bacterial, general viral diseases or a herpes simplex with damage of eyes.

Patients, especially the children receiving therapy by GKS or other immunodepressants should be warned about possible danger of contact with sick some infectious diseases (for example, chicken pox or measles), and also about need of the address to the doctor if such contact will happen.

Associated diseases. The drug Zenkheyl®, as well as any other drug containing beta2-adrenomimetik has to be applied with care at patients with the ischemic heart disease, disturbances of a cordial rhythm (especially AV blockade of the III degree) expressed by chronic heart failure, an idiopathic hypertrophic subaortal stenosis, arterial hypertension of heavy degree, aneurism, a pheochromocytoma, a hypertrophic subaortic stenosis, a thyrotoxicosis, lengthening of interval QT (QT corrected> 0.44 sec.).

Transition from system therapy of GKS. Patients who are transferred from system therapy of GKS on inhalation therapy by the drug Zenkheyl® demand careful observation as death cases owing to adrenal insufficiency upon transition of patients from system therapy of GKS to the inhalation GKS which are characterized by smaller bioavailability were described. After cancellation of GKS of systemic action several months for function normalization гипоталамо - pituitary and adrenal system are required.

Stressful situations, such as injuries, operations, infectious diseases or attacks of bronchial asthma, can demand purpose of a short course of replacement therapy by system GKS which will need to be cancelled afterwards, gradually reducing their dose in process of disappearance of symptoms. Such patients are always recommended to have at themselves a stock of the tableted GKS and information card in which it is specified that reception of GKS orally with the indication of the recommended doses is necessary for the patient in stressful situations. Also periodic control of function of bark of adrenal glands, in particular, measurement of level of cortisol in plasma is recommended to this group of patients in the morning.

Transfer of patients from system therapy of GKS on the drug Zenkheyl® can lead to manifestation of earlier existing symptoms of some allergic diseases which were hidden against the background of the previous system therapy of GKS. In such cases the symptomatic treatment is shown.

Overdose:

Symptoms: the overdose of a mometazon of furoate at inhalation or intake can lead to function suppression гипоталамо - pituitary and adrenal system; the overdose of a formoterol of a fumarat can lead to development of symptoms characteristic of beta2-adrenomimetik (nausea, vomiting, a headache, a tremor, slackness, a heart consciousness, tachycardia, ventricular arrhythmia, a metabolic acidosis, a hypopotassemia, a hyperglycemia, increase in the ABP).

Treatment: the symptomatic and maintenance therapy, if necessary hospitalization is shown. In certain cases use of beta adrenoblockers, but only under observation of the doctor and carefully since they can cause a bronchospasm will be reasonable. Monitoring of function of adrenal glands is also necessary.

Storage conditions:

Drug should be stored in the place, unavailable to children, at a temperature not above 25 °C. Not to freeze. A period of validity - 3 years. Not to use after a period of validity.

Issue conditions:

According to the recipe

Packaging:

120 doses - cylinders aluminum (1) complete with the actuator with the built-in counter of doses - packs cardboard.