Zenhale aerosol for inhalation 100mkg + 5mkg/dose 120doz

Release form, composition
Zenheyl aerosol for inhalation dosed in suspension from white to almost white color.
1 dose:
- mometasone furoate 50 mcg *
- formoterol fumarate 5 mcg **
Excipients: ethanol - 1.2526 mg, oleic acid - 3.5 μg, heptafluoropropane - 68.2676 mg.

Zenheyl aerosol for inhalation dosed in suspension from white to almost white color.
1 dose:
- mometasone furoate 100 mcg ***
- formoterol fumarate 5 mcg **
Excipients: ethanol - 1.2526 mg, oleic acid - 3.5 μg, heptafluoropropane - 68.2071 mg.

Zenheyl aerosol for inhalation dosed in suspension from white to almost white color.
1 dose:
- mometasone furoate 200 mcg ****
- formoterol fumarate dihydrate 5 mcg **
Excipients: ethanol - 1.2526 mg, oleic acid - 3.5 μg, heptafluoropropane - 68.0861 mg.
* The nominal quantity is indicated, the actual quantity is 60.5 mcg to compensate for losses during inhalation.
** the nominal quantity is indicated, the actual quantity is 6.1 mcg to compensate for losses during inhalation.
*** The nominal quantity is indicated, the actual quantity is 121 mcg to compensate for losses during inhalation.
**** indicates the nominal amount, the actual amount is 242 mcg to compensate for losses during inhalation.
Pharmaceutical action:- Mometasone furoate:
Mometasone furoate - GCS, which has a local anti-inflammatory effect. The anti-inflammatory effect of corticosteroids is realized through glucocorticosteroid receptors (HRS). After the addition of the GCS, the GKH heterocomplex dissociates, and the part activated by the ligand passes from the cytoplasm to the nucleus, where it enhances the expression of anti-inflammatory genes by joining special DNA segments, the so-called "elements of the GCS response". At the same time, it is believed that the main way of implementing anti-inflammatory activity is the suppression of gene transcription. In this case, activated HRS interacts with transcription factors apolipoprotein 1 (AP1) or nuclear kappa B factor (NF-kV) to reduce gene expression. In addition, the corticosteroids enhance the expression of the gene responsible for the synthesis of the NF-kV inhibitor.
Mometasone furoate with high affinity binds to HRS, which leads to a pronounced inhibition of cells and a decrease in the synthesis and release of inflammatory mediators and cytokines.
Mometasone furoate significantly inhibits the release of leukotrienes from leukocytes. In mometasone cell culture, furoate expressly inhibits the synthesis and release of IL-1, IL-5, IL-6 and TNFα and is a potent inhibitor of TH2 cytokine production, IL-4 and IL-5 in human CD4 + T cells. In a mixture of white blood cells of patients with atopy, mometasone furoate inhibited the production of leukotrienes with greater activity than beclomethasone dipropionate.
In a study on preclinical models of mometasone, furoate reduced the accumulation of inflammatory cells (including eosinophils), was introduced into the walls of the upper and lower respiratory tract, and also improved lung function after a provocative test. Mometasone furoate reduced the number of lymphocytes and the mRNA concentration of cytokines IL-4 and IL-5.
- Formoterol fumarate:
Formoterol is a strong selective beta2-adrenergic agonist. On average, the bronchodilatory effect in patients with reversible bronchial obstruction lasts 12 hours. Formoterol inhibits the release of histamine and leukotrienes into lung tissue. In preclinical studies, some anti-inflammatory properties have been shown, such as inhibiting the development of edema and the accumulation of inflammatory cells.
In vitro studies on the guinea pig trachea demonstrated that the drug as a racemic mixture or separately as (R, R) - or (S, S) -enantiomers is a highly selective beta2-adrenomimetic. The activity of the (S, S) -enantiomer is 800 to 1000 times less than that of the (R, R) -enantiomer. (S, S) -enantiomer does not interfere with the effects of (R, R) -enantiomer on the smooth muscles of the trachea. Thus, the absence of a pharmacological basis for the preferred use of one of the enantiomers instead of the racemic mixture has been shown.
Pharmacokinetics:In a cross-sectional study with a single use of the drug, no information was obtained confirming the presence of pharmacokinetic interactions between mometasone furoate and formoterol, which are part of the drug Zenheyl.
Absorption and bioavailability
Mometasone furoate
After inhalation of one or several doses of the drug, mometasone furoate (200 to 800 μg) is rapidly absorbed, gradually moving into the phase of prolonged absorption. The average value of Tmax is from 0.5 to 4 hours. Mometasone furoate is rapidly removed from the plasma, the average rate of about 12.5 ml / min / kg, regardless of dose. Effective period t? 25 hours. Absolute bioavailability is about 14% in healthy volunteers and from 5 to 7% in patients with bronchial asthma.
Formoterol fumarate
After taking the drug, formoterol is rapidly absorbed, the average value is from 0.17 to 1.97 hours. In the dose range from 10 to 40 μg, the exposure is directly proportional to the dose. Average t? in plasma is 9.1 hours
Distribution
Mometasone furoate
After intravenous bolus administration at an equilibrium concentration, the volume of distribution (Vd) is 152 l. In vitro studies have shown high binding of mometasone to proteins (from 98 to 99%) in the concentration range from 5 to 500 ng / ml.
Formoterol fumarate
Binding of formoterol to plasma proteins is 61-64%, binding to serum albumin - 34%.
Metabolism
Mometasone furoate
The main metabolites of mometasone furoate were not detected. Part of the drug, swallowed during inhalation, is absorbed in the gastrointestinal tract and is metabolized with the formation of a large number of metabolites. In hepatocyte microsomes, the drug is metabolized to a large number of metabolites, including up to 6-beta hydroxymethasone furoate, which is formed under the action of the cytochrome P-450 isoenzyme 3A4.
Formoterol fumarate
The drug is mainly metabolized by glucuronization. Another way is O-demethylation followed by glucuronization. Unimportant metabolic pathways include conjugation with sulphates and deformation and subsequent conjugation with sulphates. Many isozymes catalyze glucuronidation (UGT1A1, 1A3, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7 and 2V15) and O-demethylation (CYP2D6, 2C19, 2C9 and 2A6) formoterol, suggesting low potential for drug interactions associated with the inhibition of specific enzymes. At therapeutic concentrations, the drug does not affect the isoenzymes of the cytochrome P450 system.
Removal
Mometasone furoate
The labeled drug administered by inhalation is mainly excreted by the intestine (74%) and to a lesser extent by the kidneys (8%).
Formoterol fumarate
After oral administration of 80 μg of labeled formoterol fumarate, it was found that within 104 hours from 59 to 62% of the drug is excreted by the kidneys, from 32 to 34% by the intestines. After inhalation of the drug Zenheyl renal clearance of formoterol was 217 ml / min. After a single inhalation of 10 to 40 μg of formoterol in the formulation of Zenhale by the kidneys, approximately 6.2 to 6.8% of formoterol is excreted unchanged.
Indications:The drug Senhale shown as a drug for permanent use for maintenance therapy of bronchial asthma, including to reduce the severity of asthma exacerbations in adults and children over the age of 12 years.
The drug Senhale shown:
- patients who fail to control the course of the disease, using only inhaled GCS and inhaled short-acting beta2-adrenomimetics for the relief of seizures (in the "on demand" mode);
- patients, the severity of the disease in which requires the appointment of two types of maintenance therapy.
The drug Senhale can also be assigned to patients in whom the disease is adequately controlled by the use of inhaled GCS and long-acting beta2-adrenomimetics.
Category of action on the fetus:Properly controlled studies of the use of the drug Zenheyl in pregnant women were not performed. Preclinical studies of mometasone revealed its toxicity to the reproductive system, similar to that for the entire GCS group; however, the potential risk to humans is unknown. Zenheyl drug should not be used during pregnancy, except in cases where the expected therapeutic effect for the mother far exceeds the potential risk to the fetus.
All newborns whose mothers took GCS during pregnancy should be carefully examined for adrenal dysfunction.
Formoterol, as a beta2-adrenomimetic, has a tocolytic effect (a relaxing effect on the smooth muscles of the uterus) and can suppress labor activity.
Properly controlled studies of the drug Zenheyl in nursing mothers were not performed.It has been established that formoterol is excreted in milk in rats, GCS is excreted in human milk. The decision to cancel or continue treatment should be made individually and based on a comparison of the benefits of breastfeeding for the baby and the use of the drug Zenheyl for the mother.
Contraindications:- children's age up to 12 years;
- Hypersensitivity to mometasone furoate, formoterol fumarate or other components of the drug.
Carefully
Senhale should be used with caution in patients with tuberculosis or latent tuberculosis infection, as well as in patients with untreated fungal, bacterial, systemic viral diseases or herpes simplex with eye damage.
Patients, especially children receiving GCS therapy or other immunosuppressants, should be told about the possible danger of contact with patients with certain infectious diseases (for example, chicken pox or measles), as well as the need to see a doctor if such contact occurs.
Senhenhale, like any other drug containing beta2-adrenomimetics, should be used with caution in patients with coronary artery disease, heart rhythm disorders (especially AV degree III blockade), severe chronic heart failure , idiopathic hypertrophic subaortic stenosis, severe arterial hypertension, hypertrophic obstructive cardiomyopathy, thyrotoxicosis, prolongation of the QT interval (QT corrected> 0.44 seconds).
Patients who are transferred from systemic treatment of corticosteroids to inhalation therapy with Zenhale require careful observation, since deaths due to adrenal insufficiency were described when patients switched from systemic treatment of corticosteroids to inhaled corticosteroids with lower bioavailability. After the abolition of the GCS systemic action requires several months to normalize the function of the hypothalamic-pituitary-adrenal system.
Stressful situations, such as injuries, surgeries, infectious diseases or attacks of bronchial asthma, may require the appointment of a short course of substitution therapy with systemic corticosteroids, which will then need to be canceled, gradually reducing their dose as the symptoms disappear. It is recommended that such patients always carry a supply of GCS tablets and an information card in which it is indicated that the patient needs to take GCS orally and recommended doses in stressful situations. This group of patients is also recommended periodic monitoring of the function of the adrenal cortex, in particular, measurement of the level of cortisol in the plasma in the morning.
The transfer of patients with systemic therapy of corticosteroids to Zenhale may lead to the manifestation of pre-existing symptoms of certain allergic diseases that were hidden against the background of previous systemic therapy of corticosteroids. In such cases, symptomatic treatment is indicated.
Dosing:The drug Zenheyl should be used in the form of inhalation, 2 doses 2 times / day. (in the morning and in the evening).
Selection of the optimal dose of the drug is based on the previously used therapy. The basic principles that should be followed are listed below.

For patients who have not previously received inhaled GCS, but the severity of the condition requires two-component therapy, the starting dose of the drug depends on the severity of bronchial asthma and may be 50 mcg + 5 mcg / dose, 100 mcg + 5 mcg / dose or 200 mcg + 5 mcg / dose, 2 inhalations 2 times / day.
For patients aged 12 years and older, the maximum recommended daily dose is 2 inhalations of the drug 200 μg + 5 μg / dose 2 times / day. If bronchial asthma symptoms occur between doses of the drug, a short-acting inhaled beta2-adrenergic mimic should be used to relieve symptoms immediately.
After achieving optimal control of asthma, it is recommended to titrate the dose of the drug to the minimum effective.

Recommendations for inhalation:
Preparation kit
1. The cylinder.
2Actuator.
3. Dose Counter.
4. Mouthpiece and actuator cap.
The dose counter shows the number of remaining doses of the drug. The dose counter before the start of use of the drug shows the number "124". Each time a cylinder is pressed, the dose of the drug is released, and the number on the counter decreases by 1. The dose counter will stop counting the doses when reaching the number "0".
You should not remove the cylinder from the actuator, because when you reinstall the cylinder in the actuator, you can release a single dose of the drug, and the number on the counter will decrease by 1.
The bottle of Zenhale should be used only with the appropriate actuator of the drug. The drug actuator should not be used with any other cylinders.
Cleaning the mouthpiece:
The mouthpiece should be cleaned using a dry cloth after every 7 days of use. Remove the cover from the actuator. Wipe the outer and inner surface of the mouthpiece using a dry, clean, lint-free cloth. Put the cover on the actuator. Do not disassemble the actuator using sharp objects. Do not wash or place any part of the preparation in water.
Preliminary inhalations:
Before inhalation, remove the cap from the actuator. The mouthpiece should be checked for foreign matter and ensure that the cylinder is fully inserted into the actuator.
Before using a new bottle of Zenhale, 4 pre-inhalations should be made into the air, away from the face, each time shaking the bottle. After preliminary inhalations, the number “120” will be indicated on the meter.
If the cylinder has not been used for 5 or more days in a row, this procedure should be repeated.
Inhalation:
Senhale drug is only used by inhalation through the mouth. Before each inhalation, the balloon should be shaken.
Before inhalation, remove the cap from the actuator. It is necessary to check the mouthpiece for the absence of extraneous contamination, make sure that the cylinder is fully inserted into the actuator.
Exhale as deeply as possible through the mouth and, holding the actuator with the balloon up, firmly clasp the mouthpiece with the lips. They begin to inhale slowly through the mouth, while inhaling with a finger they strongly press the balloon until it stops moving in the actuator. Remove the finger. After the cessation of inhalation, breath is held as far as possible (up to 10 seconds). Take out the mouthpiece from the mouth, exhale through the nose, while keeping the mouth closed. The second inhalation should be carried out not earlier than 30 seconds after the first.
After each use of the drug, rinse the oral cavity with water, and spit out this water without swallowing.
After carrying out inhalations put a cover on the actuator.
The drug should be discarded when the dose counter shows “0,” despite the fact that the balloon may not appear to be empty and continue to work. If you continue using it, the amount of drug released during inhalation will be incorrect. You should not try to change the number on the actuator or try to remove the dose counter.
Side effect:The side effects that were observed during the clinical trials of the use of the drug Zenhale in patients with bronchial asthma, are given depending on the frequency of their occurrence: very often (≥ 1/10); often (≥ 1/100, <1/10); infrequently (≥ 1/1000, <1/100); rarely (≥ 1/10 000, <1/1000).
Infectious and parasitic diseases: often - oral candidiasis; infrequently pharyngitis.
On the part of the immune system: hypersensitivity reactions with the following manifestations: bronchospasm (rarely), atopic dermatitis (rarely), urticaria (infrequently).
From the nervous system: often - headache; infrequently - insomnia, tremor, dizziness; rarely - neurosis.
On the part of the organ of vision: infrequently - lesions of the lens (defined as a change ≥ 1 point according to the lens opacification classification system, version III (LOCS III). Not a single case of the development of posterior subcapsular cataract was registered); rarely, increased intraocular pressure.
Since the cardiovascular system: infrequently - tachycardia, palpitations, increased blood pressure.
On the part of the respiratory system: often - dysphonia; infrequently - pain in the oropharynx, irritation of the pharynx.
On the part of the digestive system: rarely - nausea, dry mouth.
From the musculoskeletal system: infrequently - muscle spasms.
Laboratory data: rarely - prolonged QT interval.
Additional side effects: anxiety, agitation, myalgia, rash, distortion of taste, peripheral edema, paradoxical bronchospasm, dyspepsia ,weight gain; systemic side effects - depression of the hypothalamic-pituitary-adrenal system, growth retardation in children and adolescents, bone demineralization, steroid diabetes.
Post-registration data
During post-registration use of the drug Zenheyl or inhalation drugs containing mometasone furoate or formoterol fumarate, the following side effects were observed: hypokalemia, hyperglycemia, atrial fibrillation; angina pectoris; ventricular premature beats; tachyarrhythmia; hypersensitivity reactions (rash, angioedema or anaphylactic reactions), worsening symptoms of bronchial asthma (sneezing, shortness of breath, wheezing, bronchospasm).
Overdose:Symptoms:
Mometasone furoate: an overdose of GCS during inhalation or ingestion can lead to suppression of the function of the hypothalamic-pituitary-adrenal system.
Formoterol fumarate: an overdose can lead to the development of symptoms characteristic of beta2-adrenomimetics (nausea, vomiting, headache, tremor, lethargy, feeling of heartbeat, tachycardia, ventricular arrhythmia, metabolic acidosis, hypokalemia, hyperglycemia, increased blood pressure).
Treatment: symptomatic and supportive therapy is indicated, hospitalization if necessary. In some cases, it will be reasonable to use beta-blockers, but only under the supervision of a physician and with great caution, becausethey can cause bronchospasm. Monitoring of the adrenal function is also required.
Interaction:In clinical studies, the use of the drug Zenheyl together with beta2-adrenomimetics of short-acting and intranasal GCS did not lead to the development of any undesirable interaction.
A special study of drug interactions drug Zenheyl not conducted. It is assumed that the list of effects of drug interactions for a given combination drug will be a summary list of interaction effects known for each of its active ingredients.
The simultaneous use of mometasone furoate inhalation with a potent inhibitor of the CYP3A4 enzyme, Ketoconazole , leads to a significant increase in the concentration of mometasone in the blood plasma.
Simultaneous use with sympathomimetics may increase the incidence of side effects of formoterol.
Simultaneous use with xanthine derivatives and with non-calcium-sparing diuretics may enhance the hypokalemic effect of beta2-adrenomimetics.
Formoterol, like other beta2-adrenomimetics, should be used with caution in patients taking quinidine, disopyramide, procainamide, phenothiazines, terfenadine, astemizole, MAO inhibitors , tricyclic antidepressants, or any drugs that prolong the QT interval, because These drugs can enhance the adrenergic effect of Zenhale on the cardiovascular system. Drugs that prolong the QT interval increase the risk of developing ventricular arrhythmias.
Beta-blockers may weaken the effect or completely block the effect of formoterol. Therefore, drugs of these groups (including eye drops) should not be administered at the same time, unless there are undeniable reasons for this.
Special instructions:Patients should be trained by a doctor or medical staff on how to use the drug.
Exacerbation of the disease
With the use of the drug Senhale, serious side effects and complications associated with bronchial asthma can develop. Patients should not interrupt the course of treatment, however, in the absence of control of the disease or amplification of symptoms, consult a doctor immediately.
You should not start treatment with Zenhale in patients with a sharp increase in symptoms of bronchial asthma, as well as with life-threatening exacerbations. The use of the drug Senhale has not been studied in patients with rapidly advancing exacerbations of bronchial asthma.
The physician should review asthma therapy if the symptoms of bronchial asthma persist, if a constant dose increase is required to achieve disease control, if bronchodilators no longer stop bronchial asthma attacks or if the peak expiratory rate decreases, these symptoms usually indicate a worsening asthma course. In the above cases, you should consider the use of additional therapy of GCS.
Bronchial Asthma Attacks
The drug Senhale is not a drug for the rapid relief of bronchospasm or any other manifestations of an attack of asthma. In such cases, short-acting beta2-adrenomimetics should be used. In addition, the patient should be informed of the need for immediate treatment to the doctor in case of worsening of the course of bronchial asthma.
An overdose of the drug Senhale and its use with other prolonged beta2-adrenomimetikami
Zenheyl should not be used with other prolonged beta2-adrenomimetics.
For the treatment of bronchial asthma, the dose of Zenhale should be chosen individually for each patient, the dose should be minimal to achieve the desired therapeutic effect. The dose should also not exceed the maximum recommended dose. Information confirming the increase in the effectiveness of the drug with an increase in its dose higher than the recommended, no.
Oral pharyngeal candidiasis
During the clinical trials of the drug Zenhale in some patients, the development of oropharyngeal candidiasis was noted, associated with taking GCS. This kind of complication usually requires a special course of treatment with antifungal drugs, and in some cases, drug withdrawal. The patient should be advised to rinse the mouth after applying the drug.
Systemic effect of GCS
The systemic effect of inhaled GCS may manifest itself, in particular, with long-term use of the drug in high doses. However, the probability of its occurrence is much lower than when taking GCS orally.Among the potential systemic effects, there is an inhibition of adrenal function, growth retardation in children and adolescents, a decrease in bone mineral density, cataracts and glaucoma. It is important to titrate doses of the drug Senhale to the minimum effective dose.
Cases of development of cataracts and glaucoma with mometasone furoate are rarely described.
Suppression of adrenal function
As a rule, the dose of the drug Zenheyl, necessary for complete control of asthma, causes significantly less suppression of the function of the hypothalamic-pituitary-adrenal system than the equivalent efficacy of the oral dose of prednisolone.
The probability of suppression of adrenal function when using the drug Zenheyl exists, especially in the case of the use of doses of the drug that exceed the recommended. Particular attention to the suppression of adrenal function should be paid in stressful situations or before planned operations, when patients will receive additional therapy of SCS. However, in the course of conducting clinical studies, no clinically significant effect of Zenhale (in a dose of mometasone fumarate 800 mcg / day) on the level of blood plasma cortisol was detected.
Inhalation bronchospasm
As with any other inhaled drug, it is necessary to take into account the development possibilities of inhaled bronchospasm. In the case of its development, you should immediately cancel the drug and choose an alternative method of treatment.
Hypokalemia and Hyperglycemia
Against the background of the use of beta2-adrenomimetics, serious hypokalemia may develop.Hypokalemia may increase the likelihood of developing arrhythmias.
Patients with severe bronchial asthma should be treated with caution, since the development of hypokalemia can be potentiated by hypoxia and concomitant treatment. In such situations, it is recommended to continuously monitor the level of serum potassium.
Beta2-adrenomimetics, including and formoterol, have a hyperglycemic effect, therefore, patients with diabetes mellitus are recommended additional monitoring of blood glucose.
Influence on ability to drive motor transport and control mechanisms
With the development of side effects from the nervous system should refrain from driving or working with mechanisms during the period of taking the drug.