Composition, form of production and packaging
Aerosol for inhalation dosed in the form of a suspension from white to almost white.
1 dose
mometasone furoate 50 mcg *
formoterol fumarate dihydrate 5 Ојg **
Excipients: ethanol - 1.2526 mg, oleic acid - 3.5 mcg, heptafluoropropane - 68.2676 mg.
120 doses - aluminum cylinders (1) complete with an actuator with a built-in dose counter - packs of cardboard.
Aerosol for inhalation dosed in the form of a suspension from white to almost white.
1 dose
mometasone furoate 100 Ојg ***
formoterol fumarate dihydrate 5 Ојg **
Excipients: ethanol - 1.2526 mg, oleic acid - 3.5 mcg, heptafluoropropane - 68.2071 mg.
120 doses - aluminum cylinders (1) complete with an actuator with a built-in dose counter - packs of cardboard.
Aerosol for inhalation dosed in the form of a suspension from white to almost white.
1 dose
mometasone furoate 200 Ојg ****
formoterol fumarate dihydrate 5 Ојg **
Excipients: ethanol - 1.2526 mg, oleic acid - 3.5 mcg, heptafluoropropane - 68.0861 mg.
120 doses - aluminum cylinders (1) complete with an actuator with a built-in dose counter - packs of cardboard.
* The nominal amount is indicated, the actual amount is 60.5 Ојg to compensate for losses during inhalation.
** The nominal amount is indicated, the actual amount is 6.1 Ојg to compensate for losses during inhalation.
*** The nominal amount is indicated, the actual amount is 121 Ојg to compensate for losses during inhalation.
**** indicated the nominal amount, the actual amount is 242 mkg to compensate for losses during the inhalation.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2015.
PHARMACHOLOGIC EFFECT
Mometasone furoate
Mometasone furoate - GCS, which has a local anti-inflammatory effect. The anti-inflammatory effect of GCS is realized through the receptors of glucocorticosteroids (GCR). After the addition of GCS, the HCR heterocomplex dissociates, and the ligand-activated part passes from the cytoplasm to the nucleus, where it enhances the expression of anti-inflammatory genes by joining the special sections of DNA, the so-called "GCS response elements". At the same time, it is believed that the main way of implementing anti-inflammatory activity is to suppress gene transcription. In this case, the activated GKR interacts with transcription factors apolipoprotein 1 (AP1) or nuclear factor kappa B (JAF-KB) to reduce gene expression. In addition, GCS enhances the expression of the gene responsible for the synthesis of the inhibitor of JA-kV.
Mometasone furoate with high affinity binds to HRS, which leads to marked 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 the culture of cells, mometasone furoate significantly inhibits the synthesis and release of IL-1, IL-5, IL-6 and TNF? and is a potent inhibitor of the production of TN2 cytokines, IL-4 and IL-5 in human CD4 + T cells. In a mixture of leukocytes in patients with atopy, mometasone furoate inhibited the production of leukotrienes with greater activity than beclomethasone dipropionate.
In studies on preclinical models, 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 concentration of mRNA cytokines IL-4 and IL-5.
Formoterol fumarate
Formoterol is a strong selective beta 2 -adrenomimetic. On average, bronchodilator effect in patients with reversible bronchial obstruction lasts 12 hours. Formoterol inhibits the release of histamine and leukotrienes in lung tissue. Pre-clinical studies have shown some anti-inflammatory properties, such as inhibiting the development of edema and accumulation of inflammatory cells.
In vitro studies on the guinea pig trachea demonstrated that the preparation in the form of a racemic mixture or separately as a (R, R) - or (S, S) -enantiomer is a highly selective beta 2 -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 prevent the (R, R) -enantiomer from affecting the smooth muscles of the trachea. Thus, the absence of a pharmacological justification for the preferred use of one of the enantiomers in place of the racemic mixture was shown.
PHARMACOKINETICS
In a cross-sectional study with a single application of the drug, no evidence was obtained confirming the presence of pharmacokinetic interactions between mometasone furoate and formoterol, which are part of the preparation of ZenheilВ®.
Suction
Mometasone furoate. After inhalation of one or several doses of the drug, mometasone furoate (200 to 800 mcg) is rapidly absorbed, gradually passing into the phase of prolonged absorption. The average T max is 0.5 to 4 hours. Mometasone furoate is rapidly excreted from the plasma, with an average rate of about 12.5 ml / min / kg regardless of the dose. The effective period T 1/2 is 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 of 10 to 40 Ојg, the exposure is directly proportional to the dose. The average value of T 1/2 in plasma is 9.1 hours.
Distribution
Mometasone furoate. After IV bolus injection at an equilibrium concentration of V d is 152 liters. 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. The binding of formoterol to plasma proteins is 61-64%, binding to serum albumin is 34%.
Metabolism
Mometasone furoate. The main metabolites of mometasone furoate were not detected. Part of the drug swallowed during inhalation is absorbed into the digestive tract and metabolized with the formation of a large number of metabolites. In microsomes of hepatocytes, the drug is metabolized to a large number of metabolites, incl. and up to 6-beta-hydroxymetasone furoate, which is formed by the action of the CYP3A4 isoenzyme.
Formoterol fumarate. The drug is mainly metabolized by glucuronization. Another way is O-demethylation followed by glucuronization. Low-value metabolic pathways include conjugation with sulfates and deformation, followed by conjugation with sulfates. Many isozymes catalyze glucuronization (UGT1A1, 1A3, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7 and 2B15) and O-demethylation of formoterol (CYP2D6, 2C19, 2C9 and 2A6), suggesting a low probability of drug interactions associated with inhibition of specific enzymes. In therapeutic concentrations, the preparation does not affect the isoenzymes of the cytochrome P450 system.
Excretion
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 ingestion of 80 Ојg of labeled formoterol fumarate, it was found that from 1994 to 1994, 59% to 62% of the drug is excreted by the kidneys, from 32% to 34% through the intestine. After the inhalation of ZenheilВ®, the renal clearance of formoterol was 217 ml / min. After a single inhalation of 10 to 40 Ојg of formoterol in the formulation of Zenheil В®, the kidneys remove approximately 6.2% to 6.8% of formoterol in unchanged form.
INDICATIONS
For the constant use as a maintenance therapy of bronchial asthma, incl. to reduce the severity of exacerbations of bronchial asthma in adults and children over the age of 12:
- patients who can not control the course of the disease, using only inhaled glucocorticosteroids and inhaled beta 2 -adrenomimetics of short-acting for arresting seizures (in "on demand" mode);
- patients whose severity of the disease requires the appointment of two types of maintenance therapy.
Zenheil В® can also be administered to patients who are adequately controlled by inhaled glucocorticosteroids and long-acting beta 2 -adrenomimetics.
DOSING MODE
The drug Zenheil В® should be used in the form of inhalation 2 doses 2 times / day (morning and 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.
Recommended doses of the preparation ZenheilВ®
Previously used therapy Recommended dose The maximum recommended daily dose
Low doses of inhaled glucocorticosteroids 50 Ојg + 5 Ојg / dose 2 inhalations 2 times / day 200 Ојg + 20 Ојg
Average doses of inhaled glucocorticoids 100 Ојg + 5 Ојg / dose 2 inhalations 2 times / day 400 Ојg + 20 Ојg
High doses of inhaled glucocorticosteroids 200 Ојg + 5 Ојg / dose 2 inhalations 2 times / day 800 Ојg + 20 Ојg
For patients who did not receive inhaled glucocorticosteroids before, but whose severity requires two-component therapy, the starting dose of the drug depends on the severity of bronchial asthma and can be 50 Ојg + 5 Ојg / dose, 100 Ојg + 5 Ојg / dose or 200 Ојg + 5 Ојg / 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 Ојg + 5 Ојg / dose 2 times / day. If symptoms of bronchial asthma occur between doses, inhaled beta 2 -adrenomimetic should be used for immediate relief of symptoms.
After achieving optimal control of bronchial asthma, it is recommended to titrate the dose of the drug to a minimum effective.
Recommendations for inhalation
Complete preparation
1. Cylinder.
2. The actuator.
3. The counter of doses.
4. Mouthpiece and actuator cover.
The dose counter shows the number of remaining doses of the drug. The dose counter before the use of the drug shows the number "124". Each time after pressing the balloon, the dose of the drug is released, and the number on the counter decreases by 1. The dose counter stops counting the dose when the number "0" is reached.
Do not remove the balloon from the actuator, because when reinstalling the balloon in the actuator, it is possible to release one dose of the drug, while the number on the meter will decrease by 1.
The canister of Zenheyl В® should only be used with the appropriate actuator of the drug. The actuator of the drug should not be used with any other balloons.
Cleaning the mouthpiece
The mouthpiece should be cleaned using a dry cloth, after every 7 days of use. To do this, remove the cover from the actuator; wipe the outer and inner surfaces 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 inhaler in water.
Carrying out preliminary inhalations
Before carrying out inhalations, remove the cover from the actuator. You should check the mouthpiece for the absence of foreign contaminants and make sure that the balloon is fully inserted into the actuator.
Before starting the use of the new canister Zenheil В® , 4 preliminary inhalations should be performed in the air, away from the face, each time shaking the balloon.After the preliminary inhalations on the counter, the number "120" will be indicated.
If the balloon has not been used for 5 days or more, repeat this procedure.
Carrying out inhalations
The drug Zenheil В® is used only by inhalation through the mouth. Before each inhalation, the can should be shaken.
Before carrying out inhalations, remove the cover from the actuator. You should check the mouthpiece for the absence of foreign contaminants and make sure that the balloon is fully inserted into the actuator.
As deep as possible breathe out through the mouth and, holding the actuator balloon up, firmly grasp the mouthpiece with his lips. Begin slowly inhale through the mouth, during inspiration with a finger press strongly on the balloon until it stops moving in the actuator. Remove the finger. After stopping the inhalation, hold the breath 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 the inhalation, put the cover on the actuator.
The drug should be discarded when the dose counter shows "0", despite the fact that the balloon may not seem empty and continue to work. If you continue to use it, the amount of drug released by inhalation will be incorrect. Do not try to change the number on the actuator or attempt to remove the dose counter.
SIDE EFFECT
Side effects that were observed during the clinical trials of the use of the preparation Zenheil В® 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).
Side Effects Frequency
Infectious and parasitic diseases
candidiasis of the oral cavity of pharyngitis often infrequently
Allergic reactions
bronchospasm atopic dermatitis urticaria rarely seldom infrequently
Disorders of the psyche
insomnia nervous rarely infrequently
From the nervous system
headache tremor dizziness often infrequent
From the side of the organ of vision
loss of the lens * increased intraocular pressure infrequently rare
From the side of the cardiovascular system
tachycardia, palpitations, increased blood pressure infrequently
From the respiratory system
dysphonia of pain in the oropharynx, irritation of the pharynx often infrequently
From the digestive system
nausea, dry mouth rarely
From the musculoskeletal system
muscle spasms infrequently
Laboratory and instrumental data
lengthening of the QT interval rarely
* - defined as change? 1 point according to the lens opacification classification system, version III (LOCS III). No case of development of posterior subcapsular cataract was recorded.
Additional side effects: anxiety, agitation, myalgia, exanthema, distortion of taste sensations, peripheral edema, paradoxical bronchospasm, dyspepsia, weight gain;systemic side effects - oppression of the hypothalamic-pituitary-adrenal system, growth retardation in children and adolescents, demineralization of bones, steroid diabetes.
Post registration period data
During the post-marketing application of ZenheilВ® or inhalation preparations containing mometasone furoate or formoterol fumarate, the following side effects were observed: hypokalemia, hyperglycemia, angina pectoris, cardiac arrhythmias (eg, atrial fibrillation, ventricular extrasystole, tachyarrhythmia); hypersensitivity reactions (rash, angioedema or anaphylactic reactions), worsening of symptoms of bronchial asthma (sneezing, dyspnea, wheezing, bronchospasm).
CONTRAINDICATIONS
- children's age till 12 years;
- Hypersensitivity to mometasone furoate, formoterol fumarate or other components of the drug.
With caution
Immunodepression. Zenheyl В® 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 SCS or other immunosuppressant therapy, should be warned 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.
Accompanying illnesses. Zenheil В® , like any other preparation containing beta 2 -adrenomimetics, should be used with caution in patients with ischemic heart disease, cardiac rhythm disturbances (especially AV blockade III degree), severe chronic heart failure, idiopathic hypertrophic subaortal stenosis, severe arterial hypertension degree, aneurysm, pheochromocytoma, hypertrophic obstructive cardiomyopathy, thyrotoxicosis, QT interval prolongation (QT adjusted> 0.44 sec).
Transition from systemic therapy to GCS. Patients who are transferred from systemic therapy to SCS for inhalation therapy with ZenheylВ® require careful monitoring, since deaths due to adrenal insufficiency have been described in patients who switched from systemic therapy to SCS for inhaled glucocorticosteroids, which are less bioavailable. After cancellation of SCS systemic action takes several months to normalize the function of the hypothalamic-pituitary-adrenal system.
Stressful situations, such as injuries, surgeries, infectious diseases or asthma attacks, may require a short course of replacement therapy with systemic SCS, which will subsequently need to be canceled, gradually reducing their dose as the symptoms disappear. Such patients are advised to always have a stock of tableted GCS and an information card, which indicates that the patient in stressful situations needs to receive GCS orally, indicating the recommended doses. Also, this group of patients is recommended periodic monitoring of adrenocortical function, particularly measurement of plasma cortisol levels in the morning.
Translation of patients with systemic corticosteroids therapy in drug Zenheyl В® can lead to the manifestation of symptoms of some pre-existing allergic diseases which have been hidden in the background of the prior system GCS therapy. In such cases it is shown symptomatic treatment.
PREGNANCY AND LACTATION
Adequate and well-controlled trials of drug Zenheyl В® was not performed in pregnant women. Mometasone Preclinical studies have shown toxicity to the reproductive system, similar to that for the entire GCS group; however, the potential risk for humans is unknown. The drug Zenheyl В® should not be used during pregnancy except in cases where the expected therapeutic effect for the mother outweighs the potential significant risk to the fetus.
All newborns whose mothers received corticosteroids during pregnancy should be carefully examined for the presence of adrenal dysfunction.
Formoterol, as beta 2-adrenomimetik has tocolytic effect (relaxing action on smooth muscles of the uterus) and can suppress the generic activities.
Adequate and well-controlled trials of drug Zenheyl В® nursing mothers was not performed. It was found that the formoterol is excreted in the milk of rats, corticosteroids are excreted in milk in humans. Making the decision to cancel or continue treatment should be individualized and based on a comparison of the benefits of breastfeeding for the child and the drug Zenheyl В® for the mother.
APPLICATION FOR CHILDREN
Contraindicated in children under 12 years.
Children receiving therapy corticosteroids or other immunosuppressants should be warned about the possible danger of contact with sick certain infectious diseases (e.g., varicella, or measles) and the need to see a doctor, when such contact occurs.
SPECIAL INSTRUCTIONS
Stressful situation such as trauma, surgery, infectious disease or asthma attacks may require the assignment of short course substitution therapy system SCS, which later will be required to cancel, gradually decreasing the dose as the disappearance of symptoms. Such patients should always carry a supply of tablets in the form of corticosteroids and information card, which indicates that the patient is in stress situations required GCS orally and recommended dose. Also, this group of patients is recommended periodic monitoring of adrenocortical function, particularly measurement of plasma cortisol levels in the morning.
Translation of patients with systemic corticosteroids therapy to the drug Zenheyl В®It can lead to the manifestation of symptoms of some pre-existing allergic diseases which have been hidden in the background of the prior system GCS therapy. In such cases it is shown symptomatic treatment.
Patients should be trained physician or medical personnel rules of use of the drug.
Aggravation of the disease
on the background of the drug Zenheyl В® may develop serious side effects and complications associated with bronchial asthma. Patients should not interrupt the course of treatment, but in the absence of disease control or enhance the symptoms should immediately seek medical attention.
You should not start treatment with Zenheyl В®in patients with a sharp increase in symptoms of asthma, as well as life-threatening exacerbations. Use of the drug Zenheyl В® has not been studied in patients with rapidly advancing exacerbations of asthma.
The physician must revise therapy of bronchial asthma, if asthma symptoms persist, if in order to achieve control of the disease requires constant increase the dose if bronchodilators is not cropped attacks of asthma or if reduced peak expiratory flow rate, since these symptoms are usually evidenced by the deterioration of bronchial asthma. In the above cases, you should consider the use of complementary therapies GCS.
Bronchial asthma
drug Zenheyl В®not the drug for rapid relief of bronchospasm or any other manifestations of asthma attacks. In such cases it is necessary to apply the beta 2 -adrenomimetiki short-acting. In addition, the patient should be informed of the need for immediate treatment to the doctor in case of worsening of bronchial asthma.
Overdosing Zenheyl preparation В® and its application to other prolonged beta 2 -adrenomimetikami
drug Zenheyl В® should not be used with other long-acting beta 2 -adrenomimetikami.
For asthma treatment drug dose Zenheyl В®should be individualized for each patient, the dose should be the minimum necessary to achieve a therapeutic effect. The dose should also not exceed the maximum recommended dose. DETAILED DESCRIPTION OF increase drug efficacy by increasing the dose recommended above, no.
Oropharyngeal candidiasis
during clinical trials of the drug Zenheyl В® some patients noted the development of oropharyngeal candidiasis associated with GCS. This kind of complication usually requires special treatment with antifungal drugs, and in some cases, discontinuation of the drug. Patients should be advised to rinse the mouth after treatment.
Systemic effects of GCS
Systemic effects of inhaled corticosteroids use may manifest itself in particular in long-term use of the drug at high doses. However, the probability of its occurrence is much lower than when taking oral corticosteroids. Among the potential systemic effects of isolated adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma. It is important to titrate doses of the drug Zenheyl В® to the minimum effective dose.
Cases of cataracts and glaucoma in patients receiving mometasone furoate rarely described.
Suppression of adrenal function
Generally, the drug dose Zenheyl В®Required for complete control of asthma is minimal significantly suppress the hypothalamic-pituitary-adrenal axis than the equivalent efficacy oral dose of prednisolone.
Probability suppression of adrenal function in the application formulation Zenheyl В® exists, especially in the case of doses exceeding recommended. Particular attention to the suppression of adrenal function should be paid in stressful situations or before elective surgery when the patient will be assigned additional SCS therapy. However, during clinical trials did not reveal any clinically significant effect of drug Zenheyl В® (mometasone fumarate at a dose of 800 mg / day) on blood plasma cortisol.
Bronchospasm occurring during inhalation
Like any other inhaled drugs, it is necessary to take into account the possibility of inhalation-induced bronchospasm. In the case of development, you should immediately remove the drug and choose an alternative method of treatment.
Hypokalemia and hyperglycemia
Against the background of the beta 2 -adrenomimetikov may develop severe hypokalemia. Hypokalemia may increase the chance of developing an arrhythmia.
Precautions should be taken to patients with severe asthma as hypokalaemia may potentiate the development of hypoxia and concomitant treatment. In such situations, it is recommended to conduct continuous monitoring of serum potassium.
beta 2-adrenomimetiki, including and formoterol, have a hyperglycemic effect, so patients with diabetes mellitus recommended additional monitoring of blood glucose.
Impact on the ability to drive vehicles and manage mechanisms
With the development of side effects in the nervous system should refrain from driving a car or operate machinery during ingestion.
OVERDOSE
Symptoms: overdose mometasone furoate inhalation or ingestion can lead to suppression of the hypothalamic-pituitary-adrenal axis; overdose of formoterol fumaratemay lead to the development of symptoms characteristic of the beta 2 -adrenomimetikov (nausea, vomiting, headache, tremor, drowsiness, palpitations, tachycardia, ventricular arrhythmias, metabolic acidosis, hypokalemia, hyperglycemia, increased blood pressure).
Treatment:Symptomatic and supportive therapy, if required hospitalization. In some cases, be justified use of beta-blockers, but only under the supervision of a physician and with extreme caution, as they can cause bronchospasm. Also requires monitoring of adrenal function.
DRUG INTERACTION
In clinical trials the drug application Zenheyl В® together with the beta 2 -adrenomimetikami short steps and intranasal corticosteroids did not lead to the development of any undesirable interaction.
Special formulation studies of drug interactions Zenheyl В® was conducted. It is assumed, that the list of drug interaction effects for the combined formulation will constitute a total list of interaction effects known for each of its active ingredients.
The simultaneous use of inhaled mometasone furoate with potent inhibitor of CYP3A4 enzyme ketoconazoleIt leads to a significant increase mometasone plasma concentrations.
The simultaneous use of sympathomimetics may increase the incidence of side effects of formoterol.
The simultaneous use of xanthine derivatives and nekaliysberegayuschimi diuretics can enhance the effect of beta hypokalemic 2 -adrenomimetikov.
Formoterol, as other beta 2 -adrenomimetiki should be used with caution in patients taking quinidine, disopyramide, procainamide, phenothiazines, terfenadine, astemizole, macrolides, MAO inhibitors, tricyclic antidepressant medications or any prolonging the interval QT,because these drugs can enhance the effect of adrenergic drug Zenheyl В® on the cardiovascular system. Drugs prolonging the QT interval, increase the risk of ventricular arrhythmias.
Beta-blockers may weaken the effect of, or completely block the effect of formoterol. Therefore, the preparations of these groups (including eye drops) should not be administered concurrently, except when there is conclusive grounds.
There is an increased risk of arrhythmias in patients with concomitant use of anesthetics halogenated hydrocarbon .
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children at a temperature of no higher than 25 В° C. Do not freeze. Shelf life - 3 years. Do not use after expiry date.
