Instruction for use: Mometasone + Formoterol (Ipratropii bromidum + Phenoterolum)

Pharmacotherapeutic group:

Beta-adrenergic agonist in combination

Glucocorticosteroids in combinations

The 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

Bronchodilator agent combination: beta2-agonists selective GCS + local.

Mometasone furoate - white powder, practically insoluble in water; slightly soluble in methanol, ethanol and isopropanol; soluble in acetone. Molecular Weight - 521.44.

Formoterol fumarate dihydrate - white or yellowish powder, freely soluble in glacial acetic acid; soluble in methanol; sparingly soluble in ethanol and isopropanol; slightly soluble in water and practically insoluble in acetone, ethyl acetate and diethyl ether. Molecular weight - 840.9.

Pharmacological action.

bronchodilatory, anti-local.

Mechanism of action

Mometasone furoate. Mometasone furoate - GCS has local anti-inflammatory effect. Anti-inflammatory effect of GCS GCS is realized through receptors (SERS). After joining GCS heterocomplex SERS is dissociated and activated by a ligand of the proceeds from the cytoplasm to the nucleus, where it increases the expression of inflammatory genes by joining the special sections of DNA, the so-called "Response elements at GCS". At the same time, it is believed that the basic realization of anti-inflammatory activity by a suppression of gene transcription. In this case, the SERS activated transcription factors interact with apolipoprotein 1 (AP1) or nuclear factor kappa B (NF-kB) to reduce gene expression. Additionally corticosteroids increase the expression of the gene responsible for synthesis of NF-kB inhibitor.

Formoterol fumarate. Formoterol is a potent selective beta2-agonists. On average bronchodilatory effect in patients with reversible airflow obstruction lasts 12 hours. Formoterol inhibits the release of histamine and radiation therapy in the lung tissue. Preclinical studies have shown some anti-inflammatory properties, such as inhibition of edema and inflammatory cell accumulation.

pharmacodynamics

Mometasone furoate. Mometasone furoate binds with high affinity to SERS, which leads to a marked reduction in the cells and inhibiting the synthesis and release of inflammatory mediators and cytokines.

Mometasone furoate greatly inhibits the release of leukocytes RT. In cell culture mometasone furoate markedly inhibits the synthesis and release of IL-1, IL-5, IL-6 and FNOα and is a potent inhibitor of Th2-cytokine production, IL-4 and IL-5 in human CD4 + T cells. In a mixture of patients with atopic leukocytes mometasone furoate inhibited RT products with greater potency than beclomethasone dipropionate.

In the study in preclinical models of mometasone furoate reduces the accumulation of inflammatory cells (including eosinophils), was implemented in the walls of the upper and lower respiratory tract, as well as improved lung function after provocation test. Mometasone furoate reduced number of lymphocytes and the concentration of the messenger RNA of cytokines IL-4 and IL-5.

Formoterol fumarate. Studies on the in vitro guinea pig trachea demonstrated that formoterol fumarate as a racemic mixture or in separate form (R, R) - or (S, S) enantiomer is a highly selective beta2-agonists. The activity of (S, S) -enantiomer of 800 to 1000 times less than that of (R, R) -enantiomer. (S, S) -enantiomer does not prevent the effects of (R, R) -enantiomer on tracheal smooth muscle. Thus, it was demonstrated no pharmacological rationale for the preferred application instead of a racemic mixture of enantiomers

Pharmacokinetics

In a crossover study with a single application of the drug has not been received any information confirming the existence of pharmacokinetic interactions between mometasone furoate and formoterol, are part of a combination of mometasone + formoterol.

Absorption and bioavailability

Mometasone furoate. After inhalation of one or more doses of drugs (from 200 to 800 mcg) of mometasone furoate is rapidly absorbed, gradually moving into a phase of prolonged absorption. The average Tmax value is from 0.5 to 4 hours. Mometasone furoate is rapidly cleared from the plasma, the average rate of about 12.5 ml / min / kg, regardless of the dose. Effective T1 / 2 is 25 h. The 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 mean ranges from 0.17 to 1.97 hours. At the dose range from 10 to 40 mg directly proportional to the exposure dose. The average value of T1 / 2 in plasma was 9.1 hours.

Distribution

Mometasone furoate. After the on / in the bolus Vss is 152 liters. Studies in vitro show high protein binding mometasone (from 98 to 99%) in the concentration range from 5 to 500 ng / ml.

Formoterol fumarate. formoterol Plasma protein binding is 61-64%, the binding to serum albumin - 34%.

Metabolism

Mometasone furoate. The major metabolites of mometasone furoate is not revealed. Part mometasone furoate, swallowed during inhalation, absorbed in the intestine and is metabolized to form large amounts of metabolites. The hepatocyte microsomes mometasone furoate metaboliziruegsya to form a large number of metabolites, including 6-beta-gidroksimometazona furoate, which is formed by the action of cytochrome P450 isoenzyme CYP3A4.

Formoterol fumarate. Formoterol fumarate is mainly metabolized by glucuronidation. Another way is O-demethylation followed by glucuronidation. Irrelevant pathways include conjugation with sulphate and deformilirovanie followed by conjugation with sulphate. Many isozymes catalyze the glucuronidation (UGT1A1, 1A3, 1A6, 1A7, 1A8, 1A9, 1A10, 2V7 and 2V15) and O-demethylation (CYP2D6, CYP2C19, CYP2C9 and CYP2A6) of formoterol, suggesting a low probability of drug-drug interactions associated with the inhibition of specific enzymes. At therapeutic concentrations of formoterol fumarate has no effect on cytochrome P450 isoenzymes.

breeding

Mometasone furoate. Labeled mometasone furoate administered by inhalation, generally derived intestine (74%) and to a lesser extent - kidneys (8%).

Formoterol fumarate. After oral administration of 80 mcg formoterol fumarate it labeled has been found that for 104 hours from 59 to 62% of the drug is excreted by the kidneys, from 32 to 34% - the intestine. After inhalation + formoterol combination of mometasone renal clearance of formoterol was 217 ml / min. After a single inhalation of 10 to 40 micrograms of formoterol in combination consisting mometasone + formoterol kidneys derived approximately from 6.2 to 6.8% of formoterol unchanged.

Special patient groups

Hepatic / renal failure. I do not have any data on usage patterns mometasone + formoterol combination in patients with hepatic or renal insufficiency.

In a study evaluating the use of single inhaled doses of 400 mcg of mometasone furoate in the dry powder using an inhaler subjects with mild (n = 4), moderate (n = 4) and severe (n = 4) liver failure only 1 or 2 persons each group determined Cmax of mometasone furoate in plasma (in the range of 50-105 pg / ml). Observed Cmax plasma apparently increased in accordance with the severity of liver disease; but the number of samples with detectable levels were few.

Gender and race. Specific studies to examine the impact of gender and race on the pharmacokinetics of the combination of mometasone + formoterol absent.

Geriatrics. Specific studies to evaluate the pharmacokinetics of the combination of mometasone + formoterol have not been conducted in the elderly.

The use of substances mometasone + Formoterol

The combination of mometasone + formoterol is shown as a drug for use in the continuous maintenance therapy of asthma, including to reduce the severity of exacerbations of asthma in adults and children over the age of 12 years.

The combination of mometasone + formoterol is indicated in patients:

- Who are unable to control the course of the disease, using only inhaled corticosteroids and inhaled beta2-agonists short action for relief of attacks (in the "on demand" mode);

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

The combination of mometasone + formoterol can also be assigned to patients who have the disease adequately controlled through the use of inhaled corticosteroids and beta2-agonists long-acting.

Contraindications

Hypersensitivity to mometasone furoate, formoterol fumarate; Children up to age 12 years (safety and efficacy when used in children younger than 12 years has not been established).

Restrictions apply

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 infections or herpes simplex eye lesions.

Patients, particularly children receiving therapy corticosteroids or other immunosuppressants should be warned of the possible danger of contact with sick certain infectious diseases (such as chicken pox or measles), as well as 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 block III degree), severe chronic heart failure, idiopathic hypertrophic subaortal stenosis, hypertension, severe, aneurysm, phaeochromocytoma, hypertrophic obstructive cardiomyopathy, thyrotoxicosis, extended interval QT (QTc > 0.44).

Switching from systemic therapy SCS

Patients who are transferred from systemic corticosteroids to inhalation therapy, combination therapy mometasone + formoterol, require careful monitoring, because deaths due to adrenal insufficiency when switching patients from systemic therapy corticosteroids to inhaled corticosteroids, are characterized by lower bioavailability have been described. After the abolition of the SCS system action takes several months to normalize the function of the hypothalamic-pituitary-adrenal system.

Stressful situations such as trauma, surgery, infections or asthma attacks may require the appointment of a short course of systemic corticosteroids replacement therapy, which will subsequently be necessary to cancel, gradually reducing the dose as symptoms disappearance. Therefore patients are advised to always carry a supply of oral glucocorticosteroids and information card, which indicates that the patient in stressful situations needs GCS orally, indicating the recommended doses. Also, this group of patients is recommended periodic monitoring of adrenocortical function, particularly measurement of cortisol levels in plasma in the morning.

Translation patients with systemic corticosteroids therapy to a combination of mometasone + formoterol may lead to the manifestation of symptoms of some pre-existing allergic conditions, which were hidden in the background of previous systemic corticosteroids therapy. In such cases, symptomatic treatment is shown.

Pregnancy and breast-feeding

Properly controlled studies of the use of a combination of mometasone + formoterol in pregnant women have not performed. Mometasone Preclinical studies have shown toxicity to the reproductive system, similar to that of the entire group of corticosteroids, but the potential risk for humans is unknown.

The combination of mometasone + formoterol 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 is a beta2-agonists has a tocolytic effect (relaxing effect on the smooth muscles of the uterus) and can inhibit labor.

Properly controlled studies of the use of a combination of mometasone + formoterol in nursing mothers have not performed. It is found that formoterol is excreted with the milk in rats; GCS excreted in human milk. The decision to cancel or continue treatment should be individualized, taking into account the benefit of breast-feeding for the child and using a combination of mometasone + formoterol for the mother.

Category effects on the fetus by FDA - C.

Labor and delivery. Adequate and well-controlled studies in women for the study of the influence of a combination of mometasone + formoterol on labor and delivery is not carried out. Since beta-agonists could potentially interfere with uterine contractions, a combination of mometasone + formoterol should be used during labor and delivery only if the potential benefit justifies the potential risk.

The combination of mometasone + formoterol. It is unknown whether the combination of mometasone + formoterol is excreted into breast milk. Because many drugs are excreted in human milk, caution should be exercised when using the combination of nursing women. Since no data is well-controlled clinical trials of the combination of mometasone + formoterol in nursing mothers, based on the data for the individual components of the combination, should stop breastfeeding or the use of a combination of mometasone + formoterol, taking into account the importance of the drug to the mother.

Mometasone furoate. It is not known if mometasone furoate is excreted in breast milk. However, other corticosteroids are excreted into breast milk in humans.

Formoterol fumarate. In reproduction studies in rats have shown that formoterol is excreted into the milk. It is not known whether formoterol excreted in human milk.

Side effects of substances mometasone + Formoterol

Side effects that have been observed during clinical trials of the combination of mometasone + formoterol in asthmatic patients are shown depending on the frequency of occurrence: very common (≥1 / 10); commonly (≥1 / 100, <1/10); uncommon (≥1 / 1000, <1/100); rare (≥1 / 10,000, <1/1000).

Infectious and parasitic diseases: often - oral candidiasis; infrequently - pharyngitis.

Immune system: Hypersensitivity reactions with the following manifestations: rarely - bronchospasm, atopic dermatitis; rarely - urticaria.

Mental disorders: rarely - insomnia; rarely - nervousness.

From the nervous system: often - headache; infrequent - tremor, dizziness.

From a sight organ: rare - the defeat of the lens *; rarely - increased IOP.

From the heart: rarely - tachycardia, palpitations.

On the part of the vessels: Infrequent - increased blood pressure.

The respiratory system, organs, thoracic and mediastinal disorders: often - dysphonia; infrequently - oropharyngeal pain, throat irritation.

On the part of the digestive tract: rarely - nausea, dry mouth.

On the part of the musculoskeletal system and connective tissue disorders: rarely - muscle spasms.

Laboratory and instrumental data: seldom - a lengthening of the interval QT.

* Defined as the change in classification score ≥1 clouding of the lens system, version III (LOCS III). No cases of posterior subcapsular cataracts have been registered.

Additional side effects

Anxiety, agitation, myalgia, rash, distorted sense of taste, peripheral edema, paradoxical bronchospasm, indigestion, weight gain; systemic side effects: inhibition of the hypothalamic-pituitary-adrenal axis (HPA axis), growth retardation in children and adolescents, bone demineralization, steroid diabetes.

These post-marketing period of application

During post-marketing use of a combination of mometasone + formoterol or inhaled formulations containing mometasone furoate and formoterol fumarate, observed the following side effects: hypokalemia, hyperglycemia, angina pectoris, cardiac arrhythmias (such as atrial fibrillation, ventricular extrasystoles, tachyarrhythmia), hypersensitivity reactions (rash, angioedema or anaphylactic reactions), worsening of asthma symptoms (sneezing, shortness of breath, wheezing, bronchospasm).

As the clinical trials conducted with a different set of conditions, the frequency of occurrence of adverse reactions observed in these studies may not be directly compared with the frequency of other clinical trials and prediction of side effects in clinical practice impossible.

Experience in clinical research

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 treated with a combination of mometasone + formoterol for 12 to 26 weeks, and 271 patients treated with the combination for 1 year.

Safety mometasone + formoterol combination was evaluated in two placebo and active-controlled clinical trials (n = 781 and n = 728, respectively) and in the long 52-week trial (n = 404). In clinical trials, lasting 12 to 26 weeks, the age of the participants was 12 to 84 years, 41% were male and 59% - women, 73% - of Caucasians, 27% - neevropeoidnoy. Patients received a combination of two mometasone inhalation twice daily + formoterol (100/5 or 200/5 ug ug), mometasone furoate (100 or 200 micrograms) formoterol (5 micrograms) or placebo.

In the long-term 52-week active-controlled trial of safety age of participants was 12 to 75 years, 37% - men and 63% - women, 47% - of Caucasians, 53% - neevropeoidnoy. Participants received twice a day for two combinations of mometasone inhalation, formoterol + 100 mg / 5 mg, or 200 mg / 5 mg, or the reference preparation.

The frequency of treatment emergent adverse reactions associated with the use of a combination of mometasone + formoterol and presented below is based on pooled data from two clinical trials lasting from 12 to 26 weeks in patients 12 years or older treated twice a day for two inhalations combination of mometasone + formoterol 100/5 mg (n = 424) or 200/5 mg (n = 255) of mometasone furoate 100 mg (n = 192) or 200 mg (n = 240), 5 mg of formoterol (n = 202) or placebo (n = 196).

Presented associated with the treatment combination of mometasone + formoterol adverse reactions recorded since the frequency of ≥3% and more frequent than in the placebo group. Also indicated is the duration of the application of the combination.

Beside the name of the side effect indicated the number of patients who have to use a combination of background mometasone + formoterol dose 100/5 or 200/5 ug ug This effect was observed; in parentheses - percentage frequency effect; separated by semicolons - similar data in patients treated with inhaled mometasone furoate (100 or 200 mg); further - data in patients treated with inhaled formoterol (5 mg); and the data in the patient group treated with 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).

The 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 with the combination of mometasone + formoterol 100/5 ug, 0.8% - at a dose of 200/5 mcg and 0.5% in the placebo group.

The experience of a long clinical trial

In the long-term safety testing, patients 12 years and older for 52 weeks were treated with a combination of mometasone + formoterol in a dose of 100 mg / 5 mg (n = 141) at a dose of 200 mg / 5 mg (n = 30) or the comparison drug (n = 133), the results were generally similar to those noted in controlled trials lasting 12 to 26 weeks. No recorded asthma-related deaths. With a higher rate in the long-term test was observed dysphonia - 7/141 (5%) of patients receiving a combination of mometasone + formoterol 100/5 mcg dose of, and 5/130 (3.8%) patients treated with the combination at a dose of 200/5 g. There were no clinically significant changes in parameters: biochemical, hematological, or ECG.

Post-marketing experience

The following adverse reactions were reported during postmarketing use of a combination of formoterol and mometasone + use with inhaled mometasone furoate and formoterol fumarate.

Since the reports of these reactions have been reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency and the causal link with taking drugs.

From the Heart: angina pectoris, cardiac arrhythmia, such as atrial fibrillation, ventricular extrasystoles, tachyarrhythmia.

Immune system: immediate hypersensitivity reactions and delayed-type, including anaphylactic reactions, angioedema, severe hypotension, rash, pruritus.

Research data: lengthening of the QT interval on an electrocardiogram, increased blood pressure (including hypertension).

Metabolism and nutritional disorders: hypokalemia, hyperglycemia.

From the side of respiratory, thoracic and mediastinal disorders: asthma, which may include coughing, shortness of breath, wheezing and bronchospasm.

Interaction

In clinical trials the combination of mometasone + formoterol together with beta2-agonists and short-acting intranasal corticosteroids has not led to the development of any adverse interactions. Special studies of drug interactions combination of mometasone + formoterol was carried out. It is assumed that the list of drug interactions for a given combined formulation will be a total list of interactions known for each of its active ingredients.

Ketoconazole. Concomitant use with the inhalation of mometasone furoate potent inhibitor of CYP3A4 isoenzyme ketoconazole results in a significant increase mometasone plasma concentrations.

Inhibitors of CYP3A4 of cytochrome P450. Basically, the metabolism of corticosteroids, including mometasone furoate - a combination of mometasone + formoterol component - performed by CYP3A4 isoenzyme of cytochrome P450. Following oral administration of ketoconazole - a potent inhibitor of CYP3A4 - the average plasma concentration of inhaled mometasone furoate used increases. Concomitant use of CYP3A4 inhibitors may interfere with the metabolism and increase the systemic exposure of mometasone furoate. Caution should be exercised with concomitant use of a combination of mometasone + formoterol with long-term use of ketoconazole and other strong inhibitors of CYP3A4 (eg ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin), since due to increased systemic exposure of mometasone furoate may increased side effects.

Adrenergic drugs. Concomitant use with sympathomimetics may increase the incidence of side effects of formoterol.

Xanthine derivatives and diuretics. The simultaneous use of xanthine derivatives and nekaliysberegayuschimi diuretics may enhance the hypokalemic effect of beta2-agonists.

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

Beta-adrenergic antagonists of receptors. Beta-blockers may weaken the effect, or completely block the effect of formoterol. Therefore, the preparations of these groups (including eye drops) should not be administered concurrently, except when there are conclusive grounds.

Beta-adrenergic antagonists of receptors. Beta-blockers and formoterol, while the application can inhibit the effect of each other. Beta blockers inhibit not only the therapeutic effect of a beta2-agonist, such as formoterol - mometasone + component combination formoterol, but may lead to a pronounced bronchoconstriction in patients with bronchial asthma. Therefore, patients with asthma are generally not prescribed beta-blockers. However, under certain circumstances, such as the prevention of post-myocardial infarction, there may not be an acceptable alternative to the use of beta-blockers in patients with asthma. In this case, it may be considered cardioselective beta adrenobokatory, although they should be used with caution.

Halogenated hydrocarbons. There is an increased risk of arrhythmias in patients with concomitant use of anesthesia a halogenated hydrocarbon.

Overdose

symptoms

Mometasone furoate. Overdose GCS by inhalation or ingestion can lead to suppression of HPA axis function.

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

Mometasone furoate. Chronic overdose can lead to the appearance of signs / symptoms of Cushing (see. "Precautions"). Single oral doses of 8000 mcg of mometasone furoate was studied in volunteers; no adverse reactions were noted.

Formoterol fumarate. Expected signs and formoterol overdose symptoms are due to excessive beta-adrenergic stimulation and can manifest the emergence or intensification of any of the following signs and symptoms: angina, hypertension or hypotension, tachycardia up to 200 beats / min, arrhythmias, nervousness, headache, tremor, convulsions. cramping, dry mouth, palpitations, nausea, dizziness, fatigue, discomfort, hypokalemia, hyperglycemia, insomnia. It is also possible the development of metabolic acidosis. With an overdose of formoterol may be associated cardiac arrest and even death.

Treatment

Symptomatic and supportive therapy, if necessary - hospitalization. In some cases, the sound will use beta2-adrenergic blockers, but only under the supervision of a physician and with extreme caution, because they can cause bronchospasm. Also requires monitoring of adrenal function.

Routes of administration

Inhalation.

Precautions of substances mometasone + Formoterol

Patients should be trained physician or medical personnel rules of use of drugs.

Mortality from asthma

Long-acting beta2-adrenergic agonists, including formoterol - the active ingredient combination of mometasone + formoterol, - increase the risk of mortality associated with asthma.

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 receiving salmeterol versus 3 of 13 179 patients receiving placebo; hazard ratio 4.37, 95% CI: 1.25, 15.34). Astmaassotsiirovannoy Increased risk of mortality is considered to be a class-effect of long-acting beta2-agonists, including formoterol - one of the components of the combination of mometasone + formoterol. No adequate studies conducted to determine whether the increased risk of mortality associated with asthma, patients with the combination of formoterol +mometasone.

Based on data from clinical studies with formoterol, one can assume a greater frequency of severe asthma exacerbations in patients who received formoterol fumarate than in those who received placebo. Sample sizes in these studies were insufficient to accurately quantify the differences in the incidence of serious asthma exacerbations between treatment groups.

Currently available data are insufficient to determine whether reducing the simultaneous use of inhaled corticosteroids or other long-acting asthma control means an increased risk of mortality in the background astmaassotsiirovannoy beta2-agonists long-acting. Available data from controlled clinical trials suggest that the beta2-agonists increase the risk of long-acting asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma, physicians should prescribe a combination of mometasone + formoterol only to those patients who do not provide adequate control of the disease with the help of long-term treatment with these drugs as inhaled corticosteroids, or severity of the disease requires the appointment of two types of maintenance therapy - inhaled corticosteroid and long-acting beta2-agonists. Once achieved and maintained control of asthma, it is necessary to assess the patient at regular intervals and step by step to reduce drug therapy (such as the abolition of the combination mometasone + formoterol), if it is possible, without losing control of the disease and to continue long-term treatment with inhaled corticosteroids . Do not use the combination formoterol mometasone + for patients whose asthma is adequately controlled low or moderate doses of corticosteroids.

The aggravation of the disease

Against the background of a combination of mometasone + formoterol 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 or gain control of symptoms should immediately seek medical attention.

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

The doctor should review the treatment of asthma, if asthma symptoms persist, if the disease in order to achieve control of constant increase in the dose is required if bronchodilators are no longer cropped asthma attacks or if the reduced peak expiratory flow rate, as these symptoms usually indicate a worsening of bronchial asthma. In the above cases, you should consider using additional SCS therapy.

Asthma attacks

The combination of mometasone + formoterol is not intended for rapid relief of bronchospasm or any other manifestations of asthma attack. In such cases, should be used beta2-agonists of short action. In addition, the patient should be informed of the need for immediate treatment to the doctor in case of worsening of bronchial asthma.

An overdose of a combination of mometasone + formoterol and its use with other long-acting beta2-agonists

The combination of mometasone + formoterol should not be used with other long-acting beta2-agonists.

For the treatment of bronchial asthma dose combination of mometasone + formoterol should be individualized for each patient. The dosage should be the minimum necessary to achieve a therapeutic effect. The dose should also not exceed the maximum recommended dose (see. "Dosage and administration"). DETAILED increase the effectiveness of the combination with increasing doses above the recommended her, no.

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

Like other inhaled drugs containing beta 2-agonists, mometasone + formoterol combination should not be used more than recommended, at higher doses than recommended, or in combination with other drugs containing beta 2-agonists, long-acting, because this may lead to an overdose. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic. Patients using a combination of mometasone + formoterol should not use additional beta2 agonist long-acting (e.g. salmeterol, formoterol), regardless of the cause, including prevention of exercise-induced bronchospasm and asthma treatment.

oropharyngeal Candidiasis

During clinical trials the combination of mometasone + formoterol in some patients it was observed the development of oropharyngeal candidiasis associated with GCS. Such complication usually requires special treatment with antifungal agents, and in some cases, and discontinuation of treatment. The patient should be advised to rinse the mouth after use of combinations.

Systemic effects of GCS

Systemic effects of inhaled corticosteroids may occur the use of, in particular, for long-term use of the drug in high doses. However, the probability of its occurrence is much lower than with 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 combination of mometasone + formoterol to the minimum effective dose.

The cases of cataract and glaucoma in patients receiving mometasone furoate rarely described.

adrenal suppression

Typically, the dose of mometasone combination + formoterol required for complete control of asthma, causes significantly less suppression of HPA axis function than an equivalent dose on the effectiveness of oral prednisolone.

Probability suppression of adrenal function with the combination of formoterol, mometasone + exists, especially in the case of doses exceeding recommended. Special attention adrenal suppression should be paid in stressful situations or before elective surgery, when patients will be assigned additional SCS therapy. However, during the clinical trials showed no clinically significant effect of the combination of mometasone + formoterol (dose of mometasone furoate 800 mcg / day) on the level of plasma cortisol.

Effect on cardiovascular and central nervous system

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

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

Reduced bone mineral density

The decline in BMD was observed during long-term use of drugs containing inhaled corticosteroids, including mometasone furoate - one of the components of the combination of mometasone + formoterol. The clinical significance of small changes in BMD on long-term consequences, such as a fracture, is not known. In patients with high risk factors reduce the mineral content in the bones, such as prolonged immobilization, osteoporosis, family history, 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 cataracts

There are reports of increased intraocular pressure, glaucoma and cataract development after long-term use of inhaled corticosteroids, including mometasone furoate - a combination of mometasone + formoterol component. Therefore, careful monitoring is justified in patients with impaired vision or elevated IOP, glaucoma and / or a history of cataract.

Bronchospasm that occurs during inhalation

As for any other inhaled drugs, it is necessary to take into account the possibility of inhalation-induced bronchospasm. In the case of the development of the drug should be lifted immediately, and to choose an alternative method of treatment.

Hypokalemia and hyperglycemia

Against the background of the use of beta2-agonists 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 carry out continuous monitoring of serum potassium.

Beta2-adrenoceptor agonists, including and formoterol, have a hyperglycemic effect, so patients with diabetes mellitus recommended additional monitoring of blood glucose.

Special patient groups

The use in pediatrics. Safety and efficacy of the combination of mometasone + formoterol have been established in patients 12 years and older in 3 clinical trials for up to 52 weeks. In these 3 clinical trials, 101 patients between 12 and 17 years have used a combination of mometasone + formoterol. The patients in this age group have demonstrated the efficacy results similar to those observed in patients 18 years or older. There were no obvious differences in the type or frequency of adverse events reported in this age group, as compared with patients 18 years and older. Similar results on the efficacy and safety has been observed in 22 patients from 12 to 17 years who used a combination of mometasone + formoterol, in another clinical trial. Safety and efficacy of the combination of mometasone + formoterol have not been established in children under 12 years.

Controlled clinical studies have shown that inhaled corticosteroids may lead to a decrease in the rate of growth in pediatric patients. In these studies, the mean decrease in growth rate was approximately 1 cm per year (range 0.3 to 1.8) and appear to depend on the dose and duration of exposure. This effect was observed in the absence of laboratory evidence of HPA axis suppression, testifying in favor of the fact that the growth rate is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests assess HPA axis function. Long-term effects of reduction of growth associated with the use of orally inhaled corticosteroids, including the impact on final adult height, are unknown. The ability to "catch up" growth following discontinuation of treatment orally inhaled corticosteroids has not been adequately studied.

The growth of children and adolescents who use orally inhaled corticosteroids, including mometasone combination + formoterol, should be monitored regularly (eg with height meter). If a child or adolescent to any background corticosteroid growth retardation seen, probability that he / she is particularly sensitive to this effect must be considered. Taking into account the potential consequences of the impact of long-term treatment on growth, should be weighed against the clinical benefits and risks associated with alternative therapies. To minimize the systemic effects of orally inhaled corticosteroids, including mometasone + formoterol combination, the dose should be titrated for each patient to the minimum effective.

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

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

Effects on ability to drive and use machines. With the development of side effects in the nervous system should refrain from driving or using machinery while taking the drug.