Instruction for use: Mometasone + Formoterol

Pharmacological group

Glucocorticosteroids in combinations

Beta-adrenomimetics in combinations

Nosological classification (ICD-10)

J45 Asthma

Asthma physical effort, status asthmaticus, Bronchial asthma, Asthma lung flow, Bronchial asthma with obstruction of sputum discharge, Bronchial asthma heavy currents, Bronchial asthma physical effort, hypersecretory asthma, Hormone-dependent form of bronchial asthma, Relief of asthma attacks in bronchial asthma, Non-allergic asthma, nocturnal asthma, Exacerbation of asthma, Asthma attacks, Endogenous forms of asthma, Night asthma, Cough with bronchial asthma

Characteristics of Mometasone + Formoterol

Bronchodilator combination: beta2-adrenomimetic selective + GCS (glucocorticosteroids) local.

Mometasone furoate is a white powder, practically insoluble in water; Slightly soluble in methanol, ethanol and isopropanol; Soluble in acetone. The molecular weight is 521.44.

Formoterol fumarate dihydrate is a white or yellowish powder, freely soluble in glacial acetic acid; Soluble in methanol; Moderately soluble in ethanol and isopropanol; Slightly soluble in water and practically insoluble in acetone, ethyl acetate and diethyl ether. Molecular weight is 840.9.

Pharmacology

Pharmacological action - bronchodilating, anti-inflammatory local.

Mechanism of action

Mometasone furoate. Mometasone furoate - GCS, which has a local anti-inflammatory effect. The anti-inflammatory effect of GCS is realized through the GCS receptors (HRS). After the addition of GCS, the HCR heterocomplex dissociates, and the ligand-activated portion passes from the cytoplasm into the nucleus, where it enhances the expression of anti-inflammatory genes by joining special DNA regions, the so-called. "Elements of the answer to the GCS." 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 (JA-κB) to reduce gene expression. In addition, GCS enhances the expression of the gene responsible for the synthesis of the inhibitor of JA-κB.

Formoterol fumarate. Formoterol is a strong selective beta2-adrenomimetic. On average, bronchodilator effect in patients with reversible bronchial obstruction lasts 12 hours. Formoterol inhibits the release of histamine and LT in lung tissue. Pre-clinical studies have shown some anti-inflammatory properties, such as inhibiting the development of edema and accumulation of inflammatory cells.

Pharmacodynamics

Mometasone furoate. Mometasone furoate with high affinity binds to HCC, 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 LT from the leukocytes. In the cell culture, mometasone furoate strongly inhibits the synthesis and release of IL-1, IL-5, IL-6 and TNF-α and is a potent inhibitor of the production of Th2-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 LT with more activity than beclomethasone dipropionate.

In studies on preclinical models, mometasone furoate reduced the accumulation of inflammatory cells (including eosinophils), was implanted in 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 the matrix RNA of cytokines IL-4 and IL-5.

Formoterol fumarate. In vitro studies on the guinea pig trachea demonstrated that formoterol fumarate 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 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 combination mometasone + formoterol.

Absorption and bioavailability

Mometasone furoate. After inhalation of one or several doses of drugs (from 200 to 800 mcg), mometasone furoate is rapidly absorbed, gradually passing into the phase of prolonged absorption. The average value of Tmax is from 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. Effective T1 / 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 μg, the exposure is directly proportional to the dose. The mean plasma T1 / 2 is 9.1 hours.

Distribution

Mometasone furoate. After IV bolus VSS 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 mometasone furoate, ingested during inhalation, is absorbed into the digestive tract (gastrointestinal tract) and metabolized to form a large number of metabolites. In the hepatocyte microsome, mometasone furoate is metabolized with the formation of a large number of metabolites, incl. 6-beta-hydroxymetasone furoate, which is formed by the action of the isoenzyme CYP3A4 (cytochrome P450 isoenzyme) cytochrome P450.

Formoterol fumarate. Formoterol fumarate 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 (CYP2D6 (cytochrome P450 isoenzyme), CYP2C19 (cytochrome P450 isoenzyme), CYP2C9 (cytochrome P450 isoenzyme) and CYP2A6 (Isoenzyme cytochrome P450)) formoterol, suggesting a low probability of drug interactions associated with inhibition of specific enzymes. In the therapeutic concentrations of formoterol fumarate does not affect the isoenzymes of the cytochrome P450 system.

Excretion

Mometasone furoate. The labeled mometasone furoate, 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 μg of labeled formoterol fumarate, it was found that within the period of 104 hours, from 59 to 62% of the drug is excreted by the kidneys, from 32 to 34% by the intestine. After the inhalation of the combination mometasone + formoterol, the renal clearance of formoterol was 217 ml / min. After a single inhalation of 10 to 40 μg of formoterol in the combination mometasone + formoterol, the kidneys yield approximately 6.2 to 6.8% of formoterol in unchanged form.

Special patient groups

Hepatic / kidney failure. There is no data on the peculiarities of using the combination mometasone + formoterol in patients with hepatic or renal insufficiency.

In a study on the evaluation of the application of a 400 mg monomethasone furoate powder as a dry powder with an inhaler to a subject with a light (n = 4), moderate (n = 4) and severe (n = 4) liver failure, only 1 or 2 people in Cmax of mometasone furoate in plasma (within the range of 50-105 pg / ml) was determined for each group. Observed Cmax in plasma, apparently, increased in accordance with the severity of liver failure; But the number of samples with detectable levels was small.

Sex and race. Specific studies to study the effect of sex and race on the pharmacokinetics of the combination mometasone + formoterol are absent.

Geriatrics. Special studies to assess the pharmacokinetics of the combination mometasone + formoterol in the elderly were not performed.

Application of Mometasone + Formoterol

The combination of mometasone + formoterol is indicated as a drug for permanent use for maintenance therapy of bronchial asthma, incl. To reduce the severity of exacerbations of bronchial asthma in adults and children over the age of 12 years.

The combination of mometasone + formoterol is indicated to patients:

- who do not manage to control the course of the disease, using only inhaled glucocorticosteroids and short-acting inhaled beta2-adrenomimetics for arresting seizures (in "on demand" mode);

- the severity of the disease requires the appointment of two types of maintenance therapy.

The combination of mometasone + formoterol can also be prescribed to patients in whom the disease is adequately controlled by the use of inhaled GCS and long-acting beta2-adrenomimetics.

Contraindications

Hypersensitivity to mometasone furoate, formoterol fumarate; Children under 12 years of age (safety and efficacy in children under 12 years of age not established).

Restrictions for use

Infectious diseases

It 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 immunosuppressants, should be warned of the possible danger of contact with patients with certain infectious diseases (eg, chicken pox or measles), and the need to see a doctor if such contact occurs.

Accompanying illnesses

With caution in patients with coronary heart disease, heart rhythm disturbances (especially AV blockade of grade III), chronic heart failure, idiopathic hypertrophic subaortic stenosis, severe arterial hypertension, aneurysm, pheochromocytoma, hypertrophic obstructive cardiomyopathy, thyrotoxicosis, prolonged QT interval (QTc > 0.44 s).

Transition from systemic therapy to GCS (glucocorticosteroids)

Patients who are transferred from systemic therapy to SCS for inhalation therapy with the combination mometasone + formoterol require careful monitoring, since deaths due to adrenal insufficiency have been described in the transition of patients from systemic SCS therapy to 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 trauma, surgery, infectious diseases or asthma attacks, may require the appointment of a short course of replacement therapy for 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 that states that the patient under stress requires taking GCS orally, indicating the recommended doses. Also, this group of patients is recommended periodic monitoring of the function of the adrenal cortex, in particular, measuring the level of cortisol in the plasma in the morning.

Transfer of patients with systemic therapy of GCS to a combination of mometasone + formoterol may lead to the appearance of pre-existing symptoms of some allergic diseases that were hidden against the background of previous systemic GCS therapy. In such cases, symptomatic treatment is indicated.

pregnancy and lactation

Properly controlled studies of the use of the combination mometasone + formoterol in pregnant women have not been conducted. Pre-clinical studies of mometasone revealed its reproductive toxicity similar to that of the whole SCS group, but the potential risk to humans is unknown.

The combination of mometasone + formoterol should not be used during pregnancy, except when the expected therapeutic effect for the mother is significantly greater than the potential risk to the fetus.

All newborns whose mothers took SCS during pregnancy should be carefully examined for adrenal dysfunction.

Formoterol as beta2-adrenomimetic has a tocolytic effect (a relaxing effect on the smooth muscles of the uterus) and can suppress generic activity.

Properly controlled studies of the use of the combination mometasone + formoterol in nursing mothers have not been conducted. It has been established that formoterol is excreted in milk in rats; SCS is excreted in human milk. The decision to cancel or continue treatment should be made individually, taking into account the benefits of breastfeeding for the baby and the use of mometasone + formoterol for the mother.

The action category for fetus by FDA is C.

Childbirth and delivery. Adequate and strictly controlled studies in women to study the effect of the combination mometasone + formoterol on labor and delivery were not carried out. Because beta-agonists can potentially inhibit uterine contractions, the combination mometasone + formoterol should be used during labor only if the potential benefit justifies the potential risk.

The combination of mometasone + formoterol. It is not known whether the combination mometasone + formoterol is excreted in breast milk. Because many drugs are excreted into human milk, caution should be exercised when using a combination of lactating women. Since there are no well-controlled clinical trials of the use of mometasone + formoterol in nursing mothers, based on data for individual combination components, breastfeeding or the combination of mometasone + formoterol should be discontinued, taking into account the importance of drugs for the mother.

Mometasone furoate. It is not known whether mometasone furoate is excreted into breast milk. However, other GCS are excreted into human breast milk.

Formoterol fumarate. In studies of reproduction in rats, it was shown that formoterol is excreted into milk. It is not known whether formoterol is excreted into human milk.

Side effects of Mometasone + Formoterol

The side effects that were observed during the clinical trials of the application of the combination mometasone + formoterol 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 / 10000, <1/1000).

Infectious and parasitic diseases: often - candidiasis of the oral cavity; Infrequently - a pharyngitis

From the side of the immune system: hypersensitivity reactions with the following manifestations: rarely - bronchospasm, atopic dermatitis; Infrequently - hives.

Disorders of the psyche: infrequently - insomnia; Rarely - nervousness.

From the nervous system: often - headache; Infrequently - a tremor, a giddiness.

From the side of the organ of vision: infrequently - loss of the lens *; Rarely - an increase in IOP.

From the heart: infrequent - tachycardia, a feeling of palpitations.

From the side of the vessels: infrequently - raising blood pressure.

From the respiratory system, chest and mediastinum: often - dysphonia; Infrequently - pain in the oropharynx, irritation of the pharynx.

From the gastrointestinal tract: infrequently - nausea, dry mouth.

From the musculoskeletal system and connective tissue: infrequently - muscle spasms.

Laboratory and instrumental data: rarely - prolongation of the QT interval.

* Defined as a change of ≥1 points 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 (GGNS), growth retardation in children and adolescents, demineralization of bones, steroid diabetes.

Post registration period data

During the post-marketing application of the combination mometasone + formoterol 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).

Because clinical trials are conducted with a different set of conditions, the incidence of adverse reactions observed in these studies can not be directly compared with the frequency in other clinical trials, and the prognosis of the occurrence of side effects in clinical practice is impossible.

Clinical research experience

The safety data presented below are based on the results of three randomized clinical trials involving 1913 patients with asthma at the age of 12 years and older, including. 679 patients who used the combination mometasone + formoterol for 12 to 26 weeks, and 271 patients who used the combination for 1 year.

The safety of the combination mometasone + formoterol was evaluated in two placebo and active-controlled clinical trials (n = 781 and n = 728, respectively) and in a long 52-week trial (n = 404). In clinical trials, lasting from 12 to 26 weeks, the age of participants was 12 to 84 years, 41% were men and 59% were women, 73% were representatives of the Caucasoid race, and 27% were non-neuropean. Patients received twice daily two inhalations of the combination mometasone + formoterol (100/5 μg or 200/5 μg), mometasone furoate (100 or 200 μg), formoterol (5 μg) or placebo.

In the long 52-week active-controlled safety test, participants were aged 12 to 75 years, 37% were men and 63% were women, 47% were members of the European race, 53% were non-European. Participants received twice daily two inhalations of a combination mometasone + formoterol 100 μg / 5 μg or 200 μg / 5 μg or a reference preparation.

The incidence of adverse events associated with the use of the combination mometasone + formoterol and presented below is based on the pooled data from 2 clinical trials lasting 12 to 26 weeks in patients 12 years of age and older who received twice daily two mometasone + formoterol combinations 100/5 μg (n = 424) or 200/5 μg (n = 255), mometasone furoate 100 μg (n = 192) or 200 μg (n = 240), formoterol 5 μg (n = 202) or placebo = 196).

Mimetasone + formoterol-related adverse reactions reported with a frequency of ≥ 3% and more frequently than in the placebo group are presented. The duration of the combination is also indicated.

Next to the name of the side effect is the number of patients who, with a combination of mometasone + formoterol at a dose of 100/5 μg or 200/5 μg, had this effect; In parentheses - the frequency of the effect in percent; Through the semicolon - similar data in the group of patients receiving inhaled mometasone furoate (100 or 200 μg); Further - data in the group of patients who received inhaled formoterol (5 μg); As well as data in the group of patients receiving placebo.

Nasopharyngitis: 20 (4.7) and 12 (4.7); 15 (7.8) and 13 (5.4); 13 (6.4); 7 (3.6).

Sinusitis: 14 (3.3) and 5 (2); 6 (3.1) and 4 (1.7); 7 (3.5); 2 (1).

Headache: 19 (4.5) and 5 (2); 10 (5.2) and 8 (3.3); 6 (3); 7 (3.6).

Average duration of exposure (days): 116 and 81; 165 and 79; 131; 138.

In clinical trials, the incidence of oral candidiasis was 0.7% in patients using the combination mometasone + formoterol 100/5 μg, 0.8% at a dose of 200/5 μg and 0.5% in the placebo group.

Long-term clinical trial experience

In prolonged safety tests patients 12 years or older for 52 weeks were treated with a combination of mometasone + Formoterol at a dose of 100 mg / 5 mg (n = 141), at a dose of 200 mg / 5 mg (n = 30) or reference preparation (n = 133), while the results were generally similar to those observed in controlled trials lasting from 12 to 26 weeks. No asthma-related deaths have been reported. With higher frequency in the long-term test was observed dysphonia - 7/141 (5%) of patients receiving the combination of mometasone + formoterol dose in micrograms 100/5 and 5/130 (3.8%) patients receiving the combination at a dose of 200/5 Mcg. There were no clinically significant changes in parameters: biochemical, hematological or ECG.

Post-marketing experience

The following adverse reactions were recorded during the post-marketing application of the combination mometasone + formoterol or use with inhalations of mometasone furoate or formoterol fumarate.

Since reports of these reactions come in voluntarily from a population of undetermined size, it is not always possible to reliably estimate their frequency and cause-and-effect relationship with drug use.

From the heart: stenocardia, cardiac arrhythmias, for example atrial fibrillation, ventricular extrasystole, tachyarrhythmia.

From the immune system: immediate and delayed hypersensitivity reactions, including anaphylactic reactions, angioedema, severe hypotension, rash, itching.

Research data: prolongation of QT interval on ECG, increase in blood pressure (including hypertension).

Metabolism and malnutrition: hypokalemia, hyperglycemia.

On the part of the respiratory, thorax and mediastinum: exacerbation of asthma, which may include coughing, shortness of breath, wheezing and bronchospasm.

Interaction

In clinical trials, the use of the combination mometasone + formoterol with short-acting beta-2-adrenomimetics and intranasal GCS did not lead to the development of any undesirable interactions. Special studies of drug interactions of the combination mometasone + formoterol were not conducted. It is assumed that the list of drug interactions for a given combination drug will be a summary list of interactions known for each of its active substances.

Ketoconazole. The simultaneous use of inhaled mometasone furoate with potent inhibitor of CYP3A4 isoenzyme ketoconazole results in a significant increase mometasone plasma concentrations.

Inhibitors of the isoenzyme CYP3A4 cytochrome P450. In general metabolism of corticosteroids, including mometasone furoate - component of the combination formoterol mometasone + - carried by isoenzyme CYP3A4 cytochrome P450. After oral administration of ketoconazole, a potent inhibitor of CYP3A4, the average plasma concentration of the inhaled mometasone furoate used is increased. Simultaneous use of CYP3A4 inhibitors may interfere with metabolism and increase the systemic exposure of mometasone furoate. Caution should be exercised when combining mometasone + formoterol with prolonged use of ketoconazole and other strong inhibitors of CYP3A4 (for example, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) should be used with caution, as the system exposure of mometasone furoate Increased side effects.

Adrenergic drugs. Simultaneous use with sympathomimetics can increase the incidence of side effects of formoterol.

Xanthine derivatives and diuretics. Simultaneous use with xanthine derivatives and non-potassium-sparing diuretics can enhance the hypokalemic effect of beta2-adrenomimetics.

MAO inhibitors, tricyclic antidepressants and drugs that extend the QT interval. Formoterol, as other beta2-agonists, should be used with caution in patients taking quinidine, disopyramide, procainamide, phenothiazines, terfenadine, astemizole, macrolides, MAO inhibitors, tricyclic antidepressants or any drug prolonging the interval QT, since The listed drugs can enhance the adrenergic effect of the combination mometasone + formoterol on CCC. Drugs that extend the QT interval increase the risk of ventricular arrhythmia.

Antagonists of beta-adrenergic receptors. Beta-blockers can weaken the effect or completely block the effect of formoterol. Therefore, the preparations of these groups (including eye drops) should not be administered simultaneously, except when there are indisputable grounds for this.

Antagonists of beta-adrenergic receptors. Beta-adrenoblockers and formoterol can be used to inhibit the effect of each other. Beta-blockers are not only block the therapeutic effects of beta2-agonists such as formoterol - component combination mometasone + formoterol, but can lead to severe bronchospasm in asthmatic patients. Therefore, patients with asthma, as a rule, do not prescribe beta-blockers. However, under certain circumstances, for example, as a prophylaxis after myocardial infarction, there may not be an acceptable alternative to using beta-blockers in patients with asthma. In this case, cardioselective beta adrenoceptors may be considered, although they should be used with caution.

Halogen derivatives of hydrocarbons. There is an increased risk of arrhythmias in patients with concomitant use of anesthesia with halogenated hydrocarbons.

Overdose

Symptoms

Mometasone furoate. Overdose of GCS with inhalation or ingestion may lead to suppression of the function of the GGNS.

Formoterol fumarate. Overdose can lead to the development of symptoms characteristic of beta2-agonists: nausea, vomiting, headache, tremor, drowsiness, palpitations, tachycardia, ventricular arrhythmias, metabolic acidosis, hypokalemia, hyperglycemia, increased blood pressure.

Mometasone furoate. Chronic overdose may lead to signs / symptoms of hypercortisy (see "Precautions"). Single oral doses up to 8,000 μg mometasone furoate were studied in volunteers; No adverse reactions were noted.

Formoterol fumarate. Expected signs and formoterol overdosage symptoms are due to excessive beta-adrenergic stimulation and may manifest appearance or amplification of any of the following signs and symptoms of angina, hypertension or hypotension, tachycardia to 200 beats / min, arrhythmia, nervousness, headache, tremors, convulsions. Muscle spasm, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, insomnia. It is also possible to develop metabolic acidosis. With an overdose of formoterol, cardiac arrest and even death may be associated.

Treatment

Symptomatic and supportive therapy is shown, if necessary - hospitalization. In some cases, the use of beta2-adrenoblockers will be justified, but only under the supervision of a doctor and with great care, because They can cause bronchospasm. It is also necessary to monitor the function of the adrenal glands.

Routes of administration

Inhalation.

Precautions

Patients should be instructed by a doctor or medical personnel on the use of drugs.

Mortality from asthma

Long-acting agonists of beta2-adrenergic receptors, incl. Formoterol - the active component of the combination mometasone + formoterol, - increase the risk of mortality associated with asthma.

A massive 28-week placebo-controlled trial in the US to evaluate the safety of other beta2-agonists long-acting (salmeterol) in patients with asthma showed that the addition of salmeterol to standard asthma therapy led to an increase in mortality associated with asthma (13 of 13176 patients, in addition Of patients receiving salmeterol versus 3 of the 13179 patients receiving placebo, the risk ratio was 4.37, 95% CI: 1.25, 15.34). The increased risk of asthma-associated mortality is considered a class effect of long-acting beta2-agonists, including formoterol, one of the components of the combination mometasone + formoterol. No adequate studies have been conducted to determine whether the risk of asthma-related mortality increases in patients using the combination mometasone + formoterol.

Based on clinical studies with formoterol, a higher incidence of severe exacerbations of asthma in patients receiving formoterol fumarate can be expected than in those receiving a placebo. Sample sizes in these studies were insufficient to accurately quantify differences in the incidence of severe exacerbations of asthma between treatment groups.

Currently available data are inadequate to determine whether concurrent reduces the use of inhaled corticosteroids or other long-acting asthma control means an increased risk of mortality in the background astmaassotsiirovannoy beta2-agonists long-acting. The available data from controlled clinical trials indicate that long-acting beta2-adrenomimetics increase the risk of asthma-related hospitalization in patients of childhood and adolescence. Therefore, the treatment of patients suffering from asthma, physicians must assign sequence mometasone + formoterol Only those patients who have not provided adequate control of the disease by using the long-term treatment with these drugs as inhaled corticosteroids, or severity of the disease requires the designation of the two kinds of maintenance therapy - inhaled corticosteroid and Long-acting beta2-adrenomimetic. Once asthma control is achieved and maintained, it is necessary to assess the patient's condition at regular intervals and step by step to reduce drug therapy (for example, abolition of mometasone + formoterol combination), if possible, without losing control of the disease and continue long-term treatment with inhaled corticosteroids . Mometasone + formoterol should not be used for patients in whom asthma is adequately controlled by low or moderate doses of corticosteroids.

Exacerbation of the course of the disease

With the combination of mometasone + formoterol, serious side effects and complications associated with bronchial asthma can develop. Patients should not interrupt the course of treatment, but in the absence of disease control or increased symptoms should immediately consult a doctor.

You should not begin treatment with a combination of mometasone + formoterol in patients with a sharp increase in the symptoms of bronchial asthma, as well as in life-threatening exacerbations. The use of the combination mometasone + formoterol has not been studied in patients with rapidly advancing exacerbations of bronchial asthma.

The physician should review the therapy of bronchial asthma if the symptoms of bronchial asthma persist if a constant dose increase is required if the bronchodilators no longer stop the attacks of bronchial asthma or if the peak exhalation rate decreases because these signs usually indicate a worsening of the course of bronchial asthma. In the above cases, the possibility of using additional GCS therapy should be considered.

Attacks of bronchial asthma

The combination of mometasone + formoterol is not intended for rapid relief of bronchospasm or any other manifestation of an attack of bronchial asthma. In such cases, short-acting beta2-adrenomimetics should be used. In addition, the patient should be informed of the need to immediately seek medical attention in the event of a worsening of the course of bronchial asthma.

Overdose combination mometasone + formoterol and its use with other prolonged beta2-adrenomimetics

The combination of mometasone + formoterol should not be used with other prolonged beta2-adrenomimetics.

For the therapy of bronchial asthma, the dose of the combination mometasone + formoterol should be selected individually for each patient. The dose should be minimal to achieve the desired therapeutic effect. The dose also should not exceed the maximum recommended dose (see "Method of administration and dose"). Information confirming the increase in the effectiveness of the combination at an increase in its dose above the recommended dose is not available.

Exceeding the dose and frequency of use of the combination mometasone + formoterol and the use with other long-acting beta2 agonists

Like other inhaled drugs containing beta2-adrenomimetics, the combination of mometasone + formoterol should not be used more often than recommended at higher doses than recommended, or in combination with other drugs containing long-acting beta2-agonists, This can lead to an overdose. Clinically significant cardiovascular effects and fatal outcomes have been reported due to the excessive use of inhaled sympathomimetics. Patients using the combination mometasone + formoterol should not use an additional long-acting beta2-agonist (eg salmeterol, formoterol), regardless of the cause, including the prevention of exercise-induced bronchospasm and the treatment of bronchial asthma.

Candidiasis of the oropharynx

During the clinical trials of the combination mometasone + formoterol in some patients, the development of candidosis of the oropharynx associated with the use of GCS was noted. This kind of complication, as a rule, requires a special course of treatment with antifungal agents, and in some cases, cancellation of treatment. The patient should be advised to rinse the mouth after applying the combination.

Systemic effect of GCS

The systemic effect of inhaled glucocorticosteroids may be manifested, in particular, in the long-term use of the drug in high doses. However, the likelihood of its occurrence is much lower than with oral administration of GCS. Among the potential systemic effects, suppression of adrenal function, growth retardation in children and adolescents, decreased BMD, cataract and glaucoma. It is important to titrate the doses of the combination mometasone + formoterol to the lowest effective dose.

The cases of cataract and glaucoma development against the background of mometasone furoate are rarely described.

Suppression of adrenal function

As a rule, the dose of the combination mometasone + formoterol, which is necessary for the complete control of bronchial asthma, causes significantly less suppression of the function of the GHGs than the equivalent oral dose of prednisolone.

The likelihood of suppression of adrenal function when using the combination mometasone + formoterol exists, especially in the case of doses above the recommended dosage. Particular attention to suppression of adrenal function should be addressed in stressful situations or before planned operations, when patients will be prescribed additional therapy for SCS. However, during the clinical trials, there was no clinically significant effect of the combination mometasone + formoterol (in the dose of 800 mcg / day mometasone furoate) on the level of plasma cortisol.

Influence on CAS (cardiovascular system) and CNS (central nervous system)

Excessive beta-adrenergic stimulation is associated with the development of seizures, angina pectoris, hypertension or hypotension, tachycardia up to 200 beats / min, arrhythmia, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise and insomnia. Therefore, the combination mometasone + formoterol should be used with caution in patients with cardiovascular diseases, especially with coronary insufficiency, cardiac arrhythmia and hypertension.

Formoterol fumarate, a component of the combination mometasone + formoterol, can cause clinically significant cardiovascular effects in some patients that are detected by pulse rate, BP value and / or symptomatically. Although such effects after application of the combination mometasone + formoterol in recommended doses are rare, if they develop, it may be necessary to stop using the combination. In addition, it was reported that beta-agonists cause changes in the ECG, such as flattening of the T wave, prolongation of the QTc interval and depression of the ST segment. The clinical significance of these changes is unknown. Fatal cases have been reported due to the excessive use of inhaled sympathomimetics.

Decreased BMD

Decreased BMD was observed with long-term use of drugs containing inhaled glucocorticosteroids, including mometasone furoate - one of the components of the combination mometasone + formoterol. The clinical significance of small changes in BMD with respect to long-term effects, such as fracture, is unknown. Patients with high risk factors for reducing bone mineral content, such as prolonged immobilization, family history of osteoporosis, or the constant use of drugs that can reduce bone mass (eg anticonvulsants and corticosteroids) should be monitored and treated in accordance with established standards of care.

Glaucoma and cataract

There are reports of an increase in IOP, the development of glaucoma and cataracts after prolonged use of inhaled glucocorticosteroids, including mometasone furoate - a component of the combination mometasone + formoterol. In this regard, careful monitoring is justified in patients with visual impairment or increased IOP, glaucoma and / or cataract in the anamnesis.

Bronchospasm arising from inhalation

As for any other inhalant, it is necessary to consider the possibility of developing an inhaled bronchospasm. If it develops, immediately discontinue the drug and choose an alternative treatment.

Hypokalemia and hyperglycemia

Against the background of the use of beta2-adrenomimetics, it is possible to develop severe hypokalemia. Hypokalemia may increase the likelihood of arrhythmia.

Caution should be given to patients with severe bronchial asthma, since the development of hypokalemia can be potentiated by hypoxia and concomitant medication. In such situations, it is recommended that the level of serum potassium be monitored continuously.

Beta2-adrenomimetics, incl. And formoterol, have a hyperglycemic effect, so patients with diabetes recommended additional monitoring of blood glucose.

Special patient groups

Application in pediatrics. The safety and effectiveness of the combination mometasone + formoterol have been established in patients 12 years of age and older in 3 clinical trials up to 52 weeks. In these 3 clinical trials, 101 patients from 12 to 17 years used a combination of mometasone + formoterol. Patients in this age group demonstrated efficacy results similar to those observed in patients 18 years of age or older. There were no obvious differences in the type or frequency of adverse reactions recorded in this age group, compared with patients 18 years of age and older. Similar results on efficacy and safety were observed in 22 patients from 12 to 17 years who used the combination mometasone + formoterol in another clinical trial. The safety and efficacy of the combination mometasone + formoterol have not been established in children younger than 12 years of age.

Controlled clinical studies have shown that inhaled corticosteroids can reduce the rate of growth in pediatric patients. In these studies, the average decrease in the growth rate was approximately 1 cm per year (in the range from 0.3 to 1.8 per year) and seemed to depend on the dose and duration of exposure. This effect was observed in the absence of laboratory signs of suppression of the GGNS, suggesting that growth rate was a more sensitive indicator of the effects of systemic corticosteroids in pediatric patients than some of the commonly used tests of the function of the GGNS. The long-term effects of reduced growth rates associated with the use of orally inhaled corticosteroids, including effects on the final growth of adults, are unknown. The ability to "catch up" growth after discontinuing oral treatment with inhaled corticosteroids has not been adequately studied.

The growth of children and adolescents using orally inhaled corticosteroids, including the combination mometasone + formoterol, should be monitored regularly (for example, using a growth meter). If a child or adolescent has a growth retardation against any corticosteroid, the likelihood that he / she is particularly sensitive to this effect should be considered. Taking into account the potential consequences of prolonged treatment for growth, clinical benefits and risks associated with alternative treatments should be compared. In order to minimize the systemic effects of orally inhaled corticosteroids, including the combination mometasone + formoterol, the dose for each patient should be titrated to a minimum effective.

Application in geriatrics. A total of 77 patients aged 65 years and over (11 of whom were 75 years of age or older) used a combination of mometasone + formoterol in 3 clinical trials up to 52 weeks. Similar efficacy and safety outcomes were observed in 28 patients aged 65 years and older who used the combination mometasone + formoterol in another clinical trial. There was no difference in safety or efficacy between these patients and younger patients, but the greater sensitivity of some elderly people can not be ruled out. As with other drugs containing beta2-agonists, special care should be taken when using the combination mometasone + formoterol in geriatric patients with concomitant cardiovascular diseases due to the adverse effect of beta2 agonists. Based on the available data, for the combination of mometasone + formoterol or its active ingredients, dose adjustment in geriatric patients is not required.

Liver failure. Concentrations of mometasone furoate appear to increase with increasing severity of liver failure (see "Pharmacokinetics").

Influence on the ability to drive and work with machinery. 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.